CD38 and airway hyper-responsiveness: Studies on human airway smooth muscle cells and mouse models

Alonso G P Guedes, Deepak A. Deshpande, Mythili Dileepan, Timothy F. Walseth, Reynold A. Panettieri, Subbaya Subramanian, Mathur S. Kannan

Research output: Contribution to journalArticle

22 Scopus citations

Abstract

Asthma is an inflammatory disease in which altered calcium regulation, contractility, and airway smooth muscle (ASM) proliferation contribute to airway hyper-responsiveness and airway wall remodeling. The enzymatic activity of CD38, a cell-surface protein expressed in human ASM cells, generates calcium mobilizing second messenger molecules such as cyclic ADP-ribose. CD38 expression in human ASM cells is augmented by cytokines (e.g., TNF-α) that requires the activation of MAP kinases and the transcription factors, NF-κB and AP-1, and is post-transcriptionally regulated by miR-140-3p and miR-708 by binding to 3′ Untranslated Region of CD38 as well as by modulating the activation of signaling mechanisms involved in its regulation. Mice deficient in Cd38 exhibit reduced airway responsiveness to inhaled methacholine relative to the response in wild-type mice. Intranasal challenge of Cd38-deficient mice with TNF-α or IL-13, or the environmental fungus Alternaria alternata, causes significantly attenuated methacholine responsiveness compared with wild-type mice, with comparable airway inflammation. Reciprocal bone marrow transfer studies revealed partial restoration of airway hyper-responsiveness to inhaled methacholine in the Cd38-deficient mice. These studies provide evidence for CD38 involvement in the development of airway hyper-responsiveness; a hallmark feature of asthma. Future studies aimed at drug discovery and delivery targeting CD38 expression and (or) activity are warranted.

Original languageEnglish (US)
Pages (from-to)145-153
Number of pages9
JournalCanadian Journal of Physiology and Pharmacology
Volume93
Issue number2
DOIs
StatePublished - Nov 19 2014

Keywords

  • Bone marrow chimeras
  • Cyclic ADP-ribose
  • Inflammatory cytokines
  • MicroRNAs

ASJC Scopus subject areas

  • Medicine(all)
  • Physiology
  • Pharmacology
  • Physiology (medical)

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    Guedes, A. G. P., Deshpande, D. A., Dileepan, M., Walseth, T. F., Panettieri, R. A., Subramanian, S., & Kannan, M. S. (2014). CD38 and airway hyper-responsiveness: Studies on human airway smooth muscle cells and mouse models. Canadian Journal of Physiology and Pharmacology, 93(2), 145-153. https://doi.org/10.1139/cjpp-2014-0410