Liver cirrhosis induces renal and liver phospholipase A2 activity in rats.

Vishwanath, Bannikuppe S.; Frey, Felix J.; Escher, Geneviève; Reichen, J.; Frey, Brigitte M.

doi:10.1172/jci118801

Cited by 28 publications

(20 citation statements)

References 76 publications

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“…Moreover, an increased amount of sPLA 2 protein was found in the renal cortex from cirrhotic rats with ascites, a finding also observed by Vishwanath et al in rats with biliary cirrhosis. 11 In this latter study, however, cPLA 2 activity or protein was not increased in the kidneys from rats with biliary cirrhosis compared to controls. Although these results appear to be in contradiction with our findings, they are not mutually exclusive and may be related to differences in the design of the two studies.…”

Section: Discussionmentioning

confidence: 53%

“…15 By contrast, in the study by Vishwanath et al, rats were studied at a fixed time (8 weeks) after bile duct ligation and excision. 11 Because the development of ascites after bile duct ligation is very unpredictable and usually occurs as a very late event, 40 it is likely that in the study by Vishawanah et al, rats were studied in earlier periods of cirrhosis, at least with respect to the development of ascites, compared with our study. Therefore, it could be that sPLA 2 is activated as an early event, whereas cPLA 2 is activated later in the disease in coincidence with the development of massive ascites and activation of vasoconstric- FIG.…”

Section: Discussionmentioning

confidence: 74%

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Increased renal and vascular cytosolic phospholipase A2 activity in rats with cirrhosis and ascites

et al. 1998

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Indirect evidence suggests that the renal and vascular production of prostaglandins is increased in cirrhosis with ascites. However, the activity of the enzymes regulating the prostaglandin pathway has not been investigated in cirrhosis. The aim of the current study was to determine the activity of phospholipase A 2 (PLA 2 ), the key enzyme in the regulation of prostaglandin synthesis, in kidney and vascular tissue obtained from rats with carbon tetrachlorideinduced cirrhosis and ascites (n ‫؍‬ 9) and control rats (n ‫؍‬ 6). PLA 2 activity was assayed in vitro using [ 14 C]arachidonylphosphatidylcholine (PC) and [ 14 C]arachidonyl-phosphatidylethanolamine (PE) as substrates in the presence of Ca 2؉ . Kidneys from cirrhotic rats had significantly higher PLA 2 activity compared with control rats, with both PC and PE (35 ؎ 5 and 40 ؎ 6 vs. 21 ؎ 2 and 26 ؎ 3 pmol/mg/min, respectively; P F .05 for both). PLA 2 activity was increased in the renal cortex as well as in the renal medulla. Fractionation of the kidney extracts by Mono-Q anionexchange chromatography showed that the elution position of PLA 2 activity corresponded to the cytosolic PLA 2 isoform (cPLA 2 ). Increased amounts of cPLA 2 protein were found in kidney extracts immunoblotted with an anti-cPLA 2 antibody. However, reverse-transcriptase polymerase chain reaction (RT-PCR) analysis did not detect any difference in cPLA 2 mRNA. PLA 2 activity was also higher in aortic tissue from cirrhotic rats than in controls (PC 38 ؎ 5 vs. 26 ؎ 1 and PE 66 ؎ 8 vs. 41 ؎ 3 pmol/mg/min; P F .05 for both). Incubation of renal and aortic extracts from cirrhotic rats with anti-cPLA 2 antibody reduced PLA 2 activity by 64% and 88%, respectively. In conclusion, PLA 2 activity is increased in kidneys and vascular tissue from cirrhotic rats with ascites. This can be accounted for by an induction of cPLA 2 , which would mediate, at least in part, the increased renal and vascular production of prostaglandins in cirrhosis.(HEPA-TOLOGY 1998;27:42-47.)

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Section: Discussionmentioning

confidence: 53%

Section: Discussionmentioning

confidence: 74%

Increased renal and vascular cytosolic phospholipase A2 activity in rats with cirrhosis and ascites

et al. 1998

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“…However, there was an exaggerated response in the BDL cirrhotic rats with sustained elevation of plasma F 2 -isoprostanes and increased levels in the liver and kidney. The rapid decrease in levels of tissue esterified F 2 -isoprostanes most probably occurs as a consequence of activation of a phospholipase, which has been observed by others after biliary cirrhosis in the rat 35 and after exposure of cells to LPS 36 or injection of LPS into the perfused liver. 37 Hatch et al 37 showed that Kupffer cell phospholipase A 2 activity increased by 4-fold in the rat within 2 hours of LPS injection, and activity continued to increase thereafter.…”

Section: Figmentioning

confidence: 51%

Increased sensitivity to endotoxemia in the bile duct-ligated cirrhotic rat

et al. 1999

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Sepsis is a common complication of cirrhosis with a high mortality. In this study, we have investigated some of the pathways that may be involved in tissue injury and death. Bile duct-ligated (BDL) cirrhotic and control rats were challenged with lipopolysaccharide (LPS). Sensitivity to LPS was markedly enhanced in the BDL group, and was associated with increased liver injury and mortality. There was a 5-fold constitutive activation of nuclear factor B (NFB) in the liver of BDL rat controls (P F .001), and this was activated further, but to a similar extent, in the liver of both sham and BDL rats after injection of LPS. Plasma tumor necrosis factor ␣ (TNF-␣) increased more markedly in the BDL cirrhotic rats (2,463 ؎ 697 pg/mL in BDL rats versus 401 ؎ 160 pg/mL in the controls at 3 hours; P F .01). Plasma nitrite/nitrate concentrations were increased in the BDL controls at baseline, and increased further after LPS (P F .05), but did not differ from sham controls at 6 hours. Plasma F 2 -isoprostanes increased 6-fold in the cirrhotic rats and 2-fold in the controls (P F .01) indicative of lipid peroxidation. Esterified F 2 -isoprostanes in the liver increased 2-to 3-fold at 1 hour in control and BDL rats, but returned to baseline levels by 3 hours. Esterified F 2 -isoprostanes in the kidney increased by 2-fold in the BDL rats after LPS administration, but remained unchanged in sham controls. We conclude that there is a marked increase in sensitivity to LPS in BDL cirrhotic rats. This is associated with an enhanced TNF-␣ response and increased lipid peroxidation. These may be directly and causally related to mortality. (HEPATOLOGY 1999;30:1198-1205.)Sepsis and associated endotoxemia occur in approximately 40% of hospitalized patients with cirrhosis and is a major cause of death.

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“…It has been reported that a secreted type of PLA 2 , PLA 2 IIA, which plays a crucial role in inflammation, was upregulated in the liver and kidney of rats with cirrhosis. 5 Although the mechanism accounting for the enhanced release of PLA 2 IIA in cirrhosis is unknown, several possible hypotheses have been described. The PLA 2 IIA enzyme is activated by endotoxins and proinflammatory cytokines such as interleukin (IL)-1, IL-6, and tumor necrosis factor alpha (TNF-␣).…”

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confidence: 99%