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DIFFERENTIAL EXPRESSION OF TRANSFORMING GROWTH FACTOR-β TYPE I AND II RECEPTORS BY PULMONARY CELLS IN BLEOMYCIN-INDUCED LUNG INJURY: CORRELATION WITH REPAIR AND FIBROSIS

In a rat model of lung injury induced bythe antineoplastic antibiotic, bleomycin, there is loss of type I alveolar epithelial cells (AECs) followed by infiltration of activated inflammatory cells, type II AEC proliferation, and fibrosis. At 4 and 7 days after bleomycin administration alveolar macrophages have increased production and release of active transforming growth factor (TGF)- β 1, an inhibitor of epithelial cell proliferation. Paradoxically at these same time intervals there is a concomitant induction of type II AEC proliferation. For TGF- β -mediated signal transduction to occur, the expression of both TGF- β receptor types I (T β R-I) and II (T β R-II) must be present. Using immunohistochemistry and in situ hybridization, 4 and 7 days after bleomycin administration the expression of T β R-I on AECs was reduced whereas that of T β R-II was unaltered. However, 14 and 28 days after bleomycin injury, when there is decreased proliferation and induction of differentiation of type II AECs, there was a return of T β R-I expression on AECs. In contrast, T β R-I and T β R-II were observed on interstitial fibroblasts at all time intervals after bleomycin administration. Because both T β R-I and T β R-II are required for signal transduction, the reduction of T β R-I levels on the alveolar epithelium may alter the sensitivity of AECs to the antiproliferative effects of TGF- β 1 present in increased quantities following bleomycin injury. The loss of an antiproliferative response to TGF- β 1 may be important for the regeneration of the alveolar epithelium by proliferation while the expression of both receptors on fibroblasts would result in TGF- β 1 signaling for the synthesis of connective tissue proteins. Our findings suggest that during bleomycin-induced pulmonary fibrosis, the effects of TGF- β 1 on cells may be regulated by the expression of T β Rs.