A role for neutrophils in asthma

The prevalence of asthma is increasing, and it continues to be one of the leading diagnoses in emergency rooms. Analysis of the cellular and biochemical characteristics of airway secretions can provide valuable information about asthma pathogenesis, and sputum induction has recently emerged as a useful noninvasive method for collecting airway secretions. Sputum induction relies on the inhalation of hypertonic saline that causes cough and sputum production, even in patients free of airway disease. This observation has been leveraged in clinical medicine for many decades in which sputum induction and analysis of induced sputum have been used to diagnose lung cancer and lung infections. Despite this proven utility as a diagnostic test, it was only in the early 1990s that clinical researchers began to use sputum induction for research purposes in airway disease (1,2). Standardized protocols were developed, and cytologic analyses evolved beyond sputum smears to more rigorous processing methods involving cytocentrifugation and quantitative total and differential cell counts. The fluid phase of induced sputum was also analyzed for various inflammatory mediators using specific immunoassays or enzymatic assays. In direct comparisons with bronchoalveolar lavage, sputum induction held up well; induced sputum samples are more concentrated and more reflective of airway secretions. A major advantage of sputum induction over bronchoscopy is that it can be applied to larger groups of patients. This advantage has facilitated relatively large studies on airway inflammation and airway function in asthma. One such study by Little et al. (3) is presented in this issue of the Journal. They analyze the relation between best achievable forced expiratory volume in 1 second (FEV1) and the cellular constituents of induced sputum in 59 patients with asthma. Best achievable FEV1 was determined by treatment for 2 weeks with oral or highdose inhaled corticosteroids. The average baseline FEV1 rose from 67% to 76% predicted. The best achievable FEV1 was inversely associated with the number of neutrophils in sputum, measures of neutrophil activation, and the duration of asthma. The authors concluded that long disease duration predisposes to the development of irreversible airway obstruction in chronic asthma and that neutrophils may play a role in the pathophysiology of this airway obstruction. Although current concepts of asthma pathogenesis focus on the role of CD4 T cells and eosinophilic inflammation in asthma (4), Little et al. are not alone in finding that neutrophilic inflammation may be important in the pathophysiology of asthma. About 15 years ago, Seltzer and colleagues (5) reported that nonasthmatic subjects who had been exposed acutely to ozone developed airway hyperresponsiveness in association with airway neutrophilia. Other clinical studies have since found, as have Little et al., that measures of chronic asthma severity, such as FEV1, correlate with the degree of neutrophilia in sputum or bronchial biopsy specimens (6 –9). Neutrophilic inflammation in the airway is also increasingly recognized in acute exacerbations of asthma and in status asthmaticus (10,11). Are neutrophils therefore causally related to acute or chronic airway obstruction in asthma? How can a role for these cells be reconciled with the dominant hypothesis that asthma is a T-cell–mediated disease characterized by Th2 cytokines, immunoglobulin E (IgE), and eosinophils? The answers to these questions cannot be definitive at this time, but several points are worth making. First, the consistency of the finding that neutrophils are present in airway secretions and tissues from patients with more severe forms of chronic asthma cannot be ignored or disregarded as nonspecific. The effects of smoking and concomitant acute infections do not explain this observation. Second, analysis of induced sputum from nonselected patients with asthma estimates that up to 60% of patients have noneosinophilic airway inflammation (12). In addition, treatment of asthma with anti-IgE has little effect on measures of airway obstruction (13). These suggest that other mechanisms, such as neutrophils, contribute to the pathogenesis of chronic airway narrowing in asthma. Third, it is biologically plausible that neutrophils can cause acute or chronic airway obstruction in asthma. Neutrophils secrete a variety of inflammatory mediators, including proteases, cytokines (e.g., tumor necrosis factor , transforming growth factor ), and reactive oxygen species, which can cause airway epithelial injury and mucus hypersecretion. Finally, although most animal models of asthma seek to model allergic T-cell and eosinophilic airway inflammation, some show that airway neutrophilia and airway hyperresponsiveness can occur together. These include murine models of asthma in which airway infection with mycoplasma or sendai virus cause neutrophilia and hyperresponsiveness (14,15). These animals develop airway hyperresponsiveness that persists long after the resolution of the acute viral infection. In this respect, these models mimic severe forms of human asthma better than do models that are based on allergen sensitization. We can only hypothesize about the mechanisms of airAm J Med. 2002;112:498 –500. From the Department of Medicine and the Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California.