title: Specific inhibition of nitric oxide synthases at different time points in a murine model of pulmonary sepsis.
abstract: Excessive production of nitric oxide (NO) by NO synthase (NOS) and a subsequent oxidative stress reaction are thought to be critically involved in the pathophysiology of sepsis. Previous studies suggested that NO production by neuronal NOS (nNOS) and inducible NOS (iNOS) is implemented in the disease process at different time points after the injury. Here we tested the roles of selective pharmacological inhibition of nNOS and iNOS at different time points in a murine model of pulmonary sepsis. The injury was induced by intranasal administration of live Pseudomonas aeruginosa (3.2×10(7) colony-forming units) in C57BL/6 wild-type mice. The animals received no treatment (control) or treatment with a specific nNOS inhibitor (4 or 8h), iNOS inhibitor (4 or 8h), or non-specific NOS inhibitor (4 or 8h). In controls, the injury was associated with excessive releases of pro-inflammatory cytokines in the plasma, enhanced tissue lipid peroxidation, and decreased survival. Non-specific NOS inhibition at either time point did not influence survival and was not further investigated. While nNOS inhibition at 4h was associated with a trend toward improved survival and significantly reduced contents of lung nitrite/nitrate (NO(x)) and liver malondialdehyde, the blockade of nNOS at 8h had no effect on these parameters. In contrast, early iNOS inhibition was associated with a trend toward decreased survival and no effects on lung NO(x) and liver malondialdehyde contents, whereas later iNOS blockade was associated with decreased malondialdehyde content in liver homogenates. In conclusion, pulmonary sepsis in mice may be beneficially influenced by specific pharmacological nNOS inhibition at an earlier time point and iNOS inhibition at a later time points post-injury. Future investigations should identify the time changes of the expression and activation of NOS isoforms.
authors.affiliation: Department of Anesthesiology, Investigational Intensive Care Unit, The University of Texas Medical Branch and Shriners Hospitals for Children, Galveston, TX 77550, USA. lanm@gmx.de
authors.forename: Matthias
authors.initials: M
authors.lastname: Lange
authors.forename: Atsumori
authors.initials: A
authors.lastname: Hamahata
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Traber
authors.forename: Yoshimitsu
authors.initials: Y
authors.lastname: Nakano
authors.forename: Lillian D
authors.initials: LD
authors.lastname: Traber
authors.forename: Perenlei
authors.initials: P
authors.lastname: Enkhbaatar
mesh_terms: D000818:Animals; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D005260:Female; D008099:Liver / Q000378:metabolism; D008171:Lung Diseases / Q000188:drug therapy* / Q000201:enzymology / Q000382:microbiology; D008315:Malondialdehyde / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D017942:Nitric Acid / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors*; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors*; D011550:Pseudomonas aeruginosa; D018805:Sepsis / Q000188:drug therapy* / Q000201:enzymology
chemical_list: D016207:Cytokines; D017942:Nitric Acid; D008315:Malondialdehyde; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; C496321:Nos1 protein, mouse; C496317:Nos2 protein, mouse