Abstract
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 (Vt) was increased after LPS treatment. The increase in Vtwas inhibited by amiloride and indomethacin. Concentration-response curves for changes in Vtin response to serosally and mucosally applied MCh were biphasic (hyperpolarization, <3 × 10-7M; depolarization, >3 ×10-7M); 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.
Footnotes
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↵1 Hypertonic solutions are those that cause cell shrinkage. Hyperosmolar solutions have osmolarity greater than that of the physiological extracellular solution. For simplicity, in this report we do not draw distinctions between the two terms when describing general phenomena.
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This work was supported, in part, by National Institutes of Health Grant 5-T32-GM07039 (to R.A.J.). Mention of brand name does not constitute product endorsement. This article is the fourth one of a series of four companion articles that report the effects of hyperosmolar solutions in guinea pig airways (Fedan et al., 2003a,b; Wu et al., 2003).
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DOI: 10.1124/jpet.103.051672.
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ABBREVIATIONS:LPS, lipopolysaccharide; EpDRF, epithelium-derived relaxing factor; MCh, methacholine; SRaw, specific airway resistance; Vt, transepithelial potential difference;l-NAME,NG-nitro-l-arginine methyl ester;l-M,l-mannitol; NO, nitric oxide; MKHS, modified Krebs-Henseleit solution; CI, confidence interval; SNP, sodium nitroprusside; PC200, the provocative methacholine concentration producing a 2-fold increase in specific airway resistance above the value after saline administration.
- Received March 14, 2003.
- Accepted October 8, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
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