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This Article Full Text Full Text (PDF) All Versions of this Article: 294/2/L290    most recent 00367.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Guedes, A. G. P. Articles by Kannan, M. S. PubMed PubMed Citation Articles by Guedes, A. G. P. Articles by Kannan, M. S.

Role of CD38 in TNF--induced airway hyperresponsiveness

Departments of ¹Veterinary Small Animal Clinical Sciences, Texas A&M University, College Station, Texas; ²Veterinary and Biomedical Sciences, ³Veterinary Population Medicine, and ⁶Pediatrics, University of Minnesota, St. Paul, Minnesota; ⁴Department of Medicine and Immunology, Mayo Clinic, Rochester, Minnesota; and ⁵Trudeau Institute, Saranac Lake, New York

Submitted 6 September 2007 ; accepted in final form 26 November 2007

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

tumor necrosis factor-