Inflammation and Airway Function in Asthma
What You See Is Not Necessarily What You Get

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Asthma is defined by three characteristic features, namely, intermittent reversible airway obstruction, airway hyperresponsiveness, and airway inflammation. Although each of these components is recognized as an important part of the asthmatic phenotype, the primary underlying abnormality in this disease is thought to be the unique form of airway inflammation that gives rise to reversible obstruction and hyperresponsiveness (see Table 1). Considerable attention has been paid to the cellular inflammatory component of asthmatic airway inflammation as defined by histopathologic analysis of airway biopsies. These studies have shown an inflammatory infiltrate consisting of eosinophils, lymphocytes, and macrophages extending throughout the bronchial tree. Such infiltrates are present in patients with clinically mild disease (1, 2) as well as in materials obtained from patients with fatal asthma (3). The holy grail of much recent asthma research has been the establishment of strong links between the profusion or activation state of inflammatory cells and functional changes, i.e., airway obstruction and responsiveness in asthma. If such links could be established, then functional changes could be used as a surrogate for airway inflammation. As yet, no one has succeeded in this quest, and we believe it is unlikely that anyone will succeed.

Part of the complexity facing investigators trying to relate the contributions of airway-infiltrating cells to the functional abnormalities in asthma arises from the ability of inflammatory cells to modify airway responses in at least two distinct ways. In the first, cells release mediators such as histamine, leukotrienes, platelet-activating factor and various proteases. These factors, which have very short half-lives, can mediate changes in both airway patency and airway responsiveness. If such factors were the only link between inflammatory cells and altered airway function in asthma, then it would be reasonable to expect a relationship between the presence of inflammatory changes in the airway and functional abnormalities. However, there is a second way in which inflammatory cells can modify airway patency and responsivenessthrough the release of cytokines and chemokines. These molecules have profound and long-lasting biologic effects in the microenvironment of their release and at distant sites. The predominant effects of chemokines such as IL-5, RANTES, IL-8, and eotaxin are recruitment and activation of additional inflammatory cells at the site of the lesion. The newly recruited cells in turn can modify the airway microenvironment directly or by activating resident cells (7, 8). For example, eosinophilic cationic protein can stimulate fibroblasts, causing increased DNA synthesis (9) and modifications in proteoglycan metabolism (10), which in turn can lead to thickening of airway wall components (11). The other closely related class of agents released by inflammatory cells in asthma is cytokines such as IL-4, TNF, or IL-1. Cytokines can modify a number of different facets of airway biology, including antigen processing (12), nitric oxide synthesis (13), and the response to -agonists (14). Because the biologic effects of cytokines and chemokines need not occur immediately and are sustained, they are reasonably grouped under the rubric of "airway remodeling" even though there may be no observable histopathologic changes. It is easy to conceive of changes in the airway wall that could modify airway responsiveness because of cytokines or chemokines secreted by cells not present when the physiological abnormalities are documented. For example, eosinophils recruited to the airway after allergen exposure release major basic protein, which has been correlated with disruption of airway epithelium (15). Collagen degradation products could feasibly be released with the epithelial damage, and they have been shown to activate macrophages (16). Activated macrophages produce IL-1, which has been demonstrated to decrease the responsiveness of human airway smooth muscle cells to -agonists (14). The influx of eosinophils after antigen exposure decreases to near baseline values by 72 h after intrabronchial challenge (17). However, the maximal stimulation of macrophages after exposure to collagen occurs after an additional 72 h, and the effects of IL-1 on smooth muscle cells were observed after several hours of exposure (14, 16). Therefore, the original inciting cell may well be no longer present at the time the effects of the cytokine are apparent. Thus, in contrast to mediators whose effects are restricted to the microenvironment of their release and are short-lived in nature, the effects of cytokines and chemokines may be prolonged and appreciated far from the site of their release. The critical point is that, like Caesar, the evil that cytokines and chemokines do may live after them.

The study by Crimi and colleagues (18) in this issue of the Journal provides additional data about cellular infiltration and the functional asthmatic phenotype. The investigators examined 71 atopic subjects with mild to moderate asthma, all of whom were free of respiratory infections or exacerbations for at least 1 mo. In addition, none of the patients had received steroids in the month preceding the study. After a methacholine challenge, subjects were evaluated by sputum analysis (n = 28) or bronchoalveolar lavage (BAL; n = 43); in 20 of the latter patients, BAL was followed by endobronchial biopsy. Multiple regression analysis was used to show that the baseline FEV₁ was inversely related to the number of eosinophils in either sputum or BAL samples (18). In contrast, a similar multiple regression analysis failed to reveal any correlation between methacholine responsiveness and the number of inflammatory cells evaluated by any method. The findings of Crimi and colleagues with respect to the relationships among airway responsiveness, airway obstruction, and the inflammatory infiltrates in asthma provide a basis for considering studies relating the functional and inflammatory aspects of the asthmatic phenotype.

Several investigative groups have demonstrated an increased profusion of inflammatory cells in clinically stable asthmatics (15, 19). In a number of these studies, a correlation between baseline airway obstruction and inflammatory cell density has been documented, including an inverse relationship between the profusion of eosinophils (29), mast cells (24), or activated T-cells (27) and the FEV₁. The data presented by Crimi and colleagues in this month's Journal recapitulate aspects of these observations, but the correlation between FEV₁ and the number of inflammatory cells found by this group is weak, suggesting that the presence of inflammatory cells explains only a fraction of the variance observed in FEV₁ in patients with mild asthma. This variance could be explained by effects of airway wall remodeling or the inaccessibility of the pertinent inflammatory cells to sampling via sputum analysis or endobronchial biopsy. With respect to the latter, a cellular infiltrate localized largely to the smooth muscle may have functional consequences distinct from those of any inflammatory infiltrate localized predominantly to the epithelium. This is more than simple speculation, as it has been demonstrated that eosinophils in the central airway wall, but not in the intraepithelial space, are more abundant in cases of fatal asthma than in cases of mild asthma (30). These are but a few of the possible reasons that a number of research groups have failed to establish a relationship between the profusion of any infiltrating inflammatory cell and airway obstruction and/or assessments of clinical severity (19, 23, 26, 31).

There is also discordance in findings among the investigative groups who have studied the relationship between airway inflammation, as assessed by cellular infiltration, and airway responsiveness. Some groups have shown a strong relationship between the presence of inflammatory cells and enhanced airway responsiveness (15, 20, 24, 25, 27, 28), whereas others, including Crimi and colleagues in this month's Journal, have failed to establish such a relationship (19, 23, 26, 31, 32). We believe that this apparent discordance is what one should expect given the nature of the factors that modulate chronic airway responsiveness. Airway responsiveness can be modified by factors that change the airway hemostatic response to bronchoconstrictor agonists such as the endogenous production of nitric oxide (33) and nonadrenergic-noncholinergic neural or systemic adrenergic responses (34). It can also be modified by the enzymatic capacity of the airway epithelium (35), by the ability of smooth muscle to relax to beta agonists (14), by failure of smooth muscle to relax after stretch (36), or by thickening of the airway wall (37, 38). Indeed, these are only a few of the many possible mechanisms that can lead to airway hyperresponsiveness. In a given group of patients with asthma, one or more of these and related, mechanisms may induce airway hyperresponsiveness. If one postulates that airway hyperresponsiveness is the final phenotypic expression of a number of distinct pathobiologic processes, then in some patients cellular infiltration may occur during hyperresponsiveness, whereas in others the cellular events leading to the hyperresponsive state may be dissipated by the time that the hyperresponsive phenotype is manifest. The former phenomenon is demonstrated by airway hyperresponsiveness during a late-phase asthmatic response (17, 39), the latter by airway hyperresponsiveness because of chronic thickening of the airway wall (37, 38).

What is the overall message to be derived from this work for both the practitioner caring for patients with asthma and the researcher trying to unravel the complex of physiological and pathological findings that we recognize as asthma? Taking asthma as an inflammatory disorder, there is a relationship between the magnitude of airway inflammation, as measured by the profusion of inflammatory cells in the asthmatic airway, and function. Although such a relationship exists, it is not a very strong one, thus suggesting that other factors such as airway remodeling also modify airway patency. There is even less compelling evidence for a relationship between the magnitude of the airway inflammation, as assessed by anatomic techniques at a single time point, and airway responsiveness. As a research and practicing community, we are still in need of better markers of airway inflammation that indicate the integrated effects of the inflammation over time. Until better noninvasive indicators of airway inflammation are identified, all three components of the asthmatic phenotypeairway obstruction, airway hyperresponsiveness, and airway inflammation will need to be assessed.

Pulmonary and Critical Care Medicine
Brigham and Women's Hospital
Boston, Massachusetts

	Footnotes

Supported by a grant from the U.S. National Heart, Lung, and Blood Institute, HL-56383.

Correspondence and requests for reprints should be addressed to Jeffrey M. Drazen, M.D., Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115.

(Received in original form August 29, 1997).

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