Claudin‐5 decreases alveolar epithelial barrier function

Abstract

Chronic alcohol abuse increases lung epithelial permeability and impairs lung fluid balance. Patients with impaired alveolar fluid clearance are three times more likely to die from acute lung injury (ALI) or acute respiratory distress syndrome (ARDS). The extent of permeability between alveolar epithelial cells is carefully regulated by intercellular tight junctions. Transmembrane tight junction proteins known as claudins have distinctive distribution throughout various tissues including the lungs. Different claudins form paracellular ion channels with different permeability characteristics. We previously found that in the “alcoholic lung” several claudins, such as claudin‐7, are down regulated; however, claudin‐5 is upregulated. To test the effect of altering claudin expression on lung epithelial permeability, we transfected rat type II primary alveolar cells with different adenovirus claudin expression constructs. Barrier function of cells transfected with claudin‐4 or claudin‐7 is not significantly different than that of cells transfected with control adenovirus vector. However, cells transfected with claudin‐5 demonstrated a “leaky” phenotype. These cells showed increased paracellular flux of calcein and Texas Red Dextran and lower transepithelial electrical resistance (TER). This data suggests the increased claudin‐5 expression observed in the alcoholic lung could account for the observed increase in permeability. These findings are discussed in the context of current models, which suggest that the slow paracellular solute flux is regulated by either junction strand turnover or by pores that oscillate between open and closed conformations.