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-Induced Alveolar Remodeling and Pulmonary Emphysema1
* Department of Internal Medicine, Yale University School of Medicine, Section of Pulmonary and Critical Care Medicine, New Haven, CT 06520; Pulmonary and Critical Care Division, University of California, San Francisco, CA 94143; Department of Pathology, Yale University School of Medicine, New Haven, CT 06520 and Pathology and Laboratory Medicine Service, Veterans Affairs-Connecticut Health Care System, West Haven, CT 06516; Department of Respiratory and RA Disease Group, Aventis Pharmaceuticals, Inc., Bridgewater, NJ 08807; ¶ Celera Pharmaceuticals Inc., South San Francisco, CA 94080; and || Section of Immunobiology and Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT, 06520
Th1/Tc1 inflammation and remodeling responses characterized by tissue atrophy and destruction frequently coexist in human diseases and disorders. However, the mechanisms that are used by Th1/Tc1 cytokines, like IFN-
, to induce these responses have not been defined. To elucidate the mechanism(s) of IFN--induced tissue remodeling and destruction, we characterized the pathway that lung-targeted, transgenic IFN- uses to induce alveolar remodeling in a murine pulmonary emphysema modeling system. In these mice, transgenic IFN- caused epithelial cell DNA injury and apoptosis detectable with TUNEL (Roche) and dual annexin V and propidium iodide staining. These responses were associated with death receptor and mitochondrial apoptosis pathway activation. Importantly, apoptosis inhibition with a caspase inhibitor (N-benzylcarboxy-Val-Ala-Asp-fluoromethyl-ketone) or a null mutation of caspase-3 blocked this DNA injury and apoptosis response and significantly ameliorated IFN--induced emphysema. These interventions also ameliorated IFN--induced inflammation and decreased pulmonary protease burden. Selective cathepsin S inhibition and a null mutation of cathepsin S also decreased IFN--induced DNA injury, apoptosis, emphysema, inflammation, and protease accumulation. These studies demonstrate that cathepsin S-dependent epithelial cell apoptosis is a critical event in the pathogenesis of IFN--induced alveolar remodeling and emphysema. They also link inflammation, protease/antiprotease alterations, and protease-dependent apoptosis in the pathogenesis of Th1/Tc1 cytokine-induced tissue remodeling and destructive responses.
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