1 3931 84 LIVER INJURY AND THE ACTIVATION OF THE HEPATIC MYOFIBROBLASTS. LIVER FIBROSIS IS A WOUND HEALING PROCESS, THE END RESULT OF CHRONIC LIVER INJURY ELICITED BY DIFFERENT NOXIOUS STIMULI. ACTIVATED HEPATIC STELLATE CELLS OR MYOFIBROBLASTS AND PORTAL MYOFIBROBLASTS ARE CONSIDERED AS THE MAIN PRODUCERS OF THE EXTRACELLULAR MATRIX IN THE LIVER. UPON LIVER INJURY THE QUIESCENT STELLATE CELLS TRANSDIFFERENTIATE INTO MYOFIBROBLASTS A PROCESS HIGHLIGHTED BY THE LOSS OF VITAMIN A STORES, UPREGULATION OF INTERSTITIAL TYPE COLLAGENS, SMOOTH MUSCLE ALPHA ACTIN, MATRIX METALLOPROTEINASES, PROTEOGLYCANS, AND THE INDUCTION OF CELL SURVIVAL PATHWAYS. ACTIVATION OF HEPATIC STELLATE CELLS IS A RESULT OF A COMPLEX INTERPLAY BETWEEN THE PARENCHYMAL CELLS, IMMUNE CELLS, EXTRACELLULAR MATRIX MECHANICS AND EXTRAHEPATIC MILIEU SUCH AS THE GUT MICROBIOME. IN THIS REVIEW WE WILL FOCUS ON THE PATHOMECHANISM OF STELLATE CELL ACTIVATION FOLLOWING CHRONIC LIVER INJURY; WITH THE AIM OF IDENTIFYING POSSIBLE TREATMENT TARGETS FOR ANTI-FIBROGENIC AGENTS. 2013 2 3512 25 IDIOPATHIC PULMONARY FIBROSIS. IDIOPATHIC PULMONARY FIBROSIS IS A DEVASTATING, AGE-RELATED LUNG DISEASE OF UNKNOWN CAUSE THAT HAS FEW TREATMENT OPTIONS. THIS DISEASE WAS ONCE THOUGHT TO BE A CHRONIC INFLAMMATORY PROCESS, BUT CURRENT EVIDENCE INDICATES THAT THE FIBROTIC RESPONSE IS DRIVEN BY ABNORMALLY ACTIVATED ALVEOLAR EPITHELIAL CELLS (AECS). THESE CELLS PRODUCE MEDIATORS THAT INDUCE THE FORMATION OF FIBROBLAST AND MYOFIBROBLAST FOCI THROUGH THE PROLIFERATION OF RESIDENT MESENCHYMAL CELLS, ATTRACTION OF CIRCULATING FIBROCYTES, AND STIMULATION OF THE EPITHELIAL TO MESENCHYMAL TRANSITION. THE FIBROBLAST AND MYOFIBROBLAST FOCI SECRETE EXCESSIVE AMOUNTS OF EXTRACELLULAR MATRIX, MAINLY COLLAGENS, RESULTING IN SCARRING AND DESTRUCTION OF THE LUNG ARCHITECTURE. THE MECHANISMS THAT LINK IDIOPATHIC PULMONARY FIBROSIS WITH AGEING AND ABERRANT EPITHELIAL ACTIVATION ARE UNKNOWN; EVIDENCE SUGGESTS THAT THE ABNORMAL RECAPITULATION OF DEVELOPMENTAL PATHWAYS AND EPIGENETIC CHANGES HAVE A ROLE. IN THIS SEMINAR, WE REVIEW RECENT DATA ON THE CLINICAL COURSE, THERAPEUTIC OPTIONS, AND UNDERLYING MECHANISMS THOUGHT TO BE INVOLVED IN THE PATHOGENESIS OF IDIOPATHIC PULMONARY FIBROSIS. 2011 3 4501 25 MORPHOGENS AND HEPATIC STELLATE CELL FATE REGULATION IN CHRONIC LIVER DISEASE. HEPATIC STELLATE CELLS (HSC) ARE THE LIVER MESENCHYMAL CELL TYPE WHICH RESPONDS TO HEPATOCELLULAR DAMAGE AND PARTICIPATES IN WOUND HEALING. ALTHOUGH HSC MYOFIBROBLASTIC TRANS-DIFFERENTIATION (ACTIVATION) IS IMPLICATED IN EXCESSIVE EXTRACELLULAR MATRIX DEPOSITION, MOLECULAR UNDERSTANDING OF THIS PHENOTYPIC SWITCH FROM THE VIEWPOINT OF CELL FATE REGULATION IS LIMITED. RECENT STUDIES DEMONSTRATE THE ROLES OF ANTI-ADIPOGENIC MORPHOGENS (WNT, NECDIN, SHH) IN EPIGENETIC REPRESSION OF THE HSC DIFFERENTIATION GENE PPARGAMMA AS A CAUSAL EVENT IN HSC ACTIVATION. THESE MORPHOGENS HAVE POSITIVE CROSS-INTERACTIONS WHICH CONVERGE TO EPIGENETIC REPRESSION OF PPARGAMMA INVOLVING THE METHYL-CPG BINDING PROTEIN MECP2. HOWEVER, THESE MORPHOGENS EXPRESSED BY ACTIVATED HSC MAY ALSO PARTICIPATE IN CROSS-TALK BETWEEN HSC AND HEPATOBLASTS/HEPATOCYTES TO SUPPORT LIVER REGENERATION, AND THEIR ABERRANT REGULATION MAY CONTRIBUTE TO LIVER TUMORIGENESIS. IMPLICATIONS OF HSC-DERIVED MORPHOGENS IN THESE POSSIBILITIES ARE DISCUSSED. 2012 4 6910 21 [TRANSFORMING GROWTH FACTOR-BETA AND RENAL FIBROSIS]. TRANSFORMING GROWTH FACTOR-BETA (TGF-BETA) IS A DRIVING FORCE OF RENAL FIBROSIS, WHICH MAY LEAD TO CHRONIC KIDNEY DISEASES AND EVEN END STAGE RENAL DISEASES. BY ACTIVATING CANONICAL AND NON-CANONICAL SIGNALING PATHWAYS, TGF-BETA PROMOTES THE SYNTHESIS OF EXTRACELLULAR MATRIX WHILE PREVENTING THEIR DEGRADATION. IN THE INJURED KIDNEY, TGF-BETA INDUCES APOPTOSIS, PROLIFERATION AND FIBROTIC RESPONSE OF RENAL CELLS INCLUDING EPITHELIAL CELLS, ENDOTHELIAL CELLS, PODOCYTES, FIBROBLASTS, PERICYTES AND MACROPHAGES, AND IT ALSO PROMOTES TRANSDIFFERENTIATION, ACTIVATION AND PROLIFERATION OF MYOFIBROBLASTS. ADDITIONALLY, TGF-BETA EXERTS PROFIBROTIC EFFECTS BY INTERPLAYING WITH OTHER SIGNALING PATHWAYS LIKE BMP-7, WNT/BETA-CATENIN AND MAP KINASE. SMAD3 IS THE CENTRAL PATHOLOGICAL GENE IN RENAL FIBROSIS, AND EPIGENETIC REGULATION OF TGF-BETA/SMAD3 IS A HOT TOPIC IN KIDNEY FIELD. ALTHOUGH DIRECT TARGETING TGF-BETA MAY CAUSE SIDE EFFECTS INCLUDING TUMORIGENESIS AND IMMUNE DISEASES, THE THERAPEUTIC STRATEGIES TARGETING THE BALANCE OF DOWNSTREAM SMAD3 AND SMAD7 MAY PREVENT OR DELAY THE PROGRESSION OF FIBROTIC KIDNEY DISEASE. 2018 5 4749 24 NOVEL PROSPECTS FOR SCARLESS WOUND HEALING: THE ROLES OF MYOFIBROBLASTS AND ADIPOCYTES. DISTURBANCES OR DEFECTS IN THE PROCESS OF WOUND REPAIR CAN DISRUPT THE DELICATE BALANCE OF CELLS AND MOLECULES NECESSARY FOR COMPLETE WOUND HEALING, THUS LEADING TO CHRONIC WOUNDS OR FIBROTIC SCARS. MYOFIBROBLASTS ARE ONE OF THE MOST IMPORTANT CELLS INVOLVED IN FIBROTIC SCARS, AND REPROGRAMMING PROVIDES A POTENTIAL AVENUE TO INCREASE MYOFIBROBLAST CLEARANCE. ALTHOUGH MYOFIBROBLASTS HAVE LONG BEEN RECOGNIZED AS TERMINALLY DIFFERENTIATED CELLS, RECENT STUDIES HAVE SHOWN THAT MYOFIBROBLASTS HAVE THE CAPACITY TO BE REPROGRAMMED INTO ADIPOCYTES. THIS REVIEW INTENDS TO SUMMARIZE THE POTENTIAL OF REPROGRAMMING MYOFIBROBLASTS INTO ADIPOCYTES. WE WILL DISCUSS MYOFIBROBLAST LINEAGE TRACING, AS WELL AS THE KNOWN MECHANISMS UNDERLYING ADIPOCYTE REGENERATION FROM MYOFIBROBLASTS. IN ADDITION, WE INVESTIGATED DIFFERENT CHANGES IN MYOFIBROBLAST GENE EXPRESSION, TRANSCRIPTIONAL REGULATORS, SIGNALLING PATHWAYS AND EPIGENETIC REGULATORS DURING SKIN WOUND HEALING. IN THE FUTURE, MYOFIBROBLAST REPROGRAMMING IN WOUND HEALING WILL BE BETTER UNDERSTOOD AND APPRECIATED, WHICH MAY PROVIDE NEW IDEAS FOR THE TREATMENT OF SCARLESS WOUND HEALING. 2022 6 4358 24 MIR-338-3P BLOCKS TGFBETA-INDUCED MYOFIBROBLAST DIFFERENTIATION THROUGH THE INDUCTION OF PTEN. IDIOPATHIC PULMONARY FIBROSIS (IPF) IS A CHRONIC INTERSTITIAL LUNG DISEASE. THE PATHOGENESIS OF IPF IS NOT COMPLETELY UNDERSTOOD. HOWEVER, NUMEROUS GENES ARE ASSOCIATED WITH THE DEVELOPMENT AND PROGRESSION OF PULMONARY FIBROSIS, INDICATING THERE IS A SIGNIFICANT GENETIC COMPONENT TO THE PATHOGENESIS OF IPF. EPIGENETIC INFLUENCES ON THE DEVELOPMENT OF HUMAN DISEASE, INCLUDING PULMONARY FIBROSIS, REMAIN TO BE FULLY ELUCIDATED. IN THIS PAPER, WE IDENTIFY MIR-338-3P AS A MICRORNA SEVERELY DOWNREGULATED IN THE LUNGS OF PATIENTS WITH PULMONARY FIBROSIS AND IN EXPERIMENTAL MODELS OF PULMONARY FIBROSIS. TREATMENT OF PRIMARY HUMAN LUNG FIBROBLASTS WITH MIR-338-3P INHIBITS MYOFIBROBLAST DIFFERENTIATION AND MATRIX PROTEIN PRODUCTION. PUBLISHED AND PROPOSED TARGETS OF MIR-338-3P SUCH AS TGFBETA RECEPTOR 1, MEK/ERK 1/2, CDK4, AND CYCLIN D ARE ALSO NOT RESPONSIBLE FOR THE REGULATION OF PULMONARY FIBROBLAST BEHAVIOR BY MIR-338-3P. MIR-338-3P INHIBITS MYOFIBROBLAST DIFFERENTIATION BY PREVENTING TGFBETA-MEDIATED DOWNREGULATION OF PHOSPHATASE AND TENSIN HOMOLOG (PTEN), A KNOWN ANTIFIBROTIC MEDIATOR. 2022 7 5733 24 SMALL MOLECULES AGAINST THE ORIGIN AND ACTIVATION OF MYOFIBROBLAST FOR RENAL INTERSTITIAL FIBROSIS THERAPY. RENAL INTERSTITIAL FIBROSIS (RIF) IS A COMMON PATHOLOGICAL RESPONSE IN A BROAD RANGE OF PREVALENT CHRONIC KIDNEY DISEASES AND ULTIMATELY LEADS TO RENAL FAILURE AND DEATH. ALTHOUGH RIF CAUSES A HIGH MORBI-MORTALITY WORLDWIDE, EFFECTIVE THERAPEUTIC DRUGS ARE URGENTLY NEEDED. MYOFIBROBLASTS ARE IDENTIFIED AS THE MAIN EFFECTOR DURING THE PROCESS OF RIF. MULTIPLE TYPES OF CELLS, INCLUDING FIBROBLASTS, EPITHELIAL CELLS, ENDOTHELIAL CELLS, MACROPHAGES AND PERICYTES, CONTRIBUTE TO RENAL MYOFIBROBLASTS ORIGIN, AND LOTS OF MEDIATORS, INCLUDING SIGNALING PATHWAYS (TRANSFORMING GROWTH FACTOR-BETA1, MAMMALIAN TARGET OF RAPAMYCIN AND REACTIVE OXYGEN SPECIES) AND EPIGENETIC MODIFICATIONS (HISTONE ACETYLATION, MICRORNA AND LONG NON-CODING RNA) ARE PARTICIPATED IN RENAL MYOFIBROBLASTS ACTIVATION DURING RENAL FIBROGENESIS, SUGGESTING THAT THESE MEDIATORS MAY BE THE PROMISING TARGETS FOR TREATING RIF. IN ADDITION, MANY SMALL MOLECULES SHOW PROFOUND THERAPEUTIC EFFECTS ON RIF BY SUPPRESSING THE ORIGIN AND ACTIVATION OF RENAL MYOFIBROBLASTS. TAKEN TOGETHER, THE REVIEW FOCUSES ON THE MECHANISMS OF THE ORIGIN AND ACTIVATION OF RENAL MYOFIBROBLASTS IN RIF AND THE SMALL MOLECULES AGAINST THEM IMPROVING RIF, WHICH WILL PROVIDE A NEW INSIGHT FOR RIF THERAPY. 2021 8 3674 27 INFLAMMATION AND DYSREGULATED FIBROBLAST PROLIFERATION--NEW MECHANISMS? IDIOPATHIC PULMONARY FIBROSIS (IPF) IS A DEVASTATING, AGE-RELATED LUNG DISEASE OF UNKNOWN CAUSE THAT HAS FEW TREATMENT OPTIONS. ONCE THOUGHT TO BE A CHRONIC INFLAMMATORY PROCESS, CURRENT EVIDENCE INDICATES THAT THE FIBROTIC RESPONSE MAY PRIMARILY BE DRIVEN BY ABNORMALLY ACTIVATED ALVEOLAR EPITHELIAL CELLS AND THE UNDERLYING MESENCHYME. THE MEDIATORS PRODUCED AND PRESENT IN THIS MICROENVIRONMENT INDUCE THE FORMATION OF FIBROBLAST FOCI THROUGH THE PROLIFERATION OF RESIDENT MESENCHYMAL CELLS, ATTRACTION OF CIRCULATING FIBROCYTES, AND STIMULATION OF EPITHELIAL TO MESENCHYMAL TRANSITION. THE FIBROBLAST AND MYOFIBROBLAST FOCI SECRETE EXCESSIVE AMOUNTS OF EXTRACELLULAR MATRIX, MAINLY COLLAGENS, RESULTING IN SCARRING AND DESTRUCTION OF THE LUNG ARCHITECTURE. THE DETAILED MECHANISMS THAT LINK IPF WITH AGEING AND ABERRANT EPITHELIAL ACTIVATION ARE UNKNOWN, BUT SOME EVIDENCE SUGGESTS THAT THE ABNORMAL RECAPITULATION OF DEVELOPMENTAL PATHWAYS AND EPIGENETIC CHANGES MAY PLAY A ROLE. THIS REVIEW PROVIDES A BRIEF SYNOPSIS OF HIGHLIGHTS IN THE CURRENT UNDERSTANDING OF THE PATHOPHYSIOLOGY OF IPF, AS WELL AS NOVEL THERAPEUTICS BEING EXPLORED IN CLINICAL TRIALS FOR THE TREATMENT OF THIS DEVASTATING DISEASE. 2013 9 3245 23 HEPATIC STELLATE CELLS AS KEY TARGET IN LIVER FIBROSIS. PROGRESSIVE LIVER FIBROSIS, INDUCED BY CHRONIC VIRAL AND METABOLIC DISORDERS, LEADS TO MORE THAN ONE MILLION DEATHS ANNUALLY VIA DEVELOPMENT OF CIRRHOSIS, ALTHOUGH NO ANTIFIBROTIC THERAPY HAS BEEN APPROVED TO DATE. TRANSDIFFERENTIATION (OR "ACTIVATION") OF HEPATIC STELLATE CELLS IS THE MAJOR CELLULAR SOURCE OF MATRIX PROTEIN-SECRETING MYOFIBROBLASTS, THE MAJOR DRIVER OF LIVER FIBROGENESIS. PARACRINE SIGNALS FROM INJURED EPITHELIAL CELLS, FIBROTIC TISSUE MICROENVIRONMENT, IMMUNE AND SYSTEMIC METABOLIC DYSREGULATION, ENTERIC DYSBIOSIS, AND HEPATITIS VIRAL PRODUCTS CAN DIRECTLY OR INDIRECTLY INDUCE STELLATE CELL ACTIVATION. DYSREGULATED INTRACELLULAR SIGNALING, EPIGENETIC CHANGES, AND CELLULAR STRESS RESPONSE REPRESENT CANDIDATE TARGETS TO DEACTIVATE STELLATE CELLS BY INDUCING REVERSION TO INACTIVATED STATE, CELLULAR SENESCENCE, APOPTOSIS, AND/OR CLEARANCE BY IMMUNE CELLS. CELL TYPE- AND TARGET-SPECIFIC PHARMACOLOGICAL INTERVENTION TO THERAPEUTICALLY INDUCE THE DEACTIVATION WILL ENABLE MORE EFFECTIVE AND LESS TOXIC PRECISION ANTIFIBROTIC THERAPIES. 2017 10 699 24 BROMODOMAIN PROTEIN 4 IS A KEY MOLECULAR DRIVER OF TGFBETA1-INDUCED HEPATIC STELLATE CELL ACTIVATION. LIVER FIBROSIS IS CHARACTERIZED BY THE EXCESSIVE DEPOSITION OF EXTRACELLULAR MATRIX IN LIVER. CHRONIC LIVER INJURY INDUCES THE ACTIVATION OF HEPATIC STELLATE CELL (HSCS), A KEY STEP IN LIVER FIBROGENESIS. THE ACTIVATED HSC IS THE PRIMARY SOURCE OF ECM AND CONTRIBUTES SIGNIFICANTLY TO LIVER FIBROSIS. TGFBETA1 IS THE MOST POTENT PRO-FIBROTIC CYTOKINE. BROMODOMAIN PROTEIN 4 (BRD4), AN EPIGENETIC READER OF HISTONE ACETYLATION MARKS, WAS CRUCIAL FOR PROFIBROTIC GENE EXPRESSION IN HSCS. THE PRESENT STUDY AIMED TO INVESTIGATE THE ROLES OF BRD4 IN TGFBETA1-DEPENDENT HSC ACTIVATION AND LIVER FIBROSIS, FOCUSING ON TGFBETA1-INDUCED ALTERATIONS OF THE LEVELS OF THE FIBROTIC-RELATED IMPORTANT PROTEINS IN HSCS BY EMPLOYING THE HETEROZYGOUS TGFBETA1 KNOCKOUT MICE AND BRD4 KNOCKDOWN IN VIVO AND IN VITRO. RESULTS REVEALED THAT BRD4 PROTEIN LEVEL WAS SIGNIFICANTLY UPREGULATED BY TGFBETA1 AND BRD4 KNOCKDOWN REDUCED TGFBETA1-INDUCED HSC ACTIVATION AND LIVER FIBROSIS. BRD4 WAS REQUIRED FOR THE INFLUENCES OF TGFBETA1 ON PDGFBETA RECEPTOR AND ON THE PATHWAYS OF SMAD3, STAT3, AND AKT. BRD4 ALSO MEDIATED TGFBETA1-INDUCED INCREASES IN HISTONE ACETYLTRANSFERASE P300, THE PIVOTAL PRO-INFLAMMATORY NFKB P65, AND TISSUE INHIBITOR OF METALLOPROTEINASE 1 WHEREAS BRD4 REDUCED CASPASE-3 PROTEIN LEVELS IN HSCS DURING LIVER INJURY, INDEPENDENT OF TGFBETA1. FURTHER EXPERIMENTS INDICATED THE INTERACTION BETWEEN TGFBETA1-INDUCED BRD4 AND NFKB P65 IN HSCS AND IN LIVER OF TAA-INDUCED LIVER INJURY. HUMAN CIRRHOTIC LIVERS WERE DEMONSTRATED A PARALLEL INCREASE IN THE PROTEIN LEVELS OF BRD4 AND NFKB P65 IN HSCS. THIS STUDY REVEALED THAT BRD4 WAS A KEY MOLECULAR DRIVER OF TGFBETA1-INDUCED HSC ACTIVATION AND LIVER FIBROSIS. 2023 11 5993 19 TGFBETA PROMOTES FIBROSIS BY MYST1-DEPENDENT EPIGENETIC REGULATION OF AUTOPHAGY. ACTIVATION OF FIBROBLASTS IS ESSENTIAL FOR PHYSIOLOGICAL TISSUE REPAIR. UNCONTROLLED ACTIVATION OF FIBROBLASTS, HOWEVER, MAY LEAD TO TISSUE FIBROSIS WITH ORGAN DYSFUNCTION. ALTHOUGH SEVERAL PATHWAYS CAPABLE OF PROMOTING FIBROBLAST ACTIVATION AND TISSUE REPAIR HAVE BEEN IDENTIFIED, THEIR INTERPLAY IN THE CONTEXT OF CHRONIC FIBROTIC DISEASES REMAINS INCOMPLETELY UNDERSTOOD. HERE, WE PROVIDE EVIDENCE THAT TRANSFORMING GROWTH FACTOR-BETA (TGFBETA) ACTIVATES AUTOPHAGY BY AN EPIGENETIC MECHANISM TO AMPLIFY ITS PROFIBROTIC EFFECTS. TGFBETA INDUCES AUTOPHAGY IN FIBROTIC DISEASES BY SMAD3-DEPENDENT DOWNREGULATION OF THE H4K16 HISTONE ACETYLTRANSFERASE MYST1, WHICH REGULATES THE EXPRESSION OF CORE COMPONENTS OF THE AUTOPHAGY MACHINERY SUCH AS ATG7 AND BECLIN1. ACTIVATION OF AUTOPHAGY IN FIBROBLASTS PROMOTES COLLAGEN RELEASE AND IS BOTH, SUFFICIENT AND REQUIRED, TO INDUCE TISSUE FIBROSIS. FORCED EXPRESSION OF MYST1 ABROGATES THE STIMULATORY EFFECTS OF TGFBETA ON AUTOPHAGY AND RE-ESTABLISHES THE EPIGENETIC CONTROL OF AUTOPHAGY IN FIBROTIC CONDITIONS. INTERFERENCE WITH THE ABERRANT ACTIVATION OF AUTOPHAGY INHIBITS TGFBETA-INDUCED FIBROBLAST ACTIVATION AND AMELIORATES EXPERIMENTAL DERMAL AND PULMONARY FIBROSIS. THESE FINDINGS LINK UNCONTROLLED TGFBETA SIGNALING TO ABERRANT AUTOPHAGY AND DEREGULATED EPIGENETICS IN FIBROTIC DISEASES AND MAY CONTRIBUTE TO THE DEVELOPMENT OF THERAPEUTIC INTERVENTIONS IN FIBROTIC DISEASES. 2021 12 5992 25 TGF-BETA: THE MASTER REGULATOR OF FIBROSIS. TRANSFORMING GROWTH FACTOR-BETA (TGF-BETA) IS THE PRIMARY FACTOR THAT DRIVES FIBROSIS IN MOST, IF NOT ALL, FORMS OF CHRONIC KIDNEY DISEASE (CKD). INHIBITION OF THE TGF-BETA ISOFORM, TGF-BETA1, OR ITS DOWNSTREAM SIGNALLING PATHWAYS SUBSTANTIALLY LIMITS RENAL FIBROSIS IN A WIDE RANGE OF DISEASE MODELS WHEREAS OVEREXPRESSION OF TGF-BETA1 INDUCES RENAL FIBROSIS. TGF-BETA1 CAN INDUCE RENAL FIBROSIS VIA ACTIVATION OF BOTH CANONICAL (SMAD-BASED) AND NON-CANONICAL (NON-SMAD-BASED) SIGNALLING PATHWAYS, WHICH RESULT IN ACTIVATION OF MYOFIBROBLASTS, EXCESSIVE PRODUCTION OF EXTRACELLULAR MATRIX (ECM) AND INHIBITION OF ECM DEGRADATION. THE ROLE OF SMAD PROTEINS IN THE REGULATION OF FIBROSIS IS COMPLEX, WITH COMPETING PROFIBROTIC AND ANTIFIBROTIC ACTIONS (INCLUDING IN THE REGULATION OF MESENCHYMAL TRANSITIONING), AND WITH COMPLEX INTERPLAY BETWEEN TGF-BETA/SMADS AND OTHER SIGNALLING PATHWAYS. STUDIES OVER THE PAST 5 YEARS HAVE IDENTIFIED ADDITIONAL MECHANISMS THAT REGULATE THE ACTION OF TGF-BETA1/SMAD SIGNALLING IN FIBROSIS, INCLUDING SHORT AND LONG NONCODING RNA MOLECULES AND EPIGENETIC MODIFICATIONS OF DNA AND HISTONE PROTEINS. ALTHOUGH DIRECT TARGETING OF TGF-BETA1 IS UNLIKELY TO YIELD A VIABLE ANTIFIBROTIC THERAPY DUE TO THE INVOLVEMENT OF TGF-BETA1 IN OTHER PROCESSES, GREATER UNDERSTANDING OF THE VARIOUS PATHWAYS BY WHICH TGF-BETA1 CONTROLS FIBROSIS HAS IDENTIFIED ALTERNATIVE TARGETS FOR THE DEVELOPMENT OF NOVEL THERAPEUTICS TO HALT THIS MOST DAMAGING PROCESS IN CKD. 2016 13 6053 14 THE CRUCIAL ROLE OF NLRP3 INFLAMMASOME IN VIRAL INFECTION-ASSOCIATED FIBROSING INTERSTITIAL LUNG DISEASES. IDIOPATHIC PULMONARY FIBROSIS (IPF), ONE OF THE MOST COMMON FIBROSING INTERSTITIAL LUNG DISEASES (ILD), IS A CHRONIC-AGE-RELATED RESPIRATORY DISEASE THAT RISES FROM REPEATED MICRO-INJURY OF THE ALVEOLAR EPITHELIUM. ENVIRONMENTAL INFLUENCES, INTRINSIC FACTORS, GENETIC AND EPIGENETIC RISK FACTORS THAT LEAD TO CHRONIC INFLAMMATION MIGHT BE IMPLICATED IN THE DEVELOPMENT OF IPF. THE EXACT TRIGGERS THAT INITIATE THE FIBROTIC RESPONSE IN IPF REMAIN ENIGMATIC, BUT THERE IS NOW INCREASING EVIDENCE SUPPORTING THE ROLE OF CHRONIC EXPOSURE OF VIRAL INFECTION. DURING VIRAL INFECTION, ACTIVATION OF THE NLRP3 INFLAMMASOME BY INTEGRATING MULTIPLE CELLULAR AND MOLECULAR SIGNALING IMPLICATES ROBUST INFLAMMATION, FIBROBLAST PROLIFERATION, ACTIVATION OF MYOFIBROBLAST, MATRIX DEPOSITION, AND ABERRANT EPITHELIAL-MESENCHYMAL FUNCTION. OVERALL, THE CROSSTALK OF THE NLRP3 INFLAMMASOME AND VIRUSES CAN ACTIVATE IMMUNE RESPONSES AND INFLAMMASOME-ASSOCIATED MOLECULES IN THE DEVELOPMENT, PROGRESSION, AND EXACERBATION OF IPF. 2021 14 4661 14 NEW ASPECTS OF THE EPIGENETIC REGULATION OF EMT RELATED TO PULMONARY FIBROSIS. PULMONARY FIBROSIS IS A CHRONIC AND PROGRESSIVE FIBROTIC DISEASE THAT RESULTS IN IMPAIRED GAS EXCHANGE, VENTILATION, AND EVENTUAL DEATH. THE PRO-FIBROTIC ENVIRONMENT IS INSTIGATED BY VARIOUS FACTORS, LEADING TO THE TRANSFORMATION OF EPITHELIAL CELLS INTO MYOFIBROBLASTS AND/OR FIBROBLASTS THAT TRIGGER FIBROSIS. EPITHELIAL MESENCHYMAL TRANSITION (EMT) IS A BIOLOGICAL PROCESS THAT PLAYS A CRITICAL ROLE IN THE PATHOGENESIS OF PULMONARY FIBROSIS. EPIGENETIC REGULATION OF TISSUE-STROMAL CROSSTALK INVOLVING DNA METHYLATION, HISTONE MODIFICATIONS, NON-CODING RNA, AND CHROMATIN REMODELING PLAYS A KEY ROLE IN THE CONTROL OF EMT. THE REVIEW INVESTIGATES THE EPIGENETIC REGULATION OF EMT AND ITS SIGNIFICANCE IN PULMONARY FIBROSIS. 2023 15 692 27 BRD4 PROMOTES HEPATIC STELLATE CELLS ACTIVATION AND HEPATIC FIBROSIS VIA MEDIATING P300/H3K27AC/PLK1 AXIS. HEPATIC FIBROSIS (HF) IS A REVERSIBLE WOUND-HEALING RESPONSE CHARACTERIZED BY EXCESSIVE EXTRACELLULAR MATRIX (ECM) DEPOSITION AND SECONDARY TO PERSISTENT CHRONIC INJURY. BROMODOMAIN PROTEIN 4 (BRD4) COMMONLY FUNCTIONS AS A "READER" TO REGULATE EPIGENETIC MODIFICATIONS INVOLVED IN VARIOUS BIOLOGICAL AND PATHOLOGICAL EVENTS, BUT THE MECHANISM OF HF REMAINS UNCLEAR. IN THIS STUDY, WE ESTABLISHED A CCL(4)-INDUCED HF MODEL AND SPONTANEOUS RECOVERY MODEL IN MICE AND FOUND ABERRANT BRD4 EXPRESSION, WHICH WAS CONSISTENT WITH THE RESULTS IN HUMAN HEPATIC STELLATE CELLS (HSCS)- LX2 CELLS IN VITRO. SUBSEQUENTLY, WE FOUND THAT DISTRICTION AND INHIBITION OF BRD4 RESTRAINED TGFBETA-INDUCED TRANS-DIFFERENTIATION OF LX2 CELLS INTO ACTIVATED, PROLIFERATIVE MYOFIBROBLASTS AND ACCELERATED APOPTOSIS, AND BRD4 OVEREXPRESSION BLOCKED MDI-INDUCED LX2 CELLS INACTIVATION AND PROMOTED THE PROLIFERATION AND INHIBITED APOPTOSIS OF INACTIVATED CELLS. ADDITIONALLY, ADENO-ASSOCIATED VIRUS SEROTYPE 8-LOADED SHORT HAIRPIN RNA-MEDIATED BRD4 KNOCKDOWN IN MICE SIGNIFICANTLY ATTENUATED CCL(4)-INDUCED FIBROTIC RESPONSES INCLUDING HSCS ACTIVATION AND COLLAGEN DEPOSITION. MECHANISTICALLY, BRD4 DEFICIENCY INHIBITED PLK1 EXPRESSION IN ACTIVATED LX2 CELLS, AND CHIP AND CO-IP ASSAYS REVEALED THAT BRD4 REGULATION OF PLK1 WAS DEPENDENT ON P300-MEDIATED ACETYLATION MODIFICATION FOR H3K27 ON THE PLK1 PROMOTER. IN CONCLUSION, BRD4 DEFICIENCY IN THE LIVER ALLEVIATES CCL(4)-INDUCED HF IN MICE, AND BRD4 PARTICIPATES IN THE ACTIVATION AND REVERSAL OF HSCS THROUGH POSITIVELY REGULATING THE P300/H3K27AC/PLK1 AXIS, PROVIDING A POTENTIAL INSIGHT FOR HF THERAPY. 2023 16 2817 23 FIBROSIS IN THE LIVER: ACUTE PROTECTION AND CHRONIC DISEASE. THE UNDERSTANDING OF THE CELLULAR AND MOLECULAR MECHANISMS OF THE FIBROTIC WOUND-HEALING RESPONSE OF THE LIVER HAS MADE DRAMATIC PROGRESS IN THE PAST 20 YEARS. HEPATIC STELLATE CELLS (HSCS), WHICH AFTER LIVER INJURY PROLIFERATE AND TRANSDIFFERENTIATE TO MYOFIBROBLASTS, HAVE EMERGED AS THE PRIMARY SOURCE OF THE FIBROTIC RESPONSE, EVEN THOUGH OTHER FIBROGENIC CELLS MAY ALSO CONTRIBUTE TO THE PRODUCTION OF EXTRACELLULAR MATRIX (ECM). ADVANCES IN THE UNDERSTANDING OF HSC REGULATION INCLUDE APOPTOTIC SIGNALING, ANGIOGENIC SIGNALING, AND RESPONSES TO OXIDATIVE STRESS. THE ECM HAS EMERGED NOT ONLY AS A STRUCTURAL SCAFFOLD, BUT ALSO AS A DYNAMIC AND INTERACTIVE MATRIX REGULATING STELLATE CELL ACTIVATION. ADDITIONALLY, THE INNATE IMMUNE SYSTEM AND IMMUNE SIGNALING, AS WELL AS A BROADENING UNDERSTANDING OF THE TRANSCRIPTIONAL REGULATION INCLUDING MICRORNAS AND EPIGENETIC EVENTS OFFER POTENTIAL THERAPEUTIC TARGETS. UNRAVELING GENETIC DETERMINANTS RELATED TO MECHANISMS OF HEPATIC FIBROGENESIS PROMISE INDIVIDUALIZED THERAPY OR PREVENTION. HEPATIC FIBROSIS AND CIRRHOSIS HAVE EMERGED AS TREATABLE AND POTENTIALLY REVERSIBLE CONSEQUENCE OF CHRONIC LIVER DISEASE. 2010 17 4448 31 MOLECULAR MECHANISM AND TREATMENT OF VIRAL HEPATITIS-RELATED LIVER FIBROSIS. HEPATIC FIBROSIS IS A WOUND-HEALING RESPONSE TO VARIOUS CHRONIC STIMULI, INCLUDING VIRAL HEPATITIS B OR C INFECTION. ACTIVATED MYOFIBROBLASTS, PREDOMINANTLY DERIVED FROM THE HEPATIC STELLATE CELLS (HSCS), REGULATE THE BALANCE BETWEEN MATRIX METALLOPROTEINASES AND THEIR TISSUE INHIBITORS TO MAINTAIN EXTRACELLULAR MATRIX HOMEOSTASIS. TRANSFORMING GROWTH FACTOR-BETA AND PLATELET-DERIVED GROWTH FACTOR ARE CLASSIC PROFIBROGENIC SIGNALS THAT ACTIVATE HSC PROLIFERATION. IN ADDITION, PROINFLAMMATORY CYTOKINES AND CHEMOKINES COORDINATE MACROPHAGES, T CELLS, NK/NKT CELLS, AND LIVER SINUSOIDAL ENDOTHELIAL CELLS IN COMPLEX FIBROGENIC AND REGRESSION PROCESSES. IN ADDITION, FIBROGENESIS INVOLVES ANGIOGENESIS, METABOLIC REPROGRAMMING, AUTOPHAGY, MICRORNA, AND EPIGENETIC REGULATIONS. HEPATIC INFLAMMATION IS THE DRIVING FORCE BEHIND LIVER FIBROSIS; HOWEVER, HOST SINGLE NUCLEOTIDE POLYMORPHISMS AND VIRAL FACTORS, INCLUDING THE GENOTYPE, VIRAL LOAD, VIRAL MUTATION, AND VIRAL PROTEINS, HAVE BEEN ASSOCIATED WITH FIBROSIS PROGRESSION. ELIMINATING THE UNDERLYING ETIOLOGY IS THE MOST CRUCIAL ANTIFIBROTIC THERAPY. GROWING EVIDENCE HAS INDICATED THAT PERSISTENT VIRAL SUPPRESSION WITH ANTIVIRAL THERAPY CAN RESULT IN FIBROSIS REGRESSION, REDUCED LIVER DISEASE PROGRESSION, DECREASED HEPATOCELLULAR CARCINOMA, AND IMPROVED CHANCES OF SURVIVAL. PRECLINICAL STUDIES AND CLINICAL TRIALS ARE CURRENTLY EXAMINING SEVERAL INVESTIGATIONAL AGENTS THAT TARGET KEY FIBROGENIC PATHWAYS; THE RESULTS ARE PROMISING AND SHED LIGHT ON THIS DEBILITATING ILLNESS. 2014 18 6757 32 WNT SIGNALING IN LIVER FIBROSIS: PROGRESS, CHALLENGES AND POTENTIAL DIRECTIONS. LIVER FIBROSIS IS A COMMON WOUND-HEALING RESPONSE TO CHRONIC LIVER INJURIES, INCLUDING ALCOHOLIC OR DRUG TOXICITY, PERSISTENT VIRAL INFECTION, AND GENETIC FACTORS. MYOFIBROBLASTIC TRANSDIFFERENTIATION (MTD) IS THE PIVOTAL EVENT DURING LIVER FIBROGENESIS, AND RESEARCH IN THE PAST FEW YEARS HAS IDENTIFIED KEY MEDIATORS AND MOLECULAR MECHANISMS RESPONSIBLE FOR MTD OF HEPATIC STELLATE CELLS (HSCS). HSCS ARE UNDIFFERENTIATED CELLS WHICH PLAY AN IMPORTANT ROLE IN LIVER REGENERATION. RECENT EVIDENCE DEMONSTRATES THAT HSCS DERIVE FROM MESODERM AND AT LEAST IN PART VIA SEPTUM TRANSVERSUM AND MESOTHELIUM, AND HSCS EXPRESS MARKERS FOR DIFFERENT CELL TYPES WHICH DERIVE FROM MULTIPOTENT MESENCHYMAL PROGENITORS. THERE IS A REGULATORY COMMONALITY BETWEEN DIFFERENTIATION OF ADIPOCYTES AND THAT OF HSC, AND THE SHIFT FROM ADIPOGENIC TO MYOGENIC OR NEURONAL PHENOTYPE CHARACTERIZES HSC MTD. CENTRAL OF THIS SHIFT IS A LOSS OF EXPRESSION OF THE MASTER ADIPOGENIC REGULATOR PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA (PPARGAMMA). RESTORED EXPRESSION OF PPARGAMMA AND/OR OTHER ADIPOGENIC TRANSCRIPTION GENES CAN REVERSE MYOFIBROBLASTIC HSCS TO DIFFERENTIATED CELLS. VERTEBRATE WNT AND DROSOPHILA WINGLESS ARE HOMOLOGOUS GENES, AND THEIR TRANSLATED PROTEINS HAVE BEEN SHOWN TO PARTICIPATE IN THE REGULATION OF CELL PROLIFERATION, CELL POLARITY, CELL DIFFERENTIATION, AND OTHER BIOLOGICAL ROLES. MORE RECENTLY, WNT SIGNALING IS IMPLICATED IN HUMAN FIBROSING DISEASES, SUCH AS PULMONARY FIBROSIS, RENAL FIBROSIS, AND LIVER FIBROSIS. BLOCKING THE CANONICAL WNT SIGNAL PATHWAY WITH THE CO-RECEPTOR ANTAGONIST DICKKOPF-1 (DKK1) ABROGATES THESE EPIGENETIC REPRESSIONS AND RESTORES THE GENE PPARGAMMA EXPRESSION AND HSC DIFFERENTIATION. THE IDENTIFIED MORPHOGEN MEDIATED EPIGENETIC REGULATION OF PPARGAMMA AND HSC DIFFERENTIATION ALSO SERVES AS NOVEL THERAPEUTIC TARGETS FOR LIVER FIBROSIS AND LIVER REGENERATION. IN CONCLUSION, THE WNT SIGNALING PROMOTES LIVER FIBROSIS BY ENHANCING HSC ACTIVATION AND SURVIVAL, AND WE HEREIN DISCUSS WHAT WE CURRENTLY KNOW AND WHAT WE EXPECT WILL COME IN THIS FIELD IN THE NEXT FUTURE. 2013 19 5939 31 TARGETING MECHANOTRANSDUCTION AT THE TRANSCRIPTIONAL LEVEL: YAP AND BRD4 ARE NOVEL THERAPEUTIC TARGETS FOR THE REVERSAL OF LIVER FIBROSIS. LIVER FIBROSIS IS THE RESULT OF A DEREGULATED WOUND HEALING PROCESS CHARACTERIZED BY THE EXCESSIVE DEPOSITION OF EXTRACELLULAR MATRIX. HEPATIC STELLATE CELLS (HSCS), WHICH ARE ACTIVATED IN RESPONSE TO LIVER INJURY, ARE THE MAJOR SOURCE OF EXTRACELLULAR MATRIX AND DRIVE THE WOUND HEALING PROCESS. HOWEVER, CHRONIC LIVER DAMAGE LEADS TO PERPETUAL HSC ACTIVATION, PROGRESSIVE FORMATION OF PATHOLOGICAL SCAR TISSUE AND ULTIMATELY, CIRRHOSIS AND ORGAN FAILURE. HSC ACTIVATION IS TRIGGERED LARGELY IN RESPONSE TO MECHANOSIGNALING FROM THE MICROENVIRONMENT, WHICH INDUCES A PROFIBROTIC NUCLEAR TRANSCRIPTION PROGRAM THAT PROMOTES HSC PROLIFERATION AND EXTRACELLULAR MATRIX SECRETION THEREBY SETTING UP A POSITIVE FEEDBACK LOOP LEADING TO MATRIX STIFFENING AND SELF-SUSTAINED, PATHOLOGICAL, HSC ACTIVATION. DESPITE THE SIGNIFICANT PROGRESS IN OUR UNDERSTANDING OF LIVER FIBROSIS, THE MOLECULAR MECHANISMS THROUGH WHICH THE EXTRACELLULAR MATRIX PROMOTES HSC ACTIVATION ARE NOT WELL UNDERSTOOD AND NO EFFECTIVE THERAPIES HAVE BEEN APPROVED TO DATE THAT CAN TARGET THIS EARLY, REVERSIBLE, STAGE IN LIVER FIBROSIS. SEVERAL NEW LINES OF INVESTIGATION NOW PROVIDE IMPORTANT INSIGHT INTO THIS AREA OF STUDY AND IDENTIFY TWO NUCLEAR TARGETS WHOSE INHIBITION HAS THE POTENTIAL OF REVERSING LIVER FIBROSIS BY INTERFERING WITH HSC ACTIVATION: YES-ASSOCIATED PROTEIN (YAP), A TRANSCRIPTIONAL CO-ACTIVATOR AND EFFECTOR OF THE MECHANOSENSITIVE HIPPO PATHWAY, AND BROMODOMAIN-CONTAINING PROTEIN 4 (BRD4), AN EPIGENETIC REGULATOR OF GENE EXPRESSION. YAP AND BRD4 ACTIVITY IS INDUCED IN RESPONSE TO MECHANICAL STIMULATION OF HSCS AND EACH PROTEIN INDEPENDENTLY CONTROLS WAVES OF EARLY GENE EXPRESSION NECESSARY FOR HSC ACTIVATION. SIGNIFICANTLY, INHIBITION OF EITHER PROTEIN CAN REVERT THE CHRONIC ACTIVATION OF HSCS AND IMPEDE PATHOLOGICAL PROGRESSION OF LIVER FIBROSIS IN CLINICALLY RELEVANT MODEL SYSTEMS. IN THIS REVIEW WE WILL DISCUSS THE ROLES OF THESE NUCLEAR CO-ACTIVATORS IN HSC ACTIVATION, THEIR MECHANISM OF ACTION IN THE FIBROTIC PROCESS IN THE LIVER AND OTHER ORGANS, AND THE POTENTIAL OF TARGETING THEIR ACTIVITY WITH SMALL MOLECULE DRUGS FOR FIBROSIS REVERSAL. 2016 20 4132 25 MECHANISMS OF HEPATIC FIBROGENESIS. SUBSTANTIAL IMPROVEMENTS IN THE TREATMENT OF CHRONIC LIVER DISEASE HAVE ACCELERATED INTEREST IN UNCOVERING THE MECHANISMS UNDERLYING HEPATIC FIBROSIS AND ITS RESOLUTION. ACTIVATION OF RESIDENT HEPATIC STELLATE CELLS INTO PROLIFERATIVE, CONTRACTILE, AND FIBROGENIC CELLS IN LIVER INJURY REMAINS A DOMINANT THEME DRIVING THE FIELD. HOWEVER, SEVERAL NEW AREAS OF RAPID PROGRESS IN THE PAST 5-10 YEARS ALSO HAVE TAKEN ROOT, INCLUDING: (1) IDENTIFICATION OF DIFFERENT FIBROGENIC POPULATIONS APART FROM RESIDENT STELLATE CELLS, FOR EXAMPLE, PORTAL FIBROBLASTS, FIBROCYTES, AND BONE-MARROW-DERIVED CELLS, AS WELL AS CELLS DERIVED FROM EPITHELIAL MESENCHYMAL TRANSITION; (2) EMERGENCE OF STELLATE CELLS AS FINELY REGULATED DETERMINANTS OF HEPATIC INFLAMMATION AND IMMUNITY; (3) ELUCIDATION OF MULTIPLE PATHWAYS CONTROLLING GENE EXPRESSION DURING STELLATE CELL ACTIVATION INCLUDING TRANSCRIPTIONAL, POST-TRANSCRIPTIONAL, AND EPIGENETIC MECHANISMS; (4) RECOGNITION OF DISEASE-SPECIFIC PATHWAYS OF FIBROGENESIS; (5) RE-EMERGENCE OF HEPATIC MACROPHAGES AS DETERMINANTS OF MATRIX DEGRADATION IN FIBROSIS RESOLUTION AND THE IMPORTANCE OF MATRIX CROSS-LINKING AND SCAR MATURATION IN DETERMINING REVERSIBILITY; AND (6) HINTS THAT HEPATIC STELLATE CELLS MAY CONTRIBUTE TO HEPATIC STEM CELL BEHAVIOR, CANCER, AND REGENERATION. CLINICAL AND TRANSLATIONAL IMPLICATIONS OF THESE ADVANCES HAVE BECOME CLEAR, AND HAVE BEGUN TO IMPACT SIGNIFICANTLY ON THE MANAGEMENT AND OUTLOOK OF PATIENTS WITH CHRONIC LIVER DISEASE. 2008