Neuropeptide neurotensin stimulates intestinal wound healing following chronic intestinal inflammation

• Published in: American journal of physiology: Gastrointestinal and liver physiology 2005-04, Vol.288 (4), p.G621-G629
• Main Authors: Brun, Paola, Mastrotto, Cristina, Beggiao, Elisa, Stefani, Annalisa, Barzon, Luisa, Sturniolo, Giacomo C, Palù, Giorgio, Castagliuolo, Ignazio
• Format: Article
• Language: English
• Subjects: Animals; Case-Control Studies; Cell Line; Chronic Disease; Colitis - chemically induced; Colitis - physiopathology; Colitis, Ulcerative - physiopathology; Dextran Sulfate; Humans; Inflammatory Bowel Diseases - metabolism; Inflammatory Bowel Diseases - pathology; Inflammatory Bowel Diseases - physiopathology; Intestinal Mucosa - metabolism; Intestinal Mucosa - physiopathology; Intestines - metabolism; Intestines - physiopathology; Male; Mice; Mice, Inbred BALB C; Neurotensin - genetics; Neurotensin - metabolism; Pyrazoles - pharmacology; Quinolines - pharmacology; Receptors, Neurotensin - antagonists & inhibitors; Receptors, Neurotensin - genetics; Receptors, Neurotensin - metabolism; RNA, Messenger - metabolism; Severity of Illness Index; Wound Healing - drug effects
• ISSN: 0193-1857; 1522-1547
• DOI: 10.1152/ajpgi.00140.2004

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.