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ORIGINAL RESEARCH ARTICLE

Fibronectin Prevents Endotoxin Shock After Partial Hepatectomy in Rats via Inhibition of Nuclear Factor-B and Apoptosis

A-Hon Kwon^*,1, Zeyu Qiu^*, Katsushige Tsuji^*, Takeshi Miyaso^* and Tadayoshi Okumura

^* Department of Surgery and Department of Medical Chemistry, Kansai Medical University, 10-15 Fumizono, Moriguchi, Osaka 570-8507, Japan

To whom requests for reprints should be addressed at ¹ Department of Surgery, Kansai Medical University, 10-15 Fumizono, Moriguchi, Osaka, 570-8507, Japan. E-mail: kon{at}takii.kmu.ac.jp

Fibronectins (Fns) are involved in a number of biologic processes, such as cellular adhesion, motility, differentiation, apoptosis, hemostasis, wound healing, and ischemic injury. We investigated the possible mechanism underlying the protective action of plasma Fn (pFn) on endotoxin shock following partial hepatectomy in rats. Lipopolysaccharide (LPS) was administered intravenously to male Sprague-Dawley rats within 48 hrs of 70% hepatectomy. Prior to LPS administration, pFn or human serum albumin was given intravenously. The survival rate of the pFn-treated group was improved markedly compared with that of the controls. The levels of inflammatory cytokines and nitric oxide (NO) in serum were significantly lower in the pFn-treated group than in the control group. Expression of inducible nitric oxide synthase (iNOS) in hepatocytes also was reduced following pFn treatment. The degree of apoptosis and necrosis in the remnant liver was significantly lower in the pFn-treated rats than the controls. Furthermore, pFn pretreatment greatly inhibited the activation of nuclear factor-B (NF-B), caspase 3 and 8 activities, and cytochrome c release, and caused a decrease in mitochondrial Bcl-x_L. Plasma Fn prevents endotoxin-induced liver injury at least in part through inhibition of NF-B activation, which causes the reduction of iNOS expression and NO production by hepatocytes, and through the downregulation of inflammatory cytokines and promotion of Bcl-x_L expression.

Key Words: fibronectin • endotoxin • hepatectomy • inflammatory cytokines • apoptosis • nuclear factor-B • nitric oxide