Hepatocellular dysfunction induced by nitric oxide production in hepatocytes isolated from rats with sepsis.
In the process of sepsis, the failing organ is not necessarily directly injured or involved in the primary disease process, and the development of distant organ failure may be induced by the host's primed response on an initial insult followed by subsequent insult. We hypothesized that enhancement of nitric oxide (NO) production in the presence of interleukin (IL)-1beta in hepatocytes, isolated under septic conditions, could be implicated in the change in liver energy metabolism, thus resulting in hepatocellular dysfunction. We performed cecal ligation and puncture (CLP group) or a sham operation (sham group) in rats and then isolated hepatocytes from the liver at 6 h postoperatively. The cultured hepatocytes were treated with IL-1beta in the absence and presence of N(G)-monomethyl-L-arginine (L-NMMA) or L-arginine. Effects on nitric oxide production, ATP content, and ketone body ratio (KBR) were then compared between the CLP and sham groups. IL-1beta augmented the induction of NO production in hepatocytes from the CLP group compared with the sham group. IL-1beta markedly decreased cellular ATP content and KBR in the CLP group. The addition of L-arginine further enhanced the decreases of ATP content and KBR concomitantly with the increase of NO production in the CLP group. In contrast, L-NMMA, an inhibitor of nitric oxide synthase, abolished the effects of IL-1beta on ATP content and KBR, as well as on NO production. These results demonstrate that enhancement of NO production by IL-1beta stimulation is involved in cellular failure through mitochondrial dysfunction in the liver of septic rats. This experimental finding may explain clinical phenomenon that an initial insult primes the host so that the host's response is greatly amplified on a second or subsequent insult, resulting in the development of distant organ failure.
Tu
Wei
W
First Department of Surgery, Kansai Medical University, Moriguchi, Osaka 570-8506, Japan.
Satoi
Sohei
S
Zhang
Zhongtao
Z
Kitade
Hiroaki
H
Okumura
Tadayoshi
T
Kwon
A-Hon
AH
Kamiyama
Yasuo
Y
D000255:Adenosine Triphosphate / Q000032:analysis; D000818:Animals; D001120:Arginine / Q000494:pharmacology; D002432:Cecum / Q000293:injuries; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D007416:Intestinal Perforation / Q000150:complications*; D007657:Ketone Bodies / Q000032:analysis; D008026:Ligation; D008107:Liver Diseases / Q000209:etiology*; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000494:pharmacology; D018746:Systemic Inflammatory Response Syndrome / Q000150:complications*; D019323:omega-N-Methylarginine / Q000494:pharmacology
D004791:Enzyme Inhibitors; D007375:Interleukin-1; D007657:Ketone Bodies; D020030:Nitric Oxide Donors; D011994:Recombinant Proteins; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D000255:Adenosine Triphosphate; D001120:Arginine; D019001:Nitric Oxide Synthase