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Heparin-binding protein (HBP/CAP37): A missing link in neutrophil-evoked alteration of vascular permeability

Nature Medicine volume 7, pages 1123–1127 (2001)Cite this article

Abstract

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 β2 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.

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Figure 1: Immunorecognition of HBP released from activated PMN.
Figure 2: Kinetics of changes in EC monolayer permeability in response to stimulation with rHBP.
Figure 3: HBP triggers macromolecular leakage in vivo and active cytoskeletal rearrangement in cultured ECs.
Figure 4: Antibodies against HBP and dextran sulfate (DxSO4) inhibit HBP- and PMN-evoked increase in EC permeability.
Figure 5: Involvement of neutrophil-derived granule proteins in PMN-evoked increase in EC permeability.

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Acknowledgements

This study was supported by the Swedish Medical Research Council (14X-4342), the Swedish Foundation for Health Care Sciences and Allergy Research (A2001 068), the Swedish National Board for Laboratory Animals, IngaBritt and Arne Lundbergs Foundation, and Karolinska Institutet.

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Authors and Affiliations

  1. Department of Physiology & Pharmacology, Karolinska Institutet, Stockholm, Sweden

    Narinder Gautam, Per Hedqvist & Lennart Lindbom

  2. Department of Cell and Molecular Biology, Lund University, Lund, Sweden

    A. Maria Olofsson, Heiko Herwald & Evy Lundgren-Åkerlund

  3. Novo Nordisk A/S, Bagsvaerd, Denmark

    Lars F. Iversen & Hans Flodgaard

  4. Sidney Kimmel Cancer Center, San Diego, California, USA

    Karl-E. Arfors

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  1. Narinder Gautam
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Correspondence to Lennart Lindbom.

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Gautam, N., Maria Olofsson, A., Herwald, H. et al. Heparin-binding protein (HBP/CAP37): A missing link in neutrophil-evoked alteration of vascular permeability. Nat Med 7, 1123–1127 (2001). https://doi.org/10.1038/nm1001-1123

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