Inactivation of CD11b in a mouse transgenic model protects against sepsis-induced lung PMN infiltration and vascular injury.
To inactivate chronically the beta2-integrin CD11b (Mac-1), we made a transgenic model in mice in which we expressed the CD11b antagonist polypeptide neutrophil inhibitory factor (NIF). Using these mice, we determined the in vivo effects of CD11b inactivation on polymorphonuclear leukocyte (PMN) function and acute lung injury (ALI) induced by Escherichia coli septicemia. In wild-type PMNs, CD11b expression was induced within 1 h after E. coli challenge, whereas this response was significantly reduced in NIF(+/+) PMNs. Coimmunoprecipitation studies showed that NIF associated with CD11b in NIF(+/+) PMNs. To validate the effectiveness of CD11b blockade, we compared PMN function in NIF(+/+) and Mac-1-deficient (Mac-1(-/-)) mice. Adhesion of both Mac-1(-/-) and NIF(+/+) PMNs to endothelial cells in response to LPS was reduced in both types of PMNs and fully blocked only by the addition of anti-CD11a monoclonal antibody. This finding is indicative of intact CD11a function in the NIF(+/+) PMNs but the blockade of CD11b function. CD11b inactivation in NIF(+/+) mice interfered with lung PMN infiltration induced by E. coli and prevented the increase in lung microvessel permeability and edema formation, with most of the protection seen in the 1-h period after the E. coli. Thus our results demonstrate that CD11b plays a crucial role in mediating lung PMN sequestration and vascular injury in the early phase of gram-negative septicemia. The NIF(+/+) mouse model, in which CD11b is inactivated by binding to NIF, is a potentially useful model for in vivo assessment of the role of PMN CD11b in the mechanism of vascular inflammation.
Gao
Xiao-Pei
XP
Department of Pharmacology, The University of Illinois College of Medicine, Chicago, Illinois 60612, USA.
Liu
Qinghui
Q
Broman
Michael
M
Predescu
Dan
D
Frey
Randall S
RS
Malik
Asrar B
AB
D000818:Animals; D039481:CD11b Antigen / Q000378:metabolism*; D002199:Capillary Permeability / Q000187:drug effects; D002448:Cell Adhesion / Q000187:drug effects; D004487:Edema / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism; D004927:Escherichia coli Infections / Q000378:metabolism; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism; D006090:Gram-Negative Bacteria / Q000378:metabolism; D015801:Helminth Proteins / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000098:blood supply / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D020556:Neutrophil Infiltration / Q000235:genetics / Q000502:physiology*; D009504:Neutrophils / Q000276:immunology*; D016877:Oxidants / Q000378:metabolism; D011485:Protein Binding; D018805:Sepsis / Q000378:metabolism*
D039481:CD11b Antigen; D006023:Glycoproteins; D015801:Helminth Proteins; D008565:Membrane Proteins; D016877:Oxidants; C086581:NIF protein, Ancylostoma caninum