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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Hyperosmolar Solution Effects in Guinea Pig Airways. IV. Lipopolysaccharide-Induced Alterations in Airway Reactivity and Epithelial Bioelectric Responses to Methacholine and Hyperosmolarity

Department of Pharmacology and Toxicology, Robert C. Byrd Health Sciences Center of West Virginia University, Morgantown, West Virginia (R.A.J., J.S.F.); Pathology and Physiology Research Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, West Virginia (R.A.J., C.K., L.L.M., J.D.-C., J.S.F.); and Department of Physiology, The Brody School of Medicine at East Carolina University, Greenville, North Carolina (M.R.V.S.)

We investigated the in vivo and in vitro effects of lipopolysaccharide (LPS) treatment (4 mg/kg i.p.) on guinea pig airway smooth muscle reactivity and epithelial bioelectric responses to methacholine (MCh) and hyperosmolarity. Hyperosmolar challenge of the epithelium releases epithelium-derived relaxing factor (EpDRF). Using a two-chamber, whole body plethysmograph 18 h post-treatment, animals treated with LPS were hyporeactive to inhaled MCh aerosol. This could involve an increase in the release and/or actions of EpDRF, because LPS treatment enhanced EpDRF-induced smooth muscle relaxation in vitro in the isolated perfused trachea apparatus. In isolated perfused tracheas the basal transepithelial potential difference (V_t) was increased after LPS treatment. The increase in V_twas inhibited by amiloride and indomethacin. Concentration-response curves for changes in V_tin response to serosally and mucosally applied MCh were biphasic (hyperpolarization, <3 x 10^-7M; depolarization, >3 x10^-7M); MCh was more potent when applied serosally. The hyperpolarization response to MCh, but not the depolarization response, was potentiated after LPS treatment. In both treatment groups, mucosally applied hyperosmolar solution (using added NaCl) depolarized the epithelium; this response was greater in tracheas from LPS-treated animals. The results of this study indicate that airway hyporeactivity in vivo after LPS treatment is accompanied by an increase in the release and/or actions of EpDRF in vitro. These changes may involve LPS-induced bioelectric alterations in the epithelium.

Address correspondence to: Dr. Jeffrey S. Fedan, Pathology and Physiology Research Branch, National Institute for Occupational Safety and Health, 1095 Willowdale Rd., Morgantown, WV 26505-2888. E-mail: jsf2{at}cdc.gov

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