Diffusion of nonelectrolytes in the canine trachea: Effect of tight junction

We recently demonstrated through theoretical modeling that the exhaled ethanol (EtOH) profile from humans is consistent with a molecular diffusion coefficient (cm(2)/s) in the bronchial mucosa (D-ti) that is only 8% of the diffusion coefficient in water (D-w; J. Appl. Physiol. 75: 2439-2449, 1993). Because of the small oil-water partition coefficient (lambda(o:w)) of EtOH (h lambda(o:w) = 0.074), the reduced diffusion coefficient may be due, in part, to the epithelial tight junction in the paracellular pathway. We hypothesized that opening the tight junction would open an aqueous pathway and increase the diffusion coefficient of small (mel wt <100) hydrophilic compounds. We mounted the mucosa from the membranous canine trachea in an Ussing-type diffusion cell and measured the diffusion coefficient of 2-ethoxyethanol (2-Ethx; lambda(o:w) = 0.042), EtOH, and methyl ethyl ketone (MEK; lambda(o:w) = 1.04) in the presence and absence of the epithelial tight junction. The tight junction was opened using a phosphate-buffered saline free Ca2+ and Mg2+ with 0.5 mM ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid, and its integrity was assessed by measuring the transepithelial electrical resistance. D-ti/D-w in the presence of Ca2+ and Mg2+ was 0.39, 0.34, and 0.39 for 2-Ethx, EtOH, and MEK, respectively, and increased 24.6, 11.7, and 1.11% in the absence of Ca2+ and Mg2+. We conclude that the effect of the tight junction on D-ti increases with increasing water solubility but can account for only a small portion of the reduced D-ti of EtOH as predicted by exhaled profiles.