Inflammation and Hepatic Fibrosis

The modern era of fibrosis research was initiated by pathologists who, through careful study of histological sections, were able to relate excess connective tissue in the liver (fibrosis) to clinical disease. They pointed out that not only is the amount of fibrosis important, but also its localization.[1] This was useful for prognosis and led to formal systems for fibrosis staging.[2] A subject of debate was the way in which the observed fibrous strands or bands formed. Some argued that the process was a passive result of hepatocyte dropout and apposition of preexisting layers of extracellular matrix (ECM, or “ground substance”). Others believed that fibrogenesis was an active process involving the elaboration of scar by specialized fibrogenic cells from within or outside the liver. Starting in the 1950s, Toshio Ito performed morphological studies of lipid-storing cells in the perisinusoidal space of the liver, establishing that this population differed from the liver macrophages named for Kupffer. Calling them “fat-storing” cells, he also showed an association of this cell type with collagen fibrils.[3] In 1976, Kent and colleagues provided ultrastructural evidence for active fibrogenesis by Ito's cells.[4] This was an influential work, confirmed by others,[5] which stimulated further efforts to define the cellular source(s) of excess ECM in injury. Proof of the fibrogenic capability of Ito/fat-storing cells/lipocytes (now known as hepatic stellate cells [HSCs]) came in the mid-1980s when HSCs were isolated, placed in culture,[6] and shown directly to undergo activation and produce ECM proteins.[7] Studies in vivo followed, confirming that this cell type is quantitatively the preeminent producer of collagen and other ECM constituents during injury and repair.[8] Given the implications for intervening in fibrosis progression and liver failure, HSCs became a focus of intensive study.

REFERENCES

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• 4 Kent G, Gay S, Inouye T, Bahu R, Minick O T, Popper H. Vitamin A-containing lipocytes and formation of type III collagen in liver injury.  Proc Natl Acad Sci U S A. 1976;  73 3719-3722
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• 9 Bissell D M, Arenson D M, Maher J J, Roll F J. Support of cultured hepatocytes by a laminin-rich gel. Evidence for a functionally significant subendothelial matrix in normal rat liver.  J Clin Invest. 1987;  79 801-812
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