The role of proinflammatory cytokines in lung ischemia-reperfusion injury.
OBJECTIVE
Proinflammatory cytokines are known to play roles in ischemia-reperfusion injury of the heart, kidney, small bowel, skin, and liver. Little is known about their roles in ischemia-reperfusion injury of the lung. This study was undertaken to define the role of 2 proinflammatory cytokines, tumor necrosis factor alpha and interleukin 1beta, in ischemia-reperfusion injury of the lung.


METHODS
Left lungs of male rats were rendered ischemic for 90 minutes and reperfused for up to 4 hours. Treated animals received anti-tumor necrosis factor alpha or anti-interleukin 1beta antibody before reperfusion. Increased vascular permeability in the lung was measured by using iodine 125-labeled bovine serum albumin. Neutrophil sequestration in the lung parenchyma was determined on the basis of activity. Bronchoalveolar lavage was performed to measure cell counts. Separate tissue samples were processed for histology, cytokine protein, and messenger RNA content by using Western blotting and the ribonuclease protection assay.


RESULTS
Animals receiving anti-tumor necrosis factor alpha and anti-interleukin 1beta demonstrated reduced injury compared with that seen in positive control animals (vascular permeability of 48.7% and 29.4% lower, respectively; P <.001). Vascular injury was reduced by 71% when antibodies to tumor necrosis factor alpha and interleukin 1beta were administered together. Lung neutrophil accumulation was markedly reduced among animals receiving anti-tumor necrosis factor alpha and anti-interleukin 1beta (myeloperoxidase content of 30.9% and 38.5% lower, respectively; P <.04) and combination blockade afforded even greater protection (52.4% decrease, P <.01). Bronchoalveolar lavage leukocyte content was also reduced by treatment with anti-tumor necrosis factor alpha, anti-interleukin 1beta, and combination treatment. Reductions in permeability, myeloperoxidase, and bronchoalveolar lavage leukocyte content also resulted in a decrease in a histologic injury. Finally, anti-tumor necrosis factor alpha and anti-interleukin 1beta treatment resulted in decreased messenger RNA expression for a number of early response and regulatory cytokines.


CONCLUSIONS
Tumor necrosis factor alpha and interleukin 1beta help regulate the development of lung ischemia-reperfusion injury. They appear to promote injury by altering expression of proinflammatory and anti-inflammatory cytokines and influencing tissue neutrophil recruitment.
Krishnadasan
Baiya
B
Division of Cardiothoracic Surgery, University of Washington, Seattle, USA.
Naidu
Babu V
BV
Byrne
Karen
K
Fraga
Charles
C
Verrier
Edward D
ED
Mulligan
Michael S
MS
D000818:Animals; D001706:Biopsy; D015153:Blotting, Western; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D002199:Capillary Permeability / Q000276:immunology; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D007249:Inflammation / Q000276:immunology; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000276:immunology*; D007958:Leukocyte Count; D008168:Lung / Q000098:blood supply*; D008297:Male; D020556:Neutrophil Infiltration / Q000276:immunology; D009195:Peroxidase / Q000032:analysis; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D020318:Rats, Long-Evans; D015427:Reperfusion Injury / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000276:immunology*
D007375:Interleukin-1; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D009195:Peroxidase