Epithelial barrier function is maintained by tight junction proteins that control paraceltular fluid flux. Among these proteins is junctional adhesion molecule A (JAM-A), an Ig fold transmembrane protein. To assess JAM-A function in the Lung, we depleted JAM-A in primary alveolar epithelial cells using shRNA. In cultured cells, toss of JAM-A caused an approximately 30% decrease in transepithelial resistance, decreased expression of the tight junction scaffold protein zonula occludens 1, and disrupted junctional localization of the structural transmembrane protein claudin-18. Consistent with findings in other organs, Loss of JAM-A decreased beta 1 integrin expression and impaired filamentous actin formation. Using a model of mild systemic endoxotemia induced by i.p. injection of lipopolysaccharide, we report that JAM-A(-/-) mice showed increased susceptibility to pulmonary edema. On injury, the enhanced susceptibility of JAM-A(-/-) mice to edema correlated with increased, transient disruption of claudin-18, zonula occLudens 1, and zonula occludens 2 localization to Lung tight junctions in situ along with a delay in upregulation of claudin-4. In contrast, wild-type mice showed no change in lung tight junction morphologic features in response to mild systemic endotoxemia. These findings support a key rote of JAM-A in promoting tight junction homeostasis and Lung barrier function by coordinating interactions among claudins, the tight junction scaffold, and the cytoskeleton.
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