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Earlier, we found that systemic administration of lipopolysaccharide (LPS; 4 mg/kg) hyperpolarized the transepithelial potential difference (Vt) of tracheal epithelium in the isolated, perfused trachea (IPT) of the guinea pig 18 h after injection. As well, LPS increased the hyperpolarization component of the response to basolateral methacholine, and potentiated the epithelium-derived relaxing factor-mediated relaxation responses to hyperosmolar solutions applied to the apical membrane. We hypothesized that LPS stimulates the transepithelial movement of Na+ via the epithelial sodium channel (ENaC)/Na+-K+ pump axis, leading to hyperpolarization of Vt. LPS increased the Vt-depolarizing response to amiloride (10 ÁM), i.e., offset the effect of LPS, indicating that Na+ transport activity was increased. The functional activity of ENaC was measured in the IPT after short-circuiting the Na+-K+ pump with basolateral amphotericin B (7.5 ÁM). LPS had no effect on the hyperpolarization response to apical trypsin (100 U/ml) in the Ussing chamber, indicating that channel-activating proteases are not involved in the LPS-induced activation of ENaC. To assess Na+-K+ pump activity in the IPT, ENaC was short-circuited with apical amphotericin B. The greater Vt in the presence of amphotericin B in tracheas from LPS-treated animals compared with controls revealed that LPS increased Na+-K+ pump activity. This finding was confirmed in the Ussing chamber by inhibiting the Na+-K+ pump via extracellular K+ removal, loading the epithelium with Na+, and observing a greater hyperpolarization response to K+ restoration. Together, the findings of this study reveal that LPS hyperpolarizes the airway epithelium by increasing the activities of ENaC and the Na+-K+ pump.