Lipid Distress Syndrome in the Pathogenesis of Acute Lung Injury in Surgical Endotoxemia and Its Correction

The dissertation is devoted to the study of the lipid distress syndrome in the pathogenesis of acute lung injury in surgical endotoxemia developing against the background of acute pancreatitis of various forms (edematous and destructive). The mechanisms of disruption of lipid metabolism of lung tissue structures are investigated, including the dynamics of the lipid composition of plasma blood and biomembranes, the state of the surfactant system, microcirculation and transcapillary fluid exchange, phospholipase A2 activity, and lipid peroxidation. The efficacy of antioxidant preparations (dimefosfon, mekendol) and laser therapy in the correction of identified disturbances is evaluated. It has been established that the lipid distress syndrome is one of the key links in the pathogenesis of acute lung injury in endotoxemia, and the degree of lipid restructuring correlates with the severity of endogenous intoxication.

Relevance

Exudative complications in surgical endotoxemias occupy a special position. Among the numerous complications of destructive forms (pancreatitis), in recent years, with the successes of resuscitology and anesthesiology, the projected survival rate in the acute period of critical states has been noted to increase the population of patients suffering from multiple organ dysfunction, which today is the leading cause of mortality in the ICU. One of the most important factors initiating the development of multiple organ insufficiency in such severe surgical pathology as acute pancreatitis is the syndrome of intoxication. Endotoxemia can be regarded as a link forming a "vicious circle" in a critical state. On the one hand, it is endotoxemia that causes the dysfunction of most organs and systems and the formation of multiple organ insufficiency, and on the other hand, it is the dysfunction of vital organs that leads to the depression of detoxification processes with the development of endotoxemia phenomena (Novochodov V. V., 2001; Pixnn I N., 2006; [JavicL-ion K. O. et al.], 2002, Cheng I W. ct at, 2001; Davidson K, G.CI al., 2002; Wyncoll D, U 1999).

A lawful consequence of pronounced endotoxemia (Ketlinsky S A, 1999; Kassil V. V., et al., 2003) can be considered the Acute Lung Injury Syndrome (ALI), which is a constant companion of any acute surgical pathology, including acute pancreatitis, but often determining the course and outcomes. Mortality in severe forms of ARDS ranges within 50% (Gritsai A. I., Kolesnenchenko A. P., 2002; Kallet R H., 2004). At present, the best tactic with regard to ALI is the prevention of its development and comprehensive early treatment, which appears possible on the basis of the expansion of knowledge about the mechanisms of formation of multiple organ insufficiency at the molecular level.

In recent studies (Vlasov A. P., 2004; Chuyin V. V. et al., 1992; Trofimov V. A. et al., 1995; Podsrov V. N., 1997; Saushchev V. S. et al., 1999), considerable attention has been devoted to disorders of lipid metabolism in the pathogenesis of multiple organ dysfunction. Linoleic acid, being a structural component of biomembranes, however, changes in the lipid spectrum are not only a consequence of the action of pathopathogenic agents but also directly characterize the lability of cellular and tissue structures to destructively damaging factors.

Thus, the in-depth study of molecular mechanisms of disorders of LIPID metabolism in terms of their pathogenetic significance in the formation of multiple organ insufficiency and in particular the Acute Lung Injury Syndrome constitutes the main guiding direction of scientific research aimed at finding effective methods of treatment of this grave pathological condition.

Objective of the Work

To determine and conceptually substantiate the role of LIPID distress syndrome in the pathogenesis of acute lung injury in surgical endotoxemia; to evaluate the efficacy of antioxidant-type drugs and laser therapy in the correction of identified changes.

Main Tasks

1. In endogenous intoxication on the model of acute biliary pancreatitis of varying severity, to establish qualitative and quantitative disturbances of lipid metabolism of tissue structures of the lungs.

2. To establish the interrelationship between disturbances of lipid metabolism of the lungs and damage to their surfactant system at various degrees of endotoxemia.

3. In experimental pancreatitis of varying severity, to investigate the role of superoxide reactions of lipid peroxidation, total proteolytic activity of blood, and phospholipase A2 activity in the restructuring of lipid components of biomembranes of cellular structures of the lungs.

4. To determine the interrelationship between disturbances of LIPID metabolism in endogenous intoxication and functional indicators of the lungs.

5. At various degrees of expression of endogenous intoxication, to establish the interrelationship between the occurrence and degree of correlation dependence of disturbances of lipid metabolism of the lungs and disorders of microcirculation and bioenergetics of tissues (in the damaged organ).

6. To investigate the influence of medicinal preparations possessing antioxidant action (dimefosfon, mekendol) on lipid metabolism of the lungs in acute pancreatitis.

7. To determine at endogenous intoxication the effects of antioxidant therapy in the correction of homeostatic disorders associated with impairment of the functional state of the lungs.

8. At varying severity of endogenous intoxication in acute pancreatitis, to establish the possibilities of laser therapy in the correction of homeostatic disorders and to determine the character of lipid restructuring in the lungs under the influence of noncoherent laser radiation.

9. To establish the influence of membrane protectors and laser radiation on key mechanisms involved in the regulation of lipid metabolism.

10. On the basis of the obtained data, to assess the role of lipid distress syndrome in the pathogenesis of acute lung injury in endogenous intoxication and the prospects for its correction through regulation of lipid metabolism.

Scientific Novelty

It has been established that in endogenous intoxication, substantial changes occur in the lipids of tissue structures of the lungs, and the lipid composition of plasma blood is altered. It has been shown that the most substantial changes in lipid homeostasis were expressed in the form of a decrease in the content of total phospholipids, phosphatidylcholine, an increase in the level of free fatty acids and lysoforms of phospholipids, which testified about membrano-destructive processes in cellular structures of the organ.

It has been revealed that disturbances of lipid metabolism in the lungs are associated with the formation of the main pathogenetic links of the respiratory distress syndrome, such as damage to the surfactant system of the lungs, disruption of transcapillary exchange of fluid in the small circle of blood circulation.

It has been established that disturbances of lipid metabolism of the lungs differ in high reactivity, the manifestation of which is substantial changes in the lipid composition of tissue structures of the organ already within a day after modeling of the pathology.

It has been demonstrated that the degree of lipid restructuring and impairment of the functional state of the lungs correlate with the severity of endogenous intoxication, the intensity of lipid peroxidation processes, depression of antioxidant protection, total proteolytic activity of blood, and phospholipase A2.

One of the most important pathogenic consequences of disturbance of the lipid composition of tissue structures of the lungs in endotoxemia is the loss of their barrier function, which determines the translocation of fluid into the extravascular space of the organ.

The established dynamic interconnection of changes in lipid metabolism and dysfunctions of the lungs under the action of a toxic factor allows determining that membrano-destructive processes of cellular structures are leading in the development of acute lung injury.

Experimental investigations have revealed that medicinal preparations with antioxidant action (dimefosfon, mekendol) impede the development of acute lung injury in endogenous intoxication.

It has been proven that the action of bioantioxidants in the correction of the respiratory distress syndrome is accompanied by the prevention of progression of disturbances of lipid homeostasis of tissue structures of the lungs.

The group has demonstrated that the lipid-regulating effect of the preparations is mediated by their influence on free-radical reactions of lipid peroxidation processes and phospholipase A2 activity.

It has been established that in pancreatitis accompanied by severe intoxication, the efficacy of antioxidant therapy is reduced.

It has been discovered that the efficacy of helium-neon laser therapy in preventing the development of acute lung damage is significantly lower than that of antioxidants, especially in severe endogenous intoxication.

It has been revealed that low-intensity laser radiation does not lead to correction or prevention of disorders of lipid metabolism of tissue structures of the lungs. The established fact confirms the crucial role of the lipid distress syndrome in the pathogenesis of acute lung damage in endotoxemia.

Practical Significance

The practical significance of the work lies in the identification of one of the most important links in the pathogenesis of acute lung injury in surgical endotoxemia — the lipid distress syndrome.

The established correlation connection of membrano-destructive processes with functional disturbances of the lungs at various degrees of endogenous intoxication determines the advisability of using agents that promote the restoration of the lipid composition of the organ's biomembranes.

The revealed efficacy of antioxidants in the correction of the lipid distress syndrome and, as a consequence, the prevention of the development of acute lung damage in endotoxemia may serve as a basis for the improvement of therapeutic schemes for this fatal complication.

It has been shown that the use of laser therapy in endotoxemia with the aim of preventing acute lung damage has limited indications, especially in severe forms and at initial stages of therapy.

It has been established that markers of the severity of acute lung damage in endogenous intoxication, having prognostic significance, may be considered modifications of the LIPID composition of plasma blood, testifying about the absorption into the bloodstream of the surfactant component, and the most informative fractions are lysophospholipids and free fatty acids. The position put forward in defense,

One of the most important ASSUMPTIONS in the pathogenesis of acute lung damage in surgical endotoxemia is the LIPID distress syndrome, the degree of expression of which correlates with the severity of endotoxemia.

The most significant changes in the lipid spectrum of tissue structures of the lungs in endogenous intoxication are manifested in the form of a decrease in the content of total phospholipids, phosphatidylcholine, an increase in the level of free fatty acids and lysoforms of phospholipids, which overall testifies about membrano-destructive processes in the organ.

Changes in the lipid spectrum of lung tissue in endotoxemia differ in high reactivity; substantial deviations in the content of most lipid fractions arise in the first days of the pathological process.

Disturbance of lipid metabolism in the lungs is associated with the formation of the main pathogenetic links of the respiratory distress syndrome, such as damage to the surfactant system of the lungs, disruption of transcapillary exchange of fluid in the small circle of blood circulation.

The degree of lipid restructuring and impairment of the functional state of the lungs correlate with the severity of endogenous intoxication, the intensity of lipid peroxidation processes, depression of antioxidant protection, total proteolytic activity of blood, and phospholipase A2.

Medicinal preparations with antioxidant type of action (dimefosfon, mekendol) impede the development of acute lung injury in endogenous intoxication by virtue of their ability to prevent the progression of disturbances of lipid homeostasis of tissue structures.

The lipid-regulating effect of antioxidants is realized not only through the reduction of the intensity of free-radical reactions of lipid peroxidation processes, but also through the decrease in total proteolytic activity of blood and phospholipase A2.

In pancreatitis accompanied by severe intoxication, the efficacy of antioxidant therapy in the correction of the respiratory distress syndrome is substantially limited.

The efficacy of laser therapy at a dose of 0.1 J/sec in preventing the development of acute lung damage is limited, especially in severe endogenous intoxication.

Publications. On the topic of the dissertation, 49 works have been published, of which 25 articles in print have been peer-reviewed by the VAK.