Fig. 1. The ‘Metro-Rail Concept’ to targeted therapy of the pathophysiology of cirrhosis.

The development of cirrhosis follows well-coordinated steps that begin with the etiology, leading to sustained chronic inflammation (the control or command center; black bubble) that activates and promotes multiple pathways (rail-pathways, colored lines) that feature prominent mediators of inflammation and fibrosis (central stations, grey bubbles) and parallel assisting pathway intermediaries (secondary stations, small white bubbles) that ultimately lead to the destination (red bubble). Therapies that target only few of the pathway mediators do not tend to improve outcomes as expected; however, targeting the command center (etiology) along with controlling the central-stations (central inflammatory and fibrosis pathways) would impede progression to destination (cirrhosis).

Abbreviations: BMDSC, bone marrow-derived stem cells; CCRs, chemokine receptors; CD, cluster of differentiation; CTGF, connective tissue growth factor; ECM, extracellular matrix; HGF, hepatocyte growth factor; HSC, hepatic stellate cell; IL, interleukin; IRF, interferon regulatory factor; JAK/STAT, Janus kinase/signal transducers and activators of transcription; LPS, lipopolysaccharide; MAP, mitogen activated protein; MCP, monocyte chemoattractant protein; MFB, myofibroblasts; NADPH, reduced form of nicotinamide adenine dinucleotide phosphate; NF-kB, nuclear factor kappa B; PDGF, platelet derived growth factor; PHT, portal hypertension; PI3K/Akt, phosphoinositide-3-kinase-protein kinase B; PPAR, peroxisome proliferator-activated receptors; SMA, smooth muscle antibody; SMADs, homologues of the Drosophila protein, mothers against decapentaplegic (Mad) and the Caenorhabditis elegans protein Sma; TGF, transforming growth factor; TIMP, tissue inhibitors of matrix metalloproteinase; TLR, toll-like receptor; TNF, tumor necrosis factor; VEGF, vascular endothelial growth factor.