Effects of iNOS in Hepatic Warm Ischaemia and Reperfusion Models in Mice and Rats: A Systematic Review and Meta-Analysis

Abstract

Warm ischaemia is usually induced by the Pringle manoeuver (PM) during hepatectomy. Currently, there is no widely accepted standard protocol to minimise ischaemia-related injury, so reducing ischaemia-reperfusion damage is an active area of research. This systematic review and meta-analysis focused on inducible nitric oxide synthase (iNOS) as an early inflammatory response to hepatic ischaemia reperfusion injury (HIRI) in mouse- and rat-liver models. A systematic search of studies was performed within three databases. Studies meeting the inclusion criteria were subjected to qualitative and quantitative synthesis of results. We performed a meta-analysis of studies grouped by different HIRI models and ischaemia times. Additionally, we investigated a possible correlation of endothelial nitric oxide synthase (eNOS) and nitric oxide (NO) regulation with iNOS expression. Of 124 included studies, 49 were eligible for the meta-analysis, revealing that iNOS was upregulated in almost all HIRIs. We were able to show an increase of iNOS regardless of ischemia or reperfusion time. Additionally, we found no direct associations of eNOS or NO with iNOS. A sex gap of primarily male experimental animals used was observed, leading to a higher risk of outcomes not being translatable to humans of all sexes.

Protective Efficiency Comparison of Direct and Remote Ischemic Preconditioning on Ischemia Reperfusion Injury of the Liver in Patients Undergoing Partial Hepatectomy

“…However, no significant differences were observed between DIPC and RIPC pretreatment, but RIPC showed some superiority than DIPC in conveniences and efficiency in alleviating liver injury and improving liver reserve capacity. Oxidation reaction and inflammatory responses are surely activated in hepatic ischemia reperfusion injury [28,29]. Massive proinflammatory factors such as TNF-α, IL-6, and IL-1β are released in the microenvironment of the liver.…”

“…Oxidation reaction and inflammatory responses are surely activated in hepatic ischemia reperfusion injury [ 28 , 29 ]. Massive proinflammatory factors such as TNF- α , IL-6, and IL-1 β are released in the microenvironment of the liver.…”

Hepatoprotection of a Standardized Extract of Cultured Lentinula edodes Mycelia against Liver Injury Induced by Ischemia-Reperfusion and Partial Hepatectomy

“…ECLM significantly increased eNOS mRNA expression ( Figure 4 C). The iNOS expression is clearly elevated in the warm HIRI [ 47 ] and ECLM significantly decreased iNOS mRNA induction and NO production ( Figure 4 A,B). In general, uncontrollable overproduction of NO by iNOS results in the liver injury caused by highly toxic compounds, including peroxynitrite and hydroxyl radicals, produced by the persistent reaction of large amounts of NO reacting with superoxide anions [ 48 ].…”

“…However, no relationship was identified between iNOS downregulation and its impact on HIRI. Furthermore, no direct association between lower iNOS expression and longer survival in warm HIRI was identified [ 47 ]. The relationship between ECLM and iNOS in HIRI requires further investigations.…”