Men and women exhibit significantly different risks for the development of a variety of chronic inflammatory diseases (1). In the case of asthma, both sex and age appear to be factors. Boys are at higher risk for the development of reactive airway disease until adolescence, but after this and into adulthood, women are more often affected. The prevalence of asthma in women continues to increase disproportionately and peaks during the fifth decade, when it is nearly twice as common as in men (2). Moreover, women are more likely to require hospitalization for asthma and are more often subject to life-threatening exacerbations of this disease (2, 3). Sex-specific differences in asthma (and the increased morbidity in women) have been attributed to estrogen level, airway caliber, glucocorticoid responsiveness, and obesity (4–7), but the true basis for the difference remains uncertain. In fact, only a few studies have addressed the possible mechanism for sex differences in asthma using animal models of inflammatory airway disease. From that work, it appears that female mice also develop more severe allergen-induced airway inflammation and disease. In the ovalbumin (OVA) allergenchallenge model, female mice have increased levels of circulating OVA-specific IgE and a greater number of lung eosinophils compared with males after induction of disease (8, 9). In addition, Melgert and coworkers showed that female mice exhibit increased lung levels of B cells and T cells and higher circulating levels of IL-4 and IL-13 after OVA challenge (10). In the May issue (pp. 595–603), the same research group presented an argument that lung macrophages, which have undergone alternative activation, are responsible for sex differences in the same OVA-challenge model (11). In this perspective, we will summarize recent work on the role of the alternative pathway for macrophage activation in chronic airway disease and place the present findings in the context of work on an immune pathway that appears critical to inflammatory disease in general, and airway disease in particular.

The likelihood that macrophages contribute to inflammatory disease derives from extensive evidence that macrophages are a key component of the innate and adaptive immune responses. In both types of responses, macrophage function requires activation that in turn depends on cytokine stimulation. The ‘‘classical’’pathway for macrophage activation is driven by IFN-g, and serves to enhance macrophage-dependent phagocytosis and killing of microbes as well as MHC-dependent antigen presentation for full clearance and long-term protection against pathogens (12). In the dichotomous world of immunology, classically activated macrophages are also designated as M1 macrophages based on their association with T helper type I (Th1) immune responses to intracellular bacteria and viruses, and are marked by production of IL-1b, IL-6, IL-12, TNF-a, and iNOS. An ‘‘alternative’’pathway for activation is triggered when macrophages are exposed to IL-4 or IL-13 (13). Alternatively activated macrophages (AAMs), also designated as M2 macrophages, express a distinct set of markers, for example, mannose-binding proteins