FK506 combined with GM6001 prevents tracheal obliteration in a mouse model of heterotopic tracheal transplantation

Yiqian Li; Ping Shu; Liang Tang; Xiaojun Yang; Junwei Fan; Xiaoqing Zhang

doi:10.1016/j.trim.2019.101244

FK506 combined with GM6001 prevents tracheal obliteration in a mouse model of heterotopic tracheal transplantation

Transpl Immunol. 2019 Dec:57:101244. doi: 10.1016/j.trim.2019.101244. Epub 2019 Sep 14.

Authors

Yiqian Li¹, Ping Shu¹, Liang Tang², Xiaojun Yang², Junwei Fan³, Xiaoqing Zhang⁴

Affiliations

¹ Department of pharmacy, Shanghai Pulmonary Hospital, Tongji University, Shanghai, China.
² Department of central Laboratory, Shanghai Pulmonary Hospital, Tongji University, Shanghai, China.
³ Department of general Surgery, Shanghai General Hospital Affiliated to Shanghai Jiao Tong University, Shanghai, China. Electronic address: [email protected].
⁴ Department of pharmacy, Shanghai Pulmonary Hospital, Tongji University, Shanghai, China; The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, China; Shanghai Municipal Key Clinical Specialty, Shanghai, China. Electronic address: [email protected].

PMID: 31526865
DOI: 10.1016/j.trim.2019.101244

Abstract

Background: Obliterative bronchiolitis (OB) is the major complication limiting the long-term survival of allografts after lung transplantation. In this study, we investigated the effect of tacrolimus (FK506) combined with GM6001，a matrix metalloproteinase (MMP) inhibitor， on the formation of OB using a mouse heterotopic tracheal transplantation model.

Methods: Syngeneic tracheal grafts were transplanted heterotopically from BALB/c mice to BALB/c mice. Allografts from C57BL/6 mice were transplanted to BALB/c mice. Isograft group, allograft group, allograft+FK506 group, allograft +GM6001 group and allograft+FK506 + GM6001 group was given respectively intraperitoneal injection of saline, saline, FK506, GM6001 and FK506 + GM6001 once a day. At 28 day after transplantation, OB incidence was determined by hematoxylin-eosin staining and the expressions of MMPs and cytokines were assessed using enzyme linked immunosorbent assay, immunohistochemical assays and western blot assay.

Results: The tracheal occlusion rates of isograft group, allograft group, allograft+FK506 group, allograft+GM6001 group and allograft+FK506 + GM6001 group were 0, 74.1 ± 9.79%, 34.4 ± 6.04%, 40.3 ± 8.77% and 26.5 ± 5.73% respectively. There were significant differences between the latter two groups (P < .001). The serum MMP-8 and MMP-9 levels of allograft group were significantly higher than those of isograft group (P < .05) and had no significant decrease when treated by FK506. The serum MMP-8 and MMP-9 levels of allograft+FK506 + GM6001 group were significantly lower than those of allograft+FK506 group (P < .05). MMP-8 and MMP-9 protein expression in the grafts of allograft+FK506 + GM6001 group were lower than those of allograft+FK506 group verified by immunohistochemical staining and western blotting.

Conclusion: FK506 combined with GM6001 could alleviate tracheal obliteration in mouse heterotopic tracheal transplantation model, due to its inhibitory effect on MMPs.

Keywords: Bronchiolitis obliterans; MMP-8; MMP-9; Matrix metalloproteinase inhibitor; Mouse heterotopic tracheal transplantation model.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Airway Obstruction / prevention & control*
Animals
Bronchiolitis Obliterans / etiology
Bronchiolitis Obliterans / prevention & control*
Dipeptides / therapeutic use*
Disease Models, Animal
Drug Therapy, Combination
Graft Survival
Humans
Lung Transplantation*
Male
Matrix Metalloproteinase 8 / metabolism
Matrix Metalloproteinase 9 / metabolism
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Postoperative Complications / prevention & control*
Tacrolimus / therapeutic use*
Trachea / pathology*
Trachea / transplantation
Transplantation, Heterotopic
Transplantation, Homologous

Substances

Dipeptides
N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide
Matrix Metalloproteinase 8
Matrix Metalloproteinase 9
Tacrolimus