Generation and functional significance of CXC chemokines for neutrophil-induced liver injury during endotoxemia

Abstract

The hypothesis that the neutrophil chemoattractant CXC chemokines KC and macrophage inflammatory protein-2 (MIP-2) are involved in neutrophil transmigration and liver injury was tested in C3Heb/FeJ mice treated with galactosamine (Gal, 700 mg/kg), endotoxin (ET, 100 microg/kg), or Gal + ET (Gal/ET). Hepatic KC and MIP-2 mRNA levels and plasma CXC chemokine concentrations were dramatically increased 1.5 h after Gal/ET or ET alone and gradually declined up to 7 h. Murine recombinant cytokines (TNF-alpha, IL-1 alpha, and IL-1 beta), but not Gal/ET, induced CXC chemokine formation in the ET-resistant C3H/HeJ strain. To assess the functional importance of KC and MIP-2, C3Heb/FeJ mice were treated with Gal/ET and control IgG or a combination of anti-KC and anti-MIP-2 antibodies. Anti-CXC chemokine antibodies did not attenuate hepatocellular apoptosis, sinusoidal neutrophil sequestration and extravasation, or liver injury at 7 h. Furthermore, there was no difference in liver injury between BALB/cJ wild-type and CXC receptor-2 gene knockout (CXCR2-/-) mice treated with Gal/ET. The higher neutrophil count in livers of CXCR2-/- than in wild-type mice after Gal/ET was caused by the elevated number of neutrophils located in sinusoids of untreated CXCR2-/- animals. The pancaspase inhibitor Z-Val-Ala-Asp-fluoromethylketone eliminated Gal/ET-induced apoptosis and neutrophil extravasation and injury but not CXC chemokine formation. Thus Gal/ET induced massive, cytokine-dependent CXC chemokine formation in the liver. However, neutrophil extravasation and injury occurred in response to apoptotic cell injury at 6-7 h and was independent of CXC chemokine formation.

Mechanisms of Liver Injury. II. Mechanisms of neutrophil-induced liver cell injury during hepatic ischemia-reperfusion and other acute inflammatory conditions

“…Because apoptotic cells can generate CXC chemokines (7), the effect may be triggered by soluble chemotactic factors. However, caspase inhibitors prevented neutrophil extravasation but had no effect on CXC chemokine formation (2). Alternatively, gaps in the sinusoidal endothelial cells may facilitate the direct contact of neutrophils through pseudopods with the underlying apoptotic hepatocytes.…”

“…However, these mediators do not always function as chemoattractant. In the galactosamine/endotoxin (Gal/ET) shock model, MIP-2 and KC are formed in substantial amounts in the liver but are not responsible for neutrophil extravasation (2). Chronic overexpression of IL-8 in transgenic mice increases the number of neutophils in sinusoids without transmigration.…”

Bile Acids Induce Inflammatory Genes in Hepatocytes

“…39 Our studies demonstrated that hepatocytes exposed to bile acids may contribute to the chemokine milieu that is responsible for lymphocyte and neutrophil recruitment into the liver. Although systemic chemokine formation may not always contribute to inflammatory liver injury, 47,48 a more selective chemokine formation by hepatocytes establishing a chemotactic gradient toward the parenchyma has been shown to trigger neutrophil extravasation and injury. 49 Collectively, these results suggest that bile acids at pathological concentrations are inflammatory mediators, and that hepatocytes may be an important source of cytokines and chemokinesduringcholestasisafterexposuretohighconcentrations of bile acids.…”

Role of Neutrophils in the Pathogenesis of Acute Inflammatory Liver Injury

“…However, CXC chemokine formation does not always lead to neutrophil extravasation (Simonet et al, 1994;Dorman et al, 2005). For CXC chemokines to have an effect, the mediators need to be produced in the right location to establish a chemotactic gradient, at the right time and in sufficient quantities relative to other potential chemoattractants.…”