In the present study, we used tumor necrosis factor-R1 knock out mice (TNF-alpha R1KO) to understand the roles of TNF-alpha on epithelial function in models of carrageenan-induced acute lung inflammation. In order to elucidate whether the observed anti-inflammatory status is related to the inhibition of TNF-alpha, we also investigated the effect of etanercept, a TNF-alpha soluble receptor construct, on lung TJ function. Pharmacological and genetic TNF-alpha inhibition significantly reduced the degree of (1) TNF-alpha production in pleural exudates and in the lung tissues, (2) the inflammatory cell infiltration in the pleural cavity as well as in the lung tissues (evaluated by MPO activity), (3) the alteration of ZO-1, Claudin-2, Claudin-4, Claudin-5 and beta-catenin (immunohistochemistry) and (4) apoptosis (TUNEL staining, Bax, Bcl-2 expression). Taken together, our results demonstrate that inhibition of TNF-alpha reduces the tight junction permeability in the lung tissues associated with acute lung inflammation, suggesting a possible role of TNF-alpha on lung barrier dysfunction.