1 1702 117 DYNAMIC SELF-GUIDING ANALYSIS OF ALZHEIMER'S DISEASE. WE APPLIED A SELF-GUIDING EVOLUTIONARY ALGORITHM TO INITIATE THE SYNTHESIS OF THE ALZHEIMER'S DISEASE-RELATED DATA AND LITERATURE. A PROTEIN INTERACTION NETWORK ASSOCIATED WITH AMYLOID-BETA PRECURSOR PROTEIN (APP) AND A SEED MODEL THAT TREATS ALZHEIMER'S DISEASE AS PROGRESSIVE DYSREGULATION OF APP-ASSOCIATED SIGNALING WERE USED AS DYNAMIC "GUIDES" AND STRUCTURAL "FILTERS" IN THE RECURSIVE SEARCH, ANALYSIS, AND ASSIMILATION OF DATA TO DRIVE THE EVOLUTION OF THE SEED MODEL IN SIZE, DETAIL, AND COMPLEXITY. ANALYSIS OF DATA AND LITERATURE ACROSS SUB-DISCIPLINES AND SYSTEM-SCALE DISCOVERY PLATFORMS SUGGESTS A KEY ROLE OF DYNAMIC CYTOSKELETAL CONNECTIVITY IN THE STABILITY, PLASTICITY, AND PERFORMANCE OF MULTICELLULAR NETWORKS AND ARCHITECTURES. CHRONIC IMPAIRMENT AND/OR DYSREGULATION OF CELL ADHESIONS/SYNAPSES, CYTOSKELETAL NETWORKS, AND/OR REVERSIBLE EPITHELIAL-TO-MESENCHYMAL-LIKE TRANSITIONS, WHICH ENABLE AND MEDIATE THE STABLE AND COHERENT YET DYNAMIC AND RECONFIGURABLE MULTICELLULAR ARCHITECTURES, MAY LEAD TO THE EMERGENCE AND PERSISTENCE OF THE DISORDERED, WOUND-LIKE POCKETS/MICROENVIRONMENTS OF CHRONICALLY DISCONNECTED CELLS. SUCH WOUND-LIKE MICROENVIRONMENTS SUPPORT AND ARE SUPPORTED BY PRO-INFLAMMATORY, PRO-SECRETION, DE-DIFFERENTIATED CELLULAR PHENOTYPES WITH ALTERED METABOLISM AND SIGNALING. THE CO-EVOLUTION OF WOUND-LIKE MICROENVIRONMENTS AND THEIR INHABITANTS MAY LEAD TO THE SELECTION AND STABILIZATION OF DEGENERATED CELLULAR PHENOTYPES, VIA ACQUISITION OF EPIGENETIC MODIFICATIONS AND MUTATIONS, WHICH EVENTUALLY RESULT IN DEGENERATIVE DISORDERS SUCH AS CANCER AND ALZHEIMER'S DISEASE. 2015 2 5239 26 PROGESTERONE ALLEVIATES ENDOMETRIOSIS VIA INHIBITION OF UTERINE CELL PROLIFERATION, INFLAMMATION AND ANGIOGENESIS IN AN IMMUNOCOMPETENT MOUSE MODEL. ENDOMETRIOSIS, DEFINED AS GROWTH OF THE ENDOMETRIAL CELLS OUTSIDE THE UTERUS, IS AN INFLAMMATORY DISORDER THAT IS ASSOCIATED WITH CHRONIC PELVIC PAIN AND INFERTILITY IN WOMEN OF CHILDBEARING AGE. ALTHOUGH THE ESTROGEN-DEPENDENCE OF ENDOMETRIOSIS IS WELL KNOWN, THE ROLE OF PROGESTERONE IN DEVELOPMENT OF THIS DISEASE REMAINS POORLY UNDERSTOOD. IN THIS STUDY, WE DEVELOPED A DISEASE MODEL IN WHICH ENDOMETRIOSIS WAS INDUCED IN THE PERITONEAL CAVITIES OF IMMUNOCOMPETENT FEMALE MICE, AND MAINTAINED WITH EXOGENOUS ESTROGEN. THE ENDOMETRIOSIS-LIKE LESIONS THAT WERE IDENTIFIED AT A VARIETY OF ECTOPIC LOCATIONS EXHIBITED ABUNDANT BLOOD SUPPLY AND EXTENSIVE ADHESIONS. HISTOLOGICAL EXAMINATION REVEALED THAT THESE LESIONS HAD A WELL-ORGANIZED ENDOMETRIAL ARCHITECTURE AND FIBROTIC RESPONSE, RESEMBLING THOSE RECOVERED FROM CLINICAL PATIENTS. IN ADDITION, AN EXTENSIVE PROLIFERATION, INFLAMMATORY RESPONSE, AND LOSS OF ESTROGEN RECEPTOR ALPHA (ERALPHA) AND PROGESTERONE RECEPTOR (PR) EXPRESSION WERE ALSO OBSERVED IN THESE LESIONS. INTERESTINGLY, ADMINISTRATION OF PROGESTERONE BEFORE, BUT NOT AFTER, LESION INDUCTION SUPPRESSED LESION EXPANSION AND MAINTAINED ERALPHA AND PR EXPRESSIONS. THESE PROGESTERONE-PRETREATED LESIONS EXHIBITED ATTENUATION IN KI67, CD31, AND PRO-INFLAMMATORY CYTOKINE EXPRESSION AS WELL AS MACROPHAGE INFILTRATION, INDICATING THAT PROGESTERONE AMELIORATES ENDOMETRIOSIS PROGRESSION BY INHIBITING CELL PROLIFERATION, INFLAMMATION AND NEOVASCULARIZATION. OUR STUDIES FURTHER SHOWED THAT SUPPRESSION OF GLOBAL DNA METHYLATION BY APPLICATION OF DNA METHYLTRANSFERASE INHIBITOR TO FEMALE MICE BEARING ECTOPIC LESIONS RESTRAINED LESION EXPANSION AND RESTORED ERALPHA AND PR EXPRESSION IN EUTOPIC ENDOMETRIUM AND ECTOPIC LESIONS. THESE RESULTS INDICATE THAT EPIGENETIC REGULATION OF TARGET GENE EXPRESSION VIA DNA METHYLATION CONTRIBUTES, AT LEAST IN PART, TO PROGESTERONE RESISTANCE IN ENDOMETRIOSIS. 2016 3 2169 28 EPIGENETIC MECHANISMS IN PARENCHYMAL LUNG DISEASES: BYSTANDERS OR THERAPEUTIC TARGETS? EPIGENETIC RESPONSES DUE TO ENVIRONMENTAL CHANGES ALTER CHROMATIN STRUCTURE, WHICH IN TURN MODIFIES THE PHENOTYPE, GENE EXPRESSION PROFILE, AND ACTIVITY OF EACH CELL TYPE THAT HAS A ROLE IN THE PATHOPHYSIOLOGY OF A DISEASE. PULMONARY DISEASES ARE ONE OF THE MAJOR CAUSES OF DEATH IN THE WORLD, INCLUDING LUNG CANCER, IDIOPATHIC PULMONARY FIBROSIS (IPF), CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD), PULMONARY HYPERTENSION (PH), LUNG TUBERCULOSIS, PULMONARY EMBOLISM, AND ASTHMA. SEVERAL LINES OF EVIDENCE INDICATE THAT EPIGENETIC MODIFICATIONS MAY BE ONE OF THE MAIN FACTORS TO EXPLAIN THE INCREASING INCIDENCE AND PREVALENCE OF LUNG DISEASES INCLUDING IPF AND COPD. INTERESTINGLY, ISOLATED FIBROBLASTS AND SMOOTH MUSCLE CELLS FROM PATIENTS WITH PULMONARY DISEASES SUCH AS IPF AND PH THAT WERE CULTURED EX VIVO MAINTAINED THE DISEASE PHENOTYPE. THE CELLS OFTEN SHOW A HYPER-PROLIFERATIVE, APOPTOSIS-RESISTANT PHENOTYPE WITH INCREASED EXPRESSION OF EXTRACELLULAR MATRIX (ECM) AND ACTIVATED FOCAL ADHESIONS SUGGESTING THE PRESENCE OF AN EPIGENETICALLY IMPRINTED PHENOTYPE. MOREOVER, MANY ABNORMALITIES OBSERVED IN MOLECULAR PROCESSES IN IPF PATIENTS ARE SHOWN TO BE EPIGENETICALLY REGULATED, SUCH AS INNATE IMMUNITY, CELLULAR SENESCENCE, AND APOPTOTIC CELL DEATH. DNA METHYLATION, HISTONE MODIFICATION, AND MICRORNA REGULATION CONSTITUTE THE MOST COMMON EPIGENETIC MODIFICATION MECHANISMS. 2022 4 3512 21 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 5 3674 23 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 6 4706 27 NMP4/CIZ CLOSES THE PARATHYROID HORMONE ANABOLIC WINDOW. CHRONIC DEGENERATIVE DISEASES ARE INCREASING WITH THE AGING U.S. POPULATION. ONE CONSEQUENCE OF THIS PHENOMENON IS THE NEED FOR LONG-TERM OSTEOPOROSIS THERAPIES. PARATHYROID HORMONE (PTH), THE ONLY FDA-APPROVED TREATMENT THAT ADDS BONE TO THE AGED SKELETON, LOSES ITS POTENCY WITHIN TWO YEARS OF INITIAL TREATMENT BUT THE MECHANISM REGULATING ITS LIMITED "ANABOLIC WINDOW" IS UNKNOWN. WE HAVE DISCOVERED THAT DISABLING THE NUCLEOCYTOPLASMIC SHUTTLING TRANSCRIPTION FACTOR NUCLEAR MATRIX PROTEIN 4/CAS INTERACTING ZINC FINGER PROTEIN (NMP4/CIZ) IN MICE EXTENDS THE PTH BONE-FORMING CAPACITY. NMP4 WAS DISCOVERED DURING OUR SEARCH FOR NUCLEAR MATRIX TRANSCRIPTION FACTORS THAT COUPLE THIS HORMONE'S IMPACT ON OSTEOBLAST CYTOSKELETAL AND NUCLEAR ORGANIZATION WITH ITS ANABOLIC CAPACITY. CIZ WAS INDEPENDENTLY DISCOVERED AS A PROTEIN THAT ASSOCIATES WITH THE FOCAL ADHESION-ASSOCIATED MECHANOSENSOR P130CAS. THE NMP4/CIZ-KNOCKOUT (KO) SKELETAL PHENOTYPE EXHIBITS A MODESTLY ENHANCED BONE MINERAL DENSITY BUT MANIFESTS AN EXAGGERATED RESPONSE TO BOTH PTH AND TO BMP2 AND IS RESISTANT TO DISUSE-INDUCED BONE LOSS. THE CELLULAR BASIS OF THE GLOBAL NMP4/CIZ-KO SKELETAL PHENOTYPE REMAINS TO BE ELUCIDATED BUT MAY INVOLVE AN EXPANSION OF THE BONE MARROW OSTEOPROGENITOR POPULATION ALONG WITH MODESTLY ENHANCED OSTEOBLAST AND OSTEOCLAST ACTIVITIES SUPPORTING ANABOLIC BONE TURNOVER. AS A SHUTTLING CYS(2)HIS(2) ZINC FINGER PROTEIN, NMP4/CIZ ACTS AS A REPRESSIVE TRANSCRIPTION FACTOR PERHAPS ASSOCIATED WITH EPIGENETIC REMODELING COMPLEXES, BUT THE FUNCTIONAL SIGNIFICANCE OF ITS INTERACTION WITH P130CAS IS NOT KNOWN. DESPITE NUMEROUS REMAINING QUESTIONS, NMP4/CIZ PROVIDES INSIGHTS INTO HOW THE ANABOLIC WINDOW IS REGULATED, AND ITSELF MAY PROVIDE AN ADJUVANT THERAPY TARGET FOR THE TREATMENT OF OSTEOPOROSIS BY EXTENDING PTH ANABOLIC EFFICACY. 2012 7 4358 19 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 8 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 9 3931 15 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 10 2361 20 EPIGENETIC REGULATION OF SKELETAL TISSUE INTEGRITY AND OSTEOPOROSIS DEVELOPMENT. BONE TURNOVER IS SOPHISTICATEDLY BALANCED BY A DYNAMIC COUPLING OF BONE FORMATION AND RESORPTION AT VARIOUS RATES. THE ORCHESTRATION OF THIS CONTINUOUS REMODELING OF THE SKELETON FURTHER AFFECTS OTHER SKELETAL TISSUES THROUGH ORGAN CROSSTALK. CHRONIC EXCESSIVE BONE RESORPTION COMPROMISES BONE MASS AND ITS POROUS MICROSTRUCTURE AS WELL AS PROPER BIOMECHANICS. THIS ACCELERATES THE DEVELOPMENT OF OSTEOPOROTIC DISORDERS, A LEADING CAUSE OF SKELETAL DEGENERATION-ASSOCIATED DISABILITY AND PREMATURE DEATH. BONE-FORMING CELLS PLAY IMPORTANT ROLES IN MAINTAINING BONE DEPOSIT AND OSTEOCLASTIC RESORPTION. A POOR ORGANELLE MACHINERY, SUCH AS MITOCHONDRIAL DYSFUNCTION, ENDOPLASMIC RETICULUM STRESS, AND DEFECTIVE AUTOPHAGY, ETC., DYSREGULATES GROWTH FACTOR SECRETION, MINERALIZATION MATRIX PRODUCTION, OR OSTEOCLAST-REGULATORY CAPACITY IN OSTEOBLASTIC CELLS. A PLETHORA OF EPIGENETIC PATHWAYS REGULATE BONE FORMATION, SKELETAL INTEGRITY, AND THE DEVELOPMENT OF OSTEOPOROSIS. MICRORNAS INHIBIT PROTEIN TRANSLATION BY BINDING THE 3'-UNTRANSLATED REGION OF MRNAS OR PROMOTE TRANSLATION THROUGH POST-TRANSCRIPTIONAL PATHWAYS. DNA METHYLATION AND POST-TRANSLATIONAL MODIFICATION OF HISTONES ALTER THE CHROMATIN STRUCTURE, HINDERING HISTONE ENRICHMENT IN PROMOTER REGIONS. MICRORNA-PROCESSING ENZYMES AND DNA AS WELL AS HISTONE MODIFICATION ENZYMES CATALYZE THESE MODIFYING REACTIONS. GAIN AND LOSS OF THESE EPIGENETIC MODIFIERS IN BONE-FORMING CELLS AFFECT THEIR EPIGENETIC LANDSCAPES, INFLUENCING BONE HOMEOSTASIS, MICROARCHITECTURAL INTEGRITY, AND OSTEOPOROTIC CHANGES. THIS ARTICLE CONVEYS PRODUCTIVE INSIGHTS INTO BIOLOGICAL ROLES OF DNA METHYLATION, MICRORNA, AND HISTONE MODIFICATION AND HIGHLIGHTS THEIR INTERACTIONS DURING SKELETAL DEVELOPMENT AND BONE LOSS UNDER PHYSIOLOGICAL AND PATHOLOGICAL CONDITIONS. 2020 11 5939 24 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 12 4097 21 MATRIX STIFFNESS REGULATES MACROPHAGE POLARIZATION IN ATHEROSCLEROSIS. ATHEROSCLEROSIS IS A CHRONIC INFLAMMATORY DISEASE AND THE PATHOLOGICAL BASIS OF MANY FATAL CARDIOVASCULAR DISEASES. MACROPHAGES, THE MAIN INFLAMMATORY CELLS IN ATHEROSCLEROTIC PLAQUE, HAVE A PARADOX ROLE IN DISEASE PROGRESSION. IN RESPONSE TO DIFFERENT MICROENVIRONMENTS, MACROPHAGES MAINLY HAVE TWO POLARIZED DIRECTIONS: PRO-INFLAMMATORY MACROPHAGES AND ANTI-INFLAMMATORY MACROPHAGES. MORE AND MORE EVIDENCE SHOWS THAT MACROPHAGE IS MECHANOSENSITIVE AND MATRIX STIFFNESS REGULATE MACROPHAGE PHENOTYPES IN ATHEROSCLEROSIS. HOWEVER, THE MOLECULAR MECHANISM OF MATRIX STIFFNESS REGULATING MACROPHAGE POLARIZATION STILL LACKS IN-DEPTH RESEARCH, WHICH HINDERS THE DEVELOPMENT OF NEW ANTI-ATHEROSCLEROTIC THERAPIES. IN THIS REVIEW, WE DISCUSS THE IMPORTANT ROLE OF MATRIX STIFFNESS IN REGULATING MACROPHAGE POLARIZATION THROUGH MECHANICAL SIGNAL TRANSDUCTION (HIPPO, PIEZO, CYTOSKELETON, AND INTEGRIN) AND EPIGENETIC MECHANISMS (MIRNA, DNA METHYLATION, AND HISTONE). WE HOPE TO PROVIDE A NEW PERSPECTIVE FOR ATHEROSCLEROSIS THERAPY BY TARGETING MATRIX STIFFNESS AND MACROPHAGE POLARIZATION. 2022 13 4337 22 MICROTUBULES AS MAJOR REGULATORS OF ENDOTHELIAL FUNCTION: IMPLICATION FOR LUNG INJURY. ENDOTHELIAL DYSFUNCTION HAS BEEN ATTRIBUTED AS ONE OF THE MAJOR COMPLICATIONS IN COVID-19 PATIENTS, A GLOBAL PANDEMIC THAT HAS ALREADY CAUSED OVER 4 MILLION DEATHS WORLDWIDE. THE DYSFUNCTION OF ENDOTHELIAL BARRIER IS CHARACTERIZED BY AN INCREASE IN ENDOTHELIAL PERMEABILITY AND INFLAMMATORY RESPONSES, AND HAS EVEN BROADER IMPLICATIONS IN THE PATHOGENESIS OF ACUTE RESPIRATORY SYNDROMES SUCH AS ARDS, SEPSIS AND CHRONIC ILLNESSES REPRESENTED BY PULMONARY ARTERIAL HYPERTENSION AND INTERSTITIAL LUNG DISEASE. THE STRUCTURAL INTEGRITY OF ENDOTHELIAL BARRIER IS MAINTAINED BY CYTOSKELETON ELEMENTS, CELL-SUBSTRATE FOCAL ADHESION AND ADHESIVE CELL JUNCTIONS. AGONIST-MEDIATED CHANGES IN ENDOTHELIAL PERMEABILITY ARE DIRECTLY ASSOCIATED WITH REORGANIZATION OF ACTOMYOSIN CYTOSKELETON LEADING TO CELL CONTRACTION AND OPENING OF INTERCELLULAR GAPS OR ENHANCEMENT OF CORTICAL ACTIN CYTOSKELETON ASSOCIATED WITH STRENGTHENING OF ENDOTHELIAL BARRIER. THE ROLE OF ACTIN CYTOSKELETON REMODELING IN ENDOTHELIAL BARRIER REGULATION HAS TAKEN THE CENTRAL STAGE, BUT THE IMPACT OF MICROTUBULES IN THIS PROCESS REMAINS LESS EXPLORED AND UNDER-APPRECIATED. THIS REVIEW WILL SUMMARIZE THE CURRENT KNOWLEDGE ON THE CROSSTALK BETWEEN MICROTUBULES DYNAMICS AND ACTIN CYTOSKELETON REMODELING, DESCRIBE THE SIGNALING MECHANISMS MEDIATING THIS CROSSTALK, DISCUSS EPIGENETIC REGULATION OF MICROTUBULES STABILITY AND ITS NEXUS WITH ENDOTHELIAL BARRIER MAINTENANCE, AND OVERVIEW A ROLE OF MICROTUBULES IN TARGETED DELIVERY OF SIGNALING MOLECULES REGULATING ENDOTHELIAL PERMEABILITY AND INFLAMMATION. 2021 14 6053 21 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 15 4563 23 MYELOID DNA METHYLTRANSFERASE3B DEFICIENCY AGGRAVATES PULMONARY FIBROSIS BY ENHANCING PROFIBROTIC MACROPHAGE ACTIVATION. BACKGROUND: IDIOPATHIC PULMONARY FIBROSIS (IPF) IS A CHRONIC, PROGRESSIVE AND SEVERE DISEASE CHARACTERIZED BY EXCESSIVE MATRIX DEPOSITION IN THE LUNGS. MACROPHAGES PLAY CRUCIAL ROLES IN MAINTAINING LUNG HOMEOSTASIS BUT ARE ALSO CENTRAL IN THE PATHOGENESIS OF LUNG DISEASES LIKE PULMONARY FIBROSIS. ESPECIALLY, MACROPHAGE POLARIZATION/ACTIVATION SEEMS TO PLAY A CRUCIAL ROLE IN PATHOLOGY AND EPIGENETIC REPROGRAMING IS WELL-KNOWN TO REGULATE MACROPHAGE POLARIZATION. DNA METHYLATION ALTERATIONS IN IPF LUNGS HAVE BEEN WELL DOCUMENTED, BUT THE ROLE OF DNA METHYLATION IN SPECIFIC CELL TYPES, ESPECIALLY MACROPHAGES, IS POORLY DEFINED. METHODS: IN ORDER TO DETERMINE THE ROLE OF DNA METHYLATION IN MACROPHAGES DURING PULMONARY FIBROSIS, WE SUBJECTED MACROPHAGE SPECIFIC DNA METHYLTRANSFERASE (DNMT)3B, WHICH MEDIATES THE DE NOVO DNA METHYLATION, DEFICIENT MICE TO THE BLEOMYCIN-INDUCED PULMONARY FIBROSIS MODEL. MACROPHAGE POLARIZATION AND FIBROTIC PARAMETERS WERE EVALUATED AT 21 DAYS AFTER BLEOMYCIN ADMINISTRATION. DNMT3B KNOCKOUT AND WILD TYPE BONE MARROW-DERIVED MACROPHAGES WERE STIMULATED WITH EITHER INTERLEUKIN (IL)4 OR TRANSFORMING GROWTH FACTOR BETA 1 (TGFB1) IN VITRO, AFTER WHICH PROFIBROTIC GENE EXPRESSION AND DNA METHYLATION AT THE ARG1 PROMOTOR WERE DETERMINED. RESULTS: WE SHOW THAT DNMT3B DEFICIENCY PROMOTES ALTERNATIVE MACROPHAGE POLARIZATION INDUCED BY IL4 AND TGFB1 IN VITRO AND ALSO ENHANCES PROFIBROTIC MACROPHAGE POLARIZATION IN THE ALVEOLAR SPACE DURING PULMONARY FIBROSIS IN VIVO. MOREOVER, MYELOID SPECIFIC DELETION OF DNMT3B PROMOTED THE DEVELOPMENT OF EXPERIMENTAL PULMONARY FIBROSIS. CONCLUSIONS: IN SUMMARY, THESE DATA SUGGEST THAT MYELOID DNMT3B REPRESSES FIBROTIC MACROPHAGE POLARIZATION AND PROTECTS AGAINST BLEOMYCIN INDUCED PULMONARY FIBROSIS. 2022 16 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 17 6687 21 VALIDATION OF THE EPIGENETIC READER BROMODOMAIN-CONTAINING PROTEIN 4 (BRD4) AS A THERAPEUTIC TARGET FOR TREATMENT OF AIRWAY REMODELING. STRUCTURAL REMODELING IS CENTRAL TO THE INITIATION AND PROGRESSION OF MANY CHRONIC LUNG DISEASES, REPRESENTING AN IMPORTANT UNMET NEED. WE EXAMINE THE EVIDENCE SUPPORTING BROMODOMAIN-CONTAINING PROTEIN 4 (BRD4) AS A VALIDATED BIOLOGICAL TARGET FOR TREATMENT OF AIRWAY REMODELING. IN EPITHELIAL CELLS AND FIBROBLASTS, BRD4 SERVES AS A SCAFFOLD FOR CHROMATIN REMODELING COMPLEXES IN ACTIVE SUPER-ENHANCERS. IN RESPONSE TO INFLAMMATORY STIMULI, BRD4 IS REPOSITIONED TO INNATE AND MESENCHYMAL GENES ACTIVATING THEIR PRODUCTION. PROOF-OF-CONCEPT STUDIES SHOW PROMISING BENEFIT OF SELECTIVE BRD4 INHIBITORS IN DISRUPTING EPITHELIAL MESENCHYMAL TRANSITION AND MYOFIBROBLAST TRANSITION IN DIVERSE MODELS OF LUNG INJURY. RECENT IDENTIFICATION OF BIOMARKERS OF BRD4 PROVIDES A BASIS FOR FURTHER DRUG DEVELOPMENT FOR APPLICATION IN VIRAL-INDUCED AIRWAY INFLAMMATION, COPD AND INTERSTITIAL LUNG DISEASES. 2020 18 793 21 CELLULAR RE- AND DE-PROGRAMMING BY MICROENVIRONMENTAL MEMORY: WHY SHORT TGF-BETA1 PULSES CAN HAVE LONG EFFECTS. BACKGROUND: FIBROSIS POSES A SUBSTANTIAL SETBACK IN REGENERATIVE MEDICINE. HISTOPATHOLOGICALLY, FIBROSIS IS AN EXCESSIVE ACCUMULATION OF COLLAGEN AFFECTED BY MYOFIBROBLASTS AND THIS CAN OCCUR IN ANY TISSUE THAT IS EXPOSED TO CHRONIC INJURY OR INSULT. TRANSFORMING GROWTH FACTOR (TGF)-BETA1, A CRUCIAL MEDIATOR OF FIBROSIS, DRIVES DIFFERENTIATION OF FIBROBLASTS INTO MYOFIBROBLASTS. THESE CELLS EXHIBIT ALPHA-SMOOTH MUSCLE ACTIN (ALPHA-SMA) AND SYNTHESIZE HIGH AMOUNTS OF COLLAGEN I, THE MAJOR EXTRACELLULAR MATRIX (ECM) COMPONENT OF FIBROSIS. WHILE HORMONES STIMULATE CELLS IN A PULSATILE MANNER, LITTLE IS KNOWN ABOUT CELLULAR RESPONSE KINETICS UPON GROWTH FACTOR IMPACT. WE THEREFORE STUDIED THE EFFECTS OF SHORT TGF-BETA1 PULSES IN TERMS OF THE INDUCTION AND MAINTENANCE OF THE MYOFIBROBLAST PHENOTYPE. RESULTS: TWENTY-FOUR HOURS AFTER A SINGLE 30 MIN TGF-BETA1 PULSE, TRANSCRIPTION OF FIBROGENIC GENES WAS UPREGULATED, BUT SUBSIDED 7 DAYS LATER. IN PARALLEL, COLLAGEN I SECRETION RATE AND ALPHA-SMA PRESENCE WERE ELEVATED FOR 7 DAYS. A SECOND PULSE 24 H LATER EXTENDED THE DURATION OF EFFECTS TO 14 DAYS. WE COULD NOT ESTABLISH EPIGENETIC CHANGES ON FIBROGENIC TARGET GENES TO EXPLAIN THE LONG-LASTING EFFECTS. HOWEVER, ECM DEPOSITED UNDER SINGLY PULSED TGF-BETA1 WAS ABLE TO INDUCE MYOFIBROBLAST FEATURES IN PREVIOUSLY UNTREATED FIBROBLASTS. DEPENDENT ON THE AGE OF THE ECM (1 DAY VERSUS 7 DAYS' FORMATION TIME), THIS PROPERTY WAS DIMINISHED. VICE VERSA, MYOFIBROBLASTS WERE CULTURED ON FIBROBLAST ECM AND CELLS OBSERVED TO EXPRESS REDUCED (IN COMPARISON WITH MYOFIBROBLASTS) LEVELS OF COLLAGEN I. CONCLUSIONS: WE DEMONSTRATED THAT SHORT TGF-BETA1 PULSES CAN EXERT LONG-LASTING EFFECTS ON FIBROBLASTS BY CHANGING THEIR MICROENVIRONMENT, THUS LEAVING AN IMPRINT AND CREATING A RECIPROCAL FEED-BACK LOOP. THEREFORE, THE ECM MIGHT ACT AS MID-TERM MEMORY FOR PATHOBIOCHEMICAL EVENTS. WE WOULD EXPECT THIS MICROENVIRONMENTAL MEMORY TO BE DEPENDENT ON MATRIX TURNOVER AND, AS SUCH, TO BE ERASABLE. OUR FINDINGS CONTRIBUTE TO THE CURRENT UNDERSTANDING OF FIBROBLAST INDUCTION AND MAINTENANCE, AND HAVE BEARING ON THE DEVELOPMENT OF ANTIFIBROTIC DRUGS. 2013 19 5575 28 ROLE OF MICRORNAS IN SIGNALING PATHWAYS ASSOCIATED WITH THE PATHOGENESIS OF IDIOPATHIC PULMONARY FIBROSIS: A FOCUS ON EPITHELIAL-MESENCHYMAL TRANSITION. IDIOPATHIC PULMONARY FIBROSIS (IPF) IS A CHRONIC AND PROGRESSIVE DISEASE WITH HIGH MORTALITY AND UNCLEAR ETIOLOGY. PREVIOUS EVIDENCE SUPPORTS THAT THE ORIGIN OF THIS DISEASE IS ASSOCIATED WITH EPIGENETIC ALTERATIONS, AGE, AND ENVIRONMENTAL FACTORS. IPF INITIATES WITH CHRONIC EPITHELIAL LUNG INJURIES, FOLLOWED BY BASAL MEMBRANE DESTRUCTION, WHICH PROMOTES THE ACTIVATION OF MYOFIBROBLASTS AND EXCESSIVE SYNTHESIS OF EXTRACELLULAR MATRIX (ECM) PROTEINS, AS WELL AS EPITHELIAL-MESENCHYMAL TRANSITION (EMT). DUE TO MIRNAS' ROLE AS REGULATORS OF APOPTOSIS, PROLIFERATION, DIFFERENTIATION, AND CELL-CELL INTERACTION PROCESSES, SOME STUDIES HAVE INVOLVED MIRNAS IN THE BIOGENESIS AND PROGRESSION OF IPF. IN THIS CONTEXT, THE ANALYSIS AND DISCUSSION OF THE PROBABLE ASSOCIATION OF MIRNAS WITH THE SIGNALING PATHWAYS INVOLVED IN THE DEVELOPMENT OF IPF WOULD IMPROVE OUR KNOWLEDGE OF THE ASSOCIATED MOLECULAR MECHANISMS, THEREBY FACILITATING ITS EVALUATION AS A THERAPEUTIC TARGET FOR THIS SEVERE LUNG DISEASE. IN THIS WORK, THE MOST RECENT PUBLICATIONS EVALUATING THE ROLE OF MIRNAS AS REGULATORS OR ACTIVATORS OF SIGNAL PATHWAYS ASSOCIATED WITH THE PATHOGENESIS OF IPF WERE ANALYZED. THE SEARCH IN PUBMED WAS MADE USING THE FOLLOWING TERMS: "MIRNAS AND IDIOPATHIC PULMONARY FIBROSIS (IPF)"; "MIRNAS AND IPF AND SIGNALING PATHWAYS (SP)"; AND "MIRNAS AND IPF AND SP AND IPF PATHOGENESIS". ADDITIONALLY, WE FOCUS MAINLY ON THOSE WORKS WHERE THE SIGNALING PATHWAYS INVOLVED WITH EMT, FIBROBLAST DIFFERENTIATION, AND SYNTHESIS OF ECM COMPONENTS WERE ASSESSED. FINALLY, THE IMPORTANCE AND SIGNIFICANCE OF MIRNAS AS POTENTIAL THERAPEUTIC OR DIAGNOSTIC TOOLS FOR THE TREATMENT OF IPF ARE DISCUSSED. 2022 20 1862 23 EMERGENCE OF FIBROBLASTS WITH A PROINFLAMMATORY EPIGENETICALLY ALTERED PHENOTYPE IN SEVERE HYPOXIC PULMONARY HYPERTENSION. PERSISTENT ACCUMULATION OF MONOCYTES/MACROPHAGES IN THE PULMONARY ARTERY ADVENTITIAL/PERIVASCULAR AREAS OF ANIMALS AND HUMANS WITH PULMONARY HYPERTENSION HAS BEEN DOCUMENTED. THE CELLULAR MECHANISMS CONTRIBUTING TO CHRONIC INFLAMMATORY RESPONSES REMAIN UNCLEAR. WE HYPOTHESIZED THAT PERIVASCULAR INFLAMMATION IS PERPETUATED BY ACTIVATED ADVENTITIAL FIBROBLASTS, WHICH, THROUGH SUSTAINED PRODUCTION OF PROINFLAMMATORY CYTOKINES/CHEMOKINES AND ADHESION MOLECULES, INDUCE ACCUMULATION, RETENTION, AND ACTIVATION OF MONOCYTES/MACROPHAGES. WE FURTHER HYPOTHESIZED THAT THIS PROINFLAMMATORY PHENOTYPE IS THE RESULT OF THE ABNORMAL ACTIVITY OF HISTONE-MODIFYING ENZYMES, SPECIFICALLY, CLASS I HISTONE DEACETYLASES (HDACS). PULMONARY ADVENTITIAL FIBROBLASTS FROM CHRONICALLY HYPOXIC HYPERTENSIVE CALVES (TERMED PH-FIBS) EXPRESSED A CONSTITUTIVE AND PERSISTENT PROINFLAMMATORY PHENOTYPE DEFINED BY HIGH EXPRESSION OF IL-1BETA, IL-6, CCL2(MCP-1), CXCL12(SDF-1), CCL5(RANTES), CCR7, CXCR4, GM-CSF, CD40, CD40L, AND VCAM-1. THE PROINFLAMMATORY PHENOTYPE OF PH-FIBS WAS ASSOCIATED WITH EPIGENETIC ALTERATIONS AS DEMONSTRATED BY INCREASED ACTIVITY OF HDACS AND THE FINDINGS THAT CLASS I HDAC INHIBITORS MARKEDLY DECREASED CYTOKINE/CHEMOKINE MRNA EXPRESSION LEVELS IN THESE CELLS. PH-FIBS INDUCED INCREASED ADHESION OF THP-1 MONOCYTES AND PRODUCED SOLUBLE FACTORS THAT INDUCED INCREASED MIGRATION OF THP-1 AND MURINE BONE MARROW-DERIVED MACROPHAGES AS WELL AS ACTIVATED MONOCYTES/MACROPHAGES TO EXPRESS PROINFLAMMATORY CYTOKINES AND PROFIBROGENIC MEDIATORS (TIMP1 AND TYPE I COLLAGEN) AT THE TRANSCRIPTIONAL LEVEL. CLASS I HDAC INHIBITORS MARKEDLY REDUCED THE ABILITY OF PH-FIBS TO INDUCE MONOCYTE MIGRATION AND PROINFLAMMATORY ACTIVATION. THE EMERGENCE OF A DISTINCT ADVENTITIAL FIBROBLAST POPULATION WITH AN EPIGENETICALLY ALTERED PROINFLAMMATORY PHENOTYPE CAPABLE OF RECRUITING, RETAINING, AND ACTIVATING MONOCYTES/MACROPHAGES CHARACTERIZES PULMONARY HYPERTENSION-ASSOCIATED VASCULAR REMODELING AND THUS COULD CONTRIBUTE SIGNIFICANTLY TO CHRONIC INFLAMMATORY PROCESSES IN THE PULMONARY ARTERY WALL. 2011