The LPS Responsiveness in BN and LEW Rats and Its Severity Are Modulated by the Liver

Abstract

Differences in LPS responsiveness influence the outcome of patients with sepsis. The intensity of the response is highly variable in patients and strain dependent in rodents. However, the role of the liver for initiating the LPS response remains ill defined. We hypothesize that hepatic LPS uptake is a key event for initiating the LPS response. In the present study, the severity of the LPS-induced inflammatory response and the hepatic LPS uptake was compared in two rat strains (Lewis (LEW) rats and Brown Norway (BN) rats). Using a transplantation model, we demonstrated the decisive role of the liver. The expression of hepatic TNF-α, IL-6, and IL-1β mRNA levels in BN rats was significantly lower than that in LEW rats. LEW rats were sensitized to LPS via G-CSF pretreatment. Sensitization caused by G-CSF pretreatment induced severe liver injury and mortality in LEW rats, but not in BN rats (survival rate: 0% (LEW) versus 100% (BN), p < 0.01). LEW rats presented with higher liver enzymes, more alterations in histology, and higher expression of caspase 3 and higher cytokines levels. One of the reasons could be the increased hepatic LPS uptake, which was only observed in LEW but not in BN livers. Using the transplantation model revealed the decisive role of the LPS responsiveness of the liver. Injection of LPS to the high-responding LEW recipient before transplantation of a low-responder BN liver resulted in a 50% survival rate. In contrast, injecting the same dose of LPS into the high-responding LEW recipient after transplanting the low-responding BN liver resulted in a 100% survival rate. The severity of inflammatory response in different strains might be related to the differences in hepatic LPS uptake. This observation suggests that the liver plays a genetically defined decisive role in modulating the inflammatory severity.

Granulocyte-colony stimulating factor (G-CSF) to treat acute-on-chronic liver failure: A multicenter randomized trial (GRAFT study)

“…29,30 As shown in septic liver injury models, G-CSF might enhance sensitivity to endotoxins and increase hepatocyte uptake of lipopolysaccharide through the lipopolysaccharide-binding protein/TLR4 axis, thereby aggravating tissue injury, as shown by HMGB1 translocation and mortality in rat models of septic liver injury. 31,32 G-CSF also activates neutrophils that carry TLR4 33 and migrate into injured tissues, potentially causing additional cellular damage. 34 Therefore, the effect of G-CSF, either beneficial or detrimental, might depend on the disease stage.…”

A leukotriene-dependent spleen-liver axis drives TNF production in systemic inflammation

“…Although it is well established that macrophages are the main source of TNF in systemic inflammation (13,29,30), the relative contributions of macrophages residing in different organs remain an unsettled matter. The prevailing view about the spleen being the main source of TNF in systemic inflammation is contested by a few studies showing that, like splenectomy (9,11), hepatectomy can be effective at reducing the LPS-induced surge in plasma TNF (31)(32)(33). A caveat of these studies, however, is that they have not addressed whether the effects of hepatectomy or splenectomy on plasma TNF might have been indirectly influenced by altered TNF production in one or more of the nonexcised organs.…”

Modeling trauma in rats: similarities to humans and potential pitfalls to consider

“…Furthermore, strain differences should be carefully considered when trying to perform lipopolysaccharide (LPS)-induced sepsis in rats. Brown Norway and Lewis rat strains showed different responsiveness to LPS, which was modulated by the liver of the animals [119]. In another full-thickness skin burn model, the temperature and the burned area are variable.…”