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Am J Physiol Gastrointest Liver Physiol 293: G1147-G1154, 2007. First published October 11, 2007; doi:10.1152/ajpgi.00032.2007
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LIVER AND BILIARY TRACT

Increased stiffness of the rat liver precedes matrix deposition: implications for fibrosis

Penelope C. Georges,3,4,* Jia-Ji Hui,1,* Zoltan Gombos,2 Margaret E. McCormick,3 Andrew Y. Wang,1 Masayuki Uemura,1 Rosemarie Mick,5 Paul A. Janmey,3,4 Emma E. Furth,2 and Rebecca G. Wells1,2

Departments of 1Medicine and 2Pathology and Laboratory Medicine; 3Institute for Medicine and Engineering, University of Pennsylvania School of Medicine; 4Department of Bioengineering; and 5Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, Pennsylvania

Submitted 17 January 2007 ; accepted in final form 4 October 2007

Liver fibrosis, the response to chronic liver injury, results from the activation of mesenchymal cells to fibrogenic myofibroblasts. We have recently shown that two key myofibroblast precursor populations, hepatic stellate cells and portal fibroblasts, undergo activation in culture in response to increasing substrate stiffness. We therefore hypothesized that alterations in liver stiffness precede myofibroblast activation and fibrosis in vivo as well. To test this hypothesis, we induced fibrosis in rats by twice weekly injections of carbon tetrachloride (CCl4) and then killed the animals at various time points ranging from 3 to 70 days after the initiation of injury. The shear storage modulus of the whole liver was measured on fresh tissue; fixed and frozen tissue from the same livers was used to quantify fibrosis. We observed that liver stiffness increased immediately and continued to increase, leveling out by day 28. Fibrosis, measured histologically by trichrome staining as well as by quantitative sirius red staining, increased with time, although these increases were delayed relative to changes in stiffness. There was no direct correlation between stiffness and fibrosis at early or late time points. Treatment of a second cohort of rats with the lysyl oxidase inhibitor, β-aminopropionitrile (BAPN), partially prevented early increases in liver stiffness. We concluded that increases in liver stiffness precede fibrosis and potentially myofibroblast activation. Liver stiffness appears to result from matrix cross-linking and possibly other unknown variables in addition to matrix quantity. We suggest that increased liver stiffness may play an important role in initiating the early stages of fibrosis.

hepatic stellate cells; lysyl oxidase; myofibroblast; reticulin; shear storage modulus


Address for reprint requests and other correspondence: Rebecca G. Wells, Univ. of Pennsylvania School of Medicine, Dept. of Medicine (GI), 600 CRB/6140, 415 Curie Blvd., Philadelphia, PA 19104-6140 (e-mail: rgwells{at}mail.med.upenn.edu)




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