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.

Automated summary

The study reveals the therapeutic potential of carbon monoxide (CO) in alleviating chronic lung allograft rejection pathology. In both a murine model and human lung transplant recipients, inhaled CO showed reduced immune cell infiltration, fibrosis, and airway obliteration.