Epithelial branching morphogenesis is a process by which a continuous epithelium, embedded in mesenchyme, forms tubules that extend and branch into the surrounding mesenchyme. The morphogenetic process is responsible for the architecture of many organs including the lung. Proper expression and function of extracellular matrix (ECM) molecules, such as collagens and laminins, are necessary for branching to occur normally. However, little is known about the role of epithelial cell surface molecules that mediate epithelial-matrix interactions during this process. We have studied the expression patterns of cell surface collagen and laminin integrin receptor alpha subunits, alpha 1, alpha 2, alpha 3, and alpha 6, in relation to that of collagen and laminin during lung branching morphogenesis. The alpha 1 integrin subunit was present on endothelia and smooth muscles around airways and large blood vessels. The mesenchyme expressed high levels of alpha 2 and alpha 6 but not alpha 3, whereas the epithelium expressed all three integrin subunits. In contrast to the widespread epithelial expression of alpha 3 and alpha 6, the epithelial expression of alpha 2 was restricted to branch tips. By performing in situ hybridization and immunofluorescence on serial sections, we found that alpha 2 protein expression on the epithelium correlated spatially and temporally with high level expression of collagen IV and laminin-1 mRNAs, suggesting that the alpha 2-expressing epithelial cells were in the process of producing and assembling their collagen and laminin matrices. While the expression of alpha 3 and alpha 6 on all lung epithelia suggests that these integrins may be important to lung epithelial development, the unique expression pattern of the alpha 2 subunit suggests that the alpha 2 beta 1 integrin may be important at branch tips either in the process of collagen/laminin synthesis and assembly or extension of the epithelial tubules into the mesenchyme.