The Science Journal of the American Association for Respiratory Care

1996 OPEN FORUM Abstracts

Current Concepts of Pathogenesis and Pathophysiology of Asthma

Timothy D. Bigby, MD Tuesday, November 5, 1996

Asthma is a common disorder recognized clinically as reversible airway obstruction with cough and/or wheeze. Recent advances in our understanding of the pathophysiology of asthma have expanded this definition to also include airway inflammation and hyperresponsiveness to a board range of physical, chemical, and pharmacological stimuli. An understanding of the pathogenesis and pathophysiology of this disorder provides the opportunity for improved therapeutic intervention. Estimates indicate that asthma occurs in 4% to 6% of the population in the United States, is more common in urban than in rural populations and in African Americans. There is a trend in the United States and worldwide of increasing prevalence of asthma. The cause of this increase is unknown, but it may relate to increasingly urban living conditions with resulting greater exposure to environmental and occupational pollutants. There is also a strong association between passive exposure of children to tobacco smoke and the development of asthma and atopy. Microscopic examination of postmortem specimens of airways from patients dying with asthma reveal patchy denudation of the airway epithelium, airway edema, marked mucosal inflammatory cell infiltration, and some evidence of smooth muscle hypertrophy. Numerous hypotheses have been put forth to explain the clinical syndrome of asthma. An initial focus was upon abnormalities in neural and humoral receptor control of airway smooth muscle. Although intriguing data regarding such a dysfunction has accumulated, these concepts have not provided a complete understanding of asthma. More recently, an appreciation of airway inflammation in asthma has led to a re-examination of the etiology, pathogenesis, and pathophysiology of asthma. The terms "intrinsic" and "extrinsic" no longer adequately reflect our current understanding. We now appreciate that asthma is a heterogeneous disorder, with multiple triggers initiating the development of airway hyperresponsiveness and the clinical endpoint of bronchoconstriction. During the last decade, attention has been focused on the relationship between the inflammatory response in the airway and the development of airway hyperresponsiveness and clinical asthma. Experimental work indicates that viral respiratory tract infection, oxidant pollutants, some chemicals, and exposure to antigen are associated with inflammatory cell infiltration into the airway. These agents are also associated with the development of airway hyperresponsiveness. Thus, airway inflammation may be a necessary but not sufficient reason for the development of asthma or, alternatively, there may be specific characteristics of the inflammatory response in this disorder.

The pathogenesis of allergic asthma has been studied extensively. However, no data available permit the extrapolation of this scenario for allergic inflammation of the airway to the setting of inflammatory responses induced by other asthma triggers, such as oxidant pollutants and viral respiratory tract infection. Controversy exists regarding the relative importance of different inflammatory cell types in asthma. There is substantial evidence that eosinophils play an important role in asthma. Mast cells and eosinophils are not the only inflammatory cells present in asthmatic airways. Neutrophils and macrophages are also present. These cells are capable of releasing mediators with effects on smooth muscle tone, mucus secretion, and airway edema. The link between inflammation and airway hyperresponsiveness is thought to be provided by the ability of these inflammatory cells to synthesize and release a large number of potent chemical mediators. A wide range of mediators, including histamine, prostaglandins, thromboxane A_{2}, leukotrienes, platelet-activating factor, proteases, neuropeptides, peptide chemotactic factors, and oxygen radicals have been shown to have effects on airway function. In summary, the association of inflammation with asthma is clear. Virtually all data support a causal role for airway inflammation in the development of airway hyperresponsiveness and bronchoconstriction. Considering the substantial redundancy of the inflammatory cells and mediators involved in asthma, a single cell or a single mediator is inadequate to explain the syndrome. The pathogenetic trigger for this process is best worked out for allergic asthma. In this case, the lymphocyte, specifically the TH_{2} helper cell, seems to play a key role via release of cytokines that modulate cell function in the airway. In nonallergic asthma, inflammation also plays a major pathogenetic role, but the relative importance of specific inflammatory cells is less well known. Both allergic and nonallergic airway hyperresponsiveness can be mimicked in the laboratory over the short term. However, in both allergic and nonallergic asthma, the mechanism that sustains the inflammatory and hyperresponsive state of the airway over the long term, resulting in the chronic clinical disorder we call asthma, remains unknown.

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