Cale, Alexander R.

Circulating leukocytes activated during rejection of organ allografts could potentially have generalized effects on systemic blood vessels of the transplant recipient. Experiments were designed, therefore, to determine the function of the endothelium and smooth muscle of arteries from nontransplanted organs in dogs who received single lung transplants. Dogs underwent single lung allotransplantation and were immunosuppressed for 5 days. Immunosuppression was then withheld for 3 days, allowing rejection to occur. Dogs were studied at this time (rejecting) or following treatment for rejection for an additional 6-8 days (treated). Arteries from unoperated, untreated dogs also were studied to provide baseline responses of healthy tissue. Rings cut from left circumflex coronary, nonoperated native pulmonary, and renal arteries were suspended in organ chambers for measurement of isometric force. Endothelium-dependent relaxations to the calcium ionophore A23187 were not affected by rejection in any of the arteries. Contractions to angiotensin I were reduced significantly only in native pulmonary arteries. Contractions to KCI and endothelin-1 increased in renal arteries with endothelium during rejection. These contractions in renal arteries were reduced following treatment of rejection. None of the responses of the coronary arteries were affected significantly by rejection of the lung allograft. These results demonstrate that contractions of arteries in the transplant recipient's native organs are altered during rejection of lung allografts. The effects are organ specific, may include production of endothelium-derived contractile factors in renal arteries, and can be partially reversed by treatment of rejection.

PURPOSE Experiments were designed to determine whether or not leukocytes activated by acute pulmonary rejection cause contractions of isolated pulmonary arteries. METHODS AND RESULTS Separate suspensions of (a) polymorphonuclear cells (> 95%) and (b) mononuclear cells (85% lymphocytes/10% monocytes/5% polymorphonuclear cells), respectively, were obtained from the arterial blood of four groups of adult male mongrel dogs: unoperated dogs (controls), dogs with single-lung autotransplants, dogs with rejecting single-lung allotransplants, and unoperated dogs treated with the same immunosuppressants as allotransplanted dogs. These suspensions were added to rings of control intralobar pulmonary arteries suspended in organ chambers for measurement of isometric force. The endothelium was removed mechanically from selected rings. No significant change in basal tension of pulmonary arterial rings occurred by adding suspensions of polymorphonuclear cells from any of the four groups of dogs. Significant cell-number-dependent increases in tension occurred with suspensions of mononuclear cells from unoperated dogs, autotransplanted dogs, and unoperated, medicated dogs. These increases in tension were less in rings with compared to those without endothelium. Addition of a synthetic analogue of L-arginine abolished this difference. Suspensions of mononuclear cells from rejecting allotransplanted dogs caused significantly greater contractions in rings with endothelium than those observed with suspended cells from either unoperated, autotransplanted dogs or unoperated, medicated dogs. Addition of superoxide dismutase plus catalase or an antagonist of endothelin-A receptors (BQ-123) reduced contractions in rings with endothelium but not in those without endothelium to suspensions of mononuclear cells from rejecting allotransplanted dogs. CONCLUSIONS The results of this study suggest that mononuclear cells cause contraction of pulmonary arteries, which can be partially inhibited by endothelium-derived nitric oxide. However, if the mononuclear cells are activated by acute pulmonary rejection, contractions are no longer inhibited by the endothelium. Under conditions of rejection, contractions are mediated in part by oxygen radicals and endothelin(s).