Modulating progenitor accumulation attenuates lung angiogenesis in a mouse model of asthma.
Asthmatic responses are associated with the lung homing of bone marrow (BM)-derived progenitors implicated as effectors of disease pathology. Studies have shown that increases in lung extracted vascular endothelial progenitor cells (VEPCs) correlate with airway angiogenesis and declining lung function. We investigated the effect of modulating lung homing of VEPCs on tissue remodelling and airway hyperresponsiveness (AHR). BALB/c mice were sensitised to ovalbumin, subjected to a chronic exposure protocol and given early concurrent or delayed treatment with a modulator of progenitor traffic, AMD3100 (CXC chemokine receptor 4 antagonist; inhibits chemotactic activity of stromal-derived factor-1α on VEPCs). After ovalbumin challenge, early haemopoietic stem cells (HSCs) and VEPCs were enumerated along with indices of airway inflammation, lung morphometry and AHR. Following ovalbumin challenge, there was a decrease in BM and an associated increase in the lung tissue-extracted HSCs and VEPCs, together with increases in airway eosinophilia, microvessel density and AHR. These outcomes were significantly inhibited by early concurrent treatment with AMD3100. Where lung disease was established, delayed treatment with AMD3100 significantly attenuated HSC numbers and lung angiogenesis but only partially reversed sustained AHR compared with untreated ovalbumin-exposed mice. Progenitor lung homing is associated with the development of asthma pathology, and early modulation of this accumulation can prevent airway remodelling and lung dysfunction.
Firestone Institute for Respiratory Health, St Joseph's Hospital, Hamilton, ON, Canada.
T M
TM
Doyle
R
R
Ellis
H J
HJ
Park
M D
MD
Inman
R
R
Sehmi
D000485:Allergens / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D001249:Asthma / Q000378:metabolism / Q000503:physiopathology*; D001992:Bronchoalveolar Lavage Fluid; D054377:Chemokine CXCL12 / Q000378:metabolism; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000166:cytology; D005260:Female; D006801:Humans; D008168:Lung / Q000473:pathology* / Q000503:physiopathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009389:Neovascularization, Pathologic; D010047:Ovalbumin / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology*
D000485:Allergens; D054377:Chemokine CXCL12; D010047:Ovalbumin