Pathophysiology of Asthma [Article in Croatian]

Abstract

Asthma is a chronic inflammatory disease characterized by reversible bronchial obstruc­tion, persistent bronchal hyperreactivity (BHR), inflammation and remodelation of the airways. Its pathogenesis is complex and multifactorial. Inheritance is not mendelian but poligenic. Five genomic regions are involved: 5q23-31, 12q15-24.1, 16p, 19q13 i 21q21. Contribution of heritable factors to asthmatic phenotype depends on the exposure to environmental agents that starts in pregnancy via maternal blood. Placenta is immunologicaly active and type Th2 cytokines predominate during pregnancy. Vaccination, antibiotics and good housing conditions reduce exposure to common microorganisms that otherwise direct postnatal development of the immune system towards protective pattern by means of Th1 cytokines, particularly IFN-g. Thus the type 2 cytokine pattern persists and favors allergic-type reactivity. Interaction of allergens with immunoglobulin E in early stage of allergic reaction releases histamin, leukot­rienes and prostaglandin from mast-cells and eosinophils, resulting in bronchoconstriction, mucosal secretion and inflammation. In later stages infiltration with mast-cells, eosinophils, macrophages, CD4+ T-lymphocytes and neutrophils takes place in the airways. Allergen-specific CD4+ T-lymphocytes of allergic persons belong to the cytokine Th2 pattern and produce predominantly IL-4, IL-13 and IL-5 with almost no IFN-g. They initiate and maintain pathological changes in asthma. Structural changes called airway remodelation result from interaction of inflammatory mediators with stromal cells. Collagens I, II and III, fibronectin and tenascin are deposited into lamina reticularis beneath the basal membrane. Remodelation and inflammation of the airways cause bronchal hyperreactivity (BHR) and obstruction which impede expiration and cause wheezing. Inflammation and structural changes of the airways (demonstrated by biopsies of bronchal mucosa) precede clinical symptoms of asthma by a year or two. Bronchial obstruction and wheezing become manifest when remodelation has reached critical stage. Study of immunological factors is expected to elucidate pathogenesis of persistent inflammation and remodelation of the airways in asthma. That would help design new therapeutic strategies for treatment of persistent asthmatic conditions that do not respond to presently available therapy.