Endogenous interleukin-4 and interleukin-10 regulate experimental lung ischemia reperfusion injury.
BACKGROUND
Regulatory cytokines play functional roles in experimental heart, hindlimb, and liver ischemia reperfusion injury. However, little is known about their involvement in direct lung ischemia reperfusion injury (LIRI). These studies were undertaken to investigate the role of two regulatory cytokines, interleukin-4 (IL-4) and IL-10, in an in vivo model of LIRI.


METHODS
Left lungs of Long-Evans rats underwent normothermic ischemia for 90 minutes and reperfusion for up to 4 hours. Treated animals received either recombinant IL-4 or recombinant IL-10, or antibodies to IL-4 or IL-10 immediately before reperfusion. Lung injury was quantitated by permeability indices, lung parenchymal neutrophil sequestration (myeloperoxidase [MPO] content), and alveolar leukocyte content in bronchoalveolar lavage (BAL) effluent. Expression of IL-4 and IL-10 was determined by immunoblotting, and mRNA expression for early response cytokines was evaluated by ribonuclease protection assays.


RESULTS
IL-4 and IL-10 protein expression was significant after 2 hours of reperfusion. Animals receiving anti-IL-4 (p = 0.05) and anti-IL-10 (p = 0.01) antibodies demonstrated increased permeabilities compared with positive controls. Lung tissue neutrophil accumulation (p < 0.004) and BAL leukocyte content (p < 0.04) were also significantly increased in animals receiving anti-IL-10 antibodies. Conversely, animals receiving recombinant IL-4 and recombinant IL-10 demonstrated reduced permeabilities and lung MPO content. Both anti-IL-4 and anti-IL-10 treatment increased mRNA expression for a number of early response cytokines, including TNF-alpha and IL-1beta.


CONCLUSIONS
IL-4 and IL-10 are expressed in response to LIRI and function to decrease injury severity. These effects are partly due to modulated expression of early proinflammatory cytokines.
Farivar
Alexander S
AS
Division of Cardiothoracic Surgery, University of Washington Medical Center, Seattle, Washington 98195, USA. msmmd@u.washington.edu
Krishnadasan
Baiya
B
Naidu
Babu V
BV
Woolley
Steven M
SM
Verrier
Edward D
ED
Mulligan
Michael S
MS
D000818:Animals; D015415:Biomarkers / Q000032:analysis; D015153:Blotting, Western; D018893:Bronchoalveolar Lavage; D002199:Capillary Permeability / Q000502:physiology; D004195:Disease Models, Animal; D016753:Interleukin-10 / Q000378:metabolism*; D015847:Interleukin-4 / Q000378:metabolism*; D008171:Lung Diseases / Q000378:metabolism / Q000503:physiopathology*; D011336:Probability; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D020318:Rats, Long-Evans; D012016:Reference Values; D015427:Reperfusion Injury / Q000378:metabolism / Q000503:physiopathology*; D012680:Sensitivity and Specificity
D015415:Biomarkers; D012333:RNA, Messenger; D016753:Interleukin-10; D015847:Interleukin-4