While the bronchoconstriction observed following acute antigen challenge in the guinea pig is not associated with airway edema, inflammatory edema probably plays an important role in human disease. Analysis of the protein in the bronchial mucus plugs from asthmatic patients shows large amounts of albumin and large numbers of inflammatory cells which strongly suggest that an inflammatory exudate enters the airways lumen.
The study of nonimmunologically-induced inflammatory reaction in the airways of animals has provided several insights into the development of acquired airways hyperreactivity. A single exposure to cigarette smoke in the guinea pig can produce an airways inflammatory reaction that has both an exudative and proliferative phase (Fig 2). The exudative phase is associated with an increased wet-to-dry weight ratio of the airway wall (Fig 2A) due to the inflammatory edema and an immigration of inflammatory cells into the interstitial space and through the epithelium to lie on the mucosal surface (Fig 2B). This inflammatory reaction is associated with an increased mucosal permeability which is maximum at a half-hour following the smoke exposure and returns to normal by 24 hours. This change in permeability can be readily measured by the tracer horseradish peroxidase (HRP) and this method has shown that the increase in permeability is associated with increased exposure of the irritant receptors (Fig 3).
Empey and colleagues have shown that the lower airways can become hyperreactive to nonspecific stimuli such as histamine during an acute upper respiratory tract infection. They have shown that the hyperreactivity to histamine seen with respiratory virus infections can be blocked by atropine and speculated that the inflammatory reaction caused by virus sensitized the afferent receptors and exaggerated the reflex component of the histamine response. Nitrogen dioxide, ozone and cigarette smoke have been shown to enhance bronchial reactivity to both histamine and methacholine, presumably because of increased reflex activity. Empey and colleagues attributed the acquired hyperreactivity to mucosal damage and speculated that this unspecified damage might be due to inflammation of the mucosa. It seems likely that the inflammatory reaction is the common feature of the damage produced by viral infection, NOs and ozone inhalation. Our studies suggest that an important feature of this nonspecific inflammatory reaction is increased mucosal permeability which exposes both the irritant receptors and muscle to stimuli.
As the change in mucosal permeability provides increased access to both irritant receptors and airway smooth muscle (Fig 1) the hyperreactive response associated with increased permeability could involve more than one mechanism. For example, histamine is capable of stimulating both the irritant receptors to produce reflex bronchoconstriction and of stimulating the airway smooth muscle directly. Methacholine, on the other hand, only stimulates the smooth muscle and is not usually associated with irritant receptor stimulation. Ibis fact has been elegantly demonstrated by Vidruk et al who recorded from single nerve fibers and can be clearly seen from the data of Michoud and her colleagues on intact animals. They compared antigen, methacholine and histamine challenge to Ascaris-sensitive monkeys and showed that while the antigen and histamine caused an increase in airways resistance and rapid, shallow breathing, methacholine only caused increased airway resistance without stimulating the irritant receptors to produce rapid, shallow breathing. This fact is further brought out by the study of Holtzman et al who showed that the ganglionic blocker hexmethonium could block histamine but not the methacholine response.
As the mast cell is important in initiating the inflammatory reaction in allergic asthma, the relationship of the mast cell to the airway lumen is of critical importance in the initiation of these attacks. Studies on mast cell distribution are not easy because their fixation requires alcohol rather than water-based fixatives and these are seldom in routine use. Salvato has demonstrated that mast cells are depleted in asthma and those that remain are markedly degranulated. Guerzon and associates have shown that there are relatively few mast cells in themucosa compared to the large concentration of mast cells in the submucosa of the airways (Fig 1). While there are a very important number of mast cells on the surface of the airway lumen, this number can be over-estimated by washing and brushing techniques which also harvest mast cells from the mucosa. For example, Guerzon et al estimated approximately one mast cell for every 108 epithelial cells, while Patterson found 1/200 epithelial cells in lung washings. We have previously proposed the hypothesis that large antigen molecules that penetrate the mucosa slowly must first react with the small number of mast cells on the epithelial surface and that chemical mediators released from these mast cells are responsible for stimulating irritant receptors and opening the epithelial tight junctions. This increase in permeability allows the antigen to penetrate to the larger number of mast cells that are located deeper in the airway wall (Fig 1).
As the inflammatory reaction is responsible for the epithelial damage leading to hyperreactive airways, it is important to evaluate the epithelial changes that occur with airways inflammation. An important histologic feature of the asthmatic lung is the change in the epithelial basement membrane. Callerame et al showed that the mean width of the basement membrane from asthmatic subjects was 17.5 |x while that from normal subjects was only 7 |x and attributed the thickening of the basement membrane to the deposition of immunoglobulins. Data from Hulbert et al on airway inflammation shows that the basement membrane (Fig 2D) begins to increase in thickness in association with the increased epithelial mitotic activity (Fig 2C). Ibis suggests that the increased thickness of the basement membrane may be due to increased epithelial cell turnover in the same way that the basement membrane of the diabetic microvasculature thickens in relation to the increased endothelial cell turnover. Curschman was the first to note that asthmatic patients had a large number of epithelial cells in their sputum and this has been amply confirmed by other investigators who have demonstrated squamous cells, as well as compact clusters of columnar cells known as Creola bodies in the sputum. The loss of the mucosal cells has been attributed to muscle spasm and submucosal edema, but it also seems likely that direct toxic injury to epithelial cells, perhaps by products of the eosinophil, could play a role in damaging the epithelial cells. The increased cell turnover of the epithelium brought about by increased cell death is also associated with active division of the basal cell layer with metaplasia to goblet and squamous cells.
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Figure 2. Brief exposures to cigarette smoke cause an inflammatory reaction consisting of an exudation of fluid and cells (A and B) followed by a repair phase indicated by increased mitosis of epithelial basal cells and a gradual increase in the thickness of the basement membrane (D). (From ref 8 with permission of the author and publishers.)
Figure 3. Cigarette smoke increases mucosal permeability which allows penetration of the tracer HRP into the mucosa, as well as exposing the irritant nerve ending. Inset b shows a nerve ending from a control animal and no penetration of HRP, while inset shows an irritant receptor surrounded by HRP after smoke exposure. (From Lab Invest 1980; 43:94-100, with permission of authors and publishers.)