The effect of anti-inflammatory properties of mycophenolate mofetil on the development of lung reperfusion injury.
BACKGROUND
Lung ischemia-reperfusion injury (LIRI) is associated with an increased incidence of both primary graft failure and obliterative bronchiolitis. The immunosuppressant mycophenolate mofetil (MMF) has recently been shown to attenuate inflammatory injury in acute ischemia-reperfusion models via a mechanism that is presently unclear. These experiments studied the effects of MMF in a warm, in situ LIRI model, focusing on transcriptional regulation of pro-inflammatory mediators.


METHODS
Left lungs of rats were rendered ischemic for 90 minutes and reperfused for up to 4 hours. Treated animals received 10 mg/kg of intravenous MMF at 2 hours before ischemia. Left lung injury was quantitated by myeloperoxidase (MPO) content, permeability indices and bronchoalveolar lavage (BAL) inflammatory cell counts. Lungs were analyzed by electrophoretic mobility shift assay (EMSA) for transcription factor transactivation and by enzyme-linked immunoassay for BAL chemokine protein content.


RESULTS
MMF significantly reduced lung vascular permeability indices, MPO content and alveolar leukocyte counts at 4 hours of reperfusion. There was significant attenuation of activator protein 1 (AP-1) and early growth response 1 (EGR-1) transactivation, whereas nuclear factor-kappaB (NF-kappaB) was unaffected. Reductions in bronchoalveolar lavage monocyte chemoattractant protein 1 (MCP-1) and cytokine-induced neutrophil chemoattractant (CINC) protein content were found at 4 hours of reperfusion.


CONCLUSIONS
MMF limits lung ischemia-reperfusion-induced increases in vascular permeability and inflammatory cell sequestration in lung parenchyma and alveolar spaces. The protection is mediated at the transcriptional level via an attenuation of early EGR-1 and AP-1 transactivation, which was found to be associated with reduced late MCP-1 and CINC protein secretion. The use of MMF in concert with an agent that affects NF-kappaB activation may provide even further protection against lung reperfusion injury as multiple inflammatory pathways are inhibited.
Farivar
Alexander S
AS
Division of Thoracic Surgery, Department of Surgery, University of Washington Medical Center, Seattle, Washington 98195, USA.
MacKinnon-Patterson
Brendan
B
Barnes
Andrew D
AD
Mulligan
Michael S
MS
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001989:Bronchiolitis Obliterans; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D018925:Chemokines / Q000032:analysis / Q000378:metabolism*; D024202:Electrophoretic Mobility Shift Assay; D004797:Enzyme-Linked Immunosorbent Assay; D006084:Graft Rejection; D007249:Inflammation; D008168:Lung / Q000502:physiology; D016040:Lung Transplantation; D008297:Male; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D010539:Permeability; D009195:Peroxidase / Q000032:analysis; D011183:Postoperative Complications / Q000503:physiopathology / Q000517:prevention & control*; D051381:Rats; D020318:Rats, Long-Evans; D015427:Reperfusion Injury / Q000503:physiopathology / Q000517:prevention & control*; D014157:Transcription Factors / Q000502:physiology; D014158:Transcription, Genetic / Q000187:drug effects
D000894:Anti-Inflammatory Agents, Non-Steroidal; D018925:Chemokines; D014157:Transcription Factors; D009195:Peroxidase; D009173:Mycophenolic Acid