Organ damage in zymosan-induced multiple organ dysfunction syndrome in mice is not mediated by inducible nitric oxide synthase.
OBJECTIVE
To examine the role of inducible nitric oxide synthase (iNOS) in the development of the multiple organ dysfunction syndrome (MODS) in a murine model by using either a selective iNOS inhibitor or iNOS knockout mice.


METHODS
Prospective randomized laboratory study.


METHODS
Central animal laboratory and experimental laboratory.


METHODS
Fifty inbred C57BL/6 mice, 39 iNOS knockout (-/-) mice, and 30 wild-type (+/+) mice, 7-9 wks old, weighing 20-25 g.


METHODS
Mice received an aseptic intraperitoneal injection of 40 microg of lipopolysaccharide followed by zymosan at a dose of 1 mg/g of body weight 6 days later (day 0). In experiment 1, C57BL/6 mice additionally received intraperitoneal injections with 5 mg of aminoguanidine or saline every 12 hrs, from 4 days after the injection of zymosan onward. In experiment 2, both iNOS-/- mice and corresponding wild-type (iNOS+/+) mice were treated with lipopolysaccharide and zymosan.


RESULTS
In all animals, the injection of zymosan induced an acute peritonitis, followed by an apparent recovery. From approximately day 6 onward, animals entered the third-MODS-like-phase, indicated by weight loss, a decrease in body temperature, and significant mortality rates. Quantitative reverse transcriptase polymerase chain reaction and immunochemistry revealed a strongly increased expression of iNOS messenger RNA and iNOS protein in livers of mice in the last phase. However, neither the in vivo administration of aminoguanidine to C57BL/6 mice nor the complete absence of iNOS enzyme (iNOS-/- mice) had a beneficial effect on survival rate, body temperature, or body weight. In addition, relative lung, liver, and spleen weights and lung scores were not different between experimental groups.


CONCLUSIONS
The current results strongly argue against an essential and causative role of iNOS in the development of organ damage in our murine model of MODS.
Volman
Thomas J H
TJ
Department of Surgery, University Medical Center Nijmegen, The Netherlands.
Goris
R Jan A
RJ
van der Jagt
Michel
M
van de Loo
Fons A J
FA
Hendriks
Thijs
T
D000818:Animals; D006146:Guanidines / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009102:Multiple Organ Failure / Q000139:chemically induced / Q000201:enzymology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000502:physiology*; D011897:Random Allocation; D015054:Zymosan / Q000008:administration & dosage
D006146:Guanidines; D015054:Zymosan; D019001:Nitric Oxide Synthase; C004479:pimagedine