Nonhematopoietic NADPH oxidase regulation of lung eosinophilia and airway hyperresponsiveness in experimentally induced asthma.
Pulmonary eosinophilia is one of the most consistent hallmarks of asthma. Infiltration of eosinophils into the lung in experimental asthma is dependent on the adhesion molecule vascular cell adhesion molecule-1 (VCAM-1) on endothelial cells. Ligation of VCAM-1 activates endothelial cell NADPH oxidase, which is required for VCAM-1-dependent leukocyte migration in vitro. To examine whether endothelial-derived NADPH oxidase modulates eosinophil recruitment in vivo, mice deficient in NADPH oxidase (CYBB mice) were irradiated and received wild-type hematopoietic cells to generate chimeric CYBB mice. In response to ovalbumin (OVA) challenge, the chimeric CYBB mice had increased numbers of eosinophils bound to the endothelium as well as reduced eosinophilia in the lung tissue and bronchoalveolar lavage. This occurred independent of changes in VCAM-1 expression, cytokine/chemokine levels (IL-5, IL-10, IL-13, IFNgamma, or eotaxin), or numbers of T cells, neutrophils, or mononuclear cells in the lavage fluids or lung tissue of OVA-challenged mice. Importantly, the OVA-challenged chimeric CYBB mice had reduced airway hyperresponsiveness (AHR). The AHR in OVA-challenged chimeric CYBB mice was restored by bypassing the endothelium with intratracheal administration of eosinophils. These data suggest that VCAM-1 induction of NADPH oxidase in the endothelium is necessary for the eosinophil recruitment during allergic inflammation. Moreover, these studies provide a basis for targeting VCAM-1-dependent signaling pathways in asthma therapies.
Abdala-Valencia
Hiam
H
Allergy-Immunology Division, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
Earwood
Julie
J
Bansal
Shelly
S
Jansen
Michael
M
Babcock
George
G
Garvy
Beth
B
Wills-Karp
Marsha
M
Cook-Mills
Joan M
JM
D000818:Animals; D001249:Asthma / Q000201:enzymology / Q000503:physiopathology*; D016535:Bronchial Hyperreactivity / Q000201:enzymology / Q000503:physiopathology*; D054413:Chemokine CCL11; D019742:Chemokines, CC / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D019255:NADPH Oxidases / Q000378:metabolism*; D010047:Ovalbumin / Q000633:toxicity; D011657:Pulmonary Eosinophilia / Q000201:enzymology / Q000503:physiopathology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
C515457:Ccl11 protein, mouse; D054413:Chemokine CCL11; D019742:Chemokines, CC; D016207:Cytokines; D019010:Vascular Cell Adhesion Molecule-1; D010047:Ovalbumin; D019255:NADPH Oxidases