A Role For Lung-Specific Tight Junction Protein Claudin-18 In Alveolar Epithelial Barrier Function

LaFemina, Michael J.; Bentley, Trevor; Sutherland, Katherine; Rokkam, Deepti; Allen, Lennell; Dobbs, Leland G.; Frank, James A.

doi:10.1164/ajrccm-conference.2012.185.1_meetingabstracts.a6740

Cited by 1 publication

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“…Claudin-4 has been shown to play a key role in preventing pulmonary edema by promoting lung fluid clearance. 25,28,46 Thus, the delay in claudin-4 exhibited by JAM-A À/À mice was likely to contribute to enhanced lung edema observed in JAM-A knockout mice. Previously published studies show that increased claudin-4 expression promotes lung barrier function and fluid clearance.…”

Section: Discussionmentioning

confidence: 99%

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Junctional Adhesion Molecule A Promotes Epithelial Tight Junction Assembly to Augment Lung Barrier Function

Mitchell¹,

Ward²,

Kwon³

et al. 2015

The American Journal of Pathology

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Epithelial barrier function is maintained by tight junction proteins that control paracellular 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, loss 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 β1 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 up-regulation 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 role 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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Section: Discussionmentioning

confidence: 99%

“…In wild-type and JAM-A À/À mice, claudin-4 expression returned to baseline 48 hours after injury. Given the critical role of claudin-4 in promoting lung fluid clearance, 25,28,46 this observed delay in up-regulation of claudin-4 by JAM-A À/À mice has clinical significance. Claudin-18 protein levels were also affected by i.p.…”

Section: Q14mentioning

confidence: 97%