Carbon Monoxide Protects Rat Lung Transplants From Ischemia‐Reperfusion Injury via a Mechanism Involving p38 MAPK Pathway

Abstract

Carbon monoxide (CO) provides protection against oxidative stress via anti-inflammatory and cytoprotective actions. In this study, we tested the hypothesis that a low concentration of exogenous (inhaled) CO would protect transplanted lung grafts from cold ischemia-reperfusion injury via a mechanism involving the mitogen-activated protein kinase (MAPK) signaling pathway. Lewis rats underwent orthotopic syngeneic or allogeneic left lung transplantation with 6 h of cold static preservation. Exposure of donors and recipients (1 h before and then continuously post-transplant) to 250 ppm CO resulted in significant improvement in gas exchange, reduced leukocyte sequestration, preservation of parenchymal and endothelial cell ultrastructure and reduced inflammation compared to animals exposed to air. The beneficial effects of CO were associated with p38 MAPK phosphorylation and were significantly prevented by treatment with a p38 MAPK inhibitor, suggesting that CO's efficacy is at least partially mediated by activation of p38 MAPK. Furthermore, CO markedly suppressed inflammatory events in the contralateral naïve lung. This study demonstrates that perioperative exposure of donors and recipients to CO at a low concentration can impart potent anti-inflammatory and cytoprotective effects in a clinically relevant model of lung transplantation and support further evaluation for potential clinical use.

Inhaled Hydrogen Gas Therapy for Prevention of Lung Transplant-Induced Ischemia/Reperfusion Injury in Rats

“…We evaluated the effects of therapeutic gas on proinflammatory cytokine expression during lung cold I/R injury by real-time reverse transcriptase polymerase chain reaction (RT-PCR) using frozen lung graft tissues taken 2 hr after reperfusion. This time point was determined based on our previous study, which demonstrated that maximal inflammatory mediator expression occurred 2 hr after reperfusion (13). The mRNAs for ICAM-1, TNF-␣, IL-1␤, and IL-6 were significantly upregulated compared with sham-operated animals when the recipients were ventilated with 2% N 2 or 2% He.…”

“…The macrophages were stained by immunohistochemistry for ED1, as described previously (13,46). Positively stained cells were counted in a blinded fashion in 20 high-power fields (HPFs) per each section and expressed as the number of cells per HPF.…”

“…Orthotopic left lung transplantation was performed (syngenic: LEW to LEW) using a cuff technique as described previously (13,(41)(42)(43). Briefly, donor rats (nϭ42) underwent tracheotomy and were mechanically ventilated with 100% O 2 and isoflurane (Aerrane; Baxter, Deerfield, IL).…”

CO metabolism, sensing, and signaling

“…The antiinflammatory activity of CO has been shown to involve the downregulation of pro-inflammatory cytokines, such as tumor necrosis factor-a (TNFa), IL-1b, and IL-6 together with the increase of the anti-inflammatory cytokine IL-10, via the p38 MAPK and c-Jun N-terminal kinase (JNK)-MAPK pathways [99,100]. In particular, the p38 MAPK signaling pathway has also been implicated in the antiapoptotic and antiproliferative effects of CO [18,20,97,99,[101][102][103] (Fig. 1).…”

Neonatal and Pediatric Respiratory Care: What Does the Future Hold?

“…Models of ventilator-induced lung injury, aspiration, hyperoxia, and ischemia/reperfusion injury found that inhaled CO benefited several pulmonary disorders. [46][47][48][49][50] Over the past few years, the role of H 2 S as a physiologic messenger has become a focus of scientific investigation. Although the preclinical data describing H 2 S-induced "suspended animation" are promising, extensive further investigation is required prior to any clinical application for the management of shock and other critical illnesses.…”