Asthma is regarded as an inflammatory disorder of the conducting airways characterized by a mast cell, eosinophil and T lymphocyte inflammatory response that is responsive to anti‐inflammatory therapy, such as corticosteroids. In more severe and chronic disease, corticosteroids become less effective. As in other chronic inflammatory diseases, the tissue in which the cellular and mediator processes occur plays a major role in maintaining the response and creating a basis for disease persistence. Herein, we describe evidence that the airway epithelium interacting with the underlying mesenchymal cells recapitulates branching morphogenesis, as observed in the developing lung, to create airway wall remodeling. The reciprocal signaling between the susceptible epithelium and responsive mesenchyme (epithelial mesenchymal trophic unit) offers a new paradigm for asthma and creates new opportunities for developing therapeutics based on reversing the ‘chronic wound’ phenotype of asthmatic airways.
Interleukin (IL)-4 and IL-13 are key proinflammatory cytokines in asthma. Studies in transgenic mice show that both cytokines cause inflammation, but only IL-13 causes subepithelial fibrosis, a characteristic feature of asthma. We compared the in vitro profibrogenic effects of IL-4 and IL-13 using bronchial fibroblasts from asthmatic subjects. In the presence of transforming growth factor (TGF)-beta the cells transformed into contractile myofibroblasts and expressed alpha-smooth muscle actin and procollagen I. IL-4 and IL-13 also stimulated proliferation, but were relatively ineffective in promoting myofibroblast transformation. TGF-beta was more potent than the cytokines in stimulating release of endothelin-1 and vascular endothelial growth factor, whereas IL-4 and IL-13 were more potent stimuli for eotaxin release. Although neither IL-4 nor IL-13 induced profibrotic responses, both cytokines caused a corticosteroid-insensitive stimulation of TGF-beta2 release from primary bronchial epithelial cells. These data indicate that epithelial activation by IL-13 or IL-4 plays a critical role in initiating remodeling through release of TGF-beta2. TGF-beta2 then activates the underlying myofibroblasts to secrete matrix proteins and smooth muscle and vascular mitogens to propagate remodeling changes into the submucosa. In contrast, direct activation of submucosal fibroblasts by IL-4 and IL-13 has a proinflammatory effect via eotaxin release and recruitment of eosinophils into the airways.
Abnormal apoptotic mechanisms are associated with disease pathogenesis. Because the asthmatic bronchial epithelium is characteristically damaged with loss of columnar epithelial cells, we postulated that this is due to unscheduled apoptosis. Using an antibody directed toward the caspase cleavage product of poly(ADP-ribose) polymerase, immunohistochemistry applied to endobronchial biopsies showed higher levels of staining in the bronchial epithelium of subjects with asthma as compared with normal control subjects (% epithelial staining [median (range) ؍ 10.5 (1.4-24.5) versus 0.4 (0.0-9.7)]; P Ͻ 0.001). Because we were unable to determine whether this difference was due to ongoing inflammation in vivo , cultures of normal and asthmatic bronchial epithelial cells were used to study apoptosis in vitro . In complete growth medium, these cells showed no difference in their rate of proliferation or viability. However, cells from subjects with asthma were more susceptible to the apoptotic effects of H 2 O 2 than cells from normal control subjects (% apoptotic cells ؍ 32.2 [8.8-54.9] versus 14.3 [6.4-24.7]; P Ͻ 0.05), even though both were similarly affected by treatment with actinomycin D. These data indicate that the susceptibility of asthmatic bronchial epithelium to oxidants is greater than normal. This susceptibility may contribute to the rising trends in asthma associated with air pollution and diets low in antioxidants.
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