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State of the Art. Mechanistic Heterogeneity in Chronic Obstructive Pulmonary Disease

Insights from Transgenic Mice

Section of Pulmonary and Critical Care Medicine, and Department of Pathology, Yale University School of Medicine, New Haven; and Pathology and Laboratory Medicine Service, VA-CT Health Care System, West Haven, Connecticut

Correspondence and requests for reprints should be addressed to Jack A. Elias, M.D., Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, 300 Cedar Street, S441 TAC, New Haven, CT 06519. E-mail: jack.elias{at}yale.edu

ABSTRACT

Alveolar destruction is a cardinal feature of emphysema but is not traditionally believed to contribute to the pathogenesis of "classical" asthma. However, the relationship between chronic obstructive pulmonary disease (COPD) and asthma is controversial and the variety of mechanisms that can mediate the alveolar destruction in emphysema have not been adequately defined. To address these issues, we used overexpression transgenic approaches to define the effects of Th1/Tc1 and Th2/Tc2 cytokines in the mature murine lung and compared findings in these transgenic systems to the effects of similar interventions after cigarette smoke (CS) exposure. In these experiments, the Th1/Tc1 and Th2/Tc2 cytokines IFN- and interleukin (IL)-13, respectively, both caused emphysema. The IFN- response was associated with neutrophilia but was not associated with mucus metaplasia or a major fibrotic response. In this setting, IFN- was a potent stimulator of matrix metalloproteinases (MMPs), cathepsins, and CXC and other chemokines while inhibiting secretory leukocyte proteinase inhibitor (SLPI). Interestingly, IFN- induced its destructive effects via at least two mechanisms, a CCR5/cathepsin-dependent and apoptosis-mediated pathway and an MMP-12–dependent/apoptosis-independent pathway. CS-induced inflammation, apoptosis, and emphysema were also induced by IFN-– and CCR5-dependent mechanisms. In contrast, IL-13–induced emphysema was associated with eosinophilia, mucus metaplasia, and pulmonary fibrosis. In this setting, IL-13 stimulated MMPs, cathepsins, and a variety of CC chemokines while inhibiting ₁-antitrypsin. A cathepsin-dependent apoptosis pathway also contributed to this remodeling response. Interestingly, abnormalities in vascular endothelial growth factor (VEGF) were also appreciated with VEGF₁₆₅ excess producing an asthmalike pulmonary response and IFN- abrogating this response while inducing emphysematous alveolar destruction. These findings provide molecular support for both points of view in the British/Dutch hypothesis controversy regarding the relationship between asthma and COPD. They also highlight the complexity of the pathways that can induce alveolar destruction and suggest that there is a continuum, based on VEGF, between asthma and COPD.

Key Words: asthma • chronic obstructive pulmonary disease • gamma interferon • IL-13 • vascular endothelial growth factor

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