The ratio of ELR+ to ELR- CXC chemokines affects the lung and liver injury following hepatic ischemia/ reperfusion in the rat.
Hepatic ischemia/reperfusion (I/R) results in a neutrophil-dependent 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 (gamma-IFN). gamma-IFN is known to upregulate some of the ELR- CXC chemokines, including gamma-IFN-inducible protein (IP-10) and monokine-induced by gamma-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 gamma-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 gamma-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.
Colletti
L M
LM
Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA. colletti@umich.edu
Green
M E
ME
Burdick
M D
MD
Strieter
R M
RM
D000595:Amino Acid Sequence / Q000235:genetics; D000818:Animals; D054357:Chemokine CXCL10; D054365:Chemokine CXCL5; D019743:Chemokines, CXC / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D016209:Interleukin-8 / Q000031:analogs & derivatives / Q000378:metabolism; D007511:Ischemia / Q000473:pathology*; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D008102:Liver Circulation; D008168:Lung / Q000473:pathology*; D008297:Male; D009504:Neutrophils / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000473:pathology*
C486263:CXCL5 protein, human; D054357:Chemokine CXCL10; D054365:Chemokine CXCL5; D019743:Chemokines, CXC; D016209:Interleukin-8