Absence of alpha 4 but not beta 2 integrins restrains development of chronic allergic asthma using mouse genetic models.
OBJECTIVE
Chronic asthma is characterized by ongoing recruitment of inflammatory cells and airway hyperresponsiveness leading to structural airway remodeling. Although alpha 4 beta 1 and beta2 integrins regulate leukocyte migration in inflammatory diseases and play decisive roles in acute asthma, their role has not been explored under the chronic asthma setting. To extend our earlier studies with alpha 4(Delta/Delta) and beta2(-/-) mice, which showed that both alpha 4 and beta2 integrins have nonredundant regulatory roles in acute ovalbumin (OVA)-induced asthma, we explored to what extent these molecular pathways control development of structural airway remodeling in chronic asthma.


METHODS
Control, alpha 4(Delta/Delta), and beta2(-/-) mouse groups, sensitized by intraperitoneal OVA as allergen, received intratracheal OVA periodically over days 8 to 55 to induce a chronic asthma phenotype. Post-OVA assessment of inflammation and pulmonary function (airway hyperresponsiveness), together with airway modeling measured by goblet cell metaplasia, collagen content of lung, and transforming growth factor beta1 expression in lung homogenates, were evaluated.


RESULTS
In contrast to control and beta2(-/-) mice, alpha 4(Delta/Delta) mice failed to develop and maintain the composite chronic asthma phenotype evaluated as mentioned and subepithelial collagen content was comparable to baseline. These data indicate that beta2 integrins, although required for inflammatory migration in acute asthma, are dispensable for structural remodeling in chronic asthma.


CONCLUSIONS
alpha 4 integrins appear to have a regulatory role in directing transforming growth factor beta-induced collagen deposition and structural alterations in lung architecture likely through interactions of Th2 cells, eosinophils, or mast cells with endothelium, resident airway cells, and/or extracellular matrix.
Banerjee
Ena Ray
ER
Department of Medicine, Division of Allergy and Infectious Diseases, University of Washington, Seattle, WA 98195-7710, USA.
Jiang
Yi
Y
Henderson
William R
WR
Latchman
Yvette
Y
Papayannopoulou
Thalia
T
D000818:Animals; D001249:Asthma / Q000139:chemically induced / Q000235:genetics*; D018821:CD18 Antigens / Q000235:genetics*; D002634:Chemotaxis, Leukocyte; D002908:Chronic Disease; D003094:Collagen / Q000378:metabolism; D007249:Inflammation; D039663:Integrin beta4 / Q000235:genetics*; D008168:Lung / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008957:Models, Genetic; D010047:Ovalbumin; D010641:Phenotype; D012129:Respiratory Function Tests; D016212:Transforming Growth Factor beta / Q000502:physiology
D018821:CD18 Antigens; D039663:Integrin beta4; D016212:Transforming Growth Factor beta; D010047:Ovalbumin; D003094:Collagen