Persistent and Latent Viral Infections in the Pathology of Asthma

Abstract

Asthma is characterized by variable airflow obstruction (1)and an increased responsiveness to a variety of nonspecific bronchial challenges (2-4). Osler (5) quotes histologic studies performed in the last century which established that a chronic inflammatory process was the major pathologic change observed in the airways of asthmatic lungs. Tissue swelling is one of the cardinal features of the inflammatory response (6), and there is abundant evidence that this occurs in the chronically inflamed airwaywallsin asthmatic lungs (7-12). Quantitative studies (13) have shown that the increase in tissue volume is due to an exudate of fluid and cells, an increase in collagen and extracellular matrix, hypertrophy and hyperplasia of the smooth muscle (10, 11), epithelium (7), enlargement of the bronchial glands (7, 9, 10), and an increased amount of extracellular matrix in the airway wall (13). Theoretical studies (14, 15) suggest that this wall thickening plays a critical role in the pathophysiology of asthma by acting in series with normal smooth muscle shortening to produce both variable airway obstruction and an increased responsiveness to nonspecific stimuli. In this presentation I plan to discuss mechanisms whereby viruses that produce bronchiolitis in childhood could contribute to the structural changes that occur in asthmatic lungs. Several epidemiologic studies predict that childhood viral bronchiolitis predisposes to the subsequent development of asthma (1618). For example, Sly and Hibbert (19) have reported a 920/0 cumulative incidence of asthma in a 5-yr follow-up of children hospitalized with respiratory syncytial virus (RSV) bronchiolitis as infants. Although a lyticbronchiolar infection with RSV has only a 1% mortality in these hospitalized patients, a current hypothesis is that the virus may persist in host cells and provide a potential source of foreign protein to drive the inflammatory reaction. Of particular interest in this regard is the demonstration of persistent nonlytic RSV infection in severaltissueculture celllines (20-22). A second major cause of bronchiolitis in children is the adenovirus where lytic infections are known to result in fatal respiratory disease (23, 24). The possibility that persistent (i.e.,lowlevelsof viral replication) as well as latent (i.e., presence of viral genome without replication of a complete virus) infections contribute to other forms of obstructive lung disease is a current interest of our laboratory. The adenovirus was discovered when it emerged from cultured adenoid cells derived from apparently normal tissue (25). It has an icosohedral structure (25) with an outer protein capsid and an inner core composed by a tightly packed DNA protein complex (fig-