Heparin-binding protein (HBP/CAP37): a missing link in neutrophil-evoked alteration of vascular permeability.
Polymorphonuclear leukocyte infiltration into tissues in host defense and inflammatory disease causes increased vascular permeability and edema formation through unknown mechanisms. Here, we report the involvement of a paracrine mechanism in neutrophil-evoked alteration in endothelial barrier function. We show that upon neutrophil adhesion to the endothelial lining, leukocytic beta2 integrin signaling triggers the release of neutrophil-borne heparin-binding protein (HBP), also known as CAP37/azurocidin, a member of the serprocidin family of neutrophil cationic proteins. HBP induced Ca++-dependent cytoskeletal rearrangement and intercellular gap formation in endothelial-cell monolayers in vitro, and increased macromolecular efflux in microvessels in vivo. Moreover, selective inactivation of HBP prevented the neutrophils from inducing endothelial hyperpermeability. Our data suggest a fundamental role of neutrophil-derived HBP in the vascular response to neutrophil trafficking in inflammation. Targeting this molecule in inflammatory disease conditions offers a new strategy for prevention of endothelial barrier dysfunction caused by misdirected leukocyte activation.
Gautam
N
N
Department of Physiology & Pharmacology, Karolinska Institutet, Stockholm, Sweden.
Olofsson
A M
AM
Herwald
H
H
Iversen
L F
LF
Lundgren-Akerlund
E
E
Hedqvist
P
P
Arfors
K E
KE
Flodgaard
H
H
Lindbom
L
L
D000818:Animals; D023181:Antimicrobial Cationic Peptides; D001798:Blood Proteins / Q000378:metabolism* / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002199:Capillary Permeability / Q000502:physiology*; D002352:Carrier Proteins / Q000378:metabolism* / Q000494:pharmacology; D002417:Cattle; D002463:Cell Membrane Permeability; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000502:physiology; D004730:Endothelium, Vascular / Q000166:cytology; D006801:Humans; D009504:Neutrophils / Q000378:metabolism*
C062991:AZU1 protein, human; D023181:Antimicrobial Cationic Peptides; D001798:Blood Proteins; D002352:Carrier Proteins; D002118:Calcium