Study on Therapeutic Effect of Pentoxifylline on Developmet of Multiple Organ Dysfuction Caused by Endotoxin in Rat

Lee, Gyum Cheol; Jeong, Sung Soo; Kim, Chung Kee; Su, Dae Hong; Lim, Hong Seb; Kim, Chi Dae; Hong, Ki Whan

Abstract

OBJECTIVES
Septic shock is characterized by the circulatory failure including vasodilation, hyporeactivity to vasoconstrictor agents and organ ischemia in association with multiple organ failure and increased platelet aggregation and blood coagulation. In the present study, we investigated the preventive effects of N-nitro-L-arginine methyl ester (L-NAME, 30mg/kg, i.p.), a non-selective nitric oxide synthase (NOS) inhibitor, S-methylisothiourea sulfate (SMT, 5mg/kg, i.p.) and pentoxifylline (PTX,10mg/kg, i.p.) on the multiple organ dysfunction in a rat model of circulatory shock induced by bacterial endotoxin (E. coli lipopolysaccharide: LPS) and discussed the mechanism underlying the development of multiple organ failure.
METHODS
The effect of each other N-nitro-L-arginine methyl ester(L-NAME, 30 mg/kg, i.p.), a non-selective nitric oxide synthase(NOS) inhibitor, S-methyli-sothiourea sulfate(SMT, 5mg/kg, i.p.) and pentoxifylline (PTX, 10mg/kg, i.p.) were comparatively evaluated following inducing circulatory shock by means of infusion of bacterial endotoxin to the rat model.
RESULTS
1) The systemic mean arterial blood pressure decreased by 48.7mmHg and vascular hyporeactivity to noradrenaline injection(1 g/kg, i.v.) upon intravenous administration of LPS. 2) Endotoxemia for 6hours resulted in little change in the numbers of white blood cells and neutrophils but a significant reduction in the numbers of platelets. The variables were not affected by the inhibitors. 3) Endotoxemia for 6hours caused a significant increase in serum nitric oxide level (P<0.01) which was inhibited by SMT, but not by L-NAME and PTX. 4) Upon injection of LPS, serum creatinine(0.65+/-0.08mg/dl) and urea(28.7+/-5.9mg/dl) were significantly elevated to 0.92+/-0.12 (P<0.05) and 54.3+/-2.1mg/dl (P< 0.01). These elevated levels were significantly attenuated by PTX but not by L-NAME and SMT. 5) Endotoxemia for 6 hours resulted in a significant increases in serum ALT(988.8+/-28.2 IU/L, P<0.01) and AST levels(1470.5+/-396.5 IU/L, P<0.01) from basal levels of ALT(67.8+/- 11.7IU/L) and AST(170.3+/-14.8IU/L). These increased activities were significantly attenuated by PTX, but not by L-NAME and SMT. The level of LDH(1279.8+/-156.2IU/L) was significantly increased by LPS treatment to 2932.0+/-519.9IU/L (P<0.05), which was inhibited by PTX. 6) Upon LPS treatment, the myeloperoxidase activity in the lung homogenate was significantly increased by LPS treatment (P<0.05), whereas that in the liver showed less change. The increased activity was reduced by PTX (P<0.05), but not by L-NAME and SMT. 7) The level of serum malondialdehyde, an index of lipid peroxidation by oxygen free radicals, was little influenced by LPS.
CONCLUSION
Based on these results, it is summarized that PTX characteristically inhibited the development of multiple ogran dysfunction in a murine model of endotoxemia. Thus, it is concluded that the formation of TNF and increased activity of neutrophils may importantly contribute to the development of LPS-induced endotoxemia.