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Clostridium-difficile toxin a-induced microvascular dysfunction - role of histamine

Academic Article
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Overview

authors

  • Kurose, I.
  • Pothoulakis, C.
  • Lamont, J. T.
  • Anderson, D. C.
  • Paulson, James
  • Miyasaka, M.
  • Wolf, R.
  • Granger, D. N.

publication date

  • November 1994

journal

  • Journal of Clinical Investigation  Journal

abstract

  • Clostridium difficile toxin A (Tx-A) mediates secretion and inflammation in experimental enterocolitis. Intravital video microscopy was used to define the mechanisms that underlie the inflammatory reactions elicited by direct exposure of the microvasculature to Tx-A. Leukocyte adherence and emigration, leukocyte-platelet aggregation, and extravasation of FITC-albumin were monitored in rat mesenteric venules exposed to Tx-A. Significant increases in leukocyte adherence and emigration (LAE) and albumin leakage were noted within 15-30 min of Tx-A exposure. These responses were accompanied by mast cell degranulation and the formation of platelet-leukocyte aggregates. The Tx-A-induced increases in LAE and albumin leakage were significantly attenuated by pretreatment with either monoclonal antibodies (mAbs) directed against the leukocyte adhesion glycoproteins, CD11/CD18, intercellular adhesion molecule-1, and P-selectin (but not E-selectin) or with sialyl Lewis x, a counter-receptor for P-selectin. The mast cell stabilizer, lodoxamide, an H1- (but not an H2-) receptor antagonist, and diamine oxidase (histaminase) were also effective in reducing the LAE and albumin leakage elicited by Tx-A. The platelet-leukocyte aggregation response was blunted by an mAb against P-selectin, sialyl Lewis x, and the H1-receptor antagonist. These observations indicate that Tx-A induces a leukocyte-dependent leakage of albumin from postcapillary venules. Mast cell-derived histamine appears to mediate at least part of the leukocyte-endothelial cell adhesion and platelet-leukocyte aggregation by engaging H1-receptors on endothelial cells and platelets to increase the expression of P-selectin. The adhesion glycoproteins CD11/CD18 and intercellular adhesion molecule-1 also contribute to the inflammatory responses elicited by toxin A.

subject areas

  • Animals
  • Bacterial Toxins
  • Cell Adhesion
  • Cell Adhesion Molecules
  • Clostridium difficile
  • Enterotoxins
  • Histamine
  • Leukocytes
  • Male
  • Rats
  • Rats, Sprague-Dawley
  • Serum Albumin
  • Venules
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Research

keywords

  • LEUKOCYTE-ENDOTHELIAL CELL ADHESION
  • MAST CELL DEGRANULATION
  • PLATELET-LEUKOCYTE AGGREGATION
  • POSTCAPILLARY VENULES
  • VASCULAR ALBUMIN LEAKAGE
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Identity

International Standard Serial Number (ISSN)

  • 0021-9738

Digital Object Identifier (DOI)

  • 10.1172/jci117542

PubMed ID

  • 7962537
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Additional Document Info

start page

  • 1919

end page

  • 1926

volume

  • 94

issue

  • 5

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