Inhibition of allergen-induced airway remodeling in Smad 3-deficient mice.
Intracellular signaling pathways that converge on Smad 3 are used by both TGF-beta and activin A, key cytokines implicated in the process of fibrogenesis. To determine the role of Smad 3 in allergen-induced airway remodeling, Smad 3-deficient and wild-type (WT) mice were sensitized to OVA and challenged by repetitive administration of OVA for 1 mo. Increased levels of activin A and increased numbers of peribronchial TGF-beta1(+) cells were detected in WT and Smad 3-deficient mice following repetitive OVA challenge. Smad 3-deficient mice challenged with OVA had significantly less peribronchial fibrosis (total lung collagen content and trichrome staining), reduced thickness of the peribronchial smooth muscle layer, and reduced epithelial mucus production compared with WT mice. As TGF-beta and Smad 3 signaling are hypothesized to mediate differentiation of fibroblasts to myofibroblasts in vivo, we determined the number of peribronchial myofibroblasts (Col-1(+) and alpha-smooth muscle actin(+)) as assessed by double-label immunofluorescence microscopy. Although the number of peribronchial myofibroblasts increased significantly in WT mice following OVA challenge, there was a significant reduction in the number of peribronchial myofibroblasts in OVA-challenged Smad 3-deficient mice. There was no difference in levels of eosinophilic airway inflammation or airway responsiveness in Smad 3-deficient compared with WT mice. These results suggest that Smad 3 signaling is required for allergen-induced airway remodeling, as well as allergen-induced accumulation of myofibroblasts in the airway. However, Smad 3 signaling does not contribute significantly to airway responsiveness.
Le
Annie V
AV
Division of Allergy and Immunology, Scripps Clinic and Research Institute, La Jolla, CA 92037, USA.
Cho
Jae Youn
JY
Miller
Marina
M
McElwain
Shauna
S
Golgotiu
Kirsti
K
Broide
David H
DH
D028341:Activins / Q000096:biosynthesis / Q000235:genetics; D000485:Allergens / Q000008:administration & dosage*; D000818:Animals; D001391:Azo Compounds / Q000032:analysis; D016535:Bronchial Hyperreactivity / Q000235:genetics / Q000276:immunology / Q000473:pathology; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D003094:Collagen / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism; D004801:Eosine Yellowish-(YS) / Q000032:analysis; D005347:Fibroblasts / Q000737:chemistry / Q000276:immunology / Q000473:pathology; D008168:Lung / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D008739:Methyl Green / Q000032:analysis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009093:Mucus / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D009130:Muscle, Smooth / Q000737:chemistry / Q000276:immunology / Q000473:pathology; D010047:Ovalbumin / Q000008:administration & dosage* / Q000276:immunology; D011657:Pulmonary Eosinophilia / Q000235:genetics / Q000276:immunology / Q000473:pathology; D020545:Respiratory Mucosa / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000276:immunology; D051900:Smad3 Protein / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology
D000485:Allergens; D001391:Azo Compounds; D051900:Smad3 Protein; C422405:activin A; C017768:trichrome stain; D028341:Activins; D008739:Methyl Green; D010047:Ovalbumin; D003094:Collagen; D004801:Eosine Yellowish-(YS)