Connective tissue growth factor is a regulator for fibrosis in human chronic pancreatitis.
OBJECTIVE
To evaluate the parameters that mediate fibrogenesis in chronic pancreatitis (CP).


BACKGROUND
Connective tissue growth factor (CTGF), which is regulated by transforming growth factor beta (TGF-beta), has recently been implicated in skin fibrosis and atherosclerosis. In the present study, the authors analyzed the concomitant presence of TGF-beta1 and its signaling receptors-TGF-beta receptor I, subtype ALK5 (TbetaR-I(ALK5)), and TGF-beta receptor II (TbetaR-II)-as well as CTGF and collagen type I in the pancreatic tissue of patients undergoing surgery for chronic pancreatitis.


METHODS
CP tissue samples were obtained from 40 patients (8 women, 32 men) undergoing pancreatic resection. Tissue samples of 25 previously healthy organ donors (12 women, 13 men) served as controls. The expression of TGF-beta1, TbetaR-I(ALK5), TbetaR-II, CTGF, and collagen type I was studied by Northern blot analysis. By in situ hybridization and immunohistochemistry, the respective mRNA moieties and proteins were localized in the tissue samples.


RESULTS
Northern blot analysis showed that CP tissue samples exhibited concomitant enhanced mRNA expression of TGF-beta1 (38-fold), TbetaR-II (5-fold), CTGF (25-fold), and collagen type I (24-fold) compared with normal controls. In addition, TbetaR-I(ALK5) mRNA was increased in 50% of CP tissue samples (1.8-fold). By in situ hybridization, TGF-beta1, TbetaR-I(ALK5), and TbetaR-II mRNA were often seen to be colocalized, especially in the ductal cells and in metaplastic areas where atrophic acinar cells appeared to dedifferentiate into ductal structures. In contrast, CTGF was located in degenerating acinar cells and principally in fibroblasts surrounding these areas. Moreover, CTGF mRNA expression levels correlated positively with the degree of fibrosis in CP tissues.


CONCLUSIONS
The concomitant overexpression of CTGF, collagen type I, TGF-beta1, and its signaling receptors in CP suggests that these proteins contribute to enhanced extracellular matrix synthesis and accumulation, resulting finally in the fibrogenesis observed in CP.
Department of Visceral and Transplantation Surgery, University of Bern, Inselspital, Switzerland.
F F
FF
di Mola
H
H
Friess
M E
ME
Martignoni
P
P
Di Sebastiano
A
A
Zimmermann
P
P
Innocenti
H
H
Graber
L I
LI
Gold
M
M
Korc
M W
MW
Büchler
D000328:Adult; D000368:Aged; D015152:Blotting, Northern; D002352:Carrier Proteins / Q000032:analysis / Q000502:physiology*; D002908:Chronic Disease; D003094:Collagen / Q000032:analysis; D055513:Connective Tissue Growth Factor; D005260:Female; D005355:Fibrosis / Q000209:etiology; D006133:Growth Substances / Q000032:analysis / Q000502:physiology*; D006801:Humans; D017874:Immediate-Early Proteins; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D008875:Middle Aged; D010195:Pancreatitis / Q000473:pathology*; D018125:Receptors, Transforming Growth Factor beta / Q000032:analysis; D015291:Transforming Growth Factors / Q000032:analysis
C526317:CCN2 protein, human; D002352:Carrier Proteins; D006133:Growth Substances; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D018125:Receptors, Transforming Growth Factor beta; D055513:Connective Tissue Growth Factor; D015291:Transforming Growth Factors; D003094:Collagen