Neuropeptide neurotensin stimulates intestinal wound healing following chronic intestinal inflammation.
Because neurotensin (NT) and its high-affinity receptor (NTR1) modulate immune responses, chloride secretion, and epithelial cell proliferation, we sought to investigate their role in the repair process that follows the development of mucosal injuries during a persistent inflammation. Colonic NT and NTR1, mRNA, and protein significantly increased only after dextran sodium sulfate (DSS)-induced inflammatory damage developed. Colitis-induced body weight loss, colonic myeloperoxidase activity, and histological damage were significantly enhanced by SR-48642 administration, a nonpeptide NTR1 antagonist, whereas continuous NT infusion ameliorated colitis outcome. To evaluate the NT and NTR1 role in tissue healing, mucosal inflammatory injury was established administering 3% DSS for 5 days. After DSS discontinuation, mice rapidly gained weight, ulcers were healed, and colonic NT, NTR1, and cyclooxygenase (COX)-2 mRNA levels were upregulated, whereas SR-48642 treatment caused a further body weight loss, ulcer enlargement, and a blunted colonic COX-2 mRNA upregulation. In a wound-healing model in vitro, NT-induced cell migration in the denuded area was inhibited by indomethacin but not by an antitransforming growth factor-beta neutralizing antibody. Furthermore, NT significantly increased COX-2 mRNA levels by 2.4-fold and stimulated PGE(2) release in HT-29 cells. These findings suggest that NT and NTR1 are part of the network activated after mucosal injuries and that NT stimulates epithelial restitution at least, in part, through a COX-2 dependent pathway.
Brun
Paola
P
Dept. of Histology, Microbiology and Medical Biotechnologies, Univ. of Padua, School of Pharmacy, Via A. Gabelli 63, Padua, 35121 Italy.
Mastrotto
Cristina
C
Beggiao
Elisa
E
Stefani
Annalisa
A
Barzon
Luisa
L
Sturniolo
Giacomo C
GC
Palù
Giorgio
G
Castagliuolo
Ignazio
I
D000818:Animals; D016022:Case-Control Studies; D002460:Cell Line; D002908:Chronic Disease; D003092:Colitis / Q000139:chemically induced / Q000503:physiopathology; D003093:Colitis, Ulcerative / Q000503:physiopathology; D016264:Dextran Sulfate; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D007413:Intestinal Mucosa / Q000378:metabolism / Q000503:physiopathology; D007422:Intestines / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009496:Neurotensin / Q000235:genetics / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D018028:Receptors, Neurotensin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012720:Severity of Illness Index; D014945:Wound Healing / Q000187:drug effects
D011720:Pyrazoles; D011804:Quinolines; D012333:RNA, Messenger; D018028:Receptors, Neurotensin; C114036:neurotensin type 1 receptor; C079087:SR 48692; D009496:Neurotensin; D016264:Dextran Sulfate