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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Prostanoids Secreted by Alveolar Macrophages Enhance Ionic Currents in Swine Tracheal Submucosal Gland Cells

Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi

We examined the effect of substances released by swine alveolar macrophages (AMs) on ionic currents in airway submucosal gland cells (SGCs). AMs obtained by lavage were activated by 24-h zymosan exposure (0.1 mg/ml). Supernatant was collected and used to stimulate short-circuit current changes (I_SC) in SGC monolayers in Ussing chambers. Dexamethasone (1 µM) or indomethacin (5 µM) during zymosan exposure of AMs reduced or abolished the supernatant-induced I_SC. Zymosan exposure induced a 5-fold increase in cyclooxygenase (COX)-2 but not COX-1 protein levels in AMs. Prostaglandin E₂ (PGE₂) concentration in the supernatant from zymosan-activated AMs was 550 ± 10 nM (n = 3) compared with 28 ± 3 nM for unstimulated AMs (n = 3). PGE₂, applied serosally, induced I_SC with an EC₅₀ of 15.5 ± 1.3 nM (n = 4) and 3.6 ± 1.8 µM (n = 3) when applied apically. Four types of endoprostanoid receptors (EP_1–4) were detected in SGCs using Western blot. PGE₂-induced I_SC were inhibited by AH6809 (6-isopropoxy-9-oxoxanthene-2-carboxylic acid) but not by SC19220 (8-chloro-dibenzo[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-acetylhydrazide), suggesting that endoprostanoid (EP)₂ but not EP₁ receptors were activated by PGE₂. Pretreatment of SGCs with supernatant from zymosan-activated AMs, PGE₂, or forskolin enhanced the sensitivity to acetylcholine (ACh)-induced I_SC. PGE₂-induced I_SC were blocked by charybdotoxin (ChTX), chromanol 293B, or glibenclamide. ACh-induced I_SC were only blocked by ChTX or glibenclamide. None of these blockers altered PGE₂ pretreatment-induced sensitization of ACh-induced I_SC. These results demonstrate that prostanoids released from activated AMs directly increase cystic fibrosis transmembrane conductance regulator and K⁺ channel activity. ACh-induced I_SC are also enhanced due to enhanced activation of Ca²⁺-activated K⁺ channels (K_Ca).

Address correspondence to: Dr. Jerry M. Farley Sr., Department of Pharmacology and Toxicology, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216. E-mail: jfarley{at}pharmacology.umsmed.edu

This article has been cited by other articles:

				H. Liu and J. M. Farley Sr. Prostaglandin E2 Enhances Acetylcholine-Induced, Ca2+-Dependent Ionic Currents in Swine Tracheal Mucous Gland Cells J. Pharmacol. Exp. Ther., August 1, 2007; 322(2): 501 - 513. [Abstract] [Full Text] [PDF]