Graft Expression of p38 and Tumor Necrosis Factor-α in Heart Transplantation in Rats

Abstract

Objectives To investigate the expression of p38 mitogen-activated protein kinase and its relationship with myocardial apoptosis and tumor necrosis factor-α during acute cardiac allograft rejection and to study the effects of tacrolimus on the expression of the kinase. Methods Rats were divided into 3 groups: isograft (Lewis heart to Lewis rat; control group), allograft (Brown Norway heart to Lewis rat), and tacrolimus-treated allograft (Brown Norway heart to tacrolimus-treated Lewis rat). Grafts were collected 1, 3, 5, and 7 days after transplantation for determination of histopathological features, apoptosis of cardiac cells (by terminal deoxynucleotidyl transferase–mediated dUTP-biotin nick labeling), number of cells positive for both p38 and CD8 (by laser scanning confocal imaging), and expression of the kinase (by Western immunoblotting) and tumor necrosis factor-α (by reverse-transcriptase polymerase chain reaction). Results Compared with isografts from the control group, grafts from the untreated allograft group had significantly more apoptotic cells, greater expression of tumor necrosis factor-α and p38 mitogen-activated protein kinase, and more CD8-p38 double-positive cells at 5 and 7 days ( P<.05). The increases were prevented by treatment with tacrolimus. Conclusions The findings that the number of apoptotic cells, the number of CD8-p38 double-positive cells, the expression of tumor necrosis factor-α and p38 mitogen-activated protein kinase all increased during the same period in the allografts in nonimmunosuppressed recipients suggests that intragraft expression of p38 would be associated with the rejection in acute cardiac allograft rejection. Tacrolimus may alleviate rejection partly by inhibiting p38 mitogen-activated protein kinase.