The mitigating effect of exogenous carbon monoxide on chronic allograft rejection and fibrosis post-lung transplantation

BACKGROUND: Small airway inflammation and fibrosis or bronchiolitis obliterans (BO) is the predomi-nant presentation of chronic lung allograft dysfunction (CLAD) post-lung transplantation. Carbon mon-oxide (CO) is a critical endogenous signaling transducer with known anti-inflammatory and anti -fibrotic effects but its therapeutic potential in CLAD remains to be fully elucidated. METHODS: Here we investigate the effect of inhaled CO in modulating chronic lung allograft rejection pathology in a murine orthotopic lung transplant model of BO (B6D2F1/J!DBA/2J). Additionally, the effects of CO on the activated phenotype of mesenchymal cells isolated from human lung transplant recipients with CLAD were studied. RESULTS: Murine lung allografts treated with CO (250 ppm pound 30 minutes twice daily from days 7 to 40 post -transplantation) demonstrated decreased immune cell infiltration, fibrosis, and airway obliteration by flow cytom-etry, trichrome staining, and morphometric analysis, respectively. Decreased total collagen, with levels compara-ble to isografts, was noted in CO-treated allografts by quantitative hydroxyproline assay. In vitro, CO (250 ppm pound 16h) was effective in reversing the fibrotic phenotype of human CLAD mesenchymal cells with decreased collagen I and b-catenin expression as well as an inhibitory effect on ERK1/2 MAPK, and mTORC1/ 2 signaling. Sildenafil, a phosphodiesterase 5 inhibitor, partially mimicked the effects of CO on CLAD mesen-chymal cells and was partially effective in decreasing collagen deposition in murine allografts, suggesting the contribution of cGMP-dependent and-independent mechanisms in mediating the effect of CO. CONCLUSION: These results suggest a potential role for CO in alleviating allograft fibrosis and mitigat-ing chronic rejection pathology post-lung transplant. J Heart Lung Transplant 2023;42:317-326 (c) 2022 International Society for Heart and Lung Transplantation. All rights reserved.