New concepts in the pathogenesis of asthma

Heightened airways reactivity is a major characteristic of asthma. Several stimuli capable of producing an inflammatory reaction within the respiratory tract can increase airways reactivity in both normal and asthmatic subjects. The association between lower airways inflammation and alterations in airways function has been studied most extensively after antigen exposure leading to an immediate and/or late asthmatic response in atopic subjects. The late asthmatic response (LAR) is of special interest because it lasts for hours, is prevented by corticosteroids and not adrenergic agents, and is associated with more severe asthma as well as increases in airways responsiveness. While late phase reactions in the lung and skin were initially thought to be Arthus reactions, more recent observations in man and animal models suggest they may be initiated when antigen-specific IgE is present, and may be blunted by antigen-specific IgG. In terms of pathology, immediate reactions are characterized primarily by edema while late phase reactions are associated with infiltration of the involved tissues with inflammatory cells. The potential importance of granulocytes to the reactions in the skin of rats and the lungs of rabbits was suggested when cytotoxic drugs that produced granulocytopenia prevented late phase responses. Several other factors also appear to be important in determining if an LAR will occur. These include the antigen load, level of airways reactivity, histamine releasing factors, lymphocyte populations within the lung, and endogenous corticosteroid levels. While various mediators of inflammation and hypersensitivity such as platelet activating factor and cyclooxygenase and lipoxygenase products of arachidonic acid metabolism produce some of the clinical features seen in asthma, one mediator is unlikely to be responsible for all the manifestations of this disorder. Rather, a series of cell-to-cell interactions mediated through the products they release are likely to produce the pathologic and physiologic features of the disease.