1). However, for everyone else, the words “ductular reaction” remain an abstraction.

Although evocative in a general way, “ductular reaction” fails to convey the heterogeneity underlying the development, nature, and outcome that is necessary to give clinical or scientific relevance. That such nuances are important is clear from reviewing selleck inhibitor any contemporary literature regarding some of the key questions about hepatic physiology. DRs are now recognized to occur ubiquitously in many acute and chronic liver diseases, not just in biliary disorders, and are increasingly central to our understanding of hepatic stem and progenitor cells in liver regeneration, mechanisms underlying hepatic fibrosis, and hepatobiliary Akt inhibitor carcinogenesis. This review will focus specifically on changes and concepts derived from studies of humans,

not animal models, for concision and because much about human DRs is quite unlike their animal correlates. Although such models remain exceptionally useful, particularly for studies of hepatic regeneration, as far as fibrosis and neoplasia are concerned, the rodent models display very different processes from those seen in human livers. Where we include data from animal models, it is because they are clearly relevant to humans or they provide insights for which no human data are available. Our key emphasis will be on the diversity of DRs, the word “diverse” applying in several ways. DRs show strikingly diverse patterns that are Arachidonate 15-lipoxygenase often diagnostically specific, varying markedly, for example, between predominantly biliary and hepatocellular injuries and acute or chronic processes (Fig. 1). DRs also contain a profound diversity of cellular and tissue elements, not just the hepatobiliary epithelial cells that are most prominent on quick glance (the “ductular” component of the name), but all the other elements of the tissue “reaction” (Fig. 2). The

epithelial cells themselves show a range of differentiation states, particularly when studied by immunohistochemical expression (Fig. 3). There is also diversity of cell origin, with, in the most studied example, “intermediate hepatobiliary cells” of DRs shown to derive, variously, from activation of canals of Hering (CoH) and ductules (Fig. 4), circulating, marrow-derived precursors, biliary metaplasia of hepatocytes, and perhaps from mesenchymal-to-epithelial transition. Diverse molecular signaling pathways are also known to mediate human DRs and are the aspects of DRs perhaps best revealed by animal model analysis.5 We thus present a view of DRs from our own dual perspectives as research scientists and as diagnosticians who analyze DRs in daily clinical practice. We hope these combined perspectives will be of value for those investigators and clinicians who do not have the privilege of such intimate, daily contact with this increasingly fascinating realm, this “diversity at the interface.