The role of arachidonic acid metabolites in the onset and progression of bronchial asthma has been most studied . With this type of allergic inflammation, the variety of biological effects of eicosanoids is most fully reflected. The main processes that occur in the body during an asthmatic reaction include spasm of smooth muscles of the bronchi (PG and TxA2, MRV-A), swelling of the mucous membrane of the bronchial tree (LTS4, D4 and E4, PGE), increased secretion of mucus (PG, TETE), cellular airway wall infiltration with the development of bronchial hyperreactivity (LTV4, TETE). It is impossible to separate these processes by degree of significance, since they all occur simultaneously and are the essence of pathophysiological processes in asthma.
Among various clinical and pathogenetic variants of bronchial asthma , aspirin asthma (AA) occupies a special place. Its main feature is the association of asthma attacks with intolerance to acetylsalicylic acid (ASA) and other non-steroidal anti-inflammatory drugs (NSAIDs) that can inhibit the synthesis of PG and thus change the metabolism of AK. Most clinicians note a severe course of aspirin asthma, leading to early disability and dependence on glucocorticoid hormones. In this regard, many researchers are attracted by the study of not only the mechanisms of development of ASA intolerance in this category of patients, but also the pathogenesis of the disease.
It is known that this category of patients is characterized by the development of a prolonged and severe bronchospasm, which is difficult to stop with conventional inhaled bronchodilators . A number of researchers believe that persistent contraction of smooth muscles is associated with the influence of excessive formation of leukotrienes, since LTE4 is 5-20 times higher than LTS4 in spasmogenic effect on smooth muscles and histamine is 50-500 times higher. Given the specific effect of NSAIDs on cyclooxygenase, some researchers explain the occurrence of suffocation in patients with AA by shunting AK metabolism to a higher formation of leukotrienes, which results in either hyperproduction of 12-HETE or termination of negative control over the formation of RT by the PGE2 / PGI2 system. However, a similar effect of NSAIDs is not always detected in vivo. So, according to Ferreri N. R et. al. (1988) when conducting an oral provocative test with aspirin in five asthmatics sensitive to it, an increase in LTS4 was observed in three, and in two, on the contrary, a decrease in PGE2 preceded the appearance of clinical symptoms of ASA intolerance. With this pathology, no greater sensitivity of the airways to LTD4 and LTS was revealed. An attempt to use leukotriene inhibitors to treat AA patients has also been unsuccessful.
The participation of leukotrienes in the development of the symptom complex of this disease, apparently, is only one of the links in the chain of reactions inherent in allergic inflammation in general. The peculiarity of the symptom complex of aspirin asthma is due to both the specific action of NSAIDs on the metabolism of arachidonic acid, and the presence of biological defects associated with impaired individual functions of cells and organs. According to the viral theory of the pathogenesis of aspirin asthma, after infection of patients for a long time, the formation of specific toxic lymphocytes can occur, the activity of which is suppressed by PGE2, which is formed in pulmonary alveolar macrophages. Reception of anticyclooxygenase drugs blocks the formation of PGE, which leads to activation of the cytotoxic and killer activity of lymphocytes in relation to target cells. The latter in this case are virus-infected respiratory tract cells. During the reaction, the release of biologically active substances, oxygen radicals, lysosomal enzymes that determine the clinical manifestations of asthma. The author explains the persistence of asthma attacks in the absence of NSAIDs as chronic persistence of the virus. However, experimental evidence for this theory does not exist. Moreover, the hypothesis directly contradicts the clinical and experimental data on the effectiveness of aspirin desensitization, since in successfully desensitized patients the level of PGE2 in the nasal lavage fluid remains reduced.
Most theories of the pathogenesis of aspirin asthma concentrate on changing the function of eosinophils, basophils, mast cells that are part of the rapid response system, which carries out local regulation of bronchial patency. Platelets also enter this system, the activation of which is also accompanied by the release of eicosanoids, which are mediators of allergic inflammation. In the clinic of hospital therapy. M.V. Chernorutsky together with the Department of Pathological Physiology of St. Petersburg State Medical University named after Acad. I.P. Pavlova conducted a comprehensive study of the functional activity of platelets in patients with AA. It was found that most patients with bronchial asthma have a low plasma TxA2 level compared to healthy people. At the same time, patients with AA differ from patients with non-aspirin asthma with a lower plasma content of PGI2. A decrease in the number of cyclooxygenase metabolites of AK may indicate the depletion of prostaglandin synthetase as a result of the self-catalyzed inactivation of the enzyme under conditions of enhanced lipid peroxidation processes. It is known that lipid peroxidation (lipid peroxidation) is a normal metabolic process necessary for lipid renewal. In a cell, peroxidation can participate in the process of self-renewal or self-rearrangement of membrane structures, in the regulation of ion transport and the activity of membrane-bound enzymes.
Detected with aspirin asthma, a decrease in the level of selenium in the blood serum and, as a result, a decrease in the activity of the selenium-dependent antioxidant defense enzyme (glutamine peroxidase) in platelets can contribute to the activation of lipid peroxidation processes, which leads to deep disturbances in membrane structures. So, a study of ADP- and heparin-induced platelet aggregation, conducted in the hospital clinic of them. M.V. Chernorutsky together with the Department of Pathological Physiology of St. Petersburg State Medical University named after Acad. I.P. Pavlov, showed an increase in the functional activity of platelets and their sensitivity to the addition of ASA, which was combined with severe disturbances in capillary circulation in the lungs and the function of external respiration. A hypothesis has been formed about the role of platelets in the pathogenesis of aspirin asthma, according to which patients with AA have a congenital or acquired defect in the membrane-receptor complex of platelets. Acetylsalicylic acid for patients with AA is a causative agent that exacerbates an existing defect, which leads to the opening of ion permeability channels for calcium and, as a result, to platelet activation. Thus, according to some researchers, the addition of non-steroidal anti-inflammatory drugs to a platelet suspension led to increased chemiluminescence and the release of factors exhibiting a cytotoxic effect. Platelet activation is the basis for triggering a cascade of reactions leading to bronchospasm, vasospasm, interstitial pulmonary edema, edema of the mucous membrane of the distal bronchi, the development of bronchial obstruction syndrome and, as a result, severe disturbances in the function of external respiration. The therapeutic effect of aspirin desensitization in patients with AA at the Department of Hospital Therapy of St. Petersburg State Medical University named after Acad. I.P. Pavlova, apparently, is associated with changes in the lipid microenvironment of receptors on platelets in the process of adaptation to the stress agent aspirin. It is known that during desensitization in the membranes, the destruction of phosphatidylcholine occurs and the accumulation of its decomposition products – lysophosphatidylcholine and arachidonic acid.
Repeated periodic activation of LP can not only lead to a decrease in the number of receptors , but also induce the synthesis of antioxidant enzymes, thereby increasing tissue resistance to the LPO inducer. It was found that when the effect of desensitization is achieved, in parallel with the normalization of the functional activity of platelets, a tendency to a decrease in their sensitivity to ASA added in vitro appears. It is possible that stabilization of the membrane-receptor complex of platelets and an increase in the activity of membrane-bound enzymes occur, which ultimately helps to improve microcirculation in the lungs and indicators of the function of external respiration. Thus, the development of aspirin asthma is based on a set of congenital or acquired biological defects (decreased activity of antioxidant defense enzymes and a violation of the membrane-receptor complex of platelets), and their clinical implementation is determined by the specifics of the damaging agent (aspirin) and is characterized by impaired capillary circulation and lung ventilation.
A study of the pathogenesis of aspirin asthma makes it possible to understand that the release of prostaglandins and leukotrienes is a central and universal mediator in the development of inflammatory diseases of the lungs and bronchi. The specificity and severity of the clinical manifestations of certain diseases are determined by the characteristics of the damaging agent, the totality of biological defects at the cellular and tissue levels, as well as the reactivity of the organism as a whole. Studying the role of AK metabolites in the genesis of inflammatory reactions allows us to determine the strategy of therapy in the early stages of bronchopulmonary diseases.