1 5321 130 PULMONARY ARTERY SMOOTH MUSCLE CELL PROLIFERATION AND MIGRATION IN FETAL LAMBS ACCLIMATIZED TO HIGH-ALTITUDE LONG-TERM HYPOXIA: ROLE OF HISTONE ACETYLATION. HIGH-ALTITUDE LONG-TERM HYPOXIA (LTH) IS KNOWN TO INDUCE PULMONARY ARTERIAL SMOOTH MUSCLE CELL (PASMC) PROLIFERATION IN THE FETUS, LEADING TO PULMONARY ARTERIAL REMODELING AND PULMONARY HYPERTENSION OF THE NEWBORN. THE MECHANISMS UNDERLYING THESE CONDITIONS REMAIN ENIGMATIC HOWEVER. WE HYPOTHESIZED THAT EPIGENETIC ALTERATIONS IN FETAL PASMC INDUCED BY HIGH-ALTITUDE LTH MAY PLAY AN IMPORTANT ROLE IN MODULATING THEIR PROLIFERATION DURING PULMONARY ARTERIAL REMODELING. TO TEST THIS HYPOTHESIS, WE HAVE ANALYZED EPIGENETIC ALTERATIONS IN THE PULMONARY VASCULATURE OF FETAL LAMBS EXPOSED TO HIGH-ALTITUDE LTH [PREGNANT EWES WERE KEPT AT 3,801 M ALTITUDE FROM ~40 TO 145 DAYS GESTATION] OR TO SEA LEVEL ATMOSPHERE. INTRAPULMONARY ARTERIES WERE ISOLATED, AND FETAL PASMC WERE CULTURED FROM BOTH CONTROL AND LTH FETUSES. COMPARED WITH CONTROLS, IN LTH FETUS PULMONARY ARTERIES MEASUREMENTS OF HISTONE ACETYLATION AND GLOBAL DNA METHYLATION DEMONSTRATED REDUCED LEVELS OF GLOBAL HISTONE 4 ACETYLATION AND DNA METHYLATION, ACCOMPANIED BY THE LOSS OF THE CYCLIN-DEPENDENT KINASE INHIBITOR P21. TREATMENT OF LTH FETAL PASMCS WITH HISTONE DEACETYLASE (HDAC) INHIBITOR TRICHOSTATIN A DECREASED THEIR PROLIFERATION RATE, IN PART BECAUSE OF ALTERED EXPRESSION OF P21 AT BOTH RNA AND PROTEIN LEVEL. IN PASMC OF LTH FETUSES, HDAC INHIBITION ALSO DECREASED PDGF-INDUCED CELL MIGRATION AND ERK1/2 ACTIVATION AND MODULATED GLOBAL DNA METHYLATION. ON THE BASIS OF THESE OBSERVATIONS, WE PROPOSE THAT EPIGENETIC ALTERATIONS (REDUCED HISTONE ACETYLATION AND DNA METHYLATION) CAUSED BY CHRONIC HYPOXIA LEADS TO FETAL PASMC PROLIFERATION AND VESSEL REMODELING ASSOCIATED WITH VASCULAR PROLIFERATIVE DISEASE AND THAT THIS PROCESS IS REGULATED BY P21. 2012 2 2204 41 EPIGENETIC MODIFICATION OF THE VON WILLEBRAND FACTOR PROMOTER DRIVES PLATELET AGGREGATION ON THE PULMONARY ENDOTHELIUM IN CHRONIC THROMBOEMBOLIC PULMONARY HYPERTENSION. RATIONALE: VON WILLEBRAND FACTOR (VWF) MEDIATES PLATELET ADHESION DURING THROMBOSIS. WHILE CHRONIC THROMBOEMBOLIC PULMONARY HYPERTENSION (CTEPH) IS ASSOCIATED WITH INCREASED PLASMA LEVELS OF VWF, THE ROLE OF THIS PROTEIN IN CTEPH HAS REMAINED ENIGMATIC. OBJECTIVES: TO IDENTIFY THE ROLE OF VWF IN CTEPH. METHODS: CTEPH-SPECIFIC PATIENT PLASMA AND PULMONARY ENDARTERECTOMY MATERIAL FROM PATIENTS WITH CTEPH WERE USED TO STUDY THE RELATIONSHIP BETWEEN INFLAMMATION, VWF EXPRESSION, AND PULMONARY THROMBOSIS. CELL CULTURE FINDINGS WERE VALIDATED IN HUMAN TISSUE, AND PROTEOMICS AND CHROMATIN IMMUNOPRECIPITATION WERE USED TO INVESTIGATE THE UNDERLYING MECHANISM OF CTEPH. MEASUREMENTS AND MAIN RESULTS: VWF IS INCREASED IN PLASMA AND THE PULMONARY ENDOTHELIUM OF CTEPH PATIENTS. IN VITRO, THE INCREASE IN VWF GENE EXPRESSION AND THE HIGHER RELEASE OF VWF PROTEIN UPON ENDOTHELIAL ACTIVATION RESULTED IN ELEVATED PLATELET ADHESION TO CTEPH ENDOTHELIUM. PROTEOMIC ANALYSIS REVEALED THAT NUCLEAR FACTOR (NF)-KAPPAB2 WAS SIGNIFICANTLY INCREASED IN CTEPH. WE DEMONSTRATE REDUCED HISTONE TRI-METHYLATION AND INCREASED HISTONE ACETYLATION OF THE VWF PROMOTER IN CTEPH ENDOTHELIUM, FACILITATING BINDING OF NF-KAPPAB2 TO THE VWF PROMOTER AND DRIVING VWF TRANSCRIPTION. GENETIC INTERFERENCE OF NFKAPPAB2 NORMALIZED THE HIGH VWF RNA EXPRESSION LEVELS AND REVERSED THE PROTHROMBOTIC PHENOTYPE OBSERVED IN CTEPH-PULMONARY ARTERY ENDOTHELIAL CELLS. CONCLUSIONS: EPIGENETIC REGULATION OF THE VWF PROMOTER CONTRIBUTES TO THE CREATION OF A LOCAL ENVIRONMENT THAT FAVORS IN SITU THROMBOSIS IN THE PULMONARY ARTERIES. IT REVEALS A DIRECT MOLECULAR LINK BETWEEN INFLAMMATORY PATHWAYS AND PLATELET ADHESION IN THE PULMONARY VASCULAR WALL, EMPHASIZING A POSSIBLE ROLE OF IN SITU THROMBOSIS IN THE DEVELOPMENT OR PROGRESSION OF CTEPH. 2022 3 6053 20 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 4 2481 33 EPIGENETIC UPREGULATION OF LNCRNAS AT 13Q14.3 IN LEUKEMIA IS LINKED TO THE IN CIS DOWNREGULATION OF A GENE CLUSTER THAT TARGETS NF-KB. NON-CODING RNAS ARE MUCH MORE COMMON THAN PREVIOUSLY THOUGHT. HOWEVER, FOR THE VAST MAJORITY OF NON-CODING RNAS, THE CELLULAR FUNCTION REMAINS ENIGMATIC. THE TWO LONG NON-CODING RNA (LNCRNA) GENES DLEU1 AND DLEU2 MAP TO A CRITICAL REGION AT CHROMOSOMAL BAND 13Q14.3 THAT IS RECURRENTLY DELETED IN SOLID TUMORS AND HEMATOPOIETIC MALIGNANCIES LIKE CHRONIC LYMPHOCYTIC LEUKEMIA (CLL). WHILE NO POINT MUTATIONS HAVE BEEN FOUND IN THE PROTEIN CODING CANDIDATE GENES AT 13Q14.3, THEY ARE DEREGULATED IN MALIGNANT CELLS, SUGGESTING AN EPIGENETIC TUMOR SUPPRESSOR MECHANISM. WE THEREFORE CHARACTERIZED THE EPIGENETIC MAKEUP OF 13Q14.3 IN CLL CELLS AND FOUND HISTONE MODIFICATIONS BY CHROMATIN-IMMUNOPRECIPITATION (CHIP) THAT ARE ASSOCIATED WITH ACTIVATED TRANSCRIPTION AND SIGNIFICANT DNA-DEMETHYLATION AT THE TRANSCRIPTIONAL START SITES OF DLEU1 AND DLEU2 USING 5 DIFFERENT SEMI-QUANTITATIVE AND QUANTITATIVE METHODS (APRIMES, BIOCOBRA, MCIP, MASSARRAY, AND BISULFITE SEQUENCING). THESE EPIGENETIC ABERRATIONS WERE CORRELATED WITH TRANSCRIPTIONAL DEREGULATION OF THE NEIGHBORING CANDIDATE TUMOR SUPPRESSOR GENES, SUGGESTING A COREGULATION IN CIS OF THIS GENE CLUSTER. WE FOUND THAT THE 13Q14.3 GENES IN ADDITION TO THEIR PREVIOUSLY KNOWN FUNCTIONS REGULATE NF-KB ACTIVITY, WHICH WE COULD SHOW AFTER OVEREXPRESSION, SIRNA-MEDIATED KNOCKDOWN, AND DOMINANT-NEGATIVE MUTANT GENES BY USING WESTERN BLOTS WITH PREVIOUSLY UNDESCRIBED ANTIBODIES, BY A CUSTOMIZED ELISA AS WELL AS BY REPORTER ASSAYS. IN ADDITION, WE PERFORMED AN UNBIASED SCREEN OF 810 HUMAN MIRNAS AND IDENTIFIED THE MIR-15/16 FAMILY OF GENES AT 13Q14.3 AS THE STRONGEST INDUCERS OF NF-KB ACTIVITY. IN SUMMARY, THE TUMOR SUPPRESSOR MECHANISM AT 13Q14.3 IS A CLUSTER OF GENES CONTROLLED BY TWO LNCRNA GENES THAT ARE REGULATED BY DNA-METHYLATION AND HISTONE MODIFICATIONS AND WHOSE MEMBERS ALL REGULATE NF-KB. THEREFORE, THE TUMOR SUPPRESSOR MECHANISM IN 13Q14.3 UNDERLINES THE ROLE BOTH OF EPIGENETIC ABERRATIONS AND OF LNCRNA GENES IN HUMAN TUMORIGENESIS AND IS AN EXAMPLE OF COLOCALIZATION OF A FUNCTIONALLY RELATED GENE CLUSTER. 2013 5 5484 31 REVEALING THE PATHOGENIC AND AGING-RELATED MECHANISMS OF THE ENIGMATIC IDIOPATHIC PULMONARY FIBROSIS. AN INTEGRAL MODEL. A GROWING BODY OF EVIDENCE INDICATES THAT ABERRANT ACTIVATION OF ALVEOLAR EPITHELIAL CELLS AND FIBROBLASTS IN AN AGING LUNG PLAYS A CRITICAL ROLE IN THE PATHOGENESIS OF IDIOPATHIC PULMONARY FIBROSIS (IPF). HOWEVER, THE BIOPATHOLOGICAL PROCESSES LINKING AGING WITH IPF AND THE MECHANISMS RESPONSIBLE FOR THE ABNORMAL ACTIVATION OF EPITHELIAL CELLS AND FIBROBLASTS HAVE NOT BEEN ELUCIDATED. MANY OF THE HALLMARKS OF AGING (E.G., GENOMIC INSTABILITY, TELOMERE ATTRITION, EPIGENETIC ALTERATIONS, MITOCHONDRIAL DYSFUNCTION, AND CELLULAR SENESCENCE) HAVE BEEN PROPOSED AS ESSENTIAL MECHANISMS FOR THE DEVELOPMENT OF IPF; HOWEVER, THESE DISTURBANCES ARE NOT RESTRICTED TO IPF AND ALSO OCCUR IN OTHER AGING-RELATED LUNG DISORDERS, PRIMARILY CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). THEREFORE, AN UNANSWERED QUESTION IS WHY A CURRENT/FORMER SMOKER OF ABOUT 60 YEARS OF AGE WITH SHORTER TELOMERES, ALVEOLAR EPITHELIAL SENESCENCE, EXCESSIVE OXIDATIVE STRESS, AND MITOCHONDRIAL DYSFUNCTION DEVELOPS IPF AND NOT COPD; IN OTHER WORDS, WHAT MAKES OLD LUNGS SPECIFICALLY SUSCEPTIBLE TO DEVELOP IPF? IN THIS PERSPECTIVE, WE PROPOSE AN INTEGRAL MODEL IN WHICH THE COMBINATION OF SOME GENE VARIANTS AND/OR GENE EXPRESSION IN THE AGING LUNG RESULTS IN THE LOSS OF EPITHELIAL INTEGRITY AND CONSEQUENTLY IN THE FAILURE OF THE ALVEOLI TO CORRECTLY RESPOND TO INJURY AND TO FACE THE STRESS ASSOCIATED WITH MECHANICAL STRETCH. AFTERWARD, A DISTINCTIVE EPIGENETIC "REPROGRAMMING" THAT AFFECTS BOTH EPITHELIAL CELLS AND FIBROBLASTS PROVOKES, AMONG OTHERS, THE RECAPITULATION OF DEVELOPMENTAL PATHWAYS AND THE ABERRANT ACTIVATION AND MISCOMMUNICATION BETWEEN BOTH CELL TYPES, RESULTING IN THE EXAGGERATED PRODUCTION AND ACCUMULATION OF EXTRACELLULAR MATRIX AND THE SUBSEQUENT DESTRUCTION OF THE LUNG ARCHITECTURE. 2014 6 1478 19 DIVERSE ROLES OF HEPATITIS B VIRUS IN LIVER CANCER. HEPATITIS B VIRUS (HBV) IS A WIDESPREAD HUMAN PATHOGEN RESPONSIBLE FOR ACUTE AND CHRONIC LIVER DISEASES. THE HEPATITIS B BURDEN IS PARTICULARLY HEAVY IN ENDEMIC COUNTRIES, WHERE LIVER CIRRHOSIS AND HEPATOCELLULAR CARCINOMA ARE LEADING CAUSES OF DEATH. HOWEVER, THE ONCOGENIC ROLE OF HBV REMAINS ENIGMATIC. AS THE VIRUS HAS NO CYTOPATHIC EFFECT, LIVER DAMAGE IS ATTRIBUTED TO IMMUNE RESPONSES THAT INDUCE INFLAMMATION, APOPTOSIS AND REGENERATION, FOSTERING THE ACCUMULATION OF GENETIC AND EPIGENETIC ALTERATIONS. IN A MORE DIRECT ACTION, FREQUENT INTEGRATION OF HBV DNA INTO HOST CHROMOSOMES MAY LEAD TO INSERTIONAL MUTAGENESIS OF CANCER-RELATED GENES AND CHROMOSOMAL INSTABILITY. HBV PROTEINS, NOTABLY THE HBX TRANSACTIVATOR, PARTICIPATE AS CO-FACTORS IN ONCOGENESIS. BETTER UNDERSTANDING OF HEPATITIS B PATHOGENESIS IS MANDATORY FOR IMPROVING DISEASE MANAGEMENT. 2012 7 3351 44 HISTONE DEMETHYLASE JARID1B REGULATES PROLIFERATION AND MIGRATION OF PULMONARY ARTERIAL SMOOTH MUSCLE CELLS IN MICE WITH CHRONIC HYPOXIA-INDUCED PULMONARY HYPERTENSION VIA NUCLEAR FACTOR-KAPPA B (NFKB). CHRONIC HYPOXIA-INDUCED PULMONARY HYPERTENSION (PH) IS A DISORDER THAT IS CHARACTERIZED BY INCREASED PULMONARY ARTERIAL PRESSURE RESULTING FROM LUNG DISEASES OR SHORTAGE OF OXYGEN IN THE BODY. EXCESS PROLIFERATION OF PULMONARY VASCULAR CELLS SUCH AS PULMONARY ARTERY ENDOTHELIAL CELLS (PAECS) AND PULMONARY ARTERY SMOOTH MUSCLE CELLS (PASMCS) PLAYS A CRITICAL ROLE IN THE PATHOGENESIS OF PH. RECENT EVIDENCE INDICATES THAT, IN ADDITION TO GENETIC PREDISPOSITION AND ENVIRONMENTAL FACTORS, EPIGENETIC MECHANISMS PLAY A PIVOTAL ROLE IN ETIOLOGY OF PH. IN THIS STUDY, WE INVESTIGATED THE POSSIBLE ROLE PLAYED BY JUMONJI AT-RICH INTERACTIVE DOMAIN 1B (JARID1B), A HISTONE DEMETHYLASE, IN REGULATING THE PROLIFERATION OF VASCULAR SMOOTH MUSCLE CELLS IN CHRONIC HYPOXIA-INDUCED PH CONDITION. QUANTITATIVE POLYMERASE CHAIN REACTION ANALYSIS OF SAMPLES FROM RATS WITH PH SHOWED AN ELEVATED EXPRESSION OF JARID1B IN THEIR PASMCS, POSITIVELY CORRELATING WITH INCREASED NUCLEAR FACTOR-KAPPA B (NFKB) EXPRESSION. FURTHER FUNCTIONAL STUDIES IN VITRO INDICATED THAT OVEREXPRESSION OF JARID1B INCREASED THE PROLIFERATION AND MIGRATION OF PASMCS, WHICH WERE INHIBITED BY DEPLETION OF NFKB. GENOMEWIDE TRANSCRIPTIONAL ANALYSIS REVEALED THAT THE JARID1B REGULATED NFKB SIGNALING PATHWAY BY DIRECTLY BINDING TO ITS PROMOTER. WE HAVE ALSO SHOWN THAT JARID1B INDIRECTLY REGULATES THE EXPRESSION OF VASCULAR ENDOTHELIAL GROWTH FACTOR VIA NFKB SIGNALING AND HENCE MAY ALSO PLAY A CRUCIAL ROLE IN CONTROLLING PAECS, LEADING TO CHANGES IN VASCULAR ARCHITECTURE IN PH. OUR FINDINGS COULD LEAD TO FURTHER STUDIES ON THE ROLE OF JARID1B IN PH ETIOLOGY AND THEREFORE COULD LEAD TO A POTENTIAL THERAPEUTIC TARGET FOR CHRONIC HYPOXIA INDUCED PULMONARY HYPERTENSION. 2018 8 1602 46 DNA METHYLATION SIGNATURES OF PULMONARY ARTERIAL SMOOTH MUSCLE CELLS IN CHRONIC THROMBOEMBOLIC PULMONARY HYPERTENSION. CHRONIC THROMBOEMBOLIC PULMONARY HYPERTENSION (CTEPH) IS A LIFE-THREATENING DISEASE, WHICH IS OFTEN UNDERPINNED BY VASCULAR REMODELING. PULMONARY ARTERIAL SMOOTH MUSCLE CELLS (PASMCS) ARE THE MAIN PARTICIPANTS IN VASCULAR REMODELING. HOWEVER, THEIR BIOLOGICAL ROLE IN CTEPH IS NOT ENTIRELY CLEAR. IN THE PRESENT STUDY, WE ANALYZED THE WHOLE EPIGENOME-WIDE DNA METHYLATION PROFILE OF CULTURED PASMCS FROM CTEPH AND CONTROL CELL LINES WITH THE ILLUMINA HUMAN METHYLATION 450K BEADCHIP. A TOTAL OF 6,829 SIGNIFICANTLY DIFFERENTIALLY METHYLATED PROBES (DMPS) WERE DETECTED BETWEEN THESE TWO GROUPS. AMONG THESE, 4,246 DMPS WERE HYPERMETHYLATED, WHILE 2,583 DMPS WERE HYPOMETHYLATED. THE FUNCTIONAL ENRICHMENT ANALYSIS OF 1,743 DMPS IN THE PROMOTER REGIONS AND CORRESPONDING GENES INDICATED THAT DNA HYPERMETHYLATION AND HYPOMETHYLATION MIGHT BE INVOLVED IN THE REGULATION OF GENES THAT HAVE MULTIFARIOUS BIOLOGICAL ROLES, INCLUDING ROLES IN CANCER-RELATED DISEASES, THE REGULATION OF THE ACTIN CYTOSKELETON, CELL ADHESION, AND PATTERN SPECIFICATION PROCESSES. THE OBSERVED METHYLATIONS WERE CATEGORIZED INTO THE MOST IMPORTANT FUNCTIONS, INCLUDING THOSE INVOLVED IN CELL PROLIFERATION, IMMUNITY, AND MIGRATION. WE SPECULATE THAT THESE METHYLATIONS WERE MOST LIKELY INVOLVED IN THE POSSIBLE PATHOPHYSIOLOGY OF CTEPH. GENE INTERACTION ANALYSIS PERTAINING TO SIGNAL NETWORKS CONFIRMED THAT PIK3CA AND PIK3R1 WERE IMPORTANT MEDIATORS IN THESE WHOLE NETWORKS. THE MRNA LEVELS OF PIK3CA, HIC1, AND SSH1 WERE VERIFIED BY QPCR AND CORRESPONDED WITH DNA METHYLATION DIFFERENCES. UNDERSTANDING EPIGENETIC FEATURES ASSOCIATED WITH CTEPH MAY PROVIDE NEW INSIGHTS INTO THE MECHANISM THAT UNDERLIE THIS CONDITION. 2018 9 3512 27 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 10 3628 25 INACTIVATION OF NUCLEAR HISTONE DEACETYLASES BY EP300 DISRUPTS THE MICEE COMPLEX IN IDIOPATHIC PULMONARY FIBROSIS. IDIOPATHIC PULMONARY FIBROSIS (IPF) IS A CHRONIC, PROGRESSIVE, AND HIGHLY LETHAL LUNG DISEASE WITH UNKNOWN ETIOLOGY AND POOR PROGNOSIS. IPF PATIENTS DIE WITHIN 2 YEARS AFTER DIAGNOSIS MOSTLY DUE TO RESPIRATORY FAILURE. CURRENT TREATMENTS AGAINST IPF AIM TO AMELIORATE PATIENT SYMPTOMS AND TO DELAY DISEASE PROGRESSION. UNFORTUNATELY, THERAPIES TARGETING THE CAUSES OF OR REVERTING IPF HAVE NOT YET BEEN DEVELOPED. HERE WE SHOW THAT REDUCED LEVELS OF MIRNA LETHAL 7D (MIRLET7D) IN IPF COMPROMISE EPIGENETIC GENE SILENCING MEDIATED BY THE RIBONUCLEOPROTEIN COMPLEX MICEE. IN ADDITION, WE FIND THAT HYPERACTIVE EP300 REDUCES NUCLEAR HDAC ACTIVITY AND INTERFERES WITH MICEE FUNCTION IN IPF. REMARKABLY, EP300 INHIBITION REDUCES FIBROTIC HALLMARKS OF IN VITRO (PATIENT-DERIVED PRIMARY FIBROBLAST), IN VIVO (BLEOMYCIN MOUSE MODEL), AND EX VIVO (PRECISION-CUT LUNG SLICES, PCLS) IPF MODELS. OUR WORK PROVIDES THE MOLECULAR BASIS FOR THERAPIES AGAINST IPF USING EP300 INHIBITION. 2019 11 1862 43 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 12 6546 31 TRANSCRIPTOMIC AND EPIGENETIC PROFILING OF FIBROBLASTS IN IDIOPATHIC PULMONARY FIBROSIS. IDIOPATHIC PULMONARY FIBROSIS (IPF), A DEVASTATING, FIBROPROLIFERATIVE, CHRONIC LUNG DISORDER, IS ASSOCIATED WITH EXPANSION OF FIBROBLASTS/MYOFIBROBLASTS, WHICH LEADS TO EXCESSIVE PRODUCTION AND DEPOSITION OF EXTRACELLULAR MATRIX. IPF IS TYPICALLY CLINICALLY IDENTIFIED AS END-STAGE LUNG DISEASE, AFTER FIBROTIC PROCESSES ARE WELL-ESTABLISHED AND ADVANCED. FIBROBLASTS HAVE BEEN SHOWN TO BE CRITICALLY IMPORTANT IN THE DEVELOPMENT AND PROGRESSION OF IPF. WE HYPOTHESIZE THAT DIFFERENTIAL CHROMATIN ACCESS CAN DRIVE GENETIC DIFFERENCES IN IPF FIBROBLASTS RELATIVE TO HEALTHY FIBROBLASTS. TO THIS END, WE PERFORMED ASSAY OF TRANSPOSASE-ACCESSIBLE CHROMATIN SEQUENCING TO IDENTIFY DIFFERENTIALLY ACCESSIBLE REGIONS WITHIN THE GENOMES OF FIBROBLASTS FROM HEALTHY AND IPF LUNGS. MULTIPLE MOTIFS WERE IDENTIFIED TO BE ENRICHED IN IPF FIBROBLASTS COMPARED WITH HEALTHY FIBROBLASTS, INCLUDING BINDING MOTIFS FOR TWIST1 AND FOXA1. RNA SEQUENCING IDENTIFIED 93 GENES THAT COULD BE ANNOTATED TO DIFFERENTIALLY ACCESSIBLE REGIONS. PATHWAY ANALYSIS OF THE ANNOTATED GENES IDENTIFIED CELLULAR ADHESION, CYTOSKELETAL ANCHORING, AND CELL DIFFERENTIATION AS IMPORTANT BIOLOGICAL PROCESSES. IN ADDITION, SINGLE NUCLEOTIDE POLYMORPHISM ANALYSIS SHOWED THAT LINKAGE DISEQUILIBRIUM BLOCKS OF IPF RISK SINGLE NUCLEOTIDE POLYMORPHISMS WITH IPF-ACCESSIBLE REGIONS THAT HAVE BEEN IDENTIFIED TO BE LOCATED IN GENES THAT ARE IMPORTANT IN IPF, INCLUDING MUC5B, TERT, AND TOLLIP. VALIDATION STUDIES IN ISOLATED LUNG TISSUE CONFIRMED INCREASED EXPRESSION FOR TWIST1 AND FOXA1 IN ADDITION TO REVEALING SHANK2 AND CSPR2 AS NOVEL TARGETS. THUS, MODULATION OF DIFFERENTIAL CHROMATIN ACCESS MAY BE AN IMPORTANT MECHANISM IN THE PATHOGENESIS OF LUNG FIBROSIS. 2022 13 3674 25 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 14 2169 32 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 15 172 37 ABSENCE OF HDAC3 BY MATRIX STIFFNESS PROMOTES CHROMATIN REMODELING AND FIBROBLAST ACTIVATION IN IDIOPATHIC PULMONARY FIBROSIS. IDIOPATHIC PULMONARY FIBROSIS (IPF) IS A CHRONIC AND FATAL DISEASE CHARACTERIZED BY PROGRESSIVE AND IRREVERSIBLE LUNG SCARRING ASSOCIATED WITH PERSISTENT ACTIVATION OF FIBROBLASTS. EPIGENETICS COULD INTEGRATE DIVERSE MICROENVIRONMENTAL SIGNALS, SUCH AS STIFFNESS, TO DIRECT PERSISTENT FIBROBLAST ACTIVATION. HISTONE MODIFICATIONS BY DEACETYLASES (HDAC) MAY PLAY AN ESSENTIAL ROLE IN THE GENE EXPRESSION CHANGES INVOLVED IN THE PATHOLOGICAL REMODELING OF THE LUNG. PARTICULARLY, HDAC3 IS CRUCIAL FOR MAINTAINING CHROMATIN AND REGULATING GENE EXPRESSION, BUT LITTLE IS KNOWN ABOUT ITS ROLE IN IPF. IN THE STUDY, CONTROL AND IPF-DERIVED FIBROBLASTS WERE USED TO DETERMINE THE INFLUENCE OF HDAC3 ON CHROMATIN REMODELING AND GENE EXPRESSION ASSOCIATED WITH IPF SIGNATURE. ADDITIONALLY, THE CELLS WERE GROWN ON HYDROGELS TO MIMIC THE STIFFNESS OF A FIBROTIC LUNG. OUR RESULTS SHOWED A DECREASED HDAC3 IN THE NUCLEUS OF IPF FIBROBLASTS, WHICH CORRELATES WITH CHANGES IN NUCLEUS SIZE AND HETEROCHROMATIN LOSS. THE INHIBITION OF HDAC3 WITH A PHARMACOLOGICAL INHIBITOR CAUSES HYPERACETYLATION OF H3K9 AND PROVOKES AN INCREASED EXPRESSION OF COL1A1, ACTA2, AND P21. COMPARABLE RESULTS WERE FOUND IN HYDROGELS, WHERE MATRIX STIFFNESS PROMOTES THE LOSS OF NUCLEAR HDAC3 AND INCREASES THE PROFIBROTIC SIGNATURE. FINALLY, LATRUNCULIN B WAS USED TO CONFIRM THAT CHANGES BY STIFFNESS DEPEND ON THE MECHANOTRANSDUCTION SIGNALS. TOGETHER, THESE RESULTS SUGGEST THAT HDAC3 COULD BE A LINK BETWEEN EPIGENETIC MECHANISMS AND THE FIBROTIC MICROENVIRONMENT. 2023 16 1484 26 DLEU2: A MEANINGFUL LONG NONCODING RNA IN ONCOGENESIS. BACKGROUND: LONG NON-CODING RNA (LNCRNA) WITH LITTLE OR NO CODING ABILITY HAS SHOWN A VARIETY OF BIOLOGICAL FUNCTIONS IN CANCER, INCLUDING EPIGENETIC REGULATION, DNA DAMAGE, REGULATION OF MICRORNAS, AND PARTICIPATION IN SIGNAL TRANSDUCTION PATHWAYS. LNCRNA CAN BE USED AS AN ONCOGENE AND TUMOR SUPPRESSOR GENE THROUGH TRANSCRIPTIONAL REGULATION IN CANCER. FOR EXAMPLE, THE OVER-EXPRESSED LNCRNA DLEU2 PROMOTES THE OCCURRENCE OF LARYNGEAL CANCER, LUNG CANCER, HEPATOCELLULAR CARCINOMA, ETC., AND INHIBITS THE PROGRESSION OF CHRONIC LYMPHOCYTIC LEUKEMIA. DELETED IN LYMPHOCYTIC LEUKEMIA 2 (DLEU2), AS ONE OF THE LONG NON-CODING RNAS, WAS FIRST FOUND IN CHRONIC LYMPHOBLASTIC LEUKEMIA AND DRAWN INTO THE PROGRESS OF INNUMERABLE CANCERS. THE MOLECULAR MECHANISM OF DLEU2 IN MULTIPLE TUMORS WILL BE REVEALED. METHODS: IN THIS REVIEW, CURRENT STUDIES ON THE BIOLOGICAL FUNCTIONS AND MECHANISMS OF DLEU2 IN TUMORS ARE SUMMARIZED AND ANALYZED; RELATED RESEARCHES ARE SYSTEMATICALLY RETRIEVED AND COLLECTED THROUGH PUBMED. RESULTS: DLEU2, A NOVEL CANCER-RELATED LNCRNA, HAS BEEN DEMONSTRATED TO BE ABNORMALLY EXPRESSED IN VARIOUS MALIGNANT TUMORS, INCLUDING LEUKEMIA, ESOPHAGEAL CANCER, LUNG CANCER, GLIOMA, HEPATOCELLULAR CARCINOMA, MALIGNANT PLEURAL MESOTHELIOMA, BLADDER CANCER, PANCREATIC CANCER, PHARYNX AND THROAT CANCER, RENAL CLEAR CELL CARCINOMA, BREAST CANCER, OSTEOSARCOMA. BESIDES, LNCRNA DLEU2 HAS BEEN SHOWN TO BE INVOLVED IN THE PROCESS OF PROLIFERATION, MIGRATION, INVASION AND INHIBITION OF APOPTOSIS OF CANCER CELLS. CONCLUSION: DUE TO THE BIOLOGICAL FUNCTIONS AND MECHANISMS INVOLVED IN DLEU2, IT MAY REPRESENT AN AVAILABLE BIOMARKER OR POTENTIAL THERAPEUTIC TARGET IN A VARIETY OF MALIGNANT TUMORS. 2021 17 5575 30 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 18 4661 23 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 19 6223 28 THE LEADING ROLE OF EPITHELIAL CELLS IN THE PATHOGENESIS OF IDIOPATHIC PULMONARY FIBROSIS. IDIOPATHIC PULMONARY FIBROSIS (IPF) IS A RELENTLESSLY PROGRESSIVE AND DEVASTATING INTERSTITIAL LUNG DISEASE OF UNKNOWN ETIOLOGY, WHERE THE NORMAL LUNG ARCHITECTURE IS LOST AND REPLACED BY FIBROTIC TISSUE LEADING TO AN IRREVERSIBLE AND PROGRESSIVE RESPIRATORY INSUFFICIENCY. HISTORICALLY, IPF WAS CONSIDERED A CHRONIC INFLAMMATORY DISORDER, WHICH GRADUALLY PROGRESSED TO ESTABLISHED FIBROSIS. HOWEVER, STRONG CLINICAL AND EXPERIMENTAL EVIDENCE INDICATES THAT THE DISEASE REPRESENTS AN EPITHELIAL-DRIVEN DISORDER WHICH RESULTS FROM A COMPLEX INTERPLAY OF GENETIC AND ENVIRONMENTAL RISK FACTORS, AGING-ASSOCIATED PROCESSES AND A PROFIBROTIC EPIGENETIC REPROGRAMMING. THE CONVERGENCE OF THESE FACTORS RESULTS IN THE ABERRANT ACTIVATION OF EPITHELIAL CELLS THAT INITIATE THE DEVELOPMENT OF THE DISEASE, PRODUCING VIRTUALLY ALL THE MEDIATORS THAT PARTICIPATE IN THE MIGRATION, PROLIFERATION AND ACTIVATION OF FIBROBLASTS, THEIR DIFFERENTIATION TO MYOFIBROBLASTS AND THE EXCESSIVE AND CHAOTIC SECRETION OF EXTRACELLULAR MATRIX PROTEINS. ALTHOUGH PROGRESS HAS BEEN MADE IN UNDERSTANDING THE CAUSES AND CONSEQUENCES OF THIS ABNORMAL BEHAVIOR OF DISTAL AIRWAYS AND ALVEOLAR EPITHELIUM, THE MECHANISMS THAT INITIATE AND PERPETUATE THE VICIOUS CIRCLE OF MULTIDIRECTIONAL ABNORMAL COMMUNICATIONS BETWEEN THE EPITHELIUM AND FIBROBLASTS AND OTHER RESIDENT CELLS HAVE NOT BEEN ELUCIDATED. IN THIS REVIEW, WE DISCUSS THE ROLE OF EPITHELIAL CELLS AND THE MECHANISMS UNDERLYING THE FIBROTIC RESPONSE IN IPF, AND HIGHLIGHT SOME PROMISING THERAPEUTIC TARGETS FOR THESE CELLS. 2020 20 3253 31 HEPATITIS B VIRUS X PROTEIN ACCELERATES THE DEVELOPMENT OF HEPATOMA. THE CHRONIC INFECTION OF HEPATITIS B VIRUS (HBV) IS CLOSELY RELATED TO THE OCCURRENCE AND DEVELOPMENT OF HEPATOCELLULAR CARCINOMA (HCC). ACCUMULATED EVIDENCE HAS SHOWN THAT HBV X PROTEIN (HBX PROTEIN) IS A MULTIFUNCTIONAL REGULATOR WITH A CRUCIAL ROLE IN HEPATOCARCINOGENESIS. HOWEVER, INFORMATION ON THE MECHANISM BY WHICH HBV INDUCES HCC IS LACKING. THIS REVIEW FOCUSES ON THE PATHOLOGICAL FUNCTIONS OF HBX IN HBV-INDUCED HEPATOCARCINOGENESIS. AS A TRANSACTIVATOR, HBX CAN MODULATE NUCLEAR FACTOR KAPPA-LIGHT-CHAIN-ENHANCER OF ACTIVATED B CELLS (NF-KAPPAB) AND TRANSCRIPTION FACTOR AP-2. MOREOVER, HBX CAN AFFECT REGULATORY NON-CODING RNAS (NCRNAS) INCLUDING MICRORNAS AND LONG NCRNAS (LNCRNAS), SUCH AS MIRNA-205 AND HIGHLY UPREGULATED IN LIVER CANCER (HULC), RESPECTIVELY. HBX IS ALSO INVOLVED IN EPIGENETIC MODIFICATION, INCLUDING METHYLATION AND ACETYLATION. HBX INTERACTS WITH VARIOUS SIGNAL-TRANSDUCTION PATHWAYS, SUCH AS PROTEIN KINASE B/AKT, WNT/BETA-CATENIN, SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION, AND NF-KAPPAB PATHWAYS. MOREOVER, HBX AFFECTS CELLULAR FATE BY SHIFTING THE BALANCE TOWARD CELL SURVIVAL. HBX MAY LEAD TO THE LOSS OF APOPTOTIC FUNCTIONS OR DIRECTLY CONTRIBUTES TO ONCOGENESIS BY ACHIEVING TRANSFORMING FUNCTIONS, WHICH INDUCE HEPATOCARCINOGENESIS. ADDITIONALLY, HBX CAN MODULATE APOPTOSIS AND IMMUNE RESPONSE BY DIRECT OR INDIRECT INTERACTION WITH HOST FACTORS. WE CONCLUDE THAT HBX HASTENS THE DEVELOPMENT OF HEPATOMA. 2014