Hyperosmolarity-Induced Dilation and Epithelial Bioelectric Responses of Guinea Pig Trachea In Vitro: Role of Kinase Signaling

Details

• Personal Author:
  Dowdy JA ; Fedan, Jeffery S. ; Jing Y ; Van Scott MR
• Description:
  Exercise-induced airway obstruction is thought to involve evaporative water loss and hyperosmolarity of the airway surface liquid. Hyperosmolar challenge of the epithelium of isolated, perfused guinea pig trachea rapidly alters transepithelial potential difference (V-t), and it elicits smooth muscle relaxation mediated by epithelium-derived relaxing factor (EpDRF). In many cell types, protein kinases mediate responses to hyperosmolarity and regulatory volume increase. In this study, inhibitors were used to investigate the involvement of kinases and phosphatases in bioelectric responses of epithelium to hyperosmolarity and their possible relationship to EpDRF-mediated relaxation. After contraction of the perfused trachea with extraluminal methacholine, D-mannitol applied intraluminally (<= 80 mosM) increased V-t and elicited dilation of the smooth muscle with a similar concentration-dependence; higher concentrations decreased V-t. In tracheas exposed to 30 mosM D-mannitol (similar to EC50), 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole (SB 203580) and SKF 86002 [6-(4-fluorophenyl)-2,3-dihydro-5-(4-pyridyl)imidazo[2,1-b]thiazole] (p38 inhibitors) potentiated the dilation, whereas SP 600125[anthra[1,9-cd]pyrazol-6(2H)-one-1,9-pyrazoloanthrone] and dicumarol [c-Jun NH2-terminal kinase (JNK) inhibitors], chelerythrine [nonselective protein kinase C (PKC) inhibitor], and NaAsO2 (mitogen-activated protein kinase stress inducer) and Na3VO4 (protein tyrosine phosphatase inhibitor) inhibited the hyperpolarization. Large increases in the phosphorylation of p38 and JNK occurred at concentrations higher than those needed to elicit functional responses. The phosphatidylinositol 3-kinase inhibitor 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY 294002) and Na3VO4 did not affect the V-t responses, but they inhibited methacholine-induced constriction; SP 600125 and dicumarol potentiated, and chelerythrine inhibited, methacholine-induced epithelial hyperpolarization. These results suggest that JNK, PKC, and phosphatase(s) are involved in hyperosmolarity-induced hyperpolarization of the tracheal epithelium but that p38 is involved in EpDRF-mediated relaxation. [Description provided by NIOSH]
• Subjects:
  Asthma Asthma, Occupational Hypersensitivity Laboratories Lung Lung Diseases Occupational Health Respiratory System Respiratory Tract Diseases Risk Assessment Risk Factors Safety

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• Keywords:
  Analytical-models Breathing Bronchial-asthma Cell-biology Cell-function Cell-metabolism Cellular-reactions Chemical-hypersensitivity Chemical-kinetics Laboratory-animals Laboratory-testing Pulmonary-disorders Pulmonary-function Pulmonary-system-disorders Risk-analysis Risk-factors

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• ISSN:
  0022-3565
• Document Type:
  Text
• Genre:
  Journal Article
• Place as Subject:
  OSHA Region 3 ; West Virginia
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  HELD - Health Effects Laboratory Division
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Pages in Document:
  186-195
• Volume:
  326
• Issue:
  1
• NIOSHTIC Number:
  nn:20034106
• Citation:
  J Pharmacol Exp Ther 2008 Jul; 326(1):186-195
• Contact Point Address:
  Dr. Jeffrey S. Fedan, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, 1095 Willowdale Rd., Morgantown, WV 26505-2888
• Email:
  jsf2@cdc.gov
• Federal Fiscal Year:
  2008
• NORA Priority Area:
  Manufacturing
• Peer Reviewed:
  True
• Source Full Name:
  Journal of Pharmacology and Experimental Therapeutics
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:79dd0e89d261618b6f6efd6b3c4451c63d9d3439a979d76a90d267392fc6b150fa722c6fa497a0b4ccbbd759776791ca9e5cd587a6ddd0c7701f4db5f610ce1d
• Download URL:
  https://stacks.cdc.gov/view/cdc/189472/cdc_189472_DS1.pdf
• File Type:
  [PDF - 268.08 KB ]