Nitric Oxide–Dependent Activation of P53 Suppresses Bleomycin-Induced Apoptosis in the Lung

• DOI: 10.1084/jem.192.6.857
• Publication Date: 2002-07-26T16:48:33Z
• Authors: Darren W. Davis; Douglas A. Weidner; Andrij Holian; David J. McConkey
• Keywords: Mice, Knockout; 0301 basic medicine; Nitric Oxide Synthase Type II; Apoptosis; Epithelial Cells; DNA Fragmentation; Nitric Oxide; Antioxidants; Acetylcysteine; 3. Good health; Mice, Inbred C57BL; Bleomycin; Mice; 03 medical and health sciences; Macrophages, Alveolar; Animals; Nitric Oxide Donors; Nitric Oxide Synthase; Tumor Suppressor Protein p53; Reactive Oxygen Species; Lung

Chronic inflammation leading to pulmonary fibrosis develops in response environmental pollutants, radiotherapy, or certain cancer chemotherapeutic agents. We speculated that lung injury might be mediated by p53, a proapoptotic transcription factor widely implicated the of cells DNA damage. Intratracheal administration bleomycin led caspase-mediated fragmentation characteristic apoptosis. The effects were associated with translocation p53 from cytosol nucleus only alveolar macrophages had been exposed drug vivo, suggesting microenvironment regulated activation. Experiments thiol antioxidant (N-acetylcysteine) vivo and nitric oxide (NO) donors vitro confirmed reactive oxygen species required for A specific role NO was demonstrated experiments inducible synthase (iNOS)(-/)- macrophages, which failed demonstrate nuclear localization after exposure. Strikingly, rates bleomycin-induced apoptosis at least twofold higher p53(-/)- C57BL/6 mice compared heterozygous wild-type littermates. Similarly, levels also lungs iNOS(-/)- than observed controls. Consistent chronic injury, substantially Together, our results iNOS mediate novel apoptosis-suppressing pathway lung.