Carbon Monoxide Induces Cytoprotection in Rat Orthotopic Lung Transplantation via Anti-Inflammatory and Anti-Apoptotic Effects

Abstract

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.

Inhaled Carbon Monoxide Confers Antiinflammatory Effects against Ventilator-induced Lung Injury

“…Our laboratory and others have shown that HO-1 induction in response to cellular and tissue stress, in vitro or in vivo, is not only a reliable marker of cellular injury but also a physiologic response to defend against the inciting stress or cellular insult. Recently, our laboratory has provided evidence that CO, a major by-product of heme catalysis by HO-1, mediates the protective effect of HO-1 (15)(16)(17)(18)(19). Thus, in view of our observation that HO-1 was markedly increased in VILI, we sought to assess whether CO could be responsible in mitigating VILI.…”

“…One mechanism by which HO-1 or CO mediate a cytoprotective effect is via its potent antiinflammatory properties (13,14). Our laboratory has recently demonstrated that exogenous administration of low concentration of inhaled CO can markedly decrease lung inflammation and confer potent cytoprotection in various tissue injury models (15)(16)(17)(18)(19).…”

“…Western blot analysis was performed as previously described for HO-1 and p38 MAPK phosphorylation (18). Total cellular RNA was extracted from lung tissue and Northern blot analysis was performed for HO-1 gene expression as previously described (17).…”

“…One mechanism by which HO-1 or CO mediate a cytoprotective effect is via its potent antiinflammatory properties (13,14). Our laboratory has recently demonstrated that exogenous administration of low concentration of inhaled CO can markedly decrease lung inflammation and confer potent cytoprotection in various tissue injury models (15)(16)(17)(18)(19).The primary goal of the present study was to test the hypothesis that inhaled CO can confer protective effects in an animal model of VILI. We used intravenous LPS injection and/or a relatively injurious ventilator setting to induce lung inflammation, in ventilated animals in the presence or absence of inhaled CO. A protective effect of CO was observed.…”

“…In addition, the previously diseased or injured lungs are more susceptible to subsequent mechanical ventilation, releasing more proinflammatory cytokines than healthy lungs, perhaps reflecting the cumulative effects of multiple injuries (8, 9). Lipopolysaccharide (LPS), acid aspiration, and cecal ligation/perforation-induced sepsis are commonly used models for approximating previous lung injury in .Accumulating data exist in the literature supporting the paradigm that the stress-inducible heme oxygenase-1 (HO-1), or its catalytic by-product, carbon monoxide (CO), can confer potent cytoprotective effects in various models of tissue and cellular injury (13)(14)(15)(16)(17)(18)(19). One mechanism by which HO-1 or CO mediate a cytoprotective effect is via its potent antiinflammatory properties (13,14).…”