title: Regulatory effects of iNOS on acute lung inflammatory responses in mice.
abstract: The role of endogenous NO in the regulation of acute lung injury is not well defined. We investigated the effects of inducible nitric oxide synthase (iNOS) and endothelial NOS (eNOS) on the acute inflammatory response in mouse lungs. Acute lung injury was induced by intratracheal instillation of bacterial lipopolysaccharide (LPS) into wild-type (WT) mice and mice deficient in iNOS (iNOS(-/-)) or eNOS (eNOS(-/-)). Endpoints of inflammatory injury were myeloperoxidase (MPO) content and leak of albumin into lung. Inflammatory injury was similar in WT and eNOS(-/-) mice but was substantially increased in iNOS(-/-) mice. Bronchoalveolar lavage (BAL) fluids of iNOS(-/-) and WT mice showed similar levels of CXC chemokines (MIP-2, KC) but enhanced levels of CC chemokines (MCP-1, MCP-3). Increased lung content of MPO in iNOS(-/-) mice was reduced by anti-MCP-1 to values found in WT mice. In vitro stimulation of microvascular endothelial cells with LPS and IFN gamma revealed elevated production of CXC and CC chemokines in cells from iNOS(-/-) mice when compared to endothelial cells from iNOS(+/+) mice. Peritoneal macrophages from iNOS(-/-) donors also revealed increased production of CC chemokines after stimulation with LPS and interferon (IFN gamma). These data indicate that absence of iNOS causes enhanced lung inflammatory responses in mice which may be related to enhanced production of MCP-1 by endothelial cells and macrophages. It appears that iNOS affects the lung inflammatory response by regulating chemokine production.
authors: Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109-0602, USA.
authors: Cecilia L
authors: CL
authors: Speyer
authors: Thomas A
authors: TA
authors: Neff
authors: Roscoe L
authors: RL
authors: Warner
authors: Ren-Feng
authors: RF
authors: Guo
authors: J Vidya
authors: JV
authors: Sarma
authors: Niels C
authors: NC
authors: Riedemann
authors: Megan E
authors: ME
authors: Murphy
authors: Hedwig S
authors: HS
authors: Murphy
authors: Peter A
authors: PA
authors: Ward
mesh_terms: D000208:Acute Disease; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002199:Capillary Permeability; D018932:Chemokine CCL2 / Q000378:metabolism; D018925:Chemokines / Q000378:metabolism; D019742:Chemokines, CC / Q000378:metabolism; D019743:Chemokines, CXC / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008070:Lipopolysaccharides; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008833:Microcirculation; D020556:Neutrophil Infiltration; D009569:Nitric Oxide / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D009195:Peroxidase / Q000378:metabolism; D011014:Pneumonia / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D011652:Pulmonary Circulation; D012709:Serum Albumin / Q000378:metabolism; D012867:Skin / Q000098:blood supply
chemical_list: D018932:Chemokine CCL2; D018925:Chemokines; D019742:Chemokines, CC; D019743:Chemokines, CXC; D008070:Lipopolysaccharides; D012709:Serum Albumin; D009569:Nitric Oxide; D009195:Peroxidase; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse