Role of CD38 in TNF-α-induced airway hyperresponsiveness

Abstract

CD38 is involved in normal airway function, IL-13-induced airway hyperresponsiveness (AHR), and is also regulated by tumor necrosis factor (TNF)-α in airway smooth muscle (ASM) cells. This study aimed to determine whether TNF-α-induced CD38 upregulation in ASM cells contributes to AHR, a hallmark of asthma. We hypothesized that AHR would be attenuated in TNF-α-exposed CD38-deficient (CD38KO) mice compared with wild-type (WT) controls. Mice ( n = 6–8/group) were intranasally challenged with vehicle control or TNF-α (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-α (50 ng/ml) to assess contractile changes in the ASM. While a single TNF-α challenge caused no airway inflammation, both multiple-challenge protocols induced equally significant inflammation in CD38KO and WT mice. A single intranasal TNF-α 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-α increased ASM contractile properties in tracheal rings from WT but not from CD38KO mice. In conclusion, CD38 contributes to TNF-α-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-α. The mechanisms involved in this remission remain to be determined.

miR-140-3p regulation of TNF-α-induced CD38 expression in human airway smooth muscle cells

“…It is suggested that the downregulation of miR-133a leads to elevated RhoA, a procontractile protein in the ASM cells. CD38 contributes to the development of AHR in mouse models of asthma (10,11). The CD38-null mouse developed significantly lower levels of airway responsiveness than the wild-type mouse in response to the contractile agonist methacholine (7).…”

“…The CD38-null mouse developed significantly lower levels of airway responsiveness than the wild-type mouse in response to the contractile agonist methacholine (7). The CD38-null mouse also developed reduced AHR compared with the wild-type mouse following brief exposure to TNF-␣ or IL-13 (10,11). Therefore, investigating the miRNAs that target CD38 gene expression in HASM cells may lead to an understanding of the signaling pathways involved in the pathogenesis of AHR and asthma.…”

Regulation of CD38 Expression in Human Airway Smooth Muscle Cells

“…In this context, reports from our laboratory and from others indicate a central role of CD38 in mouse models of airway inflammation and airway hyperresponsiveness (AHR), the hallmark features of asthma. For example, CD38-deficient mice develop significantly lower airway resistance to inhaled methacholine challenge after intranasal challenge with IL-13 or TNF-a compared with the wild-type mice, suggesting a role for this protein in the pathogenesis of AHR in airway inflammatory disorders (5,6). CD38 expression and ADP-ribosyl cyclase activity are enhanced in human ASM (HASM) cells after exposure to inflammatory cytokines such as IFN-g, IL1b, and TNF-a and the T H 2 cytokine IL-13 (4).…”

Airway Smooth Muscle: Is There a Phenotype Associated with Asthma?

“…Compared to CD38 −/− mice, airway myocytes isolated from wild-type mice exhibit higher agonist-induced intracellular Ca 2+ responses in vitro while CD38 +/+ mice develop a higher magnitude of AHR after allergen challenge (Gally et al, 2009;Guedes et al, 2008;Guedes et al, 2006). Later studies in human ASM imply that differential expression of CD38 by heightened induction of common signaling cascades likely mediates AHR in asthma (Jude et al, 2010).…”