Role of cathepsin S-dependent epithelial cell apoptosis in IFN-gamma-induced alveolar remodeling and pulmonary emphysema.
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.
Zheng
Tao
T
Department of Internal Medicine, Yale University School of Medicine, Section of Pulmonary and Critical Care Medicine, New Haven, CT 06520, USA.
Kang
Min Jong
MJ
Crothers
Kristina
K
Zhu
Zhou
Z
Liu
Wei
W
Lee
Chun Geun
CG
Rabach
Lesley A
LA
Chapman
Harold A
HA
Homer
Robert J
RJ
Aldous
David
D
De Sanctis
George T
GT
Desanctis
George
G
Underwood
Stephen
S
Graupe
Michael
M
Flavell
Richard A
RA
Schmidt
John A
JA
Elias
Jack A
JA
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology*; D002403:Cathepsins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D004249:DNA Damage / Q000276:immunology; D004195:Disease Models, Animal; D004790:Enzyme Induction / Q000235:genetics / Q000276:immunology; D006801:Humans; D007249:Inflammation / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D007371:Interferon-gamma / Q000502:physiology*; D008168:Lung / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009928:Organ Specificity / Q000235:genetics / Q000276:immunology; D011650:Pulmonary Alveoli / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D011656:Pulmonary Emphysema / Q000201:enzymology / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D020545:Respiratory Mucosa / Q000166:cytology* / Q000201:enzymology / Q000276:immunology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology
D007371:Interferon-gamma; D002403:Cathepsins; C028217:cathepsin S