OP21 The role of Toll like receptor-4 in the pathogenesis of hepatorenal syndrome in a Bile duct ligated model of cirrhosis in the rat. (16th November 2010)

• Record Type: Journal Article
• Authors: Shah, N; Dhar, D; Mohamed, F; Mookerjee, R; Davies, N A; Jalan, R
• Is Part Of: Gut. Volume 59(2010)Supplement 2
• Page Start: A9
• Page End: A9
• Publication Date: 2010-11-16
• Subjects: Gastroenterology -- Periodicals; 616.33
• DOI: 10.1136/gut.2010.223362.21
• Languages: English
• ISSNs: 0017-5749

Abstract

Abstract : Introduction: Hepatorenal syndrome (HRS) is a frequent presenting complication in patients with cirrhosis and usually occurs with a superimposed infection/inflammation. It is associated with high morbidity and mortality. The pathogenesis of the HRS is not delineated. Toll like receptors (TLR's) play an important role in the recognition of molecules derived from microbes, which upon stimulation leads to activation of NFkB and pro inflammatory cascade. We hypothesised that cirrhosis associated endotoxaemia primes the kidney resulting in upregulation of TLR4 making the kidney susceptible to further endotoxaemia. Aim: The aims of this study were to determine whether (1) cirrhosis is associated with an upregulation of TLR4, NFkB and proinflammatory cytokines in the kidney and (2) whether selective decontamination would result in a reduction in TLR4 expression, attenuate NFkB and cytokines and make the kidneys less susceptible to further endotoxemic insult. Method: Six groups of Sprague–Dawley rats were studied; n=6 in each group (Sham operated, Sham-operated+LPS; BDL (4 weeks), BDL+LPS (1 mg/kg); BDL+Norfloxacin and BDL+LPS+Norfloxacin. The Norfloxacin groups were pretreated with Norfloxacin, 20 mg/kg administered orally daily for 10 days. The animals were studied 3 h after administration of placebo or LPS. Blood was for collected for biochemistry and cytokines. Kidney was collected for protein expression of TLR4 and NFkBp65 on Western blot and immunohistochemistry. Results: TLR4 and NFkBp65 protein expression was significantly upregulated in BDL rat kidney compared to sham (p=0.03 and 0.02), respectively, this increased further on LPS administration (p=0.02 and p=0.01). TLR4 was mainly localised in the proximal tubule and its brush border with ongoing apoptosis as evident by the presence of caspase-3 positivity on immunohistochemistry. Selective decontamination with Norfloxacin attenuated the inflammatory response by reducing the protein expression of TLR4 and NFkBp65 in BDL vs BDL group administered with LPS (p=0.02 and p=0.01). It also led to an improvement in the creatinine in BDL and BDL+LPS group administered Norfloxacin (p=0.02 and p=0.03), respectively. Norfloxacin ameliorated the kidney cytokine surge in BDL and BDL+LPS group (TNF p=0.09 and p=0.04, respectively). Conclusion: Our data provide strong evidence indicating an important pathogenic role of TLR4 in mediating susceptibility to the development of HRS in an experimental model of cirrhosis following inflammation/infection. Selective gut decontamination attenuates this pathological inflammatory process and prevents renal failure induced by LPS. TLR4 antagonist may be a therapeutic target for HRS.