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Organ damage in zymosan-induced multiple organ dysfunction syndrome in mice is not mediated by inducible nitric oxide
Thomas J H Volman1, R Jan A Goris, Michel van der Jagt
1Department of Surgery, University Medical Center Nijmegen, The Netherlands.
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.
Insights
Inducible nitric oxide synthase (iNOS) does not play a critical role in the development of multiple organ dysfunction syndrome (MODS). Studies using iNOS inhibitors or knockout mice showed no protective effects against MODS progression in this murine model.
Area of Science:
- Immunology
- Pathophysiology
- Pharmacology
Background:
- Multiple organ dysfunction syndrome (MODS) is a complex condition with high mortality.
- The role of inducible nitric oxide synthase (iNOS) in MODS pathogenesis remains unclear.
- Understanding iNOS's contribution is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the involvement of iNOS in MODS development.
- To evaluate the therapeutic potential of iNOS inhibition in a murine MODS model.
- To compare the effects of iNOS inhibition versus genetic ablation of iNOS.
Main Methods:
- A murine model of MODS was established using lipopolysaccharide and zymosan.
- Experiment 1: C57BL/6 mice received an iNOS inhibitor (aminoguanidine).
- Experiment 2: iNOS knockout mice and wild-type littermates were subjected to the MODS protocol.
Main Results:
- MODS induction led to weight loss, hypothermia, and mortality.
- Increased iNOS expression was observed in the liver during the MODS phase.
- Neither iNOS inhibition nor iNOS deficiency improved survival, body temperature, or body weight.
- Organ weights and lung scores remained unchanged across experimental groups.
Conclusions:
- The findings do not support an essential role for iNOS in the development of organ damage in this MODS model.
- Targeting iNOS may not be a viable therapeutic strategy for MODS.
- Further research is needed to elucidate other pathways involved in MODS pathogenesis.
