Interactions between cells and extracellular matrix are in large part mediated by integrins in divalent cation-dependent processes. Integrins are important for cell differentiation, proliferation, and migration during development and repair of diverse tissue types. The roles played by integrin adhesion receptors in the lung are just beginning to be investigated. It is plausible that integrins play a central role in mediating lung basement membrane influences on alveolar epithelial type II cell localization and differentiation. The current studies were carried out to determine the patterns of alveolar epithelial cell adherence and spreading on different substrata and their divalent cation and RGD requirements. We utilized a rat type II cell-derived cell line, LM5, and a human alveolar cell carcinoma cell line A549. Both cell types showed similar responses to divalent cations. Adhesion and spreading on different extracellular matrix components had different divalent cation requirements. Mn2+ enhanced adhesion and spreading on fibronectin (FN), type IV collagen, and laminin, but not on type I collagen or plastic. Mn(2+)-enhanced cell adhesion to FN was RGD-dependent and partially inhibited by an anti-alpha 5 integrin antibody. Small increases in Ca2+ concentration (0.1-0.5 mM), but not Mg2+, suppressed Mn(2+)-mediated adhesion and spreading. Thus, variations in the relative divalent cation concentrations in the vicinity of the integrin-ligand complex may modulate the receptor-acceptor interactions. These results support the view that alterations in extracellular divalent cations are important regulators of alveolar epithelial cell interactions with lung basement membrane.