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1 Department of Medicine, McGill University Health Center, Montreal, Quebec, Canada
2 Department of Pharmacology, University of Sherbrooke, Sherbrooke, Quebec, Canada
3 Department of Medicine, University of Sherbrooke, Sherbrooke, Quebec, Canada
* To whom correspondence should be addressed. E-mail: sabah.hussain{at}muhc.mcgill.ca.
Apoptosis (programmed cell death) is induced in pulmonary cells and contributes to the pathogenesis of acute lung injury in septic humans. Previous studies have shown that nitric oxide (NO) is an important modulator of apoptosis, however, the functional role of NO derived from inducible nitric oxide synthase (iNOS) in sepsis-induced pulmonary apoptosis remains unknown. We measured pulmonary apoptosis in a rat model of E. coli lipopolysaccharide (LPS)- induced sepsis in the absence and presence of 1400W, a selective iNOS inhibitor. Four groups were studied 24 hrs after saline (control) or LPS injection in the absence and presence of 1400W pre-treatment. Apoptosis was evaluated with DNA fragmentation, TUNEL staining and caspase activation. LPS administration significantly augmented pulmonary cell apoptosis and caspase-3 activity in airway and alveolar epithelial cells. Pre-treatment with 1400W significantly enhanced LPS-induced pulmonary apoptosis and increased caspase-3 and -7 activation. The anti-apoptotic effect of iNOS was confirmed in iNOS-/- mice which developed a greater degree of pulmonary apoptosis, both under control conditions and in response to LPS as compared with wild type mice. By comparison, genetic deletion of the neuronal nitric oxide synthase had no effect on LPS-induced pulmonary apoptosis. We conclude that NO derived from iNOS plays an important protective role against sepsis-induced pulmonary apoptosis.
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