Role of CD38 in TNF-alpha-induced airway hyperresponsiveness.
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.
Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, 1971 Commonwealth Avenue, St. Paul, MN 55108, USA.
Alonso G P
AG
Guedes
Joseph A
JA
Jude
Jaime
J
Paulin
Hirohito
H
Kita
Frances E
FE
Lund
Mathur S
MS
Kannan
D051997:ADP-ribosyl Cyclase 1 / Q000378:metabolism*; D000281:Administration, Intranasal; D000403:Airway Resistance / Q000187:drug effects; D000818:Animals; D016535:Bronchial Hyperreactivity / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D018925:Chemokines / Q000378:metabolism; D066298:In Vitro Techniques; D007249:Inflammation; D007537:Isometric Contraction / Q000187:drug effects; D016210:Methacholine Chloride / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000473:pathology; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology; D014132:Trachea / Q000187:drug effects / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000494:pharmacology
D018925:Chemokines; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D016210:Methacholine Chloride; D051997:ADP-ribosyl Cyclase 1