Transforming growth factor-beta pathway is activated in cholecystolithiasis.
BACKGROUND
The etiopathogenesis of cholecystolithiasis is not well defined. Primary dysmotility of the organ, due to fibrosis of the gallbladder wall or muscular dysfunction, is suggested as a crucial factor. Transforming growth factor-beta (TGF-beta) and connective tissue growth factor (CTGF) are involved in several fibrotic disorders and play a critical role in fibrogenesis, thereby changing the physiological function of the organs. In the present study we analyzed the role of TGF-beta and its downstream target CTGF in patients with cholecystolithiasis.


METHODS
Gallbladders were obtained from 16 individuals undergoing surgery for symptomatic cholecystolithiasis. Normal human gallbladder tissue samples from five individuals without any history of gallbladder disease were obtained through an organ donor transplantation program. Northern blot analysis, in situ hybridization, and immunohistochemistry were used to analyze the expression of TGF-beta1 and CTGF in the gallbladder tissue samples.


RESULTS
By northern blot analysis there was an enhanced TGF-beta1 mRNA expression (eightfold increase; P < 0.04) in the cholecystolithiasis tissue samples in comparison with normal controls. There was also a concomitant increase in CTGF (41-fold increase; P < 0.01). By in situ hybridization and immunohistochemistry, CTGF mRNA was localized mainly in the mucosa layer, while intensive staining of the smooth muscle cells with TGF-beta1 and CTGF was observed. In addition, TGF-beta1 immunoreactivity was also localized in the fibroblasts and inflammatory cells. TGF-beta1 m-RNA levels showed a significant relationship with the degree of fibrosis in the tissue samples (P < 0.04, r = 0.5).


CONCLUSIONS
Our data indicate that TGF-beta and CTGF are involved in ultrastructural tissue changes in patients with cholecystolithiasis. Activation of the "TGF-beta pathway," predominantly in the remaining mucosa and submucosal layer, indicates that extracellular matrix (ECM) synthesis with subsequent gallbladder wall fibrosis is an important step in gallbladder dysfunction in this disorder.
Köninger
Jörg
J
Department of General Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany.
di Mola
Fabio F
FF
Di Sebastiano
Pierluigi
P
Gardini
Andrea
A
Brigstock
David R
DR
Innocenti
Paolo
P
Büchler
Markus W
MW
Friess
Helmut
H
D000328:Adult; D015152:Blotting, Northern; D041761:Cholecystolithiasis / Q000378:metabolism*; D055513:Connective Tissue Growth Factor; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005260:Female; D005355:Fibrosis; D005704:Gallbladder / Q000378:metabolism* / Q000473:pathology; D016473:Gallbladder Emptying; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D018969:Insulin-Like Growth Factor Binding Proteins / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008297:Male; D012333:RNA, Messenger / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*
C526317:CCN2 protein, human; D016326:Extracellular Matrix Proteins; D017874:Immediate-Early Proteins; D018969:Insulin-Like Growth Factor Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D055513:Connective Tissue Growth Factor