Carbon monoxide induces cytoprotection in rat orthotopic lung transplantation via anti-inflammatory and anti-apoptotic effects.
Successful lung transplantation has been limited by the high incidence of acute graft rejection. There is mounting evidence that the stress response gene heme oxygenase-1 (HO-1) and/or its catalytic by-product carbon monoxide (CO) confers cytoprotection against tissue and cellular injury. This led us to hypothesize that CO may protect against lung transplant rejection via its anti-inflammatory and antiapoptotic effects. Orthotopic left lung transplantation was performed in Lewis rat recipients from Brown-Norway rat donors. HO-1 mRNA and protein expression were markedly induced in transplanted rat lungs compared to sham-operated control lungs. Transplanted lungs developed severe intraalveolar hemorrhage, marked infiltration of inflammatory cells, and intravascular coagulation. However, in the presence of CO exposure (500 ppm), the gross anatomy and histology of transplanted lungs showed marked preservation. Furthermore, transplanted lungs displayed increased apoptotic cell death compared with the transplanted lungs of CO-exposed recipients, as assessed by TUNEL and caspase-3 immunostaining. CO exposure inhibited the induction of IL-6 mRNA and protein expression in lung and serum, respectively. Gene array analysis revealed that CO also down-regulated other proinflammatory genes, including MIP-1alpha and MIF, and growth factors such as platelet-derived growth factor, which were up-regulated by transplantation. These data suggest that the anti-inflammatory and antiapoptotic properties of CO confer potent cytoprotection in a rat model of lung transplantation.
Song
Ruiping
R
Division of Pulmonary, Allergy and Critical Care Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.
Kubo
Masatoshi
M
Morse
Danielle
D
Zhou
Zhihong
Z
Zhang
Xuchen
X
Dauber
James H
JH
Fabisiak
James
J
Alber
Sean M
SM
Watkins
Simon C
SC
Zuckerbraun
Brian S
BS
Otterbein
Leo E
LE
Ning
Wen
W
Oury
Tim D
TD
Lee
Patty J
PJ
McCurry
Kenneth R
KR
Choi
Augustine M K
AM
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000378:metabolism*; D017209:Apoptosis / Q000502:physiology*; D002248:Carbon Monoxide / Q000378:metabolism*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D019610:Cytoprotection; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D020869:Gene Expression Profiling; D006084:Graft Rejection; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics / Q000378:metabolism; D051547:Heme Oxygenase-1; D006801:Humans; D020287:In Situ Nick-End Labeling; D015850:Interleukin-6 / Q000378:metabolism; D008168:Lung / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D016040:Lung Transplantation; D008297:Male; D008565:Membrane Proteins; D020411:Oligonucleotide Array Sequence Analysis; D009195:Peroxidase / Q000378:metabolism; D051381:Rats
D000893:Anti-Inflammatory Agents; D015850:Interleukin-6; D008565:Membrane Proteins; D002248:Carbon Monoxide; D009195:Peroxidase; C496541:HMOX1 protein, human; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C505407:CASP3 protein, human; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases