Am. J. Respir. Crit. Care Med., Volume 162, Number 5, November 2000, 1859-1866

Inducible Nitric Oxide SynthaseKnockout Mice Exhibit Resistance to Pleurisy and Lung Injury Caused by Carrageenan

SALVATORE CUZZOCREA, EMANUELA MAZZON, GIUSI CALABRO, LAURA DUGO, ANGELA DE SARRO, FONS A. J. van de LOO, and ACHILLE P. CAPUTI

Institute of Pharmacology and Department of Biomorphology School of Medicine, University of Messina, Messina, Italy; and Department of Rheumatology, University Hospital Nijmegen, Nijmegen, The Netherlands

In the present study, we investigated the role of inducible (or type 2) nitric oxide synthase (iNOS) in the development of acute inflammation by comparing the responses in wild-type mice (WT) and mice lacking (knockout [KO]). When compared with carrageenan-treated iNOS-WT mice, iNOS-KO mice that had received carrageenan exhibited a reduced degree of pleural exudation and polymorphonuclear cell migration. Lung myeloperoxidase (MPO) activity and lipid peroxidation were significantly reduced in iNOS-KO mice in comparison with iNOSWT mice. Immunohistochemical analysis for nitrotyrosine revealed positive staining in lungs from carrageenan-treated iNOS-WT mice. Lung tissue sections from carrageenan-treated iNOS-WT mice showed positive staining for poly adenosine diphosphate (ADP)-ribose synthetase that was mainly localized in alveolar macrophages and in airway epithelial cells. The intensity and degree of staining for nitrotyrosine and poly-ADP-ribose synthetase were markedly reduced in tissue sections from carrageenan-treated iNOS-KO mice. The inflamed lungs of iNOS-KO mice also showed an improved histologic status. Furthermore, a significant reduction in the suppression of energy status, in DNA strand breakage, and in decreased cellular levels of nicotinamide adenine dinucleotide (NAD⁺) was observed ex vivo in macrophages harvested from the pleural cavity of iNOS-KO mice subjected to carrageenan-induced pleurisy. Taken together, our results clearly show that iNOS plays an important role in the acute inflammatory response.

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