| First Author | Zheng T | Year | 2005 |
| Journal | J Immunol | Volume | 174 |
| Issue | 12 | Pages | 8106-15 |
| PubMed ID | 15944319 | Mgi Jnum | J:100854 |
| Mgi Id | MGI:3589829 | Doi | 10.4049/jimmunol.174.12.8106 |
| Citation | Zheng T, et al. (2005) Role of cathepsin S-dependent epithelial cell apoptosis in IFN-gamma-induced alveolar remodeling and pulmonary emphysema. J Immunol 174(12):8106-15 |
| abstractText | 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-gamma, to induce these responses have not been defined. To elucidate the mechanism(s) of IFN-gamma-induced tissue remodeling and destruction, we characterized the pathway that lung-targeted, transgenic IFN-gamma uses to induce alveolar remodeling in a murine pulmonary emphysema modeling system. In these mice, transgenic IFN-gamma 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-gamma-induced emphysema. These interventions also ameliorated IFN-gamma-induced inflammation and decreased pulmonary protease burden. Selective cathepsin S inhibition and a null mutation of cathepsin S also decreased IFN-gamma-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-gamma-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. |
