Asthma airway wall

Another potential advantage of extra-fine corticosteroid aerosols is their apparently greater accessibility to peripheral airways (< mm in diameter) which appear to be poorly penetrated by conventional CFC-based aerosols. Recent data indicate that airway inflammation is present in both large and small airways, as well as alveolar tissue, and that airway wall remodeling occurs in small airways. The clinical significance of small airways involvement in asthma, its contribution to fatal asthma or to the accelerated rate of decline in lung function with age that occurs in asthma, and the consequences of treating the small airways component... 

Mechanical forces that occur during breathing have been reported to be capable of causing failure of the ECM at loci of stress and to contribute to the progression of emphysema. Chronic asthma is associated with a marked increase in the airway wall thickness, and an increased muscle cell mass. Hyperplasia of airway smooth muscle cells in vivo is probably accompanied by a change in contractile capacity and appears to be a consequence of the increased forces required for breathing through narrowed airways. 

Asthma is a respiratory illness characterized by variable and reversible airflow obstruction. Over 100 years ago. Osier, in his influential Textbook of Medicine (Osier, 1892), concluded that airway wall edema, bronchoconstriaion and mucus plugging are responsible for the airflow obstruction in asthma. Since that time, edema of the airway mucosa has been assumed to be one of the central features of asthma, but comparatively few studies have addressed the issue directly. Therefore, there is litde information about the onset, duration, magnitude, location, mechanism, consequences and management of mucosal edema in asthma. 

In the first definitive monograph on asthma, published in 1864, Sir Henry Hyde Salter concluded that the airway obstruction in asthma results from bronchoconstriction, mucus plu ng of the airway lumen, and edema of the airway wall (Salter, 1864). Salter s interpretations were probably based on clinical observations rather than on pathological examinations, because post-mortem findings were not described at that time. In fact, the initial histopathological studies of the airways of asthmatics did not recognize the presence of mucosal edema For example, in the first description of a post-mortem examination of a patient who died in status asthmaticus, Leyden concluded that the airflow obstruction resulted from mucus in the airways and that the walls [of bronchi]. ..are not essentially changed (Leyden, 1886). 

Asthma is a disease characterized by reversible airways obstruction and increased responsiveness of the airways to specific and nonspecific bronchocon-strictor stimuli. Indeed, the latter feature may be used in diagnosis of asthma (vide infra). Obstruction to the flow of air in asthma is the product of three factors smooth muscle contraction, mucosal edema, and augmented mucus secretion. Pathological features, such as infiltration of the airway walls with inflammatory cells (e.g., eosinophils, neutrophils), and the efficacy of antiinflammatory steroids in treating the disease have pointed to an important role of inflammation in the disease process. 

Asthma is characterized by either the intermittent or persis- tent presence of highly variable degrees of airway obstruction from airway wall inflammation and bronchial smooth muscle constriction. 

Lung diseases characterized by remodeling of the lung parenchyma or airway wall involve alterations in PGs. Changes in PGs have been best characterized in pulmonary fibrosis and, to a lesser extent, in asthma. Their roles in such diseases as emphysema, lung cancer, and ventilation-induced lung injury have not been as well defined. 

A further issue is the effect of PGs on the structural cells present in the airway wall. Asthma is characterized by increased smooth muscle mass (64). PGs could potentially affect the rate of proliferation and/or apoptosis of these cells. Some information is available from in vitro studies. Hirst et al. (77) have shown that various ECM proteins, such as collagen and fibronectin, have the capacity to affect ASM proliferation. Johnson et al. (30) have reported that ECM proteins secreted by asthmatic ASM, which likely include PG, enhanced ASM proliferation in an autocrine fashion. We have obtained some preliminary data showing that human ASM cells grown on decorin matrices show decreased proliferation (28). Finally, the interaction between TGF-p and decorin may be important in the asthmatic airway wall (60). TGF-p is increased in the asthmatic airway wall (78) and plays an important role in asthmatic airway inflammation. Hence, the effect of changes in PG deposition in the airway wall in asthma could have a number of important consequences on asthmatic airway pathophysiology. 

The most important functional abnormality in asthma is increased resistance to airflow. This is the basis of most striking clinical manifestation of asthma, including breathlessness and wheezing. The mechanisms of increased airflow resistance include (1) decreased physical dimensions of the airways as a consequence of bronchoconstriction, (2) luminal narrowing due to airway wall edema, and (3) luminal obstruction resulting from h)q)ersecretion of mucus (McFadden, 1998). Those changes induced by the various inflammatory mediators released by mast cells as part of hypersensitivity reactions are reversible. Another functional abnormality... 

Another characteristic feature in asthma is airway wall remodeling. This refers to a variety of structural changes in the airway wall. Most prominent is the accumulation of a band of t5 e III and t5 e V collagens (Hoshino et ah, 1998) and other matrix components in the subepithelial region of the airway wall. Airway wall thickening and shortening of airway smooth muscle may occur and these may cause airway resistance. 

As discussed previously (Sec. II.B), bronchial smooth muscle tone is under autonomic control. Cold air and stimulation of receptors by irritants such as cigarette smoke, dust particles, and sulfur dioxide can also cause increased tone and hence bronchoconstriction (229). Bronchomotor tone is also modulated by vagal stretch reflexes and varies inversely with lung volume. Paradoxically, the rise in bronchomotor tone and/or increase in FRC during an attack of asthma may partially reverse the reduction in airway caliber that occurs in this condition, making assessment of response to therapy complex. Similarly, bronchodilators have been shown to cause paradoxical reductions in airflow and desaturation in some infants with history of wheeze, a phenomenon that has been attributed at least partially to changes in airway wall compliance (230-232). 

During autopsy, Hossain et al. detennined the amount of smooth muscle in the airway walls of patients who died of asthma. She then compared her findings to the amount of smooth muscle found in the airways of healthy controls. She found that the amount of smooth muscle decreased from the larger airways toward the lung periphery in the controls. In the asthmatics, there was an increase in the amount of smooth muscle in all airways compared to the controls and less of a decrease in the amount of muscle toward the lung periphery (20). 

A number of studies indicate that irreversible airflow obstruction may occur in asthma, associated with structural changes consistent with an airway remodeling process (153). Morphometric studies have shown prominent smooth muscle hyperplasia and hypertrophy in both large and small airways (154), increased angiogenesis (155), prominent mucus gland hyperplasia (156), and airway wall thickening particularly in cases of fatal asthma (157). 

Redington A, Howarth P. Airway wall remodelling in asthma. Thorax 1997 52 310-312. 

The development of techniques such as bronchial biopsies during endoscopic procedures made it possible to explore the effects of allergens on airway structure and components more thoroughly. In stable asthma, variable increases in eosinophils, mast cells, lymphocytes, and neutrophils in the airway wall have been observed in comparison with normal subjects, even when asthma was of recent onset or mild (57,73). After allergen challenges, bronchial biopsies have shown an increased expression of some adhesion molecules and an influx of mast cells. 

One feature of asthma that appears to be particularly important is the thickening of the basement membrane of the airway epithelium and the deposition of collagen and other matrix products in the airway wall. It has been suggested that these changes constitute the basis for remodeling of the airway, a process that may predispose to airway hyperresponsiveness and to the development of chronic, persistent asthma symptoms. Thus, therapeutic strategies for wheezy infants must address the possibility that for those who will go on to develop asthma, a prolonged delay in anti-inflammatory treatment leads to permanent loss in pulmonary function. 

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