Clarithromycin attenuates acute and chronic rejection via matrix metalloproteinase suppression in murine cardiac transplantation.
OBJECTIVE
Clarithromycin (CAM), a major macrolide antibiotic, has many biological functions, including matrix metalloproteinases (MMPs) regulation. However, little is known about the effect of CAM in heart transplantation via MMP-9. The purpose of this study was to clarify the role of MMPs regulated by CAM in the progression of rejection.


BACKGROUND
The MMPs are critical in the development of inflammation and tissue remodeling. The MMP-9 level is associated with the rejection of heart transplantation.


METHODS
We orally administered CAM into murine cardiac allograft recipients. Total allomismatch combination and class II mismatch combination were used for the analysis of graft survival, pathology and molecular.


RESULTS
Clarithromycin improved acute rejection judged by graft survival and by myocardial cell infiltrating area in a total allomismatch combination. The CAM-treated allografts showed affected expression of T-cells, macrophages, and MMP-9 in immunohistochemistry. Zymography indicated that enhanced MMPs activities were observed in nontreated hearts, whereas CAM suppressed the levels. In chronic rejection, CAM suppressed the development of graft arterial disease and myocardial remodeling compared with that of nontreatment. Clarithromycin inhibited the expression of MMP-9, whereas the treatment did not alter the expression of MMP-2 and tissue inhibitor metalloproteinase-1 in macrophages and smooth muscle cells. Inhibition of MMP-9 by CAM was associated with suppression of smooth muscle cell migration and proliferation.


CONCLUSIONS
Clarithromycin is useful to suppress allograft remodeling, because it is critically involved in the prevention of cardiac rejection through the suppression of MMP-9.
Ogawa
Masahito
M
Department of Cardiovascular Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
Suzuki
Jun-ichi
J
Hishikari
Keiichi
K
Takayama
Kiyoshi
K
Tanaka
Hiroyuki
H
Isobe
Mitsuaki
M
D000208:Acute Disease; D000818:Animals; D002908:Chronic Disease; D017291:Clarithromycin / Q000494:pharmacology*; D015870:Gene Expression; D006084:Graft Rejection / Q000188:drug therapy*; D016027:Heart Transplantation; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D032389:Myocytes, Smooth Muscle / Q000187:drug effects; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology*
D011500:Protein Synthesis Inhibitors; D020780:Matrix Metalloproteinase 9; D017291:Clarithromycin