Airway recruitment of leukocytes in mice is dependent on alpha4-integrins and vascular cell adhesion molecule-1.
The involvement of the alpha4-integrin very late activation antigen 4 and vascular cell adhesion molecule-1 (VCAM-1) in leukocyte trafficking into the airways of ovalbumin (OA)-sensitized and OA-challenged mice was investigated using in vivo administration of anti-alpha4 monoclonal antibodies (mAb) PS/2, R1-2, and M/K-2.7 (MK2), specific for VCAM-1. VCAM-1 was upregulated on endothelial cells in lung tissue after OA inhalation. PS/2, R1-2, or MK2 significantly inhibited the recruitment of eosinophils and lymphocytes into the bronchoalveolar lavage (BAL) fluid and decreased inflammation in the lung tissues. Escalating in vivo doses of PS/2 or MK2 increased circulating levels of rat immunoglobulin G in the plasma. The binding of phycoerytherin-labeled anti-alpha4 mAb to blood T cells from PS/2-treated mice was reduced, implying that alpha4 sites were already occupied. T cells and eosinophils in BAL fluid from mice treated with PS/2 or MK2 were phenotypically different from controls. Selective decreases of alpha4+ T cells in the BAL fluid after PS/2 or MK2 treatment were coupled with changes in CD8+, CD11a, and CD62L expression. The alpha4-integrin and VCAM-1 may have important roles in the antigen-induced recruitment of T cells and eosinophils during OA-induced airway inflammation. The data suggest that these adhesion molecules may be suitable targets for therapeutic intervention in certain conditions of pulmonary inflammation.
Chin
J E
JE
Cell Biology and Inflammation Research and Drug Development Toxicology, Pharmacia and Upjohn, Kalamazoo, Michigan 49001, USA. jia-en.chin@am.pnu.com
Hatfield
C A
CA
Winterrowd
G E
GE
Brashler
J R
JR
Vonderfecht
S L
SL
Fidler
S F
SF
Griffin
R L
RL
Kolbasa
K P
KP
Krzesicki
R F
RF
Sly
L M
LM
Staite
N D
ND
Richards
I M
IM
D000818:Animals; D000911:Antibodies, Monoclonal; D015703:Antigens, CD / Q000502:physiology*; D001980:Bronchi / Q000473:pathology; D002465:Cell Movement; D005260:Female; D007114:Immunization; D007150:Immunohistochemistry / Q000379:methods; D039441:Integrin alpha4; D007962:Leukocytes / Q000473:pathology / Q000502:physiology*; D008168:Lung / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010047:Ovalbumin / Q000276:immunology; D011014:Pneumonia / Q000276:immunology / Q000473:pathology; D051381:Rats; D013194:Staining and Labeling; D019010:Vascular Cell Adhesion Molecule-1 / Q000502:physiology*
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D019010:Vascular Cell Adhesion Molecule-1; D039441:Integrin alpha4; D010047:Ovalbumin