Adenosine A(1) and prostaglandin E receptor 3 receptors mediate global airway contraction after local epithelial injury

Am J Respir Cell Mol Biol. 2013 Mar;48(3):299-305. doi: 10.1165/rcmb.2012-0174OC. Epub 2012 Dec 6.

Abstract

Epithelial injury and airway hyperresponsiveness are prominent features of asthma. We have previously demonstrated that laser ablation of single epithelial cells immediately induces global airway constriction through Ca(2+)-dependent smooth muscle shortening. The response is mediated by soluble mediators released from wounded single epithelial cells; however, the soluble mediators and signaling mechanisms have not been identified. In this study, we investigated the nature of the epithelial-derived soluble mediators and the associated signaling pathways that lead to the L-type voltage-dependent Ca(2+) channel (VGCC)-mediated Ca(2+) influx. We found that inhibition of adenosine A1 receptors (or removal of adenosine with adenosine deaminase), cyclooxygenase (COX)-2 or prostaglandin E receptor 3 (EP3) receptors, epidermal growth factor receptor (EGFR), or platelet-derived growth factor receptor (PDGFR) all significantly blocked Ca(2+) oscillations in smooth muscle cells and airway contraction induced by local epithelial injury. Using selective agonists to activate the receptors in the presence and absence of selective receptor antagonists, we found that adenosine activated the signaling pathway A1R→EGFR/PDGFR→COX-2→EP3→VGCCs→calcium-induced calcium release, leading to intracellular Ca(2+) oscillations in airway smooth muscle cells and airway constriction.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenosine A1 Receptor Antagonists / pharmacology
  • Animals
  • Calcium / metabolism
  • Calcium Channels, L-Type / metabolism
  • Calcium Signaling / drug effects
  • Cyclooxygenase 2 / metabolism
  • Cyclooxygenase 2 Inhibitors / pharmacology
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / metabolism
  • Muscle Contraction / drug effects
  • Muscle Contraction / physiology*
  • Muscle, Smooth / drug effects
  • Muscle, Smooth / metabolism
  • Muscle, Smooth / physiopathology
  • Myocytes, Smooth Muscle / drug effects
  • Myocytes, Smooth Muscle / metabolism
  • Rats
  • Receptor, Adenosine A1 / metabolism*
  • Receptors, Platelet-Derived Growth Factor / metabolism
  • Receptors, Prostaglandin E, EP3 Subtype / antagonists & inhibitors
  • Receptors, Prostaglandin E, EP3 Subtype / metabolism*
  • Respiratory Mucosa / drug effects
  • Respiratory Mucosa / injuries
  • Respiratory Mucosa / metabolism*
  • Respiratory System / drug effects
  • Respiratory System / metabolism
  • Respiratory System / physiopathology*
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Wounds and Injuries / metabolism
  • Wounds and Injuries / physiopathology*

Substances

  • Adenosine A1 Receptor Antagonists
  • Calcium Channels, L-Type
  • Cyclooxygenase 2 Inhibitors
  • Receptor, Adenosine A1
  • Receptors, Prostaglandin E, EP3 Subtype
  • Cyclooxygenase 2
  • Ptgs2 protein, rat
  • Egfr protein, rat
  • ErbB Receptors
  • Receptors, Platelet-Derived Growth Factor
  • Calcium