Osteopontin deficiency protects against airway remodeling and hyperresponsiveness in chronic asthma.
BACKGROUND
Osteopontin (OPN) is a cytokine that is upregulated in epithelial cells and macrophages in the lungs of mice during chronic allergen challenge and airway remodeling and also in lungs of patients with asthma. However, it remains unclear whether OPN has an in vivo effect on lung remodeling in allergic asthma. Based on its ability to induce smooth muscle and fibroblast proliferation and migration we hypothesize that OPN regulates lung remodeling and also affects subsequent airway hyperresponsiveness (AHR).


OBJECTIVE
Study the role of OPN in airway remodeling using OPN-knockout (KO) mice and a reversal approach administering recombinant mouse OPN (rOPN) in KO mice before challenge.


METHODS
A chronic allergen-challenge model of airway remodeling with OPN KO mice, KO mice treated with rOPN, and human bronchial smooth muscle were used.


RESULTS
OPN deficiency protected mice against ova-induced AHR, which was associated with lower collagen and mucus production, gob-5 mRNA expression, submucosal cell area infiltration, and proliferation. Administration of rOPN to KO mice, just at the final five allergen challenges, exacerbated AHR and all the remodeling characteristics measured. In addition, rOPN increased the expression of IL-13 and pro-matrix metalloproteinase-9 in the lungs. Moreover, we demonstrated that rOPN induces proliferation of human BSM through binding to its alpha(v)beta3 integrin receptor and activation of PI3K/Akt downstream signaling pathway.


CONCLUSIONS
We conclude that OPN deficiency protects against remodeling and AHR. Thus our data reveal OPN as a novel therapeutic target for airway remodeling and associated AHR in chronic asthma.
Simoes
Davina C M
DC
G.P. Livanos and M. Simou Laboratories, Evangelismos Hospital, Department of Critical Care and Pulmonary Services, University of Athens, Medical School, Athens, Greece. davinasimoes@yahoo.co.uk
Xanthou
Georgina
G
Petrochilou
Kalomira
K
Panoutsakopoulou
Vily
V
Roussos
Charis
C
Gratziou
Christina
C
D000818:Animals; D001249:Asthma / Q000276:immunology* / Q000378:metabolism; D015153:Blotting, Western; D016535:Bronchial Hyperreactivity / Q000276:immunology* / Q000378:metabolism; D048708:Cell Growth Processes / Q000187:drug effects / Q000276:immunology; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000276:immunology; D020397:Goblet Cells / Q000276:immunology; D006801:Humans; D018793:Interleukin-13 / Q000276:immunology / Q000378:metabolism; D008168:Lung / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000276:immunology; D053495:Osteopontin / Q000172:deficiency* / Q000276:immunology / Q000494:pharmacology; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D011994:Recombinant Proteins / Q000494:pharmacology
D018793:Interleukin-13; D011994:Recombinant Proteins; D053495:Osteopontin; D010047:Ovalbumin