Exogenous nitric oxide donor and related compounds protect against lung inflammatory response after hemorrhagic shock and resuscitation.

Abstract

BACKGROUND:

Resuscitation from hemorrhagic shock triggers an inflammatory response characterized by upregulation of cytokine and adhesion molecule expression, increased leukocyte activity, and accumulation of polymorphonuclear neutrophils in a variety of tissues. This study investigated the capability of an exogenous nitric oxide (NO) donor, sodium nitroprusside (NP); a NO substrate, L-arginine; and an inducible NO synthase inhibitor, L-N6-(1-iminoethyl)lysine (L-NIL) to reduce lung injury in an animal model of mixed controlled and uncontrolled hemorrhagic shock.

METHODS:

For this study, 72 Sprague-Dawley rats weighing 250 to 300 g were subjected to a model of uncontrolled hemorrhagic shock for 150 minutes. Six groups of animals were included in this study (12 per group): sham-saline, sham-NP, shock-saline, shock-NP, shock-L-arginine, and shock-L-N6-(1-iminoethyl)lysine. After the period of hemorrhagic shock, resuscitation of the groups was accomplished using normal saline (groups 1 and 3), NP (0.5 mg/kg) (groups 2 and 4), L-arginine (300 mg/kg) (group 5), or L-NIL (50 mg/kg) (group 6). The following indices were evaluated: fluid requirements for resuscitation, mean arterial pressure (MAP), arterial po2, pco2, and pH, lung wet-to-dry weight ratio, lung histology and cytokine (interleukin [IL]-1 alpha, IL-beta 1, tumor necrosis factor-beta [TNF beta], IL-3, IL-4, IL-5, IL-6, IL-10, TNF alpha, IL-2, interferon-gamma [IFN gamma]), and mRNA expression in the lung by a ribonuclease protection assay (RPA).

RESULTS:

Sodium nitroprusside significantly increased MAP and reduced fluid requirements during resuscitation after hemorrhage. There also was a significant improvement in lung function, as expressed by improvements in po2, pco2, and pH, and reduction of the wet-to-dry weight ratio. In addition, a significant reduction in acute lung injury was observed in the histologic studies. Furthermore, the expression of cytokines was reduced by NP treatment. The use of L-arginine and L-NIL offered similar protective results for the injured lung.

CONCLUSIONS:

These data suggest that limiting inducible NO synthase-generated NO availability with the exogenous NO donor, sodium nitroprusside, may reduce lung injury after severe hemorrhage, possibly, among other effects, by downregulating the expression of inflammatory cytokines. L-arginine and L-NIL also had a beneficial effect on lung function and structure.

• Authors: Roberto Anaya-Prado, Luis H Toledo-Pereyra, J Walsh, R F Guo, J Reuben, Peter A Ward
• Journal: The Journal of trauma (J Trauma) Vol. 57 Issue 5 Pg. 980-8 (Nov 2004) ISSN: 0022-5282 [Print] United States
• PMID: 15580020 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Cytokines
• Nitric Oxide Donors
• Tumor Necrosis Factor-alpha
• Nitroprusside
• Arginine
• Nitric Oxide Synthase

Topics

• Animals
• Arginine (administration & dosage, metabolism)
• Cytokines (metabolism)
• Disease Models, Animal
• Inflammation (metabolism, prevention & control)
• Lung (drug effects)
• Neutrophils (metabolism)
• Nitric Oxide Donors (administration & dosage, metabolism)
• Nitric Oxide Synthase (antagonists & inhibitors, metabolism)
• Nitroprusside (administration & dosage, metabolism)
• Rats
• Rats, Sprague-Dawley
• Respiratory Distress Syndrome (metabolism, prevention & control)
• Resuscitation
• Shock, Hemorrhagic (metabolism, prevention & control)
• Tumor Necrosis Factor-alpha (analysis)