Recombinant Alkaline Phosphatase Prevents Acute on Chronic Liver Failure

Abstract

The lipopolysaccharide (LPS)-toll-like receptor-4 (TLR4) pathway plays an important role in liver failure. Recombinant alkaline phosphatase (recAP) deactivates LPS. The aim of this study was to determine whether recAP prevents the progression of acute and acute-on-chronic liver failure (ACLF). Eight groups of rats were studied 4-weeks after sham surgery or bile duct ligation and were injected with saline or LPS to mimic ACLF. Acute liver failure was induced with Galactosamine-LPS and in both models animals were treated with recAP prior to LPS administration. In the ACLF model, the severity of liver dysfunction and brain edema was attenuated by recAP, associated with reduction in cytokines, chemokines, liver cell death, and brain water. The activity of LPS was reduced by recAP. The treatment was not effective in acute liver failure. Hepatic TLR4 expression was reduced by recAP in ACLF but not acute liver failure. Increased sensitivity to endotoxins in cirrhosis is associated with upregulation of hepatic TLR4, which explains susceptibility to development of ACLF whereas acute liver failure is likely due to direct hepatoxicity. RecAP prevents multiple organ injury by reducing receptor expression and is a potential novel treatment option for prevention of AcLf but not acute liver failure. Acute-on-chronic liver failure (ACLF) is a severe complication of chronic liver diseases characterized by acute decompensation resulting in multiorgan-failure and associated with systemic inflammation, increased liver cell death, and mortality 1-3. Endotoxins, notably lipopolysaccharides (LPS), are pathogen associated molecular patterns (PAMPs) 2,4-6 , which have been shown in animal models of chronic liver disease to induce clinical and pathophysiological features typical of ACLF 7-9. In alcoholic hepatitis elevation of circulating LPS was associated with increased risk of death and disease severity 10,11. LPS initiates an inflammatory cascade by binding to Pattern Recognition Receptors (PRR), among which the Toll-like-receptors subtype 4 (TLR4) is the most important 12. TLR4 is expressed on several cell types including immune cells, such as monocytes 13 and parenchymal cells, such as hepatocytes 14,15. The LPS-TLR4 axis is therefore a potential new therapeutic target in ACLF. Sensitivity to LPS is enhanced in fibrotic liver. Although LPS may induce liver injury in individuals with healthy liver at high doses, tolerance of healthy hepatocytes to endotoxins is substantial and a full-blown hepatic failure due to infection is rare 16. Acute liver failure (ALF) occurs in individuals with previously normal livers and is due to overwhelming liver injury and usually triggered by a hepatotoxic insult 17,18. ACLF, in contrary, is often precipitated by infection 19. These observations suggest that infection in general and the TLR4/LPS pathway may play a more important role in the pathogenesis of ACLF than ALF. Although regarded as a biomarker of cholestasis, alkaline phosphatase (ALP) also plays an important antiinflammatory role. Protective...

Pathophysiology of decompensated cirrhosis: Portal hypertension, circulatory dysfunction, inflammation, metabolism and mitochondrial dysfunction

“…TLR4 signalling inhibition and reduced receptor expression in the liver was found to protect against organ injury. 40,100 The secondary signal for inflammasome activation is typically a DAMP. 94 The inflammasome is a multiprotein complex that consists of DAMP sensors (NLRP1, NLRP2, NLRP3, NLRP4, NLRP6) and adaptor protein ASC (apoptosis-associated speck like protein containing a caspase recruitment domain).…”

A role for intestinal alkaline phosphatase in preventing liver fibrosis

“…This is likely exacerbated in the scenario of the vicious cycle between gut and liver injury. Supplemental IAP or recombinant alkaline phosphatase has been shown to prevent alcohol-induced hepatosteatosis and acute on chronic liver failure 9 , 34 . In this study, we provide evidencethat enteral supplementation of IAP in drinking water reduces the concentration of portal serum LPS that is derived from the gut lumen, thus implying that IAP may decrease the amount of active LPS that is translocated from the gut into the liver.…”

The Current Status of Granulocyte-Colony Stimulating Factor to Treat Acute-on-Chronic Liver Failure

“…It is intriguing that several animal models with different types of liver injury, ranging from liver fibrosis and acute liver failure to nonalcoholic steatohepatitis, independently showed a protective effect of G-CSF, while in humans with end-stage liver disease the results have been less convincing. This could be related to the fact that these models primarily mimic noninflammatory, single-organ diseases as distinct from late stages of chronic liver disease where-mostly lipopolysaccharide (LPS)-driven-systemic inflammation and tissue injury [65][66][67] and a subsequent lack of regenerative response become operative. 68,69 Results from preclinical studies focusing on the effect of G-CSF in sepsis and inflammatory-driven liver injury could provide some insights as to how G-CSF might act.…”

“…73 These results are important, as TLR4 is already upregulated in hepatocytes when cirrhosis develops and mediates tissue injury in rodent models of ACLF. 66,67 Furthermore, G-CSF not only mobilizes stem cell but also other immune cells, such as monocytes/macrophages and predominantly neutrophil granulocytes, which are known to carry TLR4. 74 In models of liver cirrhosis, G-CSF-mobilized neutrophils were activated with high expression of CD11b and low expression of CD62L.…”