Reversal of abnormal collagen production in Crohn's disease intestinal biopsies treated with regenerating agents.
BACKGROUND
Crohn's disease (CD) is characterised by inflammation, muscle layer overgrowth, and collagenous fibrosis of the intestinal tract, with no effective therapy against collagen accumulation.


OBJECTIVE
We quantified production of collagen in resection specimens from normal and CD patients and investigated the effect of regenerating agents (RGTAs) on collagen production. RGTAs are chemically substituted dextrans engineered to mimic the growth factor protecting effects of heparan sulphates. RGTAs have been shown to enhance tissue repair in various in vivo models and to modulate in vitro collagen phenotype differentially according to their structure.


METHODS
We studied intestinal biopsies from two groups of CD patients: treated with glucocorticoids (CD-GC group: 10 patients) or not treated (CD group: seven patients), and from seven control patients.


METHODS
After 24 hours of ex vivo incubation with (3H) proline, collagen I, III, and V were extracted by pepsin and quantitatively separated by sodium dodecyl sulphate-polyacrylamide gel electrophoresis. Biosynthesis of each collagen type was quantified on radiolabelled isolated collagen.


RESULTS
Total intestinal collagen production in CD patients compared with controls was increased up to 3.5-fold overall (p<0.001). In particular, collagen III biosynthesis was enhanced by 6.2-fold (p<0.001) in CD patients. In the CD-GC group, collagen production abnormalities were less marked. RGTAs added to the incubation medium in the CD group decreased total collagen production by 50% and decreased collagen III synthesis by 76%.


CONCLUSIONS
This finding offers a rationale for using RGTAs in the treatment of intestinal fibrosis in CD, thus opening up a potential new therapeutic field for this family of drugs.
Alexakis
C
C
CRRET/CNRS FRE 2412, Université Paris-12, 94010 Créteil, France.
Caruelle
J P
JP
Sezeur
A
A
Cosnes
J
J
Gendre
J P
JP
Mosnier
H
H
Beaugerie
L
L
Gallot
D
D
Malafosse
M
M
Barritault
D
D
Kern
P
P
D000328:Adult; D000368:Aged; D003094:Collagen / Q000032:analysis / Q000096:biosynthesis*; D024061:Collagen Type III / Q000096:biosynthesis; D003424:Crohn Disease / Q000188:drug therapy / Q000378:metabolism*; D046508:Culture Techniques; D003911:Dextrans / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D005938:Glucocorticoids / Q000627:therapeutic use; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D009844:Oligosaccharides / Q000737:chemistry / Q000494:pharmacology*
D024061:Collagen Type III; D003911:Dextrans; D005938:Glucocorticoids; D009844:Oligosaccharides; C431384:RG 1503; C475611:RG1192; D003094:Collagen