Chapter 44: The Biology of Asthma

Introduction

Asthma is characterized by recurrent attacks of breathlessness and wheezing, which vary in severity and frequency from person to person.¹ More than 18 million adults and 7 million children are affected in the United States alone, making asthma one of the most common chronic diseases in this country.² Attempts to elucidate the underlying pathophysiology of the disease have led to the realization that asthma truly is a protean disease with various cell types and mechanisms playing variable but important roles in each patient. This degree of mechanistic variation explains the numerous phenotypes of this disease as well as the differences in response to treatment.

By the simplest definition, the pathogenesis of asthma involves bronchoconstriction, airway inflammation, and airway hyperresponsiveness.³ It is, however, the complex interplay between these factors that defines the disease in general and specifically in an individual patient. A closer examination of the factors involved in each of these components allows a better understanding of this complex disease.

The Acute Inflammatory Response in Asthma

Perhaps the best illustration of the features of the acute inflammatory response, that is central to the pathogenesis of asthma, is the reaction to the initial and then subsequent exposures to inhaled antigen. While important cellular and molecular mediators will be described later in greater detail, a brief review of the acute inflammatory response serves as a foundation upon which further concepts can be introduced to illustrate the variable but persistent changes that occur in the airway in asthma. When a novel antigen is introduced to the airway of an at-risk individual, it initially becomes trapped in the mucus lining the airway. Here it can be taken up by antigen presenting cells, most notably dendritic cells, which are distributed through the epithelium of the airways.^4,5 After the uptake of allergen, the dendritic cells travel to pulmonary lymph nodes whereby the antigen is presented to naïve CD4⁺ T cells.⁵ Signals derived from the dendritic cell determine which type of CD4⁺ T cell will be produced. Prior to this event, the dendritic cell is influenced by a complex network of molecular signals that are derived from airway epithelial cells and other local cell types. In allergic inflammation, for example, thymic stromal lymphopoietin (TSLP) and granulocyte–monocyte colony stimulating factor (GM-CSF), which are derived from bronchial epithelial cells, and induce the dendritic cell to promote T_H2 differentiation of naïve CD4⁺ T cells, thus setting up an environment favorable to the eventual development of allergic inflammation.⁵ Upon rechallenge with the sensitizing antigen, these now T_H2 differentiated CD4⁺ T cells are recruited back to the airway by other signals, such as the chemokines CCL17 and CCL22, secreted by dendritic cells.⁶ Upon arrival in the airway, the CD4⁺ T_H2 cells become key sources of the T_H2 cytokines, namely IL-4, ...