Improved Effects of Viral Gene Delivery of Human uPA plus Biliodigestive Anastomosis Induce Recovery from Experimental Biliary Cirrhosis

Abstract

Gene therapy may represent a new avenue for the development of multimodal treatment for diverse forms of cirrhosis. This study explores the potential benefits of combining adenovirus-mediated human urokinase-plasminogen activator (AdHuPA) gene delivery and biliodigestive anastomosis to enhance the therapeutic efficacy of each treatment alone for cholestatic disorders resulting in secondary biliary cirrhosis. In an experimental model of secondary biliary cirrhosis, application of 6 x 10(11) vp/kg AdHuPA adenovirus vector resulted in 25.8% liver fibrosis reduction and some improvement in liver histology. The relief of bile cholestasis by a surgical procedure (biliodigestive anastomosis) combined with AdHuPA hepatic gene delivery rendered a synergistic effect, with a substantial 56.9 to 42.9% fibrosis decrease. AdHuPA transduction resulted in clear-cut expression of human uPA protein detected by immunohistochemistry and induction of up-regulation in the expression of metalloproteinases MMP-3, MMP-9, and MMP-2. Importantly, functional hepatic tests, specifically direct bilirubin, were improved. Also, hepatic cell regeneration, rearrangement of hepatic architecture, ascites, and gastric varices improved in cirrhotic rats treated with AdHuPA but not in counterpart AdGFP cirrhotic animals. We believe this might represent a novel therapeutic strategy for human cholestatic diseases.

Tissue-type plasminogen activator deficiency exacerbates cholestatic liver injury in mice

“…uPA also requires additional factors like binding to uPAR for optimal activity,48, 49 and therefore might have a different spatial and temporal activity pattern than tPA even though liver homogenates have comparable enzymatic activity for both proteases after BDL. While the role of uPA after BDL remains uncertain,50 our data demonstrate that uPA cannot substitute for tPA in this setting. Furthermore, the ability to reverse the effects of PAI‐1 deficiency on BDL‐induced liver injury using tPA‐STOP provides strong suggestive but not conclusive evidence that the protective effects of PAI‐1 deficiency are primarily mediated by increased tPA, and not uPA, activity.…”

Expression of MMPs and TIMPs in liver fibrosis – a systematic review with special emphasis on anti-fibrotic strategies

“…Several MMPs and growth factors have been suggested to contribute to this effect [85,[101][102][103][104]. Thus, declining TIMP-1 levels may lead to an increase in MMP activity thereby exerting two effects: (i) degradation of ECM to allow hepatocyte expansion and (ii) release of ECM-bound pro-HGF (hepatocyte growth factor).…”

Endogenous urokinase lacks antifibrotic activity during progressive renal injury

“…However, they do not clarify the role of endogenous renal uPA during fibrogenesis. Results from other experimental model systems fail to answer this question, as uPA has been reported to promote or attenuate fibrosis, depending on the organ and disease model that is investigated (2,7,9,13,18,21,26,27). To determine the role of uPA in the pathogenesis of chronic renal interstitial fibrosis, disease severity in response to UUO was compared between WT and uPAϪ/Ϫ mice.…”