Alpha chemokines regulate direct lung ischemia-reperfusion injury.
BACKGROUND
Alpha chemokines function predominantly to recruit and activate neutrophils, which are important effectors of acute lung injury. This study evaluated whether blockade of 2 potent alpha chemokines, macrophage inflammatory protein-2 (MIP-2) and cytokine-induced neutrophil chemoattractant (CINC), is protective against lung ischemia-reperfusion injury in a warm in situ hilar clamp model.


METHODS
Left lungs of Long-Evans rats underwent normothermic ischemia for 90 minutes and reperfusion for up to 4 hours. Treated animals received antibodies to MIP-2 or CINC immediately prior to reperfusion. Lung injury was quantitated by vascular permeability to (125)I-radiolabeled bovine serum albumin, lung tissue neutrophil sequestration (myeloperoxidase [MPO] content), and alveolar leukocyte content in bronchoalveolar lavage (BAL) fluid. CINC and MIP-2 mRNA expression were assessed by northern blot, while ribonuclease protection assays were performed to evaluate mRNA expression for a number of early response cytokines. MIP-2 and CINC protein expression in injured lungs was determined by immunoblotting.


RESULTS
Treatment with antibodies to CINC or MIP-2 was associated with significant protection against increases in vascular permeability, MPO content and alveolar leukocyte sequestration in injured lungs. Expression of CINC and MIP-2 mRNA peaked after 2 hours of reperfusion in injured lungs, and protein levels were evident on immunoblotting after 3 hours of reperfusion. Neither CINC nor MIP-2 blockade appeared to modulate cytokine mRNA expression.


CONCLUSIONS
CINC and MIP-2 are important mediators involved in direct lung ischemia-reperfusion injury. They appear to function by modulating neutrophil recruitment, but not inflammatory cytokine release.
Farivar
Alexander S
AS
University of Washington Medical Center, Division of Cardiothoracic Surgery, Seattle, Washington 98195, USA.
Krishnadasan
Baiya
B
Naidu
Babu V
BV
Woolley
Steven M
SM
Verrier
Edward D
ED
Mulligan
Michael S
MS
D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D018893:Bronchoalveolar Lavage; D002199:Capillary Permeability / Q000502:physiology; D054426:Chemokine CXCL2; D019743:Chemokines, CXC / Q000032:analysis / Q000502:physiology*; D004195:Disease Models, Animal; D036341:Intercellular Signaling Peptides and Proteins / Q000032:analysis / Q000502:physiology; D008168:Lung / Q000098:blood supply*; D009195:Peroxidase / Q000032:analysis; D051381:Rats; D020318:Rats, Long-Evans; D015427:Reperfusion Injury / Q000503:physiopathology*
D054426:Chemokine CXCL2; D019743:Chemokines, CXC; C513296:Cxcl2 protein, rat; D036341:Intercellular Signaling Peptides and Proteins; D009195:Peroxidase