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Over the past 100 years, a series of models have been proposed to account for the pathophysiologic abnormalities of asthma (summarized in Figure 1). Consistent with the nature of asthma as a complex disease, the models for asthma pathogenesis have also become increasingly complex. Nonetheless, there has been marked progress in defining cellular and molecular mechanisms of normal and abnormal airway behavior. Research has moved from a descriptive functional approach to one that relies on cellular and molecular biology, immunology, microbiology, and genetics/genomics as well as pathophysiology. These disciplines have moved current efforts to define asthma heterogeneity in quantitative and molecular terms and to determine the precise role of the airway inflammation that likely accounts for disease initiation and progression. Current proposals are attempting to incorporate the influence of the innate and adaptive immune systems as well the role of host genetics and environmental stimuli, particularly viral infection. Considerable progress has been made and is continuing at an accelerating pace. We submit that advances in genetics, genomics, proteomics, and lipidomics will further aid in the identification and characterization of distinct mechanistic pathways for driving the asthma phenotype, and that these will provide better biomarkers for the various populations with asthma as well as more effective asthma prevention and treatment regimens.    Figure 1.  Evolution of asthma paradigms. Schemes for asthma pathogenesis have ranged from bronchoconstrictor, neurogenic, allergic, inflammatory, and mediator (top panel) as outlined in the text. A current paradigm (bottom panel) attempts to incorporate abnormalities ...Notes  This work was supported by grants from the National Heart, Lung, and Blood Institute, the Martin Schaeffer Fund, and the Alan A. and Edith L. Wolff Charitable Trust.  Conflict of Interest Statement: M.J.W has no declared conflicts of interest; M.J.H. has no declared conflicts of interest.

A Centennial History of Research on Asthma Pathogenesis