The ratio of ELR+ to ELR- CXC chemokines affects the lung and liver injuryfollowing hepatic ischemia/reperfusion in the rat

Hepatic ischemia/reperfusion (I/R) results in a neutrophil-dependent lung a nd liver injury. The process of neutrophil recruitment and activation in th is injury is at least partially dependent on the presence of the ELR+ CXC c hemokines. Other investigations have shown that ELR- CXC chemokines can blo ck ELR+ CXC chemokine neutrophil recruitment and activation in vitro. To be gin to investigate the role of the balance between these 2 types of molecul es 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 phar macologic doses of gamma-interferon (gamma-IFN). gamma-IFN is known to upre gulate some of the ELR - CXC chemokines, including gamma-IFN-inducible prot ein (IP-10) and monokine-induced by gamma-IFN (MIG), as well as down-regula te ELR+ CXC chemokine production. Following hepatic I/R or sham laparotomy, hepatic and pulmonary levels of the ELR- chemokines, IP-10 and MIG, and th e ELR+ chemokines, rat cytokine-induced neutrophil chemoattractant (KC), ma crophage inflammatory protein-2 (MIP-2), and epithelial neutrophil activati ng protein (ENA-78) were determined by ELISA, and lung and liver injury wer e assessed. In response to gamma-IFN, hepatic and pulmonary levels of the E LR- chemokines were increased and the levels of the ELR+ chemokines were de creased. Immunohistochemical staining confirmed the hepatocyte as the sourc e of these molecules, as well as the changes in chemokine levels in respons e to gamma-IFN. There was an associated significant decrease in liver and l ung 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 me chanism other than through an alteration in tissue neutrophil-levels.