Critical care medicine · 2002
Organ damage in zymosan-induced multiple organ dysfunction syndrome in mice is not mediated by inducible nitric oxide synthase.
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Volman Thomas J H, Goris R Jan A, van der Jagt Michel, van de Loo Fons A J, Hendriks Thijs
Аннотация
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.
DESIGN: Prospective randomized laboratory study.
SETTING: Central animal laboratory and experimental laboratory.
SUBJECTS: Fifty inbred C57BL/6 mice, 39 iNOS knockout (-/-) mice, and 30 wild-type (+/+) mice, 7-9 wks old, weighing 20-25 g.
INTERVENTIONS: 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.
MEASUREMENTS AND MAIN 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.
DESIGN: Prospective randomized laboratory study.
SETTING: Central animal laboratory and experimental laboratory.
SUBJECTS: Fifty inbred C57BL/6 mice, 39 iNOS knockout (-/-) mice, and 30 wild-type (+/+) mice, 7-9 wks old, weighing 20-25 g.
INTERVENTIONS: 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.
MEASUREMENTS AND MAIN 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.