Modulation of beta1-integrins on hemopoietic progenitor cells after allergen challenge in asthmatic subjects.
BACKGROUND
Mobilization of hemopoietic progenitor cells from the bone marrow (BM) is a feature of inflammatory asthmatic responses. Understanding the mechanisms regulating progenitor cell mobilization and trafficking to the peripheral circulation might be important for the development of effective asthma therapies.


OBJECTIVE
We investigated the role of adhesion molecules in the mobilization of hemopoietic progenitor cells from the BM during an allergen-induced asthmatic response.


METHODS
BM and peripheral blood samples were obtained from dual-responders with mild asthma before and at several time points after allergen challenge. Fluctuations in expression and adhesive properties of beta1- and beta2-integrins on CD34(+)CD45(+) progenitor cells were assessed by using flow cytometry and adhesion to protein-coated wells, respectively.


RESULTS
On BM-derived CD34(+)CD45(+) cells, expression of very late antigen (VLA) 4, but not VLA-5 or Mac-1, decreased significantly 24 hours after allergen challenge and had begun to recover by 48 hours after challenge. In peripheral blood allergen challenge induced a significant decrease in VLA-4 levels after 6 hours, which had not recovered by 96 hours after challenge. Similarly, VLA-5 expression decreased, most prominently at 72 to 96 hours after allergen challenge. In contrast, Mac-1 levels did not change. Chemokine-stimulated adhesion of BM-derived CD34(+)CD45(+) cells to fibronectin was significantly attenuated 24 hours after challenge. Furthermore, adhesion to fibronectin and vascular cell adhesion molecule 1 was greatly reduced by anti-VLA-4 or anti-VLA-5 antibodies.


CONCLUSIONS
Preferential downregulation of beta1-integrin expression on progenitor cells can reduce the tethering forces to BM components, thus facilitating their egress to the peripheral circulation during an allergic inflammatory response.
Catalli
Adriana E
AE
Asthma Research Group, Firestone Institute for Respiratory Health, St Joseph's Healthcare, Hamilton, Ontario, Canada; Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
Thomson
Jennifer V
JV
Asthma Research Group, Firestone Institute for Respiratory Health, St Joseph's Healthcare, Hamilton, Ontario, Canada; Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
Babirad
Irene M
IM
Asthma Research Group, Firestone Institute for Respiratory Health, St Joseph's Healthcare, Hamilton, Ontario, Canada; Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
Duong
MyLinh
M
Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
Doyle
Tracey M
TM
Asthma Research Group, Firestone Institute for Respiratory Health, St Joseph's Healthcare, Hamilton, Ontario, Canada; Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
Howie
Karen J
KJ
Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
Newbold
Paul
P
AstraZeneca R&D Charnwood, Loughborough, Leicestershire, United Kingdom.
Craggs
Richard I
RI
AstraZeneca R&D Charnwood, Loughborough, Leicestershire, United Kingdom.
Foster
Martyn
M
AstraZeneca R&D Charnwood, Loughborough, Leicestershire, United Kingdom.
Gauvreau
Gail M
GM
Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
O'Byrne
Paul M
PM
Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
Sehmi
Roma
R
Asthma Research Group, Firestone Institute for Respiratory Health, St Joseph's Healthcare, Hamilton, Ontario, Canada; Department of Medicine, McMaster University, Hamilton, Ontario, Canada. Electronic address: sehmir@mcmaster.ca.