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

Autor:	Aoki Y; Divisions of Pulmonary and Critical Care Medicine, University of Michigan Health System, Ann Arbor, Michigan., Walker NM; Divisions of Pulmonary and Critical Care Medicine, University of Michigan Health System, Ann Arbor, Michigan., Misumi K; Divisions of Pulmonary and Critical Care Medicine, University of Michigan Health System, Ann Arbor, Michigan., Mimura T; Divisions of Pulmonary and Critical Care Medicine, University of Michigan Health System, Ann Arbor, Michigan., Vittal R; Divisions of Pulmonary and Critical Care Medicine, University of Michigan Health System, Ann Arbor, Michigan., McLinden AP; Divisions of Pulmonary and Critical Care Medicine, University of Michigan Health System, Ann Arbor, Michigan., Fitzgerald L; Department of Pharmacy Services, University of Michigan Health System, Ann Arbor, Michigan., Combs MP; Divisions of Pulmonary and Critical Care Medicine, University of Michigan Health System, Ann Arbor, Michigan., Lyu D; Divisions of Pulmonary and Critical Care Medicine, University of Michigan Health System, Ann Arbor, Michigan., Osterholzer JJ; Divisions of Pulmonary and Critical Care Medicine, University of Michigan Health System, Ann Arbor, Michigan; Pulmonary Section, VA Ann Arbor Health System, Ann Arbor, Michigan., Pinsky DJ; Cardiology, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan., Lama VN; Divisions of Pulmonary and Critical Care Medicine, University of Michigan Health System, Ann Arbor, Michigan. Electronic address: vlama@umich.edu.
Jazyk:	angličtina
Zdroj:	The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation [J Heart Lung Transplant] 2023 Mar; Vol. 42 (3), pp. 317-326. Date of Electronic Publication: 2022 Nov 26.
DOI:	10.1016/j.healun.2022.11.005
Abstrakt:	Background: Small airway inflammation and fibrosis or bronchiolitis obliterans (BO) is the predominant presentation of chronic lung allograft dysfunction (CLAD) post-lung transplantation. Carbon monoxide (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 × 30 minutes twice daily from days 7 to 40 post-transplantation) demonstrated decreased immune cell infiltration, fibrosis, and airway obliteration by flow cytometry, trichrome staining, and morphometric analysis, respectively. Decreased total collagen, with levels comparable to isografts, was noted in CO-treated allografts by quantitative hydroxyproline assay. In vitro, CO (250 ppm × 16h) was effective in reversing the fibrotic phenotype of human CLAD mesenchymal cells with decreased collagen I and β-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 mesenchymal 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 mitigating chronic rejection pathology post-lung transplant. (Copyright © 2022 International Society for Heart and Lung Transplantation. All rights reserved.)
Databáze:	MEDLINE
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