title: CD38 and airway hyper-responsiveness: studies on human airway smooth muscle cells and mouse models.
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.
authors.affiliation: a Department of Surgical & Radiological Sciences, University of California, Davis, CA 95616, USA.
authors.forename: Alonso G P
authors.initials: AG
authors.lastname: Guedes
authors.forename: Deepak A
authors.initials: DA
authors.lastname: Deshpande
authors.forename: Mythili
authors.initials: M
authors.lastname: Dileepan
authors.forename: Timothy F
authors.initials: TF
authors.lastname: Walseth
authors.forename: Reynold A
authors.initials: RA
authors.lastname: Panettieri
authors.forename: Subbaya
authors.initials: S
authors.lastname: Subramanian
authors.forename: Mathur S
authors.initials: MS
authors.lastname: Kannan
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001249:Asthma / Q000378:metabolism* / Q000473:pathology; D002118:Calcium / Q000378:metabolism; D036563:Cyclic ADP-Ribose / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D012130:Respiratory Hypersensitivity / Q000378:metabolism*
chemical_list: D008562:Membrane Glycoproteins; D035683:MicroRNAs; D036563:Cyclic ADP-Ribose; C498154:CD38 protein, human; D051997:ADP-ribosyl Cyclase 1; D002118:Calcium
keywords: ADP-ribose cyclique; bone marrow chimeras; cyclic ADP-ribose; cytokines inflammatoires; inflammatory cytokines; micro ARN; microRNAs; moelle osseuse chimérique