The Expression Of IGFBPrP1 In Liver Tissue From Patients With Hepatic Cirrhosis And Its Relationship With TGF-β1/Smad Pathway

Background: Liver cirrhosis is a common liver disease, which is chronic, progressive, diffusive and caused by different reasons. TGF-β1 is at present the key cytokine in this process^[4]. Smad3 is a downstream molecular and plays an important role in the TGF-β1/ Smad pathway. Researches on the function of IGFBPs are hot spots in the world. WillemBoers^[19] used the technique of serial analysis of gene expression (SAGE) to identify genes involved in the transformation of HSC into myofi-broblasts and discovered that: IGFBP-rP1 showed the highest expression in the midphase of the transdifferentiation process.Dr Lixin Liu have found that IGFBPrP1's expression increased in activated HSC induced by TGF-β1, and anti-IGFBPrP1 antibody can reverse over-production of collagenⅠinduced by TGF-β1 activated HSC^[8]; in patients with liver fibrosis and cirrhosis, the expression of IGFBPrP1 was much higher in liver tissue than in normal^[16]; IGFBPrP1 could activate HSC in vitro, which is dose independent at some extent^[21], In order to investigate the function and mechanism of IGFBPrP1 in the development of liver cirrhosis, we designed this research program.Objective: To identify the expression of IGFBPrP1 in liver tissue from patients with hepatic cirrhosis and its relationship with TGF-β1/Smad3 pathway.Methods: 31 patients in the First Hospital of Shanxi Medical University from Jan. 2002 to Dec. 2007 were recruited, including 16 cases of liver cirrhosis and 15 cases of hemangiomas of liver surrounding healthy controls. The cirrhotic group has 10 males and 6 female, between the age of 43-61 (48.63 + 9.08); the control group contains 6 males and 9 females, aged from 41 to 91 (53.13±13.73). These paraffin samples of liver tissue were collected in the Pathology department. Take continuous sections of 5μm. HE and Masson straining were used to observe the morphological differences between these two groups. The expressions of IGFBPrP1, TGF-β1 and Smad3 were detected by immunohistochemistry staining. Collect the reports of serum HA levels of the 16 patients in the cirrhotic group. Analyze these data using IPP and SPSS 13.0 softwares.Results: 1. HE staining shows that in the control group hepatocytes have normal shape and line up in order; in the cirrhotic group, the structure of the hepatic lobules are destroyed and replace by sudlobes. Hepatocytes in it are swelling and disordered. Portal areas have enlarged fibrous intervals. 2. The production of collagen was much higher than that of control group (6.347%±1.353% vs 1.120%±0.212%, P＜0.01). 3. The result of immunohistochemical staining: Very few hepatocyte and sinus hepaticus had positive expression of TGF-β1 in the normal liver; in the cirrhotic group, sinus hepaticus, portal area and fibrous interval had stronger positive staining. Smad3 had a wide and low level of expression in hepatocytes of normal liver tissue; in the cirrhotic group, the color of positive expression increased in hepatocytes, along with stellate cell plasma in sinus hepaticus, portal area and fibrous intervals. IGFBPrP1 expressed in a few hepatocytes in the normal liver; in the cirrhotic group, plasma of HSC, Kupffer cell, fibroblasts in sinus hepaticus, portal area and fibrous intervals and some hepatocytes had stronger positive expression. 4. The expressions of TGF-β1, Smad3 and IGFBPrP1 were largely increased in cirrhotic group, compared with normal control (3900.04±742.05 vs 522.56±124.77, P＜0.01; 32083.22±8270.7 vs 5401.23±1470.07, P＜0.01; 37102.82±7449.23 vs 6597.85±2041.46, P＜0.01). 5. IGFBPrP1's expression has significant positive correlation to that of ECM, TGF-β1 , Smad3(r=0.880, 0.886, 0.900; P＜0.01). 6. Serum HA levels of the 16 patients in the cirrhotic group are much higher than normal (586.84±503.95). IGFBPrP1 in cirrhotic group also has positive correlation with serum HA (r=0.524, P＜0.005).Conclusions: (1) The expressions of IGFBPrP1, TGF-β1 and Smad3 were largely increased in cirrhotic group, compared with normal control. The expressions of liver IGFBPrP1 has positive correlation with that of TGF-β1, Smad3 and serum HA. (2) IGFBPrPl may play an important role in the occurrence and development of liver cirrhosis, which is probably related to TGF-β1/Smad3 pathway.