Direct evidence of mast cell involvement in Clostridium difficile toxin A-induced enteritis in mice.
OBJECTIVE
The pathogenesis of Clostridium difficile toxin A-induced intestinal inflammation is not completely understood. The aim of this study was to define the contribution of mast cells to the fluid secretion and neutrophil infiltration associated with toxin A-induced enteritis.


METHODS
Fluid secretion and neutrophil infiltration in toxin A- or buffer-challenged ileal loops were assessed in normal, mast cell-deficient, and mast cell-deficient KitW/KitW-v mice that had undergone selective repair of their mast cell deficiency. The effect of a specific substance P-receptor antagonist was also studied.


RESULTS
Intestinal fluid secretion and neutrophil recruitment were significantly diminished in mast cell-deficient KitW/KitW-v and mast cell-deficient MgfSl/MgfSl-d mice compared with the respective normal mice. Mast cell-reconstituted KitW/KitW-v mice showed responses similar to the normal congenic mice. Administration of a specific substance P-receptor antagonist (CP-96,345) reduced toxin A-induced intestinal fluid secretion and inhibited neutrophil infiltration in normal, mast cell-deficient KitW/KitW-v, and mast cell-reconstituted KitW/KitW-v mice.


CONCLUSIONS
C. difficile toxin A elicits intestinal fluid secretion and neutrophil infiltration by both mast cell-dependent and -independent pathways, and substance P participates in both pathways.
Wershil
B K
BK
Combined Program in Pediatric Gastroenterology and Nutrition, Children's Hospital and Massachusetts General Hospital, Boston, Massachusetts, USA. bwershil@bidmc.harvard.edu
Castagliuolo
I
I
Pothoulakis
C
C
D000818:Animals; D001427:Bacterial Toxins; D001713:Biphenyl Compounds / Q000494:pharmacology; D001826:Body Fluids / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D004751:Enteritis / Q000139:chemically induced* / Q000378:metabolism; D004768:Enterotoxins; D007413:Intestinal Mucosa / Q000378:metabolism; D008297:Male; D008407:Mast Cells / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains / Q000378:metabolism; D064729:Neurokinin-1 Receptor Antagonists; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology; D012016:Reference Values
D001427:Bacterial Toxins; D001713:Biphenyl Compounds; D004768:Enterotoxins; D064729:Neurokinin-1 Receptor Antagonists; C041348:tcdA protein, Clostridium difficile; C066892:CP 96345