Role of CD38 in TNF-alpha-induced airway hyperresponsiveness

Am J Physiol Lung Cell Mol Physiol. 2008 Feb;294(2):L290-9. doi: 10.1152/ajplung.00367.2007. Epub 2007 Nov 30.

Abstract

CD38 is involved in normal airway function, IL-13-induced airway hyperresponsiveness (AHR), and is also regulated by tumor necrosis factor (TNF)-alpha in airway smooth muscle (ASM) cells. This study aimed to determine whether TNF-alpha-induced CD38 upregulation in ASM cells contributes to AHR, a hallmark of asthma. We hypothesized that AHR would be attenuated in TNF-alpha-exposed CD38-deficient (CD38KO) mice compared with wild-type (WT) controls. Mice (n = 6-8/group) were intranasally challenged with vehicle control or TNF-alpha (50 ng) once and every other day during 1 or 4 wk. Lung inflammation and AHR, measured by changes in lung resistance after inhaled methacholine, were assessed 24 h following the last challenge. Tracheal rings were incubated with TNF-alpha (50 ng/ml) to assess contractile changes in the ASM. While a single TNF-alpha challenge caused no airway inflammation, both multiple-challenge protocols induced equally significant inflammation in CD38KO and WT mice. A single intranasal TNF-alpha challenge induced AHR in the WT but not in the CD38KO mice, whereas both mice developed AHR after 1 wk of challenges. The AHR was suppressed by extending the challenges for 4 wk in both mice, although to a larger magnitude in the WT than in the CD38KO mice. TNF-alpha increased ASM contractile properties in tracheal rings from WT but not from CD38KO mice. In conclusion, CD38 contributes to TNF-alpha-induced AHR after a brief airway exposure to the cytokine, likely by mediating changes in ASM contractile responses, and is associated with greater AHR remission following chronic airway exposure to TNF-alpha. The mechanisms involved in this remission remain to be determined.

Publication types

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

MeSH terms

  • ADP-ribosyl Cyclase 1 / metabolism*
  • Administration, Intranasal
  • Airway Resistance / drug effects
  • Animals
  • Bronchial Hyperreactivity / chemically induced
  • Bronchial Hyperreactivity / metabolism*
  • Bronchial Hyperreactivity / physiopathology
  • Bronchoalveolar Lavage Fluid / cytology
  • Chemokines / metabolism
  • In Vitro Techniques
  • Inflammation
  • Isometric Contraction / drug effects
  • Methacholine Chloride / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Pulmonary Alveoli / drug effects
  • Pulmonary Alveoli / pathology
  • Recombinant Proteins / administration & dosage
  • Recombinant Proteins / pharmacology
  • Trachea / drug effects
  • Trachea / physiology
  • Tumor Necrosis Factor-alpha / administration & dosage
  • Tumor Necrosis Factor-alpha / pharmacology

Substances

  • Chemokines
  • Recombinant Proteins
  • Tumor Necrosis Factor-alpha
  • Methacholine Chloride
  • ADP-ribosyl Cyclase 1