NEW AND ALTERNATIVE PHARMACOLOGIC THERAPY IN ASTHMA

Abstract

Much has been learned about the inflammatory response in the lung, but many of the immunologic and molecular details still are not understood completely. The inflammatory response in the lung is a mechanism by which the body responds to and protects itself from infectious and noninfectious events. In the lung, the mechanism may be nonspecific or antigen specific. The inflammatory response is usually protective, but inflammation has the potential to injure tissue including the airways and lead to chronic irreversible changes. New approaches to therapy are based on understanding the pathophysiology of asthma and are directed toward blocking the inflammation. What is known about the inflammatory response in the lung is that histologically it starts with increased vascular permeability, followed by accumulation of granulocytes initially and monocytes and phagocytes later, and eventual resolution.24 Permeability changes occur within minutes after allergen exposure, and influx of inflammatory cells develop over the next several hours. Eosinophils predominate as the time after the allergic challenge passes. Monocytes and phagocytes appear in 24 to 48 hours and persist for days even without further allergen exposure. Mediators, such as histamine and the products of arachidonic acid metabolism (prostaglandins, leukotrienes), which are produced by mast cells and other inflammatory cells, produce and regulate most of the characteristic features of inflammation. Cytokines are low-molecular-weight proteins that regulate immunologic inflammation and are secreted by a variety of cells in response to specific stimuli. Cytokines function as immune mediators and originally were named on the basis of the cell origin or biologic activity. Monokines are produced by monocytes, and lymphokines are released by lymphocytes. The chemoattractant cytokines are called chemokines. Cytokines involved in stimulating growth often are designated to be growth factors. The cytokine system is redundant, and there is cross reactivity. Over 100 cytokines have been identified so far. Many cytokines have been implicated in the pathophysiology of atopic disease, although certain cytokines play a more critical role in atopic inflammation. The synthesis of many cytokines is down-regulated by corticosteroids.3, 26, 41 In asthma, the immunologic response begins with allergen sensitization leading to the production of allergen-specific immunoglobulin E (IgE).32 In genetically susceptible persons, naïve CD4+ T-helper cells (Th0) with receptors to offending antigens become activated when they come into contact with that antigen in the presence of MHC Class II and other proteins. Th0 cells can differentiate into Th1 and Th2 cells. Differentiation into Th2 cells is a key step in IgE production. Th2 lymphocytes develop from Th0 cells in the presence of interleukin 4 (IL-4). Th2 cells then produce additional cytokines, including IL-4, IL-5, IL-9, and IL-13, eventually leading to the production of IgE by B cells.32 Allergen-specific IgE antibodies bind to the high-affinity IgE receptors on the surface of mast cells and basophils and to low-affinity receptors on B cells, monocytes, and other inflammatory cells.41 When the IgE receptors are bridged by allergen, the mast cells degranulate and release histamine, cytokines, and other chemical mediators of inflammation. Histamine is primarily responsible for the early phase response that occurs within minutes after allergen exposure. Other mast-cell mediators include leukotrienes, interleukins, proteases, and platelet-activating factor. Leukotrienes increase vascular permeability and mucus production and cause bronchoconstriction. Leukotriene B4 (LTB4) is a powerful chemokine for eosinophils and neutrophils. IL-3, IL-4, and IL-5 also are produced by mast cells. IL-3 is chemotactic for basophils. IL-4 stimulates IgE formation and the differentiation of Th2 from Th0 cells. IL-5 attracts eosinophils and basophils, stimulates eosinophil proliferation and differentiation, and possibly slows eosinophils apoptosis. Other cytokines released from mast cells include tumor necrosis factor α (TNF α), granulocyte-macrophage colony-stimulating factor (GM-CSF), and platelet-activating factor (PAF).42 Mast-cell mediators initiate the early phase response that includes increased vascular permeability, bronchoconstriction, edema, increased mucus secretion, and activation of the chemical cascades that attract eosinophils and other granulocytes to the area. The late phase reaction occurs about 4 to 8 hours after allergen exposure with influx of eosinophils, neutrophils, and other inflammatory cells in the mucosa and submucosa. Eosinophils release a variety of chemical products, including major basic protein and eosinophilic cationic protein, that produce epithelial damage. Constant and repeated inflammatory reactions in the lungs may produce permanent changes and airway remodeling.9, 16 Many different treatments are available for managing asthma, and there are many new therapeutic approaches that are possible. Therapy that changes or controls the basic immunologic processes discussed previously will be a more easily available option in the near future for many patients who are not controlled with presently available medications. Several if not all of the following new therapeutic agents will definitely play important roles in the treatment of asthma in the new millennium.