Role of Cathepsin S-Dependent Epithelial Cell Apoptosis in IFN-γ-Induced Alveolar Remodeling and Pulmonary Emphysema

Abstract

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-γ, to induce these responses have not been defined. To elucidate the mechanism(s) of IFN-γ-induced tissue remodeling and destruction, we characterized the pathway that lung-targeted, transgenic IFN-γ uses to induce alveolar remodeling in a murine pulmonary emphysema modeling system. In these mice, transgenic IFN-γ 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-γ-induced emphysema. These interventions also ameliorated IFN-γ-induced inflammation and decreased pulmonary protease burden. Selective cathepsin S inhibition and a null mutation of cathepsin S also decreased IFN-γ-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-γ-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.

Pulmonary Epithelial Neuropilin-1 Deletion Enhances Development of Cigarette Smoke–induced Emphysema

“…Because mounting evidence suggests that the apoptotic machinery is also necessary to generate an emphysema phenotype (64,(67)(68)(69), an alternative and potentially complementary hypothesis to explain host susceptibility to the injurious effects of chronic smoke exposure has evolved. This hypothesis suggests that CS-induced alveolar destruction could be exacerbated by abnormalities in pathways critical for lung development and postnatal lung homeostasis, creating an imbalance between cellular programs regulating lung injury and repair (69,70).…”

Role of cathepsin S in ozone-induced airway hyperresponsiveness and inflammation

“…Zheng et al also used the same cathepsin S inhibitor at the lower dose of 10 mg kg -1 per day to inhibit IFNγ-induced DNA injury, apoptosis and emphysema in mice (17). We used the higher dose of 30 mg kg -1 because of the improved pharmacokinetics at that increased dose.…”

“…Role of Cathepsin S in ozone-induced airway hyperresponsiveness and inflammation 6 binding of cathepsin S, K i , was 0.64 nM, while with regard to cathepsins L, K and B, the K i values were 17,000, 37,000 and 200 nM, respectively (17). In mice administered with a dose of 30 mg/kg orally, a maximum plasma concentration of 8,850 ng/ml with a half-life of 1.47 hours and a bioavailability of 47% were found from assays of plasma and lung levels of Compound A taken at regular time-points after gavage.…”

“…It was kindly provided by Sanofi-Aventis, New Jersey, USA. Compound A displays excellent selectivity and activity for cathepsin S over the other cathepsin family members L, K and B (17). The dissociation constant for Compound A for inhibitory…”

“…and is an inhibitor of cathepsin S previously reported as 05141 (17). It was kindly provided by Sanofi-Aventis, New Jersey, USA.…”