Changes at the extracellular matrix during acute and chronic rejection in human liver transplantation

We have previously observed changes at the extracellular matrix (ECM) which significantly correlated with the extent of preservation and reperfusion injury. In the present study, we attempted to investigate whether the ECM may be also involved in the pathophysiological sequelae of acute and chronic rejection. Of 81 patients monitored for the ECM parameters laminin, hyaluronic acid, fibronectin receptor, and transforming growth factor (TGF)-beta, 28 patients developed acute rejection (< 1 month), in 14 patients (17.4%) acute rejection was steroid resistant, 4 patients (4.5%) developed early chronic rejection following acute steroid-resistant rejection. Acute and chronic rejection were confirmed by established clinical and histological criteria. Laminin levels were significantly increased in patients experiencing acute steroid-resistant rejection (4204 +/- 133 ng/ml; P < or = 0.01) compared with patients with steroid-sensitive rejection (1059 +/- 27.3 ng/ ml) and with an uneventful postoperative course (1214 +/- 17.4 ng/ml). No increase in laminin was observed in those four patients who developed early chronic rejection (1099 +/- 58.7 ng/ml). Hyaluronic acid, fibronectin receptor, and TGF-beta levels also increased in patients with acute steroid-resistant rejection; hyaluronic acid: 290 +/- 10.8 micrograms/l vs 154 +/- 13.6 micrograms/l and 131 +/- 11.7 micrograms/l in patients with steroid-sensitive and no rejection, respectively; fibronectin receptor: 1003 +/- 23.5 ng/ml vs 573 +/- 24.8 ng/ml and 428 +/- 13.6 ng/ ml in patients with steroid-sensitive and no rejection, respectively; and TGF-beta: 393 +/- 14.9 pg/ml versus 315 +/- 10.7 pg/ml and 233 +/- 8.9 pg/ml in patients with steroid-sensitive and no rejection, respectively. A further increase in hyaluronic acid levels was observed in patients who developed early chronic rejection, while fibronectin receptor and TGF-beta levels remained low, similarly to laminin levels. The increase in laminin, hyaluronic acid, fibronectin receptor, and TGF-beta during acute steroid-resistant rejection may be stimulated by the rejection-related release of cytokines and adhesion molecules which paralleled the increase in ECM parameters. The lack of increase in laminin and fibronectin receptor levels in those patients who developed early chronic rejection may reflect an inability to recover from acute rejection.