SMOOTH-MUSCLE CELLS OF THE CORONARY ARTERIAL TUNICA MEDIA EXPRESS TUMOR-NECROSIS-FACTOR-ALPHA AND PROLIFERATE DURING ACUTE REJECTION OF RABBIT CARDIAC ALLOGRAFTS

Graft coronary arteriosclerosis (GCA) frequently limits the long-term success of cardiac transplantation The pathogenic mechanisms of and st imuli that provoke GCA remain uncertain. Whatever the initiating facto rs, deranged control of smooth muscle cell (SMC) proliferation likely contributes to the intimal hyperplasia that produces obstructive lesio ns. To identify mediators that may contribute to ongoing modulation of SMC functions during acute rejection and to explore the mechanisms of the pathogenesis of graft coronary arteriosclerosis, we studied the k inetics of proliferation and the expression of tumor necrosis factor-a lpha (TNF-alpha), a proinflammatory and SMC growth-promoting cytokine, in coronary arterial SMCs in rabbit hearts transplanted heterotopical ly without immunosuppression Hearts were harvested at 2 (n = 5), 5 (n = 5), and 8.2 +/- 0.4 (mean +/- SD, n = 5) days after transplantation, just before graft failure as judged clinically. SMC proliferation was assessed by continuous bromodeoxyuridine labeling (BrdU 10 mg/kg/d. s .q). Whole heart cross sections were stained immunohistochemically wit h monoclonal antibodies that recognize TNF-alpha, BrdU, and SMCs (musc le alpha-actin). Major epicardial coronary arteries (five to nine prof iles in each animal) were evaluated. Histological rejection grades by the International Society for Heart and Lung Transplantation scale at 2, 5, and 10 days were 1.6 +/- 0.9, 2.8 +/- 1.1, and 4.0 +/- 0.0, resp ectively. Medial SMCs in normal hearts and 2 days after transplant exp ressed little or no TNF-alpha and displayed negligible BrdU incorporat ion. At 5 days after transplantation, some medial SMCs stained for TNF -alpha and had a low BrdU labeling index (0.5 +/- 0.8%). At 8.2 days a fter transplant, almost all medial SMCs expressed TNF-alpha intensely and had a high labeling index (29.8 +/- 8.0%). These results demonstra te that acute rejection activates medial SMCs in coronary arteries to express TNF-alpha and that SMC-derived TNF-alpha may contribute to med ial SMC proliferation in coronary arteries during acute rejection. Thi s finding of early medial SMC replication suggests a novel and heretof ore unsuspected mechanism of intimal expansion consequent to the allog eneic state. These results furnish additional insight into the possibl e mechanisms that link acute rejection with graft coronary arterioscle rosis. Furthermore, the close association of TNF-alpha expression with SMC replication provides not only a novel marker of SMC activation bu t also a potential new therapeutic target for the prevention of graft coronary disease.