Inducible nitric oxide synthase - Knockout mice exhibit resistance to pleurisy and lung injury caused by carrageenan

In the present study, we investigated the role of inducible (or type 2) nit ric oxide synthase (iNOS) in the development of acute inflammation by compa ring 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 p olymorphonuclear cell migration. Lung myeloperoxidase (MPO) activity and li pid peroxidation were significantly reduced in iNOS-KO mice in comparison w ith iNOSWT mice. Immunohistochemical analysis for nitrotyrosine revealed po sitive staining in lungs from carrageenan-treated iNOS-WT mice. Lung tissue sections from carrageenan-treated iNOS-WT mice showed positive staining fo r poly adenosine diphosphate (ADP)-ribose synthetase that was mainly locali zed in alveolar macrophages and in airway epithelial cells. The intensity a nd 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 stat us. Furthermore, a significant reduction in the suppression of energy statu s, in DNA strand breakage, and in decreased cellular levels of nicotinamide adenine dinucleotide (NAD(+)) was observed ex vivo in macrophages harveste d from the pleural cavity of iNOS-KO mice subjected to carrageenan-induced pleurisy. Taken together, our results clearly show that iNOS plays an impor tant role in the acute inflammatory response.