The mechanism of chronic lung inflammation leading to lung fibrosis is unknown, and does not have a characteristic inflammatory macrophage phenotype. This study was undertaken to determine if a change in macrophage phenotype could account for chronic lung inflammation. In this study, human alveolar macrophages (AM) from subjects with systemic sclerosis (SSc) were obtained from bronchoalveolar lavage (BAL) and characterized on the basis of function (response to lipopolysaccharide (LPS)), phenotype, and relative cell-surface B7 expression. AM from the subjects' disease-involved and non-involved lung lobes were compared to each other and to AM from normal volunteer BAL. AM from involved SSc lobes produced significantly more IL-1 and PGE₂ than AM from uninvolved lobes in response to LPS, but there was no spontaneous production of either mediator. The activator AM phenotype designated by RFD1+ surface epitope was significantly elevated in SSc BAL samples compared to normal BAL, although there were no differences comparing involved vs. non-involved lobes within SSc subjects. The MHC-II co-stimulatory molecule B7.2 was also significantly elevated in SSc AM compared to normal AM, again with no differences between involved and non-involved lobes. In an attempt to determine environmental influences on AM phenotypes, normal AM were cultured in vitro with interferon gamma (IFN), interleukin-3 (IL-3), interleukin- 4 (IL-4), interleukin-10 (IL-10), interleukin-12 (IL-12), or dexamethasone (DEX) for six days. Of the cytokines examined, only IL-4 induced significant increases in both the activator phenotype RFD1+ and B7.2 expression. Taken together, these results indicate that IL-4 could account for pro-inflammatory AM phenotype changes and B7 surfacemarker shifts as seen in subjects with SSc.