Clostridium difficile toxin A-induced microvascular dysfunction. Role of histamine.
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.
Department of Physiology, Shreveport 71130.
I
I
Kurose
C
C
Pothoulakis
J T
JT
LaMont
D C
DC
Anderson
J C
JC
Paulson
M
M
Miyasaka
R
R
Wolf
D N
DN
Granger
D000818:Animals; D001427:Bacterial Toxins / Q000633:toxicity*; D002448:Cell Adhesion / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000032:analysis / Q000502:physiology; D016360:Clostridioides difficile / Q000472:pathogenicity*; D004768:Enterotoxins / Q000633:toxicity*; D006632:Histamine / Q000502:physiology*; D007962:Leukocytes / Q000187:drug effects / Q000502:physiology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012709:Serum Albumin / Q000378:metabolism; D014699:Venules / Q000187:drug effects* / Q000502:physiology
D001427:Bacterial Toxins; D015815:Cell Adhesion Molecules; D004768:Enterotoxins; D012709:Serum Albumin; C041348:tcdA protein, Clostridium difficile; D006632:Histamine