Mercaptoethylguanidine inhibits the inflammatory response in a murine model of chronic infection with Pseudomonas aeruginosa.
Chronic airway inflammation induced by Pseudomonas aeruginosa is the eventual cause of respiratory failure in most people affected by cystic fibrosis. Recent evidence implicates the involvement of free radical and oxidant stress in the pathogenesis of the inflammatory injury. Here we report the efficacy of a novel experimental therapeutic, mercaptoethylguanidine (MEG), which has combined actions as a selective inhibitor of the inducible nitric oxide synthase and as a scavenger of peroxynitrite, a potent oxidant formed in the reaction of nitric oxide and superoxide radical. Chronic pulmonary infection was established in FVB/N mice by intratracheal administration of 10(5) colony-forming units of P. aeruginosa in agar beads. Treatment with MEG (10 mg/kg/dose every 8 h i.p.) inhibited weight loss in the first 3 days and reduced histologic injury at 8 days postinfection. MEG also reduced myeloperoxidase activity, a marker of neutrophil infiltration, at 8 days and concentrations of the proinflammatory cytokines interleukin-1beta, tumor necrosis factor-alpha, and macrophage inflammatory protein 2 in whole lung homogenates. MEG-treated animals and controls had similar perioperative mortality and comparable colony counts of P. aeruginosa at 8 days, indicating that MEG did not exacerbate infection. Our data suggest that MEG may be an effective immunomodulatory therapy of pulmonary inflammation induced by chronic infection.
Wilmott
R W
RW
Division of Pulmonary Medicine, The Children's Hospital Research Foundation, Cincinnati, OH, USA. wilmr0@chmcc.org
Kitzmiller
J A
JA
Szabó
C
C
Southan
G J
GJ
Salzman
A L
AL
D000758:Anesthesia; D000818:Animals; D015415:Biomarkers; D001835:Body Weight / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D006146:Guanidines / Q000627:therapeutic use*; D007249:Inflammation / Q000188:drug therapy* / Q000382:microbiology / Q000401:mortality; D007442:Intubation, Intratracheal; D051379:Mice; D020556:Neutrophil Infiltration; D009566:Nitrates / Q000493:pharmacokinetics; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D052247:Nitric Oxide Synthase Type II; D016877:Oxidants / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D018410:Pneumonia, Bacterial / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D011552:Pseudomonas Infections / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D013997:Time Factors
D015415:Biomarkers; D016207:Cytokines; D004791:Enzyme Inhibitors; D006146:Guanidines; D009566:Nitrates; D016877:Oxidants; C039642:peroxynitric acid; D009195:Peroxidase; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C100078:2-mercaptoethylguanidine