Lung surfactant, consisting primarily of phospholipids and protein, performs wide range protective functions, the main one of which is anti-atelectatic. A severe lack of surfactant leads to collapse of the alveoli and the development of acute respiratory failure- RDSN ( respiratory distress syndrome newborns). Surfactant reduces surface tension in the alveoli, ensures their stability during breathing, prevents their collapse at the end of the exhalation phase, ensures adequate gas exchange, and performs a decongestant function. In addition, surfactant is involved in the antibacterial protection of alveoli, increases the activity of alveolar macrophages, improves the function of the mucociliary system, and inhibits a number of inflammatory mediators in acute lung injury syndrome (ALI) and acute distress syndrome (ARDS) in adults.
If there is insufficient production of one’s own (endogenous) surfactant, exogenous surfactant preparations obtained from the lungs of humans, animals (bull, calf, pig) or synthetically are used.
Chemical composition pulmonary surfactant mammals have a lot in common. Surfactant isolated from human lungs contains: phospholipids - 80-85%, protein - 10% and neutral lipids - 5-10% (Table 1). Up to 80% of alveolar surfactant phospholipids are involved in the process of recycling and metabolism in type II alveolocytes. Surfactant includes 4 classes of proteins (Sp-A, Sp-B, Sp-C, Sp-D), each of which is encoded by its own gene. The bulk of proteins is Sp-A. Endogenous surfactant preparations of various origins differ somewhat in content from phospholipids and proteins.
Surfactant is synthesized and secreted by type II alveolocytes (a-II). On the alveolar surface, the surfactant consists of a thin phospholipid film and a hypophase in which membrane formations are located. This is a very dynamic system - more than 10% of the total surfactant pool is secreted hourly.

Table 1. Phospholipid composition of alveolar surfactant in adult lungs

Studies, including multicenter studies, have shown that early use surfactant preparations for respiratory distress syndrome newborns can significantly reduce mortality (by 40-60%), as well as the frequency of multisystem complications (pneumothorax, interstitial emphysema, bleeding, bronchopulmonary dysplasia, etc.) associated with the neonatal period in premature infants.
IN recent years Pulmonary surfactant preparations began to be used in the treatment of ALI/ARDS and other lung pathologies.
Currently known pulmonary surfactant preparations differ in the source of production and the content of phospholipids in them (Table 2).
In Russia, surfactant therapy began to be used only in lately, primarily in neonatal intensive care units, thanks to the development of a domestic natural surfactant preparation. Multicenter clinical trials this drug confirmed the effectiveness of using pulmonary surfactant preparations in the treatment of critical conditions and other respiratory diseases.

Table2. Pulmonary surfactant preparations

Surfactant name	Source receiving	Surfactant composition (% phospholipid content)	Directions for use and dose
Surfactant-BL.	Ox lung (ground)	DPPH - 66, FH - 62.2 Neutral lipids - 9-9.7 Protein - 2-2.5	On the first day for respiratory distress syndrome in newborns - microjet drip or aerosol administration (75 mg/kg in 2.5 ml of saline solution)
Survanta	Ox lung (ground)	DPPH - 44-62 FH - 66 (40-66) Neutral lipids - 7.5-20 Protein - (Er-B and Er-S) - 0.2	4 ml (100 mg)/kg, 1-4 doses, intratracheal with an interval of 6 hours
Alveofakt*	Bull lung (flush)		A single dose is 45 mg/kg in 1.2 ml per 1 kg and should be administered intratracheally during the first 5 hours of life. 1-4 doses are allowed
	Bull lung	DPPC, PC, neutral lipids, protein	Intratracheal, inhalation (100-200 mg/kg), 5 ml 1-2 times with an interval of 4 hours
Infasurf	Calf lung (chopped)	35 mg/ml PL, including 26 mg PC, neutral lipids, 0.65 mg protein, including 260 µg/ml Er-B and 390 µg/ml - Br-S	Intratracheal, dose 3 ml/kg (105 mg/kg), repeated (1-4 doses) administration after 6 12 hours
Kurosurf*	Ground pig lung	DPPH - 42-48 FH -51-58 FL - 74 mg Protein (Er-B and Er-S) - 900 mcg	Intratracheal, initial single dose 100-200 mg/kg (1.25-2.5 ml/kg). Repeatedly 1 - 2 times at a dose of 100 mg/kg with an interval of 12 hours
Exosurf	Synthetic	DPPC - 85% Hexadecanol - 9% Tyloxapol – 6%	Intratracheal, 5 ml (67.5 mg/kg), 1-4 doses at 12-hour intervals
ALEC (artificial Lung expanding compound)*	Synthetic	DPPC - 70% FGL - 30%	Intratracheal, 4-5 ml (100 mg/kg)
Surfaxin *	Synthetic	DPPC, palmitoyl-oleoyl-phosphatidiglycerol (POPGl), palmitic acid, lysine = leucine –KL4). This is a surfactant (surfactant; peptide nature, which is the first synthetic analogue protein B (Sp-B)	Used in a lung lavage solution (therapeutic BAL) through an endotracheal tube

Lung surfactants are located both extracellularly (lining complex) and intracellularly (osmiophilic lamellar bodies - OPT). Based on this localization of surfactants, 3 main methods for their isolation have been developed:

• 1) method of broncho-alveolar washings (study of lavage fluid);
• 2) lung extract method (using biopsy or surgical material);
• 3) method of collecting and studying expirate (exhaled air condensate).

To study surfactants, physicochemical, biochemical and electron microscopic methods are used.

Physicochemical methods are based on the ability of surfactants to reduce the PN of isotonic sodium chloride solution or distilled water. The extent of this reduction can be determined using various techniques and instruments.

Important information about the chemical nature of surfactants can be obtained using biochemical techniques: electrophoresis, thin layer and gas-liquid chromatography. For these purposes, various histochemical methods are widely used and various options microscopy: polarizing, fluorescent, phase contrast and electron.

Radiological methods provide valuable information about the metabolism and secretion of surfactants. They are based on the introduction of radionuclide 32P or palmitic acid, containing tritium radionuclide, which is actively involved in phospholipid metabolism.

By using various solutions broncho-alveolar washings are obtained, which serve as starting material for the study of surfactants. Most complete removal surfactants from the broncho-alveolar surface is achieved using an isotonic sodium chloride solution, which eliminates protein denaturation and destruction of cell membranes. When using distilled water, the release of surfactants into the solution increases due to the osmotic destruction of some cells and the release of intracellular surfactants, and therefore the starting material contains both mature surfactants and immature cytoplasmic surfactants and other components.

The advantage of the bronchoalveolar lavage method is the possibility of obtaining material in the process medical procedures aimed at the rehabilitation of the bronchopulmonary apparatus. The disadvantage is that the rinsing fluid does not always reach the respiratory lung zones and may not contain true surfactants. At the same time, the washing fluid contains secretion products of the bronchial glands, products of cell destruction and other components, including phospholipases that destroy surfactant. There is one more important circumstance: the results of studying the surface activity of broncho-alveolar lavages are difficult to attribute to certain segments or lobes of the lung.

According to A.V. Tsizerling and co-authors (1978), PAVl undergo extremely minor changes within 1-2 days after death. According to N.V. Syromyatnikova and co-authors (1977), storage of isolated lungs at room temperature for 36 hours is not accompanied by a change in their surface-active properties.

Obtaining surfactants from biopsy, surgical material or from a piece of tissue from the respiratory zone of the lung of an experimental animal makes it possible to homogenize the source material in order to most completely extract extra- and intracellular surfactants.

The advantage of the method is the most complete extraction of surfactants from the respiratory zone of the lung, but the disadvantage is the need to remove a piece easy way needle biopsy or during surgical operations. Biopsy or surgical material can also be examined by electron microscopy.

Of particular interest to clinical and laboratory diagnostics presents a method for obtaining surfactants from exhaled air. The method is based on the fact that the flow of exhaled air captures small particles of liquid from the surface of the respiratory lung departments and, together with the vapors, removes them from the body. The subject exhales air into the cooled system, where the vapors condense. Within 10 minutes, 2-3 ml of starting material accumulates in the system. Biochemical analysis exhaled condensate indicates that it contains phospholipids, in particular lecithin, in small concentrations.

The study of the surface activity of exhaled air condensate is carried out according to the Du Nouy method using torsion balances. U healthy people static surface tension (NSST) is 58-67 mN/m, and at inflammatory diseases lung PNST increases - 68-72 mN/m.

The advantage of the method of studying surfactants in exhaled air condensate is the non-traumatic nature of sampling the material and the possibility of repeated studies. The disadvantage is the low concentration of phospholipids in the condensate. In fact, the indicated method determines decomposition products or constituent components surfactants.

The state of surfactants is assessed by measuring surface tension using the Wilhelmy and Du Nouy method.

At 100% of the monolayer area, PNmin is recorded, and at 20% of the initial monolayer area, PNmin is recorded. From these values, the IS is calculated, which characterizes the surface activity of surfactants. For these purposes, use the formula proposed by J. A. Clements (1957). The higher the IS, the higher the surface activity of lung surfactants.

As a result of research by domestic and foreign scientists, a number of functions have been identified that are carried out due to the presence of surfactants in the lung: this is maintaining the stability of the sizes of large and small alveoli and preventing them from atelectasis during physiological conditions breathing.

It has been established that normally the monolayer and hypophase protect cell membranes from direct mechanical contact with dust microparticles and microbial bodies. By reducing the surface tension of the alveoli, surfactants contribute to an increase in the size of the alveoli during inspiration, creating the possibility of simultaneous functioning of the alveoli various sizes, play the role of a regulator air flow between actively functioning and “resting” (not ventilated) alveoli and more than halve the contractile force of the respiratory muscles necessary for straightening the alveoli and full ventilation, and also inactivate kinins that enter the lung from the blood during inflammatory diseases. In the absence of surfactants or a sharp decrease in their activity, atelectasis occurs.

During respiration, as surfactants are destroyed and removed into respiratory tract surface tension periodically increases. This leads to the fact that the alveoli with a higher surface tension reduce their size and close, switching off from gas exchange. In non-functioning alveoli, surfactants produced by cells accumulate, surface tension decreases, and the alveoli open. In other words, physiological role surfactants includes the regulation of periodic changes in functioning and resting functional units of the lung.

Surfactant lipids play an antioxidant role, which is important in protecting the elements of the alveolar wall from the damaging effects of oxidants and peroxides.

An oxygen molecule can come into contact with the plasma membrane of the alveolar epithelium and begin its journey in body fluids, passing only through the lining complex (monomolecular layer and hypophase). The results of experimental studies by a number of authors have shown that surfactants act as a factor regulating the transport of oxygen along the concentration gradient. Change biochemical composition membranes and the lining complex of the air-hematic barrier leads to a change in the solubility of oxygen in them and the conditions for its mass transfer. Thus, the presence of a monolayer of surfactants at the border with alveolar air promotes active absorption of oxygen in the lung.

The surfactant monolayer regulates the rate of water evaporation, which affects the body’s thermoregulation. The presence of a constant source of surfactant secretion in type 2 alveolocytes creates a constant flow of surfactant molecules from the alveolar cavity into the respiratory bronchioles and bronchi, resulting in clearance (cleaning) of the alveolar surface. Dust particles and microbial bodies that enter the respiratory area of ​​the lung, under the influence of a surface pressure gradient, are carried into the action zone of mucociliary transport and removed from the body.

The surfactant monolayer serves not only to reduce the compression force of the alveoli, but also protects their surface from excess water loss, reduces the absorption of fluid from the pulmonary capillaries into the air spaces of the alveoli, that is, it regulates the water regime on the surface of the alveoli. In this regard, surfactants prevent the transudation of fluid from blood capillaries into the lumen of the alveoli.

The physiological activity of surfactant may be affected by mechanical destruction of the alveolar lining, a change in the rate of its synthesis by type 2 alveolocytes, disruption of its secretion on the surface of the alveoli, its rejection by transudate or leaching through the respiratory tract due to chemical inactivation of surfactants on the surface of the alveoli, as well as as a result of changes in the rate removal of “waste” surfactant from the alveoli.

The surfactant system of the lungs is very sensitive to many endogenous and exogenous factors. Endogenous factors include: impaired differentiation of type 2 alveolocytes responsible for the synthesis of surfactant, changes in hemodynamics ( pulmonary hypertension), disorders of innervation and metabolism in the lungs, acute and chronic inflammatory processes respiratory organs, conditions associated with surgical interventions on the chest and abdominal cavities. Exogenous factors are changes in the partial pressure of oxygen in the inhaled air, chemical and dust pollution of the inhaled air, hypothermia, narcotic drugs and some pharmacological preparations. Surfactant is sensitive to tobacco smoke. In smokers, the surface-active properties of the surfactant are significantly reduced, as a result of which the lung loses its elasticity and becomes “hard” and less pliable. In persons who abuse alcoholic beverages, the surface activity of lung surfactants is also reduced.

Disruption of the processes of synthesis and secretion of surfactants or their damage by exogenous or endogenous factors is one of pathogenetic mechanisms development of many respiratory diseases, including pulmonary tuberculosis. It has been established experimentally and clinically that in active tuberculosis and nonspecific lung diseases, the synthesis of surfactant is disrupted. With severe tuberculosis intoxication, the surfactant properties of the surfactant are reduced both on the affected side and in the opposite lung. A decrease in surface activity of surfactant is associated with a decrease in phospholipid synthesis under hypoxic conditions. Lung surfactant phospholipid levels decrease markedly when exposed to low temperature. Acute hyperthermia causes functional tension of type 2 alveolocytes (their selective hypertrophy and excess phospholipid content) and promotes an increase in the surface activity of lung lavages and extracts. When fasting for 4-5 days, the content of surfactant in type 2 alveolocytes and the surface lining of the alveoli decreases.

A significant decrease in the surface activity of the surfactant causes anesthesia using ether, pentobarbital or nitrous oxide.

Inflammatory lung diseases are accompanied by certain changes in the synthesis of surfactant and its activity. So, with pulmonary edema, atelectasis, pneumosclerosis, nonspecific pneumonia, tuberculosis and hyaline membrane syndrome in newborns, the surface-active properties of surfactant are reduced, and in pulmonary emphysema they are increased. The participation of alveolar surfactant in the adaptation of the lung to extreme influences has been proven.

It is known that viruses and gram-negative bacteria have a greater ability to destroy lung surfactant compared to gram-positive bacteria. In particular, the influenza virus causes destruction of type 2 alveolocytes in mice, which leads to a decrease in the level of phospholipids in the lungs. A. I. Oleinik (1978) found that acute pneumonia accompanied by a significant decrease in the surface activity of extracts obtained from lesions.

A new promising approach to the study of surfactant in inflammatory lung diseases is associated with the study of bronchial washings obtained during bronchoscopy. The composition of washings and its surface activity make it possible to approximately judge the state of the alveolar surfactant.

Due to the fact that in clinical practice inhalations of various pharmacological agents, we conducted experimental and clinical trials on the study of the surfactant system of the lungs.

Thus, the effect of tuberculostatic agents administered in ultrasonic inhalations on the state of the surfactant system of the lungs was studied. Electron microscopic examinations were carried out lung studies in 42 rats after 1, 2 and 3 months of inhalation of streptomycin and isoniazid separately, as well as against the background of combined administration of drugs. Solutions of tuberculostatic agents were dispersed using ultrasonic inhaler TUR USI-50.

It was noted that under the influence of ultrasonic aerosols of streptomycin, the surface activity of surfactants decreased immediately after the first session (primary decrease) and by the 15th day it was partially restored.

Starting from the 16th inhalation, a gradual decrease in surface activity was observed, which continued for 3 months of inhalation and by the 90th day the stability index decreased to 0.57 + 0.01. 7 days after stopping inhalations, an increase in the activity of lung surfactants was noted. The SI value was 0.72±0.07, and 14 days after stopping inhalations, the surface activity of surfactants was almost completely restored and the SI reached a value of 0.95±0.06.

In the group of animals that were inhaled with isoniazid, a decrease in the surface activity of surfactants occurred immediately after the first inhalation. The IS value decreased to 0.85±0.08. The decrease in the surface activity of surfactants in this case was less than when using streptomycin, however, with inhalation of isoniazid, the surface activity of surfactants remained constant for 2 months and only after the 60th inhalation a decrease in surface activity was noted. By the 90th day of inhalation, surface activity decreased and SI reached 0.76±0.04. After cessation of inhalation after 7 days, a gradual restoration of the surface activity of surfactants was noted, SI was 0.87 ± ±0.06, and after 14 days its value increased to 0.99 ± ±0.05.

Electron microscopic examination of the resected lungs revealed that the alveolar surfactant complex did not change 1 month after ultrasonic inhalation with streptomycin. After 2, especially 3 months, inhalation, in certain areas of the lung parenchyma, slight swelling of the air-blood barrier was detected, and in some places, local destruction and leaching of surfactant membranes into the lumen of the alveoli. Among type 2 alveolocytes, the number of young osmiophilic lamellar bodies is reduced, mitochondria have an enlightened matrix, and the number of crypts in them is noticeably reduced. The cisterns of the granular cytoplasmic reticulum are expanded and lack some ribosomes. Ultrastructural changes in such cells indicate the development in them destructive processes and a decrease in intracellular synthesis of surfactants.

After inhalation of isoniazid aerosols for 2 months, no significant disturbances were found in the ultrastructure of the main components of lung surfactant. After 3 months of inhalation of the drug, microcirculatory disorders and signs of intracellular edema were detected in the alveoli. Apparently, the edematous fluid released into the hypophase washes the surfactant membranes into the lumen of the alveoli. In type 2 alveolocytes, the number of osmiophilic lamellar bodies and mitochondria is reduced, and the canaliculi of the cisterns, devoid of ribosomes, are unevenly dilated. This indicates a slight weakening of surfactant synthesis.

At the same time, in a number of cases, type 2 alveolocytes can be found in the lung parenchyma, almost completely filled with mature and young osmiophilic lamellar bodies. Such cells have a well-developed ultrastructure and a dark cytoplasmic matrix, resembling “dark” type 2 alveolocytes with increased potential. Their appearance is obviously associated with the need for compensatory secretion of surfactant for those areas where the activity of type 2 alveolocytes is reduced due to microcirculatory disorders in the walls of the alveoli.

After termination long-term use streptomycin and isoniazid in ultrasonic inhalations after 14 days, noticeable changes occur in the ultrastructure of type 2 alveolocytes. They are characterized by a significant accumulation of mitochondria with well-developed crypts in the cytoplasm of the cells. The canaliculi of the cisterns are in close contact with them. The number of cisternae and osmiophilic lamellar bodies increases significantly. Such cells, along with mature osmiophilic lamellar bodies, contain a significant number of young secretory granules. These changes indicate the activation of synthetic and secretory processes in type 2 alveolocytes, which are apparently caused by the cessation of toxic effect chemotherapy drugs for type 2 alveolocytes.

In our clinic, we corrected lung surfactants by adding a mixture of hydrocortisone (2 mg/kg body weight), glucose (1 g/kg body weight) and heparin (5 units) to inhaled chemotherapy drugs daily for 5 days. Under the influence of these drugs, an increase in the surface activity of lung surfactants was noted. This was evidenced by a decrease in PNST (35.6 mN/m ± 1.3 mN/m) and PNmin- (17.9 mN/m ± ± 0.9 mN/m); SI was 0.86+0.06 (P<0,05) при совместной ингаляции со стрептомицином и 0,96+0,04 (Р<0,05) - изониазидом.

To study the surface activity of surfactants and the content of certain lipids in patients with pulmonary tuberculosis in the condensate of exhaled air, we examined 119 people. From the same group of people, surfactant was studied in 52 broncho-alveolar washings (lavage fluid) and in 53 - in preparations of resected lungs (segment or lobe). In 19 patients, pulmonary resection was performed for tuberculoma, in 13 for cavernous tuberculosis, and in 21 patients for fibrous-cavernous tuberculosis. All patients were divided into 2 groups. The first group consisted of 62 people who took anti-tuberculosis drugs using the usual method and ultrasound. The second (control) group consisted of 57 people who were treated with the same chemotherapy drugs using the usual method, but without the use of tuberculostatic aerosols.

We studied the surface activity of surfactants in exhaled air condensate using the Du Nouy method using a torsion balance. At the same time, PNST was measured. The surface-active fraction of lavage fluid and lung extracts was placed in a cuvette of a Wilhelmy-Langmuir balance and PNST, PNmax and PNmin were determined. Surface activity was assessed by the value of PNmin and IS. The state of surfactant in the condensate of exhaled air was assessed as normal with PNST (62.5 mN/m± ±2.08 mN/m), lavage fluid - with PNmin 14-15 mN/m and IS 1 -1.2, extracts of resected lungs - at PNmin 9-11 mN/m and IS 1 -1.5. An increase in PNST and PNmin and a decrease in IS indicate a decrease in the surface activity of lung surfactants.

For inhalation, isoniazid (6-12 ml 5% solution) and streptomycin (0.5-1 g) were used. Isotonic sodium chloride solution was used as a solvent. A bronchodilator mixture of the following composition was added to the inhaled chemotherapy drugs: 0.5 ml of a 2.4% solution of aminophylline, 0.5 ml of a 5% solution of ephedrine hydrochloride, 0.2 ml of a 1% solution of diphenhydramine, and glucocorticoids according to indications. Inhalations of isoniazid were carried out in 32 patients, streptomycin - in 30.

During treatment, the study of surfactants in the condensate of exhaled air was carried out once a month; in the lavage fluid, the study was carried out in 47 patients after 1 month, after 2 months - in 34, after 3 months - in 18.

A decrease in the surface activity of surfactants in the condensate of exhaled air was expressed in patients with disseminated (PNST 68 mN/m±1.09 mN/m), infiltrative (PNST 66 mN/m±1.06 mN/m) and fibrous-cavernous (PNST 68 .7 mN/m+2.06 mN/m) pulmonary tuberculosis. Normally, PNTS is (60.6+1.82) mN/m. In the lavage fluid of patients with disseminated pulmonary tuberculosis, PNmin was (29.1 ± 1.17) mN/m, infiltrative - PNmin (24.5 + 1.26) mN/m and fibrous-cavernous - PNmin (29.6 + 2 .53) mN/m; IS, respectively, 0.62+0.04; 0.69+0.06 and 0.62+0.09. Normally, PNmin is equal to (14.2±1.61) mN/m, IS - 1.02±0.04. Thus, the degree of intoxication significantly affects the surface activity of lung surfactants. During treatment there was a significant decrease (P<0,05) показателей ПНСТ, ПНмин и повышение ИС отмечено параллельно уменьшению симптомов интоксикации и рассасыванию инфильтратов в легких. Эти сдвиги были выражены у больных инфильтративным (ИС 0,99) и диссеминированным туберкулезом легких (ИС 0,97).

In patients of group 2, a decrease in PNST, PNmin and an increase in IS was established at a later date. Thus, if in patients of group 1, PNST in the exhaled air condensate and PNmin in the lavage fluid decreased significantly (P<0,05), а ИС повысился (у больных инфильтративным туберкулезом через 1 мес, диссеминированным - через 2 мес), то у обследованных 2-й группы снижение ПНСТ, ПНмин и повышение ИС констатировано через 2 мес после лечения инфильтративного туберкулеза и через 3 мес - диссеминированного. У больных туберкулемой, кавернозным и фиброзно-кавернозном туберкулезом легких также отмечено снижение ПНСТ, ПНмин и повышение ИС, но статистически они были не достоверными (Р<0,05).

For the study, pieces of resected lung tissue were taken from the area located perifocally to the lesion (1-1.5 cm from the tuberculoma capsule or cavity wall), as well as pieces of unchanged lung tissue from areas most distant from the lesion (along the resection border). The tissue was homogenized, extracts were prepared in isotonic sodium chloride solution and poured into the cuvette of a Wilhelmy-Langmuir balance. The liquid was allowed to settle for 20 min to form a monolayer, after which PNMax and PNMin were measured.

Analysis of the data showed that in patients of both groups in the area of ​​pneumosclerosis, the surface-active properties of lung surfactants were sharply reduced. However, the use of anti-tuberculosis drugs, bronchodilators and pathogenetic agents in the preoperative period slightly increases the surface activity of surfactants, although not significantly (R<0,05). При микроскопическом изучении в этих зонах обнаружены участки дистелектаза, а иногда и ателектаза, кровоизлияния. Такие низкие величины ИС свидетельствуют о резком угнетении поверхностной активности сурфактантов легких. При исследовании резецированных участков легких, удаленных от очага воспаления, установлено, что поверхностно-актив-ные свойства сурфактантов легких менее угнетены. Об этом свидетельствуют более низкие показатели ПИМин и увеличение ИС по сравнению с зоной пневмосклероза. Однако и в отдаленных от туберкулем и каверн участках легочной ткани показатели активности сурфактанта значительно ниже, чем у здоровых лиц. У тех больных, которым в предоперационный период применяли аэрозольтерапию, показатели ПНСТ. ПНмин были ниже, а ИС - выше, чем у больных, леченных без ингаляций аэрозолей. При световой микроскопии участков легких у больных с низким ПНмин и высоким ИС отмечено, что легочная ткань была нормальной, а в отдельных случаях - даже повышенной воздушности.

The lipid composition of lavage fluid and exhaled air condensate in patients with pulmonary tuberculosis, determined using a chromatograph, showed that phospholipids were found both in the lavage fluid and in the exhaled air condensate. Palmitic acid (C16:0) was 31.76% in the lavage fluid and 29.84% in the exhaled air condensate, confirming the presence of surfactants in the exhaled air condensate.

Based on a study of lung surfactants using physicochemical, biochemical, morphological and electron microscopic methods and a comparison of the results obtained with clinical data, it was established that in pulmonary tuberculosis the surface activity of lung surfactants is suppressed both near the lesions (zone of pneumosclerosis) and in distant unchanged areas resected lung.

After treatment of patients with streptomycin, elements of structural organization were identified in the air-hematic barrier of the lung, as well as in areas remote from the source of damage, which impede the diffusion of gases. Their appearance is due to an increase in the number of collagen and elastic fibers, deposition of protein-fatty inclusions, and an increase in the density of basement membranes. Some sections revealed desquamation of epithelial cells into the lumen of the alveoli. Large areas of alveoli, bordered by compacted and thickened basement membranes without epithelial lining, were noted only in patients with cavernous tuberculosis; in patients with tuberculoma, similar phenomena were not detected. K.K. Zaitseva and co-authors (1985) regard such desquamation as a result of wear and tear of the alveolar wall under extreme external conditions. Note that this phenomenon is expressed in cavernous tuberculosis.

As a result of treatment with isoniazid, patients showed an improvement in the structural organization of the constituent components of the surfactant system. In type 2 alveolocytes, we observed hyperplasia of cellular components, in particular, the lamellar complex and rough endoplasmic reticulum. This indicates an increase in biosynthetic processes characteristic of compensatory-adaptive reactions. Thanks to the increased number of lysosome-like formations, the autolytic function of the cell is activated. In turn, this promotes the removal of altered lamellar bodies and edematous areas of the cytoplasm. In the lumens of the alveoli, accumulations of macrophages were detected, absorbing cellular detritus and an excessive number of lamellar bodies.

Our studies have shown that the ultrastructural organization of the air-hematic barrier and surfactant system of patients with cavernous tuberculosis is better preserved during treatment with isoniazid. These data are consistent with the results of determining the surface activity of surfactant in resected areas of the lungs.

According to our observations, studying the state of surface activity of lung surfactants in resected areas of the lungs is of clinical importance in assessing the course of the postoperative period in patients with tuberculosis. With a high level of PNmin and a low value of IS, postoperative complications in the form of hypoventilation, prolonged non-expansion, persistent atelectasis of the remaining parts of the lung after surgery occur in 36% of patients. With normal surface activity of lung surfactants, such complications occurred in 11% of patients.

Analysis of the state of surface activity of surfactants in the condensate of exhaled air, lavage fluid and in preparations of lungs resected for tuberculosis, distant from the lesions, is of great importance in the prognosis of the postoperative period and the prevention of pulmonary complications.

The results of a study of symmetrical areas in the opposite unaffected lung (sectional material) showed that surfactants are characterized by significantly reduced surface activity, although according to X-ray data, the airiness of the lung parenchyma in these areas remains within normal limits. These data indicate a significant decrease in the surface activity of surfactants at the site of a specific tuberculosis process and the general inhibitory effect of tuberculosis intoxication on the surfactant system of the lungs, which requires appropriate therapeutic measures aimed at activating the synthesis of phospholipids.

With a decrease in surfactants, patients often experienced sub- and atelectasis and hypoventilation in the postoperative period.

It has been established that the tuberculosis process in the active phase suppresses the activity of type 2 alveolocytes and inhibits the production of phospholipids. and at the same time reduces the surface activity of lung surfactants. This may be one of the reasons for the development of atelectasis that accompanies tuberculous lesions and the aggravation of impaired respiratory mechanics.

Thus, when prescribing chemotherapy drugs in ultrasonic inhalations to patients with respiratory diseases, their side effects on the surfactant system of the lungs should be taken into account. Therefore, inhalation of antibiotic aerosols, in particular streptomycin, should be carried out continuously for no more than 1 month, and isoniazid - no more than 2 months. If long-term use is necessary, aerosol therapy should be carried out in separate courses, taking a break of 2-3 weeks between them in order to create temporary rest for the mucous membrane of the respiratory tract and restore the cellular components of the air-blood barrier of the lung.

Biophysical functions

• Prevention of collapse of the alveoli and lungs during exhalation
• Supports inspiratory lung opening
• Prevention of pulmonary edema
• Stabilization and support of open small airways
• Improving mucociliary transport
• Removal of small particles and dead cells from the alveoli into the airways

Immunological, non-biophysical functions

• Phospholipids inhibit proliferation, immunoglobulin production and cytotoxicity of lymphocytes
• Phospholipids inhibit cytokines secreted by macrophages
• SB-A and SB-D promote phagocytosis, chemotaxis and oxidative damage of macrophages
• Neutralization of endogenous mediators SB-A and SB-D, opsonizing various microorganisms
• Capture bacterial toxins SB-A and SB-D

Changes in the surfactant system in various diseases

Surfactant inhibition

The functions of surfactant can be disrupted by many substances: blood plasma proteins, hemoglobin, phospholipases, bilirubin, meconium, fatty acids, cholesterol, etc. Oxygen and its compounds, inhalation of small particles containing silicon, nickel, cadmium, and various organic compounds have a toxic effect on surfactant , gases (eg chloroform, halothane), numerous drugs. The relatively lower content of surfactant proteins in premature infants compared to adults makes their surfactant system more sensitive to various damaging factors.

Primary surfactant deficiency

The importance of the surfactant system in the pathophysiology of neonatal RDS was discovered by Avery and Mead. The conclusion that the cause of RDS is a primary surfactant deficiency due to immaturity of type II pneumocytes was later confirmed by a huge number of clinical studies. The most pronounced features of the surfactant system in newborns with RDS: a decrease in the total concentration of all phospholipids, the relative concentration of phosphatidylglycerol, dipalmitoylphosphatidylcholine, SB-A. Surfactant begins to be synthesized by type II pneumocytes from approximately the 22nd week of gestation.

The amount of surfactant in these cells and the number of pneumocytes increase with gestational age. Newborns with RDS have a surfactant pool of about 10 mg/kg, while in healthy newborns it is approximately 100 mg/kg.

Congenital disorders of surfactant synthesis

Currently, RDS is considered a multifactorial disease that is associated not only with primary surfactant deficiency. The main methods for diagnosing congenital disorders of surfactant synthesis are genetic and immunohistochemical analysis, and lung biopsy. Genetic changes that disrupt surfactant metabolism and lead to decreased oxygenation are the causes of the development of severe DN in the neonatal period. The first publications describing diseases associated with them date back to the beginning of the 21st century. Mutations were identified in the genes responsible for the synthesis of SB-B, SB-S and the ABCAZ protein, which transports phosphatidylcholine and phosphatidylglycerol into the lamellar bodies, which is necessary to maintain surfactant homeostasis.

Congenital SB-B deficiency is an autosomal recessive disease, first described in 1993. To date, about 30-40 mutations of the gene responsible for the synthesis of this protein have been identified, which leads to a significant decrease in its production. The mutation is diagnosed with a frequency of 1 in 1000-3000 people, but clinical manifestations are extremely rare and amount to 1 in 1,000,000 live births. The disease is more common in full-term infants and manifests itself in severe DN, complicated by pulmonary hypertension syndrome, which leads to death.

A lung disease associated with a mutation in the gene responsible for the synthesis of SB-S and transmitted according to an autosomal dominant mode of inheritance was described by Nogee. He discovered a genetic abnormality associated with impaired synthesis of SB-S, which manifested itself as interstitial pulmonary disease in several generations of the same family. In 2002, another mutation of the gene responsible for the synthesis of SB-S was diagnosed. Currently, more than 40 mutations have been identified. The first clinical symptoms and severity of the disease are extremely variable. In 10-15% of cases it can manifest itself during the newborn period. In other cases, the disease manifests itself in the first 6 months of life, which is considered a favorable prognostic sign.

Congenital disorder of protein synthesis ABCAZ, inherited in an autosomal recessive manner, is less studied, but the most common disease compared to the above. Recently, another cause of fatal surfactant deficiency in full-term infants was found - a mutation in the ABCAZ gene, which is probably responsible for the maturation of lamellar bodies and surfactant production. The disease was first diagnosed in 2004. Currently, more than 150 mutations associated with impaired metabolism of this protein have been identified. The frequency of occurrence in the population has not been studied. Clinically, the disease occurs as severe RDS. Pathogenetic therapy for this group of diseases has not currently been developed. In most cases, replacement therapy with surfactant preparations is carried out, but the therapeutic effect is short-term or absent. The only treatment is lung transplantation, the rate of complications after which remains high. The need for it is determined by the severity of DN. In most cases, the prognosis for life is unfavorable and depends on the severity of deficiency of one of the surfactant proteins and/or ABCAZ, components of endogenous surfactant, as well as the diagnostic capabilities of the clinic.

Meconium aspiration

In the presence of meconium, the phospholipid structure of the surfactant changes, its ability to reduce surface tension decreases, and a decrease in the concentration of SB-A and SB-B, and the LA fraction is noted. Herting et al. compared the resistance of different surfactant preparations to the inhibitory effect of meconium in vitro. New synthetic drugs (Venticute, Surfaxin) turned out to be more stable compared to modified natural ones (such as Curosurf, Alveofact and Survanta).

Bronchopulmonary dysplasia

In a newborn recovering from RDS, the amount of phosphatidylglycerol in the surfactant increases. In RDS progressing to BPD, this is less pronounced due to possible damage to type II alveolocytes, which has been noted in premature baboon babies recovering from RDS. In these animals, the alveolar surfactant pool after administration at birth and an additional 6 days of mechanical ventilation was approximately 30 mg/kg and did not increase after the second dose.

Congenital diaphragmatic hernia

The main characteristics of this disease are pulmonary hypoplasia and pulmonary hypertension. Data on surfactant system deficiency in CDH are contradictory.

Pulmonary hemorrhage

Pulmonary hemorrhage is one of the causes of severe DN in newborns; it develops in 3-5% of patients with RDS. Hemoglobin, blood plasma proteins, cell membrane lipids are surfactant inhibitors.

Clinical use of surfactant

Respiratory distress syndrome

Physiological consequences of administering surfactant to newborns with RDS:

• increase in FRC;
• increased oxygenation;
• decrease in PVR;
• improvement of pulmonary compliance.

Studies have shown a reduction in neonatal mortality and a reduction in the incidence of pulmonary barotrauma (pneumothorax and IPE) in children administered surfactant. Mainly 2 surfactant strategies were tested. The first is use shortly after birth to prevent RDS and lung injury from mechanical ventilation (“prophylactic use”). The second - at the age of 2-24 hours of life, after the diagnosis of RDS (“therapeutic use”).

In addition to prophylactic use, the so-called early (before an age of less than 2 hours of life) has been described, and the analysis of these studies also showed better results than with delayed administration: a decrease in pulmonary barotrauma, the risk of death and the incidence of developing CLD.

As the clinical use of nCPAP expands, experience has shown that many newborns, even very small gestational age, will not require mechanical ventilation and surfactant. Retrospective clinical studies have demonstrated a reduction in surfactant use in this population without an increase in the incidence of BPD, mortality, or other complications of prematurity. Taking these data into account, large international studies have been conducted comparing early nCPAP with intubation and “prophylactic” surfactant administration: COIN, CURPAP and SUPPORT. Analysis of these studies showed that routine early use of nCPAP and administration of surfactant only after transfer to mechanical ventilation reduces the risk of CLD or death compared with intubation and prophylactic surfactant administration. But if babies weighing less than 1300 g require intubation immediately after birth for resuscitation or due to severe DN, they should receive surfactant as soon as possible, as a preventive measure.

Although most newborns experience persistent clinical benefit after surfactant administration, about 20-30% of patients are resistant to therapy. These newborns may have other diseases in addition to RDS: pneumonia, pulmonary hypoplasia, PPH, ARDS (“shock lung”) or congenital heart disease. A large volume of fluid administered to the patient, especially colloidal solutions, high FiC>2, low PEEP, large DO, extreme prematurity can also reduce the effectiveness of the surfactant.

The most severe complication that occurs during surfactant treatment is pulmonary hemorrhage. It occurs with the introduction of both synthetic and natural surfactant preparations. It is observed mainly in the smallest newborns. The appearance of pulmonary hemorrhage is associated with a functioning PDA and an increase in pulmonary blood flow after the administration of surfactant.

Perhaps adequate selection of PEEP or the use of HF mechanical ventilation before surfactant administration will increase its effectiveness and reduce the rate of inactivation. The use of antenatal corticosteroids increases the effectiveness of exogenous surfactant and reduces the need for repeat doses.

There is currently no evidence that exogenous surfactant inhibits the synthesis and secretion of endogenous surfactant and probably even has some beneficial effect on lung maturation.

Meconium aspiration

Meconium aspiration is one of the most severe respiratory diseases in full-term infants. Surfactant therapy may be life-saving for some children with meconium aspiration. The American Academy of Pediatrics recommends the use of surfactant during meconium aspiration.

Another method of using surfactant during aspiration is lavage of the tracheobronchial tree with diluted surfactant.

Congenital pneumonia

Several clinical studies have shown improved gas exchange in the lungs without associated complications. The study by Lotze et al. was aimed at identifying the benefits of surfactant in the treatment of full-term infants with DN, including patients with sepsis with pneumonia. Surfactant therapy increased oxygenation and decreased the need for ECMO. Recommended by the American Academy of Pediatrics.

Pulmonary hemorrhage

Several observational studies have shown increased oxygenation in children with idiopathic pulmonary hemorrhage or pulmonary hemorrhage in patients with RDS and MAS. It is not yet a standard treatment.

Adult-type respiratory distress syndrome

The incidence of ARDS requiring mechanical ventilation in full-term and near-term infants is estimated to be 7.2 per 1000 live births. A recent randomized trial of the effectiveness of surfactant in children from birth to 18 years of age for ARDS showed no effect compared with placebo.

Bronchopulmonary dysplasia

Several studies have shown a temporary improvement in respiratory function after treatment, improving the composition and function of endogenous surfactant. The use of a synthetic peptide-containing surfactant (Lucinactant) for the prevention of BPD did not affect its incidence. It should be noted that children in the treatment group were less likely to be hospitalized for respiratory problems after discharge home (28.3% vs 51.1%; P = 0.03).

Natural vs artificial

Both types of surfactant preparations have proven clinically effective in the treatment of RDS, but the natural one was preferred, probably due to the natural surfactant proteins it contains. Natural surfactants are characterized by a faster onset of action, which makes it possible to reduce the parameters of mechanical ventilation and FO 2 earlier.

The synthetic drug lucinactant (Surfaxin) contains a compound of amino acids with activity similar to SB-B. Moua and Sinha compared its effectiveness with Exosurf, Survanta and Curosurf in international randomized multicenter studies. Lucinactant was in no way inferior to these drugs.

Natural modified surfactants differ in their composition, concentration of phospholipids, proteins, viscosity and volume of application.

The 3 most studied natural surfactants are beractant (Survanta), calfactant (Infasurf) and poractant alpha (Curosurf); the latter of these contains the largest amount of phospholipids in the smallest volume. A meta-analysis of 5 studies comparing poractant alfa with beractant showed a reduction in mortality with treatment with poractant alfa. A large retrospective study in the United States examined the outcomes of treatment with three surfactant drugs (beractant, calfactant, poractant alfa) in 322 intensive care units (51,282 preterm infants) from 2005 to 2010. There was no difference in the incidence of SWS, BPD and /or mortality. The authors believe that the drugs have the same clinical effectiveness.

Currently, there are 3 imported surfactant preparations available in the Russian Federation: Curosurf, Alveofact and Survanta. The effectiveness of Curosurf and Alveofact was compared in 2 clinical studies, which found no difference in outcome. It should be noted that the concentration of phospholipids in 1 ml of substance in Curosurf is 2 times higher than in Alveofact.

There are domestic surfactant preparations, but their effectiveness is unknown to the author.

Administration technique

Surfactant is usually administered as a bolus through a thin catheter inserted into the ETT. The dose, if considered large, is sometimes administered in 2 doses. After this, the patient is connected to a ventilator breathing circuit or assisted in the promotion of surfactant using bag breathing.

The INSURE (INtubate-SURfactant-Extubate) technique, which consists of intubation, surfactant administration and rapid extubation on nCPAP, has been shown to reduce the incidence of BPD. It should be noted that a stable child on nCPAP should not be specifically intubated for surfactant administration, including for INSURE.

The use of surfactant through a thin tube during spontaneous breathing on nCPAP has been described. The technique seems promising, and interest in it is growing. Studies have reported a reduction in the need for mechanical ventilation and the incidence of BPD.

Aerosol administration of surfactant is not yet recommended, although it continues to be studied.

Contraindications

Relative contraindications for the administration of surfactant are:

• congenital anomalies incompatible with life;
• hemodynamic instability;
• active pulmonary hemorrhage.

Monitoring (before, during and after administration)

• FiO 2 >2, ventilation parameters;
• chest excursions, DO, auscultatory picture;
• SpO 2 , heart rate, blood pressure;
• chest x-ray;

Complications

Most complications of surfactant use are transient in nature and rarely destabilize the patient’s condition for a long time. They are associated mainly with the manipulation itself: the introduction of fluid into the trachea, turning the head and neck can lead to bradycardia, cyanosis, an increase or decrease in blood pressure, and surfactant reflux in the ETT.

The most severe complication after surfactant administration is pulmonary hemorrhage, which occurs in 1-5% of children.

Surfactant treatment

The synthesis of a sufficient amount of surfactant in the epithelial cells of the lungs begins from the 34th week of pregnancy. Surfactant reduces the surface tension of the alveoli, is responsible for their stability and prevents the alveoli from collapsing during exhalation. The shorter the gestational age, the more likely is surfactant deficiency and associated neonatal respiratory distress syndrome. Endogenous surfactant deficiency can be compensated for by surfactant replacement therapy.

Indications for the use of surfactant:

• X-ray confirmed neonatal respiratory distress syndrome;
• extreme immaturity of the premature newborn;
• inspiratory oxygen concentration >0.4-0.6.

Preparation:

• chest x-ray;
• pulse oximetry;
• invasive blood pressure measurement;
• analysis of the gas composition of arterial blood.

Material:

• sterile gastric tube or umbilical catheter;
• sterile gloves;
• measuring tape to determine the length of insertion;
• syringe, needle.

Carrying out

Stages of surfactant therapy

Endotracheal aspiration.

Laying: head in the middle position or in a position on its side.

Warm the surfactant to room temperature, do not shake. Assist with instillation: squeeze the endotracheal tube between the thumb and forefinger to prevent overflow.

Write down the batch number of the drug.

Monitoring the patient

Chest excursions, cyanosis: ECG, blood pressure, hemoglobin saturation O2.

Doctor's tasks:

• strictly follow the dose;
• measure the length of the tube, mark it on the catheter for instillation;
• draw up the drug under sterile conditions;
• increase ventilator pressure.

Introduction: insert the gastric tube into the tube, during instillation of the surfactant the tube is compressed by the assistant, reintroduce air to completely empty the catheter, connect the ventilator.

Alternative forms of application

Surfactant is administered through an endotracheal tube adapter with a side port; device disconnection is not required.

Complications:

• airway obstruction, drop in blood pressure;
• after the administration of surfactant, the occurrence of acute airway obstruction with an increase in pCO 2 can be compensated for by a short-term increase in airway pressure.

If possible, do not perform endotracheal aspiration for at least 6 hours after surfactant administration.

Abstract. Yershov AL. Surfactant alteration and replacement in acute respiratory distress syndrome. Review.

Inactivation of pulmonary surfactant may be important in acute lung injury and acute respiratory distress syndrome. Mechanisms of surfactant alterations in ARDS include: 1) lack of surface-active compounds (phospholipids, apoproteins) due to reduced generation/release by diseased type II cells of alveoli or to increased loss of material (this feature includes changes in the relative composition of the surfactant phospholipid and/or apoprotein profiles); 2) inhibition of surfactant function by plasma protein leakage; 3) "incorporation" of surfactant phospholipids and apoproteins into polymerizing fibrin upon hyaline membrane formation; and 4) damage/inhibition of surfactant compounds by inflammatory mediators (proteases, oxidants, nonsurfactant lipids). Treatment of surfactant dysfunction by instilling exogenous surfactants may improve gas exchange and pulmonary mechanics. Surfactants used for treatment vary in their attributes and effects, so when various surfactants are considered for therapy, resistance to inactivation is an important consideration. In addition to the classical goals of replacement therapy defined for preterm infants (rapid improvement in lung compliance and gas exchange), this approach will have to consider its impact on host defense competence and inflammatory and proliferative processes when applied in adults with respiratory failure.

1. Brief information about the physiological role of surfactant in normal conditions and in acute lung injury

Pulmonary 1 surfactant 2 - a mixture of phospholipids, consisting of 2 phases: lower (hypophase, liquid), containing glycoproteins and smoothing epithelial irregularities; as well as the surface phase (opophase) - a monomolecular phospholipid film, facing the hydrophobic areas into the lumen of the alveoli. The main biological properties of surfactant are reduced to a decrease in surface tension forces in the alveoli (almost 10 times); participation in the antimicrobial protection of the lungs and the formation of an anti-edematous barrier, by preventing the “sweating” of fluid from the pulmonary capillaries into the lumen of the alveoli.

1. Biological structures similar to lung surfactant have been found in the inner ear (organ of Corti), eustachian tube and kidneys. This review focuses on pulmonary surfactant.

2. The word "surfactant" is an abbreviation of the English phrase "surfactant"

Surfactant damage is undoubtedly one of the key links in the pathogenesis of acute lung injury (ALI 3) and its most severe form, adult respiratory distress syndrome (ARDS 4). This section of the review presents general data on the composition, metabolism and functioning of the surfactant system in the lungs of adults under normal conditions and in this pathology.

3. In English literature: acute lung injury (ALI)

4. In the English literature - acute pulmonary distress syndrome: acute respiratory distress syndrome (ARDS). The word “distress” in this title does not have an exact equivalent in Russian and can be translated as “suffering distress”, as well as “painful, abnormal”. Interestingly, in slang speech this word is also sometimes used to mean “squeezing, pinching.”

Compound. Pulmonary surfactant was isolated and described by J. A. Clements in 1957. This pulmonary structure is a secretion produced by some cells of the respiratory part of the lungs. Its most obvious and studied function to date is the reduction of surface tension forces tending to reduce the radius of the alveoli.
In all mammals, surfactant has a fairly similar composition, including approximately 90% lipids and 10% apoproteins, called surfactant proteins (SP). Currently, SP-A, -B, -C, -D are distinguished. The lipid fraction of the surfactant is represented mainly by phospholipids: dipalmitoylphosphatidylcholine (DPPC) - 45%, phosphatidylcholine - 25%, phosphatidylglycerol - 5%, the rest phospholipids - 5%. The phospholipid fraction also includes phosphatidylinositol, phosphatidylethanolamine, phosphatidylserine (total 5%). Other surfactant lipids - cholesterol, triglycerides, unsaturated fatty acids and sphygnomyelin total about 10%. Apparently, DPPC plays the most significant role in reducing surface tension forces. The physiological value of the protein components of the surfactant is also quite high: SP-B and SP-C are hydrophobic and are involved mainly in the processes of reducing surface tension, while SP-A and SP-D are hydrophilic and their role is mainly limited to participating in anti-infective protection of the lungs.

Metabolism. Surfactant is synthesized in type II alveolocytes and Clara cells, where it can accumulate in the form of osmiophilic (hence lipidic in nature) lamellar bodies and then secreted into the alveolar lumen by exocytosis (see Figure 1). During secretion, the original, spatially “twisted” structure of the surfactant (called “lamellar bodies”) is transformed by “unfolding” into tubular myelin and covers the inner surface of the alveoli in the form of a monolayer of lipids and proteins at the air/liquid interface. Phosphatidylcholine molecules are synthesized primarily through the cytidyl triphosphate pathway; this process is regulated by the enzymes phoand choline phosphotransferase. SPs are glycosylated 5 in the Golgi apparatus and then coupled to phospholipids. During cyclical changes in the area of ​​the inner surface of the alveoli associated with respiratory movements, the surfactant film is gradually destroyed and turns into small vesicles (vesicles), which are either captured by type II alveocytes for resynthesis, or are completely removed from the respiratory zone due to phagocytosis by alveolar macrophages. The synthesis of new portions of surfactant and utilization of vesicles occur quite quickly. However, if blood flow through some part of the lung stops (for example, as a result of an embolism), then the previously synthesized surfactant undergoes rapid destruction, and the production of fresh portions is suspended.

5. Glycosylation of proteins is based on the ability of glucose, fructose and galactose to enter into glycosylation reactions with amino groups included in the structure of proteins, lipids and nucleic acids.

When centrifuged in dense media, the surfactant can be separated into two fractions: the so-called “large aggregates of surfactant” (LAs), consisting of secreted lamellar bodies and tubular myelin, and also into a fraction with a lower density, called “small aggregates”. surfactant (small aggregates of surfactant, SAs), represented by vesicular formations. While large aggregates (LAs) contain SP and have valuable biophysical properties in healthy lungs, small aggregates (SAs) contain negligible amounts of SP and have been experimentally shown to exhibit weak biological activity both in vivo and in vitro .

Data from the experimental work of Veldhuizen RA et al. suggest that LAs undergo metabolic transformation into SAs under the influence of cyclic mechanical effects on the surfactant film (a typical example is the effect of the pressure of the respiratory mixture pumped into the lungs during mechanical ventilation), as well as under the influence of certain proteases, in particular an enzyme called convertase. The process of LAs As conversion, against the background of the constant synthesis of new portions of the LAs surfactant fraction, makes it possible to maintain a fairly stable L A s/SAs ratio in the alveolar lumen of healthy adults.

During pathological processes in the lungs, other enzymes (different from convertase) may appear in the respiratory zones, which are also capable of initiating the conversion of LAsSAs. First of all, neutrophil elastase should be included in this group of enzymes. As a result of pathological activation of enzymatic processes in the lumen of the alveoli, a rapid increase in the fraction of biologically passive SAs and depletion of the most biologically valuable fraction of surfactant, LAs, is possible.

Function. As mentioned above, the main function of surfactant is to reduce the surface tension forces on the inner wall of the alveoli in the air/liquid interaction zone.

Surface tension is the force, usually measured in dynes, acting in the transverse direction on an imaginary segment 1 cm long on the surface of a liquid. This force is due to the fact that intermolecular cohesion inside a liquid is much stronger than at its interface with a gas. Therefore, a unidirectional process always takes place towards a maximum reduction in the surface of the liquid. A good example of this phenomenon is the formation of soap bubbles. Their walls tend to shrink as much as possible, and as a result, a spherical surface is formed, the area of ​​which is minimal for a given volume. Inside such a bubble there is a pressure equal to Laplace’s law P = 4/r, where is the value of surface tension at the air/liquid interface; r is the radius of the bubble. In alveoli lined with liquid, only one surface is involved in creating pressure, and not two, as in a soap bubble, so the numerator of this equation should be put not 4, but 2. In this case, P represents the gradient of forces, the action of which is aimed at reducing the diameter of the alveoli and, ultimately, to its collapse.

In the absence of mechanisms to counteract the forces of surface tension, the P value will increase in parallel with the decrease in the radius of the alveoli, which in some cases of pulmonary pathology leads to atelectasis of the respiratory zones.

The mechanism by which surfactant affects surface tension is as follows. The formation of a thin layer of surfactant on the liquid covering the outer surface of the alveolar epithelium is determined by the heterogeneous physicochemical properties of DPCP molecules, which have both hydrophobic and hydrophilic ends. The molecular repulsion forces acting between them counteract the attractive forces between water molecules, which cause surface tension. Its decrease with decreasing surface area is explained by the more dense adjacency of DPPC molecules to each other, due to which the force of mutual repulsion between the molecules becomes greater.

Collapse of the alveoli may be accompanied or preceded by the phenomenon of pulmonary edema, caused by both an increase in hydrostatic pressure acting perpendicular to the alveolar-capillary barrier and an increase in the porosity of the alveolar-capillary wall.

Surfactant begins to be synthesized in the human fetus in sufficient quantities at 27-29 weeks of intrauterine development. When a premature baby is born at an earlier stage of pregnancy, the lack of surfactant leads to a sharp increase in surface tension forces in the alveoli, which significantly increases energy expenditure during breathing and contributes to rapid fatigue of the respiratory muscles. In this situation, there is usually a need for mechanical ventilation, however, its use in some cases can cause further deterioration of the situation due to ventilator-induced lung injury. In this situation, the use of exogenous surfactant is a pathogenetically justified method of treatment and can increase the effectiveness of mechanical ventilation, as well as the survival rate among premature newborns.

The use of exogenous surfactant preparations is considered as one of the most important components in the treatment of respiratory distress syndrome in premature newborns. In adult patients, with the development of ARDS, it is not so much the deficiency of surfactant production that is characteristic, but rather its damage, which naturally leads to instability of the geometry of the alveoli and a tendency to their atelectasis. This condition also requires mechanical ventilation in most cases. However, in contrast to the situation with premature infants, the administration of exogenous surfactant in this group of patients is not effective in all situations due to the significantly greater complexity of the pathogenetic mechanisms involved in the development of ARDS. Interestingly, the relative amount of surfactant in the lungs of a healthy adult is only 5-15 mg/kg body weight and this value is lower than in healthy newborn children.

In recent years, the role of surfactant in the antimicrobial defense system of the lungs has attracted attention. SP-A and SP-D belong to the collectin family, which have the ability to bind to the surface of the microbial wall and thereby facilitate the process of opsonization and subsequent phagocytosis of pathogens. Experimental confirmation of the role of surfactant in antimicrobial protection of the lungs was obtained in studies on transgenic animals that do not have SP-A and SP-D in the structure of surfactant. In the experiments conducted, these animals showed significantly higher susceptibility to bacterial and viral pulmonary infections compared to ordinary animals.

With the normal functioning of mucociliary clearance, surfactant also helps to remove foreign microparticles that enter the lumen of the alveoli with inhaled air.

Changes in the surfactant system in lung injury

Already in the first description of the ARDS clinic, performed by Ashbaugh DG et al. , it was assumed that surfactant damage plays an important role in the pathogenesis of the development of this syndrome. Subsequently, this hypothesis was confirmed many times.

Analysis of bronchoalveolar lavage fluid (BALF) obtained from patients with ARDS, as well as in experimental models, always reveals the presence of pronounced changes in the endogenous surfactant system. In particular, a decrease in the level of DPPC, phosphatidylglycerol, and surfactant-associated proteins has been described; a change in proportions between variants of surfactant aggregates was established: a decrease in the functionally active (LA) and an increase in the inactive (SA) fraction.

With ARDS, the physiological properties of the surfactant also change: it loses its elastic properties, is destroyed more quickly during cyclic stretching during breathing and has a lesser effect on the surface tension forces inside the alveoli. Recently, data have been published indicating a high predisposition to the development of ARDS in individuals with structural, genetically determined changes in SP-B [25, 56]. Interestingly, this genetic predisposition to ARDS is more common in women. Perhaps these data explain the well-known fact that ARDS develops only in a relatively small proportion of patients who have one or even a combination of several risk factors for the occurrence of this severe pathology.

The mechanisms for the occurrence of defects in the surfactant system in ARDS are associated both with a violation of the synthesis (and/or secretion) of this compound inside type II alveocytes, and with the acceleration of the degradation of lipids and proteins in the alveolar lumen. It is possible that the detection of surfactant components (in particular, SP) in the blood plasma of some ARDS patients may be associated with increased porosity of the alveolar-capillary barrier and the entry of these compounds into the systemic circulation. This still insufficiently studied process of “washing out” surfactant from the alveoli into the capillary bed can be potentiated under the influence of irrational mechanical ventilation modes leading to lung damage (lung-injury mechanical ventilation), i.e. as a result of the development of ventilator-induced lung injury. More recently, it has been proposed to use determination of plasma SP-D concentration as a prognostic criterion in individuals with ALI/ARDS. It should be noted that SP, especially SP-A, SP-B and SP-D in the human body are produced only by alveolocytes and are not detected outside the lungs under physiological conditions in healthy people. Their appearance in the blood can be used as a marker of damage to lung tissue in a fairly diverse pathology of the lower respiratory tract.

During the exudative stage of ARDS, which is expressed in the entry of a significant amount of plasma proteins into the lumen of the alveoli, new mechanisms of surfactant damage arise. In this case, there is a peculiar inhibition by plasma proteins of still preserved fragments of surfactant (LAs) due to their competitive displacement from the air/liquid interface on the inner surface of the alveolar wall. Along with other mechanisms, the process of inactivation of surfactant by blood proteins is also involved in thromboembolism of the branches of the pulmonary artery. The porosity of the alveolar-capillary barrier that develops in these cases leads to the “sweating” of plasma proteins into the lumen of the alveoli, neutralization of the surfactant film and the appearance of atelectasis. In this regard, the data of Strayer DS et al. are of interest. [77], who in experimental work revealed the protective properties of SP-A in relation to the inhibitory effects of blood fibrinogen on surfactant.

Experimental studies like in vivo, so in vitro show that the administration of high doses of exogenous surfactant during the exudative stage of ARDS in some cases can lead to a positive clinical effect due to the reverse process in the alveoli and restoration of the physiological layer L A s on the walls of the alveoli.

2. Therapy with exogenous surfactant preparations for acute lung injury
and adult respiratory distress syndrome.

Over the past two decades, a large amount of very contradictory data has been published on the effectiveness of the use of exogenous surfactant in patients with APL and ARDS. For the most part, these are descriptions of individual observations or studies in small groups of patients and experimental models. Until now, there has been a clearly insufficient number of controlled randomized clinical studies of the effectiveness of exogenous surfactant in ARDS that meet modern standards.

In one of these few studies, the synthetic surfactant “Exosurf” (GlaxoSmithkline, USA; 13.5 mg/ml DPPC) was administered to patients as an aerosol at a dose of 112 mg/kg/day for 5 days. The study was conducted on 725 patients with ARDS associated with sepsis. During the application of the “Exosurf” effect, a statistically significant decrease in the number of days spent without mechanical ventilation during the first 28 days of the disease and a decrease in the mortality rate could not be detected. The percentage of deceased patients was equal in the study and control groups (41% each).

Another study, with a smaller number of patients, was conducted in 1997 by Gregory TJ et al. [27]. In this case, a modified natural bovine surfactant “Survanta” (25 mg/ml) was used, which was installed directly into the respiratory tract of patients according to various schemes: 1) 8 doses of 50 mg/kg; 2) 4 doses of 100 mg/kg and 3) 8 doses of 100 mg/kg for 28 days. The second group of patients had the best results, the mortality rate in it was 18.8% (for comparison, in the control group that did not receive exogenous surfactant, this figure was 43.8%).

Another fairly large study was associated with a clinical trial of the recombinant surfactant “Venticute” (Byk Pharmaceuticals, Germany). Preliminary testing of the drug on a small group of patients with ARDS demonstrated quite encouraging results. In this regard, in 2001, an expanded stage of clinical trials of “Venticute” was carried out. The study was conducted in parallel in the USA, Europe and South Africa. The dose of the drug was 200 mg/kg based on phospholipids. In the reports of all countries participating in the international experiment, as a result of the use of “Venticute”, a statistically significant improvement in oxygenation was noted, but significant changes in the mortality rate and length of stay of patients on mechanical ventilation could not be obtained. However, with a subsequent general analysis of all the collected material obtained during the treatment and observation of 448 patients, it was found that patients with a secondary variant of ARDS, i.e. which arose against the background of previous bacterial or chemical damage to the lungs (pneumonia, aspiration), after treatment with “Venticute” had a statistically significant decrease in the mortality rate. At the same time, this fairly large and well-controlled study showed the clinical acceptability of exogenous surfactant therapy, as well as the absence of serious complications during the use of Venticute for patients with ARDS. The latter circumstance confirmed the data on the safety of exogenous surfactant for patients with ARDS, previously obtained in other studies.

It can be assumed that the results of the work looked somewhat discouraging to the Venticute manufacturers and the organizers of the international study. However, the lack of a convincing reduction in mortality and length of stay of patients on mechanical ventilation should not be unambiguously interpreted as a manifestation of the complete ineffectiveness of exogenous surfactant preparations. Rather, these results indicate the need for a more in-depth study of all the complex mechanisms involved in the pathogenesis of ARDS, as well as insufficient experimental consideration of various external and internal factors affecting the effectiveness of surfactant therapy. That is, a more rational and individual approach to the use of drugs in this group is required.

Understanding the need to optimize the use of commercial surfactant preparations for ARDS naturally led to the search for circumstances that increase or decrease the effectiveness of this type of therapy. Currently, among these various factors, the most significant are:

1. Pathogenetic variant and severity of ARDS;
2. Qualitative and quantitative composition of ingredients in the exogenous surfactant preparation;
3. Volume, frequency and method of drug administration; the mode of mechanical ventilation at the time of surfactant administration and in the immediate subsequent period;
4. Choosing the optimal time to start and complete replacement therapy.

Pathogenetic features of the development of ARDS

The collective concept of “ARDS” currently includes similar clinical manifestations that occur in diseases and pathological conditions that are very heterogeneous in etiopathogenesis. Here is just a cursory and far from complete listing of the reasons that can lead to the occurrence of ARDS:

1. Diffuse pulmonary infections (viral, bacterial, mycotic, Pneumocystis).
2. Aspiration of stomach contents in Mendelssohn's syndrome, water in drowning.
3. Inhalation of toxins and irritants (chlorine, NO 2, some types of smoke, ozone, high concentrations of O 2).
4. Pulmonary edema caused by an overdose of drugs (heroin, methadone, morphine, dextropropoxyphene).
5. Side effect of some non-narcotic drugs (nitrofurantoin).
6. Immunological response to various antigens (Goodpasture syndrome, systemic lupus erythematosus).
7. Any injury, including burns, accompanied by hypotension.
8. Systemic reactions of the body to extrapulmonary processes (septicemia caused by gram-negative microflora; hemorrhagic pancreatitis, amniotic fluid embolism, fat embolism).
9. Postcardiopulmonary bypass (“pump lung”, “postperfusion lung”), etc.

Pelosi P. et al. in a recently published review, as well as in his earlier work, emphasizes the advisability of distinguishing at least two variants of ARDS: 1) resulting from direct damage to the lungs (pulmonary ARDS, ARDSp) and 2) representing a secondary process as a consequence of a severe extrapulmonary pathological condition (extrapulmonary ARDS , ARDSexp). The aforementioned review substantiates the legitimacy of this approach using the example of objectively existing differences regarding the pathophysiology of the development of these two forms of ARDS, the pathways of biochemical and immune activation of pathological processes in the lungs; differences in morphological, histological and radiological data obtained in these subgroups of patients, and the advisability of differentiating approaches to the selection of mechanical ventilation modes that protect the lungs and individualizing drug therapy was noted.

A similar approach to identifying two variants of ARDS is also contained in the work of Korean researchers. For example, they found that the PaO 2 /FIO 2 indicator during mechanical ventilation in the prone position in ARDSexp patients improved by 63% in 30 minutes, while in ARDSp patients this indicator increased only by 23% and this it took 2 hours.

Taking into account the impressive diversity of causes of ARDS and the variability of response in different subgroups of patients to treatment (even to the position of the patient’s torso during mechanical ventilation), it is difficult to expect uniform results with a unified, undifferentiated approach to the administration of exogenous surfactant. This can be confirmed by the report of Seeger W. et al. about significantly lower mortality when using exogenous surfactant in patients with the primary pulmonary form of ARDS (ARDSp).

It should be noted that the desire to identify pathophysiological variants of ARDS appeared relatively recently and is not supported by all specialists working in this field. A very critical attitude towards this approach is set out in the work of Callister M.E. and Evans T.W. who believe that identifying different forms of ARDS requires a more balanced approach and should be based, among other indicators, on differences in mortality rates in subgroups of patients.

Features of the qualitative composition of exogenous surfactant

The characteristics of some commercial surfactant preparations currently produced are presented in Table 1. A summary of published data on the use of various versions of exogenous surfactant in ARDS allows us to draw the following conclusions: protein-containing dosage forms have a higher therapeutic effect, and within this group of drugs - made on the basis of BALZH. For example, the use of the drug “bLES” (Canada), the starting raw material for which is cattle BALF, in the experimental model led to a more significant improvement in gas exchange, compared with the drug “Survanta” (USA), made from cattle lung tissue livestock It should be noted that these two drugs differ significantly in lipid content (see Table 1). This circumstance, apparently, can also affect the effectiveness of their use.

In addition to differences in lipid content, the concentration of SP, especially SP-B and SP-C, may determine the therapeutic efficacy of exogenous surfactant. Relatively recently, animal experiments have shown quite comparable therapeutic efficacy for ARDS of the exogenous surfactant “Venticute” (Germany), containing recombinant SP-C in combination with DPPC and other lipids, and “bLES”, based on a lipid extract from natural surfactant of cattle .

It is possible that synthetic biologically active components of surfactant substitutes disappear from the lumen of the alveoli earlier than their natural counterparts. In the work of Beresford M.W. and Shaw N.J. It was shown that the level of SP - B in BALF, performed the next day after the administration of two different forms of exogenous surfactant, was significantly lower in the group where the drug was used from synthetic raw materials, compared with the group that received exogenous surfactant from natural raw materials.

At the same time, when using exogenous surfactant preparations made on the basis of biological raw materials, it is necessary to take into account the theoretical possibility of transfer of pathogenic microorganisms, which is practically excluded when using synthetic surfactant substitutes. Apparently, the likelihood of infection with exogenous surfactant preparations is very low; there are no descriptions of such cases in the available literature. The main technological problem in obtaining exogenous surfactant preparations of animal origin is a certain shortage of raw materials, but the emergence of synthetic analogues with good therapeutic properties makes it possible to overcome this obstacle.

Methods of administering surfactant and its dosage

Various methods of using surfactant have a common goal - to deliver an adequate dose of the drug to the alveoli without concomitant significant depression of the respiratory function of the lungs and deterioration in the general condition of the patient. Currently, the following main methods of surfactant administration are used in clinical practice and in experimental models:

1. Installation of the liquid form of the drug by bolus or drip through the endotracheal tube;
2. Administration of the drug through a bronchoscope. In this case, the administration of a surfactant may be combined with segmental bronchoalveolar lavage, in which the administered drug is used as a lavage fluid or is administered in relatively large volumes immediately after conventional lavage;
3. Aerosol application of surfactant.

Each of the presented methods has its own advantages and disadvantages, however, slow (drip) administration of the drug through a catheter installed in the endotracheal tube, according to one of the leading experts in this field, Lewis JF, is the method of choice for patients with fairly severe variants of ARDS. This recommendation is justified by the ease of use of this method and the ability to introduce significant volumes of surfactant in a relatively short period of time. As an alternative to drip administration of surfactant in patients with moderate forms of ALI and ARDS, it may be recommended to prescribe aerosol forms of the drug . Recently, an experimental study was conducted in Japan to evaluate the possibility of prolonging the effect of an exogenous surfactant aerosol by subsequent (after 15 minutes) administration of a dextran aerosol. Using an experimental model of ARDS, the authors of the work were able to show that inhaled dextran in the lumen of the alveoli is able to prevent inhibition of exogenous surfactant by plasma proteins and leads to a significant prolongation of its clinical effect.

The therapeutic and cost-effectiveness of various commercial forms of surfactant are currently under investigation.

The influence of ongoing mechanical ventilation. Numerous experimental and clinical studies conducted in the last decade indicate a rather complex interaction between various modes of mechanical ventilation and exogenous pulmonary surfactant. A significant part of experimental work indicates that the administration of exogenous surfactant against the backdrop of a “protective” ventilation strategy leads not only to a more noticeable improvement in the gas exchange function of damaged lungs, but is also accompanied by pronounced changes in lung metabolism and indicators of pulmonary mechanics. For example, in an experimental model of ARDS, it was found that during pressocyclic ventilation with high peak inspiratory pressure (PIP), the administration of exogenous surfactant “bLES” (100 mg/kg) can significantly increase the level of TNF-a and IL-d in the perfusate, flowing from the lungs; however, this effect was not associated with activation of alveolar macrophages, but rather was determined by the opening of previously atelectatic alveoli and hyperextension of alveocytes. Commenting on this message, we can conclude that the authors are describing a fairly well-known atelectotrauma of the lungs. However, despite the increase in the concentration of pro-inflammatory cytokines, improvements in pulmonary compliance and an increase in tidal volume were noted during the use of bLES.

It is interesting that the use of the drug “Alveofact” (a drug close to “Survanta”) at a dose of 60 mg/kg in a two-year-old girl with ARDS on the background of an infectious extrapulmonary pathology had the opposite effect on the concentration of cytokines: an arteriovenous difference in TNF-a and IL-d in the child decreased due to the arterial component. The authors of the observation associated this effect with the inhibitory effect of exogenous surfactant on the activation of polymorphonuclear neutrophils in the vascular bed of the lungs. The data presented in this work are in good agreement with the recommendations of Vazquez de Anda GF et al. on the use of exogenous surfactant for the treatment of ventilator-associated lung injury in order to reduce the concentration of proinflammatory cytokines.

Unfortunately, works devoted to the study of the influence of certain mechanical ventilation modes on the structure, metabolism and clinical effectiveness of exogenous surfactant in ARDS are fragmentary and extremely few in number. For example, it was found that the start of mechanical ventilation in patients with ARDS can lead to a change in the SP ratio in BALF. After just one day of mechanical ventilation, the SP-A level increases noticeably, and by the end of the second day of ventilation, the concentration of this compound becomes significantly higher than the initial level. Similar results regarding changes in the level of SP - A in the early stages of ARDS are presented in the work of Zhu BL et al. Interestingly, when ARDS was combined with a pulmonary infection, these shifts in the concentration of SP-A were not observed.

Apparently, by analogy with endogenous surfactant, during “damaging” mechanical ventilation modes, most of the exogenous surfactant quickly loses its properties due to the conversion of LAsSas or due to other mechanisms. At the same time, “protective” methods of mechanical ventilation can contribute to longer preservation of the drug in the lumen of the alveoli and restoration of the physiological balance of Las/SAs

Timing of initiation of therapy with exogenous surfactant in patients with ARDS

By now it has become quite obvious that in cases where ARDS is an integral part of severe multiple organ pathology, the prescription of drugs from this group is ineffective.

Unfortunately, there is no information in the available literature on the advisability of prophylactic administration of exogenous surfactant in patients at high risk of developing ARDS. Experimental and clinical data on the selection of the optimal timing of initiation of therapy with exogenous surfactant are scarce and boil down to recommendations for the earliest possible use of drugs, already in the initial stages of ARDS development. It has also been shown that in later stages of ARDS development, when prescribing exogenous surfactant, it is more advisable to use the bronchoscopic route of drug administration followed by bronchoalveolar lavage.

3. Promising directions in the study of the therapeutic role
exogenous surfactant preparations for lung pathology.

Despite the relatively modest results obtained in randomized studies on the use of exogenous surfactant in patients with ARDS, drugs in this group continue to remain very promising for clinical use. It seems that increasing the therapeutic effectiveness of already created surfactant preparations will lie through individualizing the dose and optimizing the timing of the start of therapy.

Probably, in the future, the feasibility of prophylactic use of drugs in this group in individuals at high risk of developing ARDS deserves a more detailed study.

Having quite pronounced antimicrobial and immunomodulatory properties, exogenous surfactant preparations can potentially be very effective in the treatment and prevention of many forms of infectious lung pathology, including one of the most common complications of long-term mechanical ventilation - ventilator-associated pneumonia (VAP). As proof of the validity of this assumption, one can cite a recent report by Nakos G. et al. about the identification of gross disturbances in the endogenous surfactant system in VAP, and the mechanisms of occurrence and clinical and laboratory manifestations of these defects turned out to be very close to ARDS (the appearance of large quantities of neutrophils in the alveolar zone with subsequent destruction of the surfactant film due to neutrophil elastase; displacement of pulmonary surfactant by plasma proteins; decrease in the proportion of biologically active fraction of LAs, etc.). It is important that structural and functional disturbances of endogenous surfactant in VAP can persist for quite a long time, even after the disappearance of signs of pulmonary pathology. The very first experience of using an aerosol of exogenous surfactant Exosurf for VAP showed that after 4 days of treatment in patients the number of neutrophils in the BALF significantly decreased. Of course, as in the case of ARDS, additional research is required to test the effectiveness of surfactant preparations in VAP, as well as the development of schemes for their differentiated use at different stages of the disease.

The combined use of exogenous surfactant and other drugs, in particular antibiotics, in the treatment of pneumonia deserves attention. So far, limited data suggest that this combination in patients with pneumonia who require mechanical ventilation reduces the risk of some side effects when antibiotics are administered through the respiratory tract. In addition, this combination makes it possible to more effectively “deliver” antibacterial drugs to collapsed alveoli in the area of ​​active inflammatory process. Apparently, this effect is achieved by facilitating the processes of recruitment of atelectatic alveoli under the influence of exogenous surfactant and the subsequent involvement of previously collapsed areas of the lungs in the respiratory cycle.

Long-term mechanical ventilation leads to damage to the surfactant even in the absence of clinically significant lung pathology. According to Tsangaris I. et al. in persons requiring mechanical ventilation for reasons not related to lung pathology, after 2 weeks from the start of ventilation, a pronounced decrease in LAs was noted and other signs of surfactant damage appeared (a comparison was made with the results of the analysis of BALF obtained on the first day of mechanical ventilation). These data deserve consideration from the point of view of the feasibility of prophylactic administration of exogenous surfactant preparations in persons requiring long-term mechanical ventilation. This may be one approach to reducing the risk of late-onset VAP.

To summarize, it should be said that, despite the rather long period of industrial production, the therapeutic potential of exogenous surfactant preparations has not yet been fully used. It can be predicted that, given the high vulnerability of endogenous surfactant both during primary processes inside the lungs and during secondary damage against the background of leading pathology of other organs, interest in this method of treatment will naturally increase. An important circumstance is the high prevalence (and, accordingly, social significance) of the APL syndrome, in which the therapeutic use of exogenous surfactant continues to be considered one of the most promising areas. According to the latest data in the United States, the incidence of APL is 64.2 cases per 100 thousand population (which, by the way, does not differ from data for developing countries), and the mortality rate is 40%.

Increasing the effectiveness of treatment using surfactant preparations will be facilitated by further accumulation of knowledge about its biological role and improvement of approaches to clinical use.

Table 1

Names, composition and manufacturers of some commercial forms of surfactant approved for use in the treatment of ARDS (cited with additions from Lewis JF, 2003).

Name	Feedstock	Compound	Manufacturer
Protein-containing forms
Alveofact	Cattle lavage fluid	99% PL, 1% SP-B and SP-C	Boehringer Ingelheim, Ingelheim, Germany
BLES*	Cattle lavage fluid	75% phosphatidylcholine and 1% SP - B and SP - C	BLES Biochemicals, London, Ontario, Canada
Curosurf	Porcine lung tissue	DPPC, SP - B and SP - C (concentration - ?)	Chiesi Farmaceutici, Parma, Italy
CLSE**	Porcine lung tissue	See “Infasurf”
HL-10	Porcine lung tissue	?	Leo Pharma, Copenhagen, Denmark
Infasurf	Calf lavage fluid	DPPC, tripalmitin, SP (B 290 g/ml, C 360 g/ml)	Forest Laboratories, New York, NY, USA
Surfaxin	Synthetic product	DPPC, synthetic peptides	Discovery Laboratories, Doylestown, PA, USA
Survanta		DPPC, tripalmitin SP (B<0.5%, C =99%)	Abbott Laboratories, Abbott Park, IL, USA
Surfactant T.A.	Cattle lung tissue	DPPC, tripalmitin, SP (B<0.5%, C =99%)	Tokyo-Tanabe Co. Ltd., Tokyo, Japan
Venticute	Synthetic product	?	Byk Pharmaceuticals, Constance, Germany
Forms that do not contain protein
ALEC***	Synthetic product	70% DPPC, 30% phosphatidylglycerol	Britannia Pharmaceuticals Limited, Redhill, UK
Exosurf	Synthetic product	85% DPPC, 9% hexadecanol, 6% tyloxapol	GlaxoSmithkline, Research triangle Park, NC, USA

* bLES – “Bovine Lipid Extract Surfactant”

** CLSE - “Calf lung surfactant extract”

** * ALEC – “Artificial Lung-Expanding Compound”

Figure 1.

Microphotographs of type II alveolocytes and variants of intra-alveolar surfactant in rats in healthy lungs (a, b) and with experimental pulmonary edema (c-f).

a) Normal ultrastructure of type II alveolocyte. Labeled: intracellular surfactant stored in lamellar bodies (lb), intracellular myelin (tm). Scale bar in lower right corner = 2 µm.

b) Tubular myelin (tm) is in close contact with the cell membrane adjacent to both the basement membrane (arrows) and the alveolar lumen. lbl – lamellar bodies. Scale = 0.5 µm.

c) Focal intra-alveolar edema. Swelling of type I alveolocytes (pI). Type II alveolocyte with slight mitochondrial swelling and lamellar bodies of normal size (lb). Various forms of surfactant in the lumen of the alveoli (in edematous fluid): resembling lamellar bodies, multilamellar, unilamellar. Scale = 2 µm.

d) Alveolar wall with partial swelling (thick arrow) and fragmentation (thin arrow) of type I alveolocyte. The lumen of the alveoli is filled with edematous fluid (ed). Multilamellar and unilamellar forms of surfactant. Scale = 2 µm.

e) Tubular myelin in the lumen of the alveoli (in the edematous fluid), signs of its disintegration. pI = type I alveolocyte swelling. Scale = 0.5 µm.

f) Disintegration of tubular myelon in the same model, but in areas of the lungs without external signs of edema: pI = type I alveolocyte swelling; en = capillary endothelium; er = red blood cell. Scale = 0.5 µm.

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Surfactant(translated from English - surfactant) - a mixture of surfactants lining the pulmonary alveoli from the inside (that is, located at the air-liquid interface). Prevents the walls of the alveoli from collapsing (sticking together) during breathing by reducing the surface tension of the film of tissue fluid covering the alveolar epithelium. Surfactant is secreted by a special variety of type II alveolocytes from blood plasma components.

Compound

Composition of pulmonary surfactant:

Phospholipids - 85%	% phospholipids
Phosphatidylcholine:	7,3
dipalmitoylphosphatidylcholine	47,0
unsaturated phosphatidylcholine	29,3
Phosphatidylglycerol	11,6
Phosphatidylinositol	3,9
Phosphatidylethanolamine	3,3
Sphingomyelin	1,5
Other	3,4
Neutral lipids - 5%
Cholesterol, free fatty acids
Proteins - 10%
Surfactant protein A	++++
Surfactant protein B	+
Surfactant protein C	+
Surfactant protein D	++
Other
The exact composition of surfactant proteins is not yet known

Properties

Surfactant is synthesized and secreted by pneumocytes (alveolocytes) (epithelial cells) type II. Due to surface-active tension, the surfactant lowers the surface tension in the alveolus, preventing its “collapse.” Surfactant also has a protective effect. The high surface-active properties of the surfactant are explained by the presence of dipalmitoylphosphatidylcholine in it, which is formed in the lungs of a full-term fetus immediately before birth.

Surfactant helps the lungs absorb and metabolize oxygen. Recently, the fashion for low-fat nutrition leads to hypoxia (oxygen starvation) in people who do not eat high-quality fats, since surfactant is approximately 90% fat.

Structure

The surfactant located on the surface of the alveolar epithelium includes 2 phases:

Hypophase

The lower one consists of tubular myelin, which has a lattice appearance and smoothes out the irregularities of the epithelium.

Apophase

A surface monomolecular film of phospholipids facing the alveolar cavity with hydrophobic areas.

Functions

1. Reducing the surface tension of the film of tissue fluid covering the alveolar epithelium, which promotes the straightening of the alveoli and prevents their walls from sticking together during breathing.
2. Bactericidal.
3. Immunomodulatory.
4. Stimulation of the activity of alveolar macrophages.
5. Formation of an anti-edematous barrier that prevents the penetration of fluid into the lumen of the alveoli from the interstitium.

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Notes

See also

Literature

• Bykov V. L. Particular human histology. - St. Petersburg. : SOTIS, 1999. - P. 144. - ISBN 5-85503-116-0.

Links

Excerpt describing pulmonary surfactant

- What did they say, crooked Kutuzov, about one eye?
- Otherwise, no! Totally crooked.
- No... brother, he has bigger eyes than you. Boots and tucks - I looked at everything...
- How can he, my brother, look at my feet... well! Think…
- And the other Austrian, with him, was as if smeared with chalk. Like flour, white. I tea, how they clean ammunition!
- What, Fedeshow!... did he say that when the fighting began, you stood closer? They all said that Bunaparte himself stands in Brunovo.
- Bunaparte is worth it! he's lying, you fool! What he doesn’t know! Now the Prussian is rebelling. The Austrian, therefore, pacifies him. As soon as he makes peace, then war will open with Bunaparte. Otherwise, he says, Bunaparte is standing in Brunovo! That's what shows that he's a fool. Listen more.
- Look, damn the lodgers! The fifth company, look, is already turning into the village, they will cook porridge, and we still won’t reach the place.
- Give me a cracker, damn it.
- Did you give me tobacco yesterday? That's it, brother. Well, here we go, God be with you.
“At least they stopped, otherwise we won’t eat for another five miles.”
– It was nice how the Germans gave us strollers. When you go, know: it’s important!
“And here, brother, the people have gone completely rabid.” Everything there seemed to be a Pole, everything was from the Russian crown; and now, brother, he’s gone completely German.
– Songwriters forward! – the captain’s cry was heard.
And twenty people ran out from different rows in front of the company. The drummer began to sing and turned to face the songwriters, and, waving his hand, began a drawn-out soldier’s song, which began: “Isn’t it dawn, the sun has broken...” and ended with the words: “So, brothers, there will be glory for us and Kamensky’s father...” This song was composed in Turkey and was now sung in Austria, only with the change that in place of “Kamensky’s father” the words were inserted: “Kutuzov’s father.”
Having torn off these last words like a soldier and waving his hands, as if he was throwing something to the ground, the drummer, a dry and handsome soldier of about forty, looked sternly at the soldier songwriters and closed his eyes. Then, making sure that all eyes were fixed on him, he seemed to carefully lift with both hands some invisible, precious thing above his head, held it like that for several seconds and suddenly desperately threw it:
Oh, you, my canopy, my canopy!
“My new canopy...”, twenty voices echoed, and the spoon holder, despite the weight of his ammunition, quickly jumped forward and walked backwards in front of the company, moving his shoulders and threatening someone with his spoons. The soldiers, waving their arms to the beat of the song, walked with long strides, involuntarily hitting their feet. From behind the company the sounds of wheels, the crunching of springs and the trampling of horses were heard.
Kutuzov and his retinue were returning to the city. The commander-in-chief gave a sign for the people to continue walking freely, and pleasure was expressed on his face and on all the faces of his retinue at the sounds of the song, at the sight of the dancing soldier and the soldiers of the company walking cheerfully and briskly. In the second row, from the right flank, from which the carriage overtook the companies, one involuntarily caught the eye of a blue-eyed soldier, Dolokhov, who especially briskly and gracefully walked to the beat of the song and looked at the faces of those passing with such an expression, as if he felt sorry for everyone who did not go at this time with the company. A hussar cornet from Kutuzov's retinue, imitating the regimental commander, fell behind the carriage and drove up to Dolokhov.
The hussar cornet Zherkov at one time in St. Petersburg belonged to that violent society led by Dolokhov. Abroad, Zherkov met Dolokhov as a soldier, but did not consider it necessary to recognize him. Now, after Kutuzov’s conversation with the demoted man, he turned to him with the joy of an old friend:
- Dear friend, how are you? - he said at the sound of the song, matching the step of his horse with the step of the company.
- How am I? - Dolokhov answered coldly, - as you see.
The lively song gave particular significance to the tone of cheeky gaiety with which Zherkov spoke and the deliberate coldness of Dolokhov’s answers.