Intereukin-10 and Kupffer cells protect steatotic mice livers from ischemia-reperfusion injury

Abstract

Steatotic livers are more sensitive to ischemia/reperfusion (I/R) and are thus routinely rejected for transplantation because of their increased rate of primary nonfunction (PNF). Lean livers have less I/R-induced damage and inflammation due to Kupffer cells (KC), which are protective after total, warm, hepatic I/R with associated bowel congestion. This protection has been linked to KC-dependent expression of the potent anti-inflammatory cytokine interleukin-10 (IL-10). We hypothesized that pretreatment with exogenous IL-10 would protect the steatotic livers of genetically obese (ob/ob) mice from inflammation and injury induced by I/R. Lean and ob/ob mice were pretreated with either IL-10 or liposomally-encapsulated bisphosphonate clodronate (shown to deplete KC) prior to total, warm, hepatic I/R. IL-10 pretreatment increased survival of ob/ob animals at 24 hrs post-I/R from 30% to 100%, and significantly decreased serum ALT levels. At six hrs post-I/R, IL-10 pretreatment increased IL-10 mRNA expression, but suppressed up-regulation of the pro-inflammatory cytokine IL-1β mRNA. However, ALT levels were elevated at six hrs post-I/R in KC-depleted animals. These data reveal that pretreatment with IL-10 protects steatotic livers undergoing I/R, and that phagocytically active KC retain a hepatoprotective role in the steatotic environment.

Extracellular vesicles from bone marrow–derived mesenchymal stem cells protect against murine hepatic ischemia/reperfusion injury

“…The number of F4/80 positive cells in liver were significantly increased in MSC-EV or sham group compared with PBS (vehicle) after reperfusion, and negatively correlated with serum ALT levels. A contribution of F4/80 expressing cells with attenuation of injury is consistent with other reports of hepatic protection linked to Kupffer cell-dependent expression of anti-inflammatory cytokines such as interleukin-10 (48). The precise involvement of Kupffer cells needs to be examined because their functional inactivation has been reported to attenuate injury during reperfusion (49, 50).…”

Use of Steatotic Grafts in Liver Transplantation: Current Status

“…This is particularly problematic in LT from cadaveric donors because of the very short period of time available in which to pretreat them in this emergency procedure. Many of the previously mentioned studies (13 of 23) were performed in rat models with moderate steatotic livers . Of these studies,11 used fatty livers from Zucker rats; 5 used a methionine‐choline deficient diet and 5 a HFD, both models of steatohepatitis.…”

“…In this sense, just 1 study (81) compared whether the effect of the drug used is dependent on the type of steatosis, although it was performed in a normothermic condition rather than LT. Furthermore, the majority of drugs/treatments were administered in donors before IRI (57,(63)(64)(65)(66)76,(78)(79)(80)(81)83,84,87,88) ; it would be interesting to evaluate whether these drugs are equally effective when applied to recipients which would make their clinical use easier. In addition, in order to ensure effective strategies, the drug pretreatment times tend to be long in donors.…”

“…Many of the previously mentioned studies (13 of 23) were performed in rat models with moderate steatotic livers. (53,57,62,63,65,66,76,(78)(79)(80)84,86,87) Of these studies,11 used fatty livers from Zucker rats (53,57,62,63,65,66,68,77,78,(87)(88)(89) ; 5 used a methionine-choline deficient diet (53,68,82,83,89) and 5 a HFD, (64,(79)(80)(81)85,88) both models of steatohepatitis. Finally, in 2 studies steatohepatitis was induced by alcohol.…”

“…Review ARticle | 779 Moreover, most of the reported studies have been performed in normothermic hepatic I/R models with or without hepatic resection (68,69,(82)(83)(84)(85)(86)(87)(88)(89) conditions that greatly differ from the clinical practice of LT. Additionally, mechanisms involved in hepatic IRI may differ depending on the method used to induce experimental steatosis. For example, as opposed to other models of steatosis, both dietary and alcohol exposure induce the production of SOD/catalase-insensitive ROS, which may partly explain steatotic failure after LT. Neutrophils, which have been implicated in the increased vulnerability of alcohol-induced steatotic livers to IRI, would not account for I/R damage in nonalcoholic steatotic livers.…”