The ratio of ELR+ to ELR− CXC chemokines affects the lung and liver injury following hepatic ischemia/reperfusion in the rat

Abstract

Hepatic ischemia/reperfusion (I/R) results in a neutrophildependent lung and liver injury. The process of neutrophil recruitment and activation in this injury is at least partially dependent on the presence of the ELR؉ CXC chemokines. Other investigations have shown that ELR؊ CXC chemokines can block ELR؉ CXC chemokine neutrophil recruitment and activation in vitro. To begin to investigate the role of the balance between these 2 types of molecules in vivo in neutrophil recruitment and activation following hepatic I/R, we used our rat model of lobar hepatic I/R and pretreated animals with pharmacologic doses of gamma-interferon (␥-IFN). ␥-IFN is known to upregulate some of the ELR؊ CXC chemokines, including ␥-IFN-inducible protein (IP-10) and monokine-induced by ␥-IFN (MIG), as well as down-regulate ELR؉ CXC chemokine production. Following hepatic I/R or sham laparotomy, hepatic and pulmonary levels of the ELR؊ chemokines, IP-10 and MIG, and the ELR؉ chemokines, rat cytokine-induced neutrophil chemoattractant (KC), macrophage inflammatory protein-2 (MIP-2), and epithelial neutrophil activating protein (ENA-78) were determined by ELISA, and lung and liver injury were assessed. In response to ␥-IFN, hepatic and pulmonary levels of the ELR؊ chemokines were increased and the levels of the ELR؉ chemokines were decreased. Immunohistochemical staining confirmed the hepatocyte as the source of these molecules, as well as the changes in chemokine levels in response to ␥-IFN. There was an associated significant decrease in liver and lung injury, although there was no significant decrease in neutrophil influx in either tissue. This suggests that the alteration in the balance of ELR؉ to ELR؊ CXC chemokines results in a decrease in tissue injury through a mechanism other than through an alteration in tissue neutrophil levels. (HEPATOLOGY 2000;31: 435-445.)

Type I, but not type II, interferon is critical in liver injury induced after ischemia and reperfusion

“…Our data in IFNGR KO mice are consistent with reports in which IFN-deficient mice developed IR-mediated kidney and liver damage, comparable with WT. 12 However, others have shown that pharmacological doses of IFN-␥ may produce anti-inflammatory effects, 18 consistent with our finding that INFRG KO mice suffered even more severe IRI damage than WT. Indeed, IFN-␥ may exert cytoprotective functions by modulating the production of proteases/reactive oxygen species from KC, 19 by decreasing CD54 20 or E/P selectin 21 expression.…”

IFN-γ-Inducible Protein-10 (CXCL10) Is Hepatoprotective During Acute Liver Injury Through the Induction of CXCR2 on Hepatocytes

“…Additionally, lymphocytes infiltrating hepatitis C-infected patients expressed CXCR3, and IP-10 was up-regulated on sinusoidal epithelium (10). In contrast, when IP-10 was elevated in response to IFN-␥ treatment, there was less injury in an ischemia-reperfusion model, as shown by a decrease in ALT values (12). Additionally, more recent data suggest that IP-10 expression correlates with a regenerative response in the liver (13).…”

“…The roles of the non-ELR-CXC chemokines, including IFN-␥-inducible protein-10 (IP-10), monokine induced by IFN-␥, and IFNinducible T cell ␣ chemoattractant, which bind to CXCR3 and are inducible by the IFNs, are controversial in liver injury. While some studies have shown that IP-10 (also known as CXCL10) levels correspond to liver injury (10,11), IP-10 has been shown to have hepatoprotective effects (12), and recent studies have shown that its elevation correlates to the peak of DNA synthesis (13). Therefore, the aim of the current study was to elucidate the role of IP-10 during APAP-induced liver injury.…”

The Effects of Granulocyte Colony-Stimulating Factor and Neutrophil Recruitment on the Pulmonary Chemokine Response to Intratracheal Endotoxin

“…Clinical observations of patients with acute respiratory distress syndrome (ARDS) and experimental studies on different animal models of lung injury have shown that sustained increases in pulmonary chemokines including IL-8, MIP-2, and CINC is a risk factor for the development of acute lung injury (17, 34 -37). Suppression of the ELR ϩ C-X-C chemokine (including MIP-2 and CINC) response has been shown to be associated with a significant decrease in lung injury irrespective of PMN influx in the lung in a rat model of hepatic ischemia and reperfusion (38). Although the inciting infection triggers the inflammatory cascade which serves to initiate an immune response, scavenging of soluble chemokines by the responding PMNs may be important in modulating the local host response.…”