REGULATION OF ALVEOLAR MACROPHAGE TRANSFORMING GROWTH-FACTOR-BETA SECRETION BY CORTICOSTEROIDS IN BLEOMYCIN-INDUCED PULMONARY INFLAMMATION IN THE RAT

In a model of pulmonary inflammation and fibrosis induced by the antin eoplastic antibiotic, bleomycin, we previously demonstrated that TGF-b eta was markedly elevated within 7 d of bleomycin administration. At t he time of maximal TGF-beta production, TGF-beta1 was localized by imm unohistochemistry to be present almost exclusively in alveolar macroph ages. In this study, we have demonstrated that alveolar macrophages st imulated by bleomycin-induced injury secrete large quantities of biolo gically active TGF-beta1 when explanted into tissue culture. However, alveolar macrophages from normal saline-treated rats secrete small qua ntities of biologically inactive TGF-beta. In contrast, splenic macrop hages secrete large quantities of inactive TGF-beta and are unaffected by the intratracheal bleomycin treatment. High doses of the corticost eroid methylprednisolone given intramuscularly before and concomitantl y with bleomycin administration prevented the influx of alveolar macro phages into the lungs, diminishing both the number of macrophages pres ent in the alveoli and the total lung content of TGF-beta. However, th e rate of secretion of TGF-beta by alveolar macrophages recovered from the alveoli was unchanged after corticosteroid treatment. When activa ted alveolar macrophages were cultured in the presence of several conc entrations of dexamethasone that completely suppressed IL-1 secretion, little effect on TGF-secretion was observed. The findings in this stu dy demonstrate that during bleomycin-induced injury, alveolar macropha ges not only secrete large quantities of active TGF-beta1, but are a p redominant source of the enhanced TGF-beta response seen in this model . Furthermore, the alveolar macrophage secretion of TGF-beta is not in hibited by the presence of high concentrations of corticosteroids.