Requirement of alpha(4)beta(1) and alpha(5)beta(1) integrin expression in bone-marrow-derived progenitor cells in preventing endotoxin-induced lung vascular injury and edema in mice.
The goal of this study was to determine the role of integrin-mediated adhesion of bone-marrow-derived progenitor cells (BMPCs) as a requirement for the endothelial barrier protection in a lung injury model. C57BL mice were used as the source for BMPCs, which were characterized as CD34(+) and fetal liver kinase-1 (Flk1)(+) and also an expression of a repertoire of integrins. We used a mouse model of bacterial lipopolysaccharide (LPS)-induced lung vascular injury and edema formation to test the effects of BMPC integrin expression in preventing endothelial barrier injury. Adhesion of BMPCs to purified extracellular matrix proteins induced focal adhesion kinase (Fak) phosphorylation and formation of branching point structures in a alpha(4) and alpha(5) integrin-dependent manner. BMPCs expressing red fluorescent protein (RFP) were administered via the retro-orbital venous route in mice treated intraperitonially with LPS (7.5 mg/kg body weight). We observed increased retention of RFP-labeled Flk1(+) and CD34(+) BMPCs for up to 8 weeks in mice injured with LPS. BMPC transplantation increased survival by 50% (at 72-96 hours after LPS) and reduced lung vascular injury and extravascular water content induced by LPS. However, blocking with anti-alpha(4) or anti-alpha(5) integrin antibody or shRNA-mediated silencing of alpha(4) or alpha(5) integrins in donor BMPCs failed to prevent the vascular injury or edema formation and mortality. Thus, alpha(4) and alpha(5) integrin-dependent adhesion of BMPCs in lung tissue plays a critical role in preventing lung vascular injury and increasing survival in a mouse model of LPS-induced acute lung injury.
Department of Pharmacology and Center for Lung and Vascular Biology, The University of Illinois, Chicago, Illinois 60612, USA. kkwary@uic.edu
Kishore K
KK
Wary
Stephen M
SM
Vogel
Sean
S
Garrean
Yidan D
YD
Zhao
Asrar B
AB
Malik
D000818:Animals; D017951:Antigen Presentation; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D016026:Bone Marrow Transplantation; D002448:Cell Adhesion; D002454:Cell Differentiation; D002465:Cell Movement; D002478:Cells, Cultured; D004487:Edema / Q000276:immunology / Q000378:metabolism*; D004731:Endotoxins / Q000276:immunology; D039041:Integrin alpha4beta1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D039081:Integrin alpha5beta1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000276:immunology; D008168:Lung / Q000098:blood supply*; D055370:Lung Injury / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D034622:RNA Interference; D013234:Stem Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism*
D004731:Endotoxins; D039041:Integrin alpha4beta1; D039081:Integrin alpha5beta1; D008070:Lipopolysaccharides