Role of cathepsin S-dependent epithelial cell apoptosis in IFN-gamma-induced alveolar remodeling and pulmonary emphysema

J Immunol. 2005 Jun 15;174(12):8106-15. doi: 10.4049/jimmunol.174.12.8106.

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-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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Apoptosis / immunology*
  • Cathepsins / biosynthesis
  • Cathepsins / deficiency
  • Cathepsins / genetics
  • Cathepsins / physiology*
  • DNA Damage / immunology
  • Disease Models, Animal
  • Enzyme Induction / genetics
  • Enzyme Induction / immunology
  • Humans
  • Inflammation / enzymology
  • Inflammation / immunology
  • Inflammation / pathology
  • Interferon-gamma / physiology*
  • Lung / enzymology
  • Lung / immunology
  • Lung / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Organ Specificity / genetics
  • Organ Specificity / immunology
  • Pulmonary Alveoli / enzymology
  • Pulmonary Alveoli / immunology*
  • Pulmonary Alveoli / pathology
  • Pulmonary Emphysema / enzymology
  • Pulmonary Emphysema / genetics
  • Pulmonary Emphysema / immunology*
  • Pulmonary Emphysema / pathology*
  • Respiratory Mucosa / cytology*
  • Respiratory Mucosa / enzymology
  • Respiratory Mucosa / immunology*
  • Signal Transduction / genetics
  • Signal Transduction / immunology

Substances

  • Interferon-gamma
  • Cathepsins
  • cathepsin S