Cathelicidins might help prevent, treat colonic fibrosis
Peptides known as cathelicidins directly inhibited collagen synthesis in human colonic fibroblasts and in mice with colitis, authors of a controlled, prospective study reported. The findings appeared Nov. 11 in Cellular and Molecular Gastroenterology and Hepatology.
“Our results strongly suggest that cathelicidin administration may be a novel approach to prevent or treat inflammatory bowel disease and IBD-related colonic fibrosis,” said Dr. Jun Hwan Yoo at the University of California, Los Angeles, and his associates.
Cathelicidins are endogenous antimicrobial peptides that exhibit “potent” anti-inflammatory effects against acute colitis, and inhibit colonic fibrosis in mice with chronic or infectious colitis, the investigators said. In past studies, cathelicidin-deficient mice were more susceptible to infections, had poorer wound healing, and developed worse colitis, compared with mice that were not cathelicidin deficient, they added. Cathelicidins also inhibit collagen synthesis in human dermal fibroblasts, they said (Cellular and Molecular Gastroenterology and Hepatology 2014 Nov. 11 10.1016/j.jcmgh.2014.08.001 [doi:10.1016/j.jcmgh.2014.08.001]).
To further explore the role of cathelicidins in intestinal fibrosis, Dr. Yoo and associates created two murine models of intestinal inflammation by infecting mice with Salmonella or by administering trinitrobenzene sulfonic acid enemas. Then they administered either intracolonic mCRAMP peptide at a dose of 5 mg/kg every 3 days, or intravenous injections of a lentivirus that overexpressed the cathelicidin gene. The researchers also exposed human intestinal fibroblasts and human colonic CCD-18Co fibroblasts to transforming growth factor beta1 (TGF-beta1) or to insulinlike growth factor 1, which induced collagen protein and mRNA expression that mimicked intestinal fibrosis. Then they exposed these cells to 3-5 mcm of the human cathelicidin LL-37.
The groups of mice with colitis had significantly higher colonic expression of collagen mRNA and significantly more colon tissue damage than did the normal controls, said the researchers. Mice with colitis that received mCRAMP or lentivirus-overexpressing cathelicidin gene had significantly lower collagen mRNA levels and less cecal and colonic collagen deposition, compared with mice that received only the vehicle control, they added (all P values less than .05). Intracolonic mCRAMP also restored body weight (P = .0178) in mice with colitis, compared with untreated controls, they added. Furthermore, LL-37 inhibited collagen synthesis in human intestinal and colonic fibroblasts (P = .0001), they said.
The research was supported by the UCLA CURE Center, the Crohn’s and Colitis Foundation of America, the National Institutes of Health, the Blinder Research Foundation for Crohn’s Disease, the Eli and Edythe Broad Chair, and the U.S. Public Health Service. The authors declared no conflicts of interest.