ENDOTHELIN-1 AND CELL-PROLIFERATION IN LUNG ORGAN-CULTURES - IMPLICATIONS FOR LUNG ALLOGRAFTS

Endothelin-1 (ET-1) is found in bronchoalveolar lavage fluid in patien ts following lung transplantation. ET-1 causes contraction of isolated pulmonary vessels and bronchi and stimulates proliferation of smooth muscle cells in culture. Therefore, ET-1 could contribute to the smoot h muscle hyperplasia and stromal proliferation seen in chronic rejecti on of lung allografts. Experiments were designed to determine whether (1) ET-1 stimulates proliferation of pulmonary tissue, (2) proliferati on is increased in rejecting allotransplanted lungs, (3) endothelin-A receptors mediate the proliferative response, and (4) ET-1 is produced by activated infiltrating immunocompetent cells. Lung organ cultures were prepared from unoperated dogs and dogs with rejecting single lung allografts. Incubation of organ cultures from unoperated dogs with ET -1 (10(-9) to 10(-7) M) increased positive staining for proliferation cell nuclear antigen (PCNA) in lung parenchyma. PCNA staining was not decreased by the endothelin-A antagonist BQ123 (10(-6) M). In addition , immunostaining for endothelin-B receptors was present in sections of unoperated but not rejecting lungs. PCNA staining in lung cultures fr om rejecting allotransplanted dogs was significantly greater than that from unoperated dogs. Positive immunohistochemical staining for ET-1 was found in mononuclear cells infiltrating rejecting transplanted lun gs. In conclusion, exogenous ET-1 is mitogenic in lung organ cultures through receptors other than endothelin-A. Proliferation in rejecting transplanted lungs is increased compared with unoperated lungs. Mononu clear cells may be a source of endothelin-1 in the rejecting lung. ET- 1, therefore could, in synergism with other cytokines, contribute to a cute and chronic pathological changes seen in pulmonary rejection.