Figure 3. Molecular determinants of tissue fibrosis.
The main pathways governing profibrotic signaling. Extracellular profibrotic signaling molecules like angiotensin-II (Ang-II), transforming growth factor-β1 (TGFβ), platelet-derived growth-factor (PDGF) and connective- tissue growth-factor (CTGF) activate membrane receptors coupled to downstream signaling which leads to enhanced gene-transcription to increase extracellular matrix (ECM) production. Fibroblast ion-channels control Ca2+-entry to regulate fibroblast activation. For additional discussion, see text. Abbreviations: bb, integrin receptor oblast activation; Ang-II, angiotensin- II; AP, activator-protein; AT1R, angiotensin-II type-1 receptor; CTGF, connective-tissue growth- factor; ER, endoplasmic reticulum; ERK1/2, extracellular signal-related kinase-1/2; ERK-P, phosphorylated extracellular signal-related kinase; Grb2, growth-factor receptor binding-protein 2; IK1, inward-rectifier K+-channel; IP3, inositol 1,4,5-trisphosphate; JAK, Janus kinase; JNK, c-jun N-terminal kinase; LOX, lysyl oxidase; MAPK, mitogen-activated protein kinase; MMP, matrix metalloproteinase; NADPH, nicotine adenine dinucleotide-phosphate; NF-κB, nuclear factor-kappa B; NLRP3, NACHT-, LRR- and PYD domains-containing protein 3; PKC, protein-kinase C; PDGF, platelet-derived growth factor; PDGFR, PDGF-receptor; PIP2, phosphatidylinositol bisphosphate; PLC, phospholipase-C; ROC, receptor-operated channel; ROS, reactive-oxygen species; Shc, src homologous and collagen protein; SMAD, sma- and mad-related proteins; SOC, store-operated channel; SOS, son of sevenless protein; Src, sarcoma proto-oncogene tyrosine kinase; STAT, signal transducers and activators of transcription; TAK1, TGFTGF TAK1, ed kinase-1; TF, transcription factor; TGFβR, transforming growth factor β receptor; TIMP, tissue inhibitor of matrix metalloproteinase; TRP, transient receptor potential; TSS, transcriptional start site.