Inhibition of inducible nitric oxide synthase attenuates acute endotoxin-induced lung injury in rats.
1. In the present study, we investigated the effects of the inducible nitric oxide (iNOS) inhibitors S-methylisothiourea (SMT) and l-N(6)-(1-iminoethyl)-lysine (l-Nil) on endotoxin-induced acute lung injury (ALI), as well as the associated physiological, biomedical and pathological changes, in anaesthetized Sprague-Dawley rats and in rat isolated perfused lungs. 2. Endotoxaemia was induced by an intravenous (i.v.) infusion of lipopolysaccharide (LPS; Escherichia coli 10 mg/kg). Lipopolysaccharide produced systemic hypotension and tachycardia. It also increased the lung weight/bodyweight ratio, lung weight gain, exhaled nitric oxide (NO), the protein concentration in bronchoalveolar lavage and microvascular permeability. 3. Following infusion of LPS, plasma nitrate/nitrite, methyl guanidine, pro-inflammatory cytokines (tumour necrosis factor-alpha and interleukin-1beta) were markedly elevated. Pathological examination revealed severe pulmonary oedema and inflammatory cell infiltration. Pretreatment with SMT (3 mg/kg, i.v.) or l-Nil (3 mg/kg, i.v.) significantly attenuated the LPS-induced changes and ALI. 4. The results suggest that the inflammatory responses and ALI following infusion of LPS are due to the production of NO, free radicals and pro-inflammatory cytokines through the iNOS system. Inhibition of iNOS is effective in mitigating the endotoxaemic changes and lung pathology. Inhibitors of iNOS may be potential therapeutic agents for clinical application in patients with acute respiratory distress syndrome.
Su
Chain Fa
CF
Department of Neurosurgery, Tzu Chi Hospital and Tzu Chi University, 701 Section 3 Chung Yang Road, Hualien 97004, Taiwan.
Yang
Fwu Lin
FL
Chen
Hsing I
HI
D000818:Animals; D019446:Endotoxemia / Q000097:blood / Q000139:chemically induced / Q000517:prevention & control; D004731:Endotoxins / Q000633:toxicity*; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D007262:Infusions, Intravenous; D053583:Interleukin-1beta / Q000096:biosynthesis / Q000097:blood; D007550:Isothiuronium / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000633:toxicity; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008239:Lysine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D008760:Methylguanidine / Q000097:blood; D009566:Nitrates / Q000097:blood; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors*; D009573:Nitrites / Q000097:blood; D009929:Organ Size / Q000187:drug effects; D011654:Pulmonary Edema / Q000097:blood / Q000139:chemically induced / Q000517:prevention & control; D051381:Rats; D017207:Rats, Sprague-Dawley; D012128:Respiratory Distress Syndrome / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000097:blood
D004731:Endotoxins; D004791:Enzyme Inhibitors; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; C090663:N(6)-(1-iminoethyl)lysine; D009566:Nitrates; D009573:Nitrites; D014409:Tumor Necrosis Factor-alpha; D007550:Isothiuronium; D009569:Nitric Oxide; D008760:Methylguanidine; D052247:Nitric Oxide Synthase Type II; C027744:S-methylisothiopseudouronium; D008239:Lysine