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

被引：1

作者：

Aoki, Yoshiro ^{[1
,2
]}

Walker, Natalie M. ^{[1
,2
]}

Misumi, Keizo ^{[1
,2
]}

Mimura, Takeshi ^{[1
,2
]}

Vittal, Ragini ^{[1
,2
]}

McLinden, Aidan P. ^{[1
,2
]}

Fitzgerald, Linda ^{[4
]}

Combs, Michael P. ^{[1
,2
]}

Lyu, Dennis ^{[1
,2
]}

Osterholzer, John J. ^{[1
,2
,5
]}

Pinsky, David J. ^{[3
]}

Lama, Vibha N. ^{[1
,2
,6
]}

机构：

[1] Univ Michigan Hlth Syst, Div Pulm, Ann Arbor, MI USA

[2] Univ Michigan Hlth Syst, Div Crit Care Med, Ann Arbor, MI USA

[3] Univ Michigan Hlth Syst, Div Cardiol, Dept Internal Med, Ann Arbor, MI USA

[4] Univ Michigan Hlth Syst, Dept Pharm Serv, Ann Arbor, MI USA

[5] VA Ann Arbor Hlth Syst, Pulm Sect, Ann Arbor, MI USA

[6] Univ Michigan Hlth Syst, Div Pulm & Crit Care Med, Dept Internal Med, 1500 W Med Ctr Dr,3916 Taubman Ctr, Ann Arbor, MI 48109 USA

来源：

JOURNAL OF HEART AND LUNG TRANSPLANTATION | 2023年 / 42卷 / 03期

关键词：

cGMP signaling; carbon monoxide; sildenafil; lung transplant; mTOR signaling; MESENCHYMAL STEM-CELLS; BETA-CATENIN; ADULT LUNG; FIBROGENESIS; INHIBITION; EXPRESSION; PROTECTS; TARGET; DRIVEN; MODEL;

D O I：

10.1016/j.healun.2022.11.005

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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.

引用

页码：317 / 326

页数：10

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