Smoke extract impairs adenosine wound healing: Implications of smoke-generated reactive oxygen species

Diane S. Allen-Gipson, Matthew C. Zimmerman, Hui Zhang, Glenda Castellanos, Jennifer K. O'Malley, Horacio Alvarez-Ramirez, Kusum Kharbanda, Joseph H. Sisson, Todd A. Wyatt

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

Adenosine concentrations are elevated in the lungs of patients with asthma and chronic obstructive pulmonary disease,where it balances betweentissuerepair andexcessiveairway remodeling.Wepreviously demonstrated that the activation of the adenosine A2A receptor promotes epithelial wound closure. However, the mechanism by which adenosine-mediated wound healing occurs after cigarette smoke exposure has not been investigated. The present study investigates whether cigarette smoke exposure alters adenosine-mediated reparative properties via its ability to induce a shift in the oxidant/ antioxidant balance. Using an in vitro wounding model, bronchial epithelial cells were exposed to 5% cigarette smoke extract, were wounded, and were then stimulated with either 10 μM adenosine or the specific A2A receptor agonist, 5'-(N-cyclopropyl)-carboxamido- adenosine (CPCA; 10 μM), and assessed for wound closure. In a subset of experiments, bronchial epithelial cells were infected with adenovirus vectors encoding human superoxide dismutase and/or catalase or control vector. In the presence of 5% smoke extract, significant delay was evident in both adenosine-mediated and CPCA-mediated wound closure. However, cells pretreated with N-acetylcysteine (NAC), a nonspecific antioxidant, reversed smoke extract-mediated inhibition. We found that cells overexpressing mitochondrial catalase repealed the smoke extract inhibition of CPCA-stimulated wound closure, whereas superoxide dismutase overexpression exerted no effect. Kinase experiments revealed that smoke extract significantly reduced the A2A-mediated activation of cyclic adenosine monophosphate-dependent protein kinase. However, pretreatment with NAC reversed this effect. In conclusion, our data suggest that cigarette smoke exposure impairs A2A-stimulated wound repair via a reactive oxygen species-dependent mechanism, thereby providing a better understanding of adenosine signalingthat may direct the development of pharmacological tools for the treatment of chronic inflammatory lung disorders.

Original languageEnglish (US)
Pages (from-to)665-673
Number of pages9
JournalAmerican journal of respiratory cell and molecular biology
Volume48
Issue number5
DOIs
StatePublished - May 2013

Keywords

  • Adenosine
  • Cigarette smoke extract
  • Oxidants
  • Wound closure

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

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