Corticotropin-releasing hormone antagonists possess anti-inflammatory effects in the mouse ileum.
OBJECTIVE
Corticotropin-releasing hormone (CRH) released at local sites of inflammation promotes inflammation in the periphery. We investigated its effects in the intestinal responses caused by toxin A from Clostridium difficile, the causative agent of antibiotic-associated colitis.


METHODS
Ileal loops were injected with 10 microg of toxin A, and enterotoxic responses were measured at various time points.


RESULTS
Pretreatment of mice with 2.5 microg/kg of the CRH receptor antagonist alpha-helical CRH((9-41)) that blocks both CRH receptor subtypes reduced toxin A-mediated ileal secretion, epithelial cell damage, mucosal edema, neutrophil infiltration, and mucosal content of interleukin 1 beta and tumor necrosis factor alpha. Pretreatment with the specific CRH(1) receptor antagonist antalarmin (20 mg/kg, IP) also inhibited toxin A-induced fluid secretion and toxin A-associated histologic changes. CRH messenger RNA and protein were increased in mouse ileum 30 minutes after intraluminal toxin A administration. In situ hybridization and immunohistochemistry demonstrated that toxin A at 1 hour caused a substantial increase in the expression of both CRH receptor subtypes in the ileal mucosa.


CONCLUSIONS
Peripheral CRH may play a proinflammatory role in toxin A-induced intestinal secretion and inflammation and that CRH(1) receptor, at least in part, is important in the mediation of these responses.
Wlk
Michael
M
Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115, USA.
Wang
Chi C
CC
Venihaki
Maria
M
Liu
Jennifer
J
Zhao
Dezheng
D
Anton
Pauline M
PM
Mykoniatis
Andreas
A
Pan
Amy
A
Zacks
Jeff
J
Karalis
Katia
K
Pothoulakis
Charalabos
C
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001427:Bacterial Toxins / Q000633:toxicity; D003346:Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000494:pharmacology* / Q000502:physiology; D004751:Enteritis / Q000188:drug therapy* / Q000209:etiology; D006727:Hormone Antagonists / Q000494:pharmacology*; D007082:Ileum / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D011743:Pyrimidines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000893:Anti-Inflammatory Agents; D001427:Bacterial Toxins; D006727:Hormone Antagonists; D011743:Pyrimidines; D011758:Pyrroles; D012333:RNA, Messenger; C069206:alpha helical corticotropin-releasing hormone; C103016:antalarmin; C029294:toxin A (Pseudomonas); D003346:Corticotropin-Releasing Hormone