1 4358 93 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 2 5575 36 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 3 4294 32 MICRORNA REGULATORY NETWORKS IN IDIOPATHIC PULMONARY FIBROSIS. IDIOPATHIC PULMONARY FIBROSIS (IPF) IS A CHRONIC, PROGRESSIVE, AND FATAL SCARRING LUNG DISEASE OF UNKNOWN ETIOLOGY, CHARACTERIZED BY CHANGES IN MICRORNA EXPRESSION. ACTIVATION OF TRANSFORMING GROWTH FACTOR (TGF-BETA) IS A KEY EVENT IN THE DEVELOPMENT OF IPF. RECENT REPORTS HAVE ALSO IDENTIFIED EPIGENETIC MODIFICATION AS AN IMPORTANT PLAYER IN THE PATHOGENESIS OF IPF. IN THIS REVIEW, WE SUMMARIZE THE MAIN RESULTS OF STUDIES THAT ADDRESS THE ROLE OF MICRORNAS IN IPF AND HIGHLIGHT THE SYNERGISTIC ACTIONS OF THESE MICRORNAS IN REGULATING TGF-BETA, THE PRIMARY FIBROGENIC MEDIATOR. WE OUTLINE EPIGENETIC REGULATION OF MICRORNAS BY METHYLATION. FUNCTIONAL STUDIES IDENTIFY MICRORNAS THAT ALTER PROLIFERATIVE AND MIGRATORY PROPERTIES OF FIBROBLASTS, AND INDUCE PHENOTYPIC CHANGES IN EPITHELIAL CELLS CONSISTENT WITH EPITHELIAL-MESENCHYMAL TRANSITION. THOUGH THESE STUDIES WERE PERFORMED IN ISOLATION, WE IDENTIFY MULTIPLE CO-OPERATIVE ACTIONS AFTER ASSEMBLING THE RESULTS INTO A NETWORK. CONSTRUCTION OF SUCH NETWORKS WILL HELP IDENTIFY DISEASE-PROPELLING HUBS THAT CAN BE TARGETED FOR THERAPEUTIC PURPOSES. 2015 4 5769 31 SPECIFIC EPIGENETIC REGULATORS SERVE AS POTENTIAL THERAPEUTIC TARGETS IN IDIOPATHIC PULMONARY FIBROSIS. IDIOPATHIC PULMONARY FIBROSIS (IPF), A DISORDER OBSERVED MOSTLY IN OLDER HUMAN BEINGS, IS CHARACTERISED BY CHRONIC AND PROGRESSIVE LUNG SCARRING LEADING TO AN IRREVERSIBLE DECLINE IN LUNG FUNCTION. THIS HEALTH CONDITION HAS A DISMAL PROGNOSIS AND THE CURRENTLY AVAILABLE DRUGS ONLY DELAY BUT FAIL TO REVERSE THE PROGRESSION OF LUNG DAMAGE. CONSEQUENTLY, IT BECOMES IMPERATIVE TO DISCOVER IMPROVED THERAPEUTIC COMPOUNDS AND THEIR CELLULAR TARGETS TO CURE IPF. IN THIS REGARD, A NUMBER OF RECENT STUDIES HAVE TARGETED THE EPIGENETIC REGULATION BY HISTONE DEACETYLASES (HDACS) TO DEVELOP AND CATEGORISE ANTIFIBROTIC DRUGS FOR LUNGS. THEREFORE, THIS REVIEW FOCUSES ON HOW ABERRANT EXPRESSION OR ACTIVITY OF CLASSES I, II AND III HDACS ALTER TGF-BETA SIGNALLING TO PROMOTE EVENTS SUCH AS EPITHELIAL-MESENCHYMAL TRANSITION, DIFFERENTIATION OF ACTIVATED FIBROBLASTS INTO MYOFIBROBLASTS, AND EXCESS DEPOSITION OF THE EXTRACELLULAR MATRIX TO PROPEL LUNG FIBROSIS. FURTHER, THIS STUDY DESCRIBES HOW CERTAIN CHEMICAL COMPOUNDS OR DIETARY CHANGES MODULATE DYSREGULATED HDACS TO ATTENUATE FIVE FAULTY TGF-BETA-DEPENDENT PROFIBROTIC PROCESSES, BOTH IN ANIMAL MODELS AND CELL LINES REPLICATING IPF, THEREBY IDENTIFYING PROMISING MEANS TO TREAT THIS LUNG DISORDER. 2022 5 2169 29 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 6 6223 37 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 7 3674 31 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 8 6053 28 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 9 3512 30 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 5992 28 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 11 4661 19 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 12 4480 35 MOLECULAR PATHWAYS AND ROLE OF EPIGENETICS IN THE IDIOPATHIC PULMONARY FIBROSIS. IDIOPATHIC PULMONARY FIBROSIS (IPF) IS A FATAL LUNG DISEASE WITH UNKNOWN ETIOLOGICAL FACTORS THAT CAN PROGRESS TO OTHER DANGEROUS DISEASES LIKE LUNG CANCER. ENVIRONMENTAL AND GENETIC PREDISPOSITION ARE THE TWO MAJOR ETIOLOGICAL OR RISK FACTORS INVOLVED IN THE PATHOLOGY OF THE IPF. AMONG THE ENVIRONMENTAL RISK FACTORS, SMOKING IS ONE OF THE MAJOR CAUSES FOR THE DEVELOPMENT OF IPF. EPIGENETIC PATHWAYS LIKE NUCLEOSOMES REMODELING, DNA METHYLATION, HISTONE MODIFICATIONS AND MIRNA MEDIATED GENES PLAY A CRUCIAL ROLE IN DEVELOPMENT OF IPF. MUTATIONS IN THE GENES MAKE THE EPIGENETIC FACTORS AS IMPORTANT DRUG TARGETS IN IPF. TRANSCRIPTIONAL CHANGES DUE TO ENVIRONMENTAL FACTORS ARE ALSO INVOLVED IN THE PROGRESSION OF IPF. THE MUTATIONS IN HUMAN TELOMERASE REVERSE TRANSCRIPTASE (HTERT) HAVE SHOWN DECREASED LIFE EXPECTANCY IN IPF PATIENTS. THE TERT-GENE IS HIGHLY EXPRESSED IN CHRONIC SMOKERS AND MAKES THE ROLE OF EPIGENETICS EVIDENT. DRUG LIKE NINTEDANIB ACTS THROUGH VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTORS (VEGFR), WHILE DRUG PIRFENIDONE ACTS THROUGH TRANSFORMING GROWTH FACTOR (TGF), WHICH IS USEFUL IN IPF. GEFITINIB, A TYROSINE KINASE INHIBITOR OF EGFR, IS USEFUL AS AN ANTI-FIBROSIS AGENT IN PRECLINICAL MODELS. NEWER DRUGS SUCH AS CELGENE-CC90001 AND FIBROGEN-FG-3019 ARE CURRENTLY UNDER INVESTIGATIONS ACTS THROUGH THE MODULATING EPIGENETIC MECHANISMS. THUS, THE STUDY ON EPIGENETICS OPENS A WIDE WINDOW FOR THE DISCOVERY OF NEWER DRUGS. THIS STUDY PROVIDES AN ELEMENTARY ANALYSIS OF MULTIPLE REGULATORS OF EPIGENETICS AND THEIR ROLES ASSOCIATED WITH THE PATHOLOGY OF IPF. FURTHER, THIS REVIEW ALSO INCLUDES EPIGENETIC DRUGS UNDER DEVELOPMENT IN PRECLINICAL AND CLINICAL STAGES. 2022 13 4450 32 MOLECULAR MECHANISMS AND CELLULAR CONTRIBUTION FROM LUNG FIBROSIS TO LUNG CANCER DEVELOPMENT. IDIOPATHIC PULMONARY FIBROSIS (IPF) IS A CHRONIC, PROGRESSIVE, FIBROSING INTERSTITIAL LUNG DISEASE (ILD) OF UNKNOWN AETIOLOGY, WITH A MEDIAN SURVIVAL OF 2-4 YEARS FROM THE TIME OF DIAGNOSIS. ALTHOUGH IPF HAS UNKNOWN AETIOLOGY BY DEFINITION, THERE HAVE BEEN IDENTIFIED SEVERAL RISKS FACTORS INCREASING THE PROBABILITY OF THE ONSET AND PROGRESSION OF THE DISEASE IN IPF PATIENTS SUCH AS CIGARETTE SMOKING AND ENVIRONMENTAL RISK FACTORS ASSOCIATED WITH DOMESTIC AND OCCUPATIONAL EXPOSURE. AMONG THEM, CIGARETTE SMOKING TOGETHER WITH CONCOMITANT EMPHYSEMA MIGHT PREDISPOSE IPF PATIENTS TO LUNG CANCER (LC), MOSTLY TO NON-SMALL CELL LUNG CANCER (NSCLC), INCREASING THE RISK OF LUNG CANCER DEVELOPMENT. TO THIS PURPOSE, IPF AND LC SHARE SEVERAL CELLULAR AND MOLECULAR PROCESSES DRIVING THE PROGRESSION OF BOTH PATHOLOGIES SUCH AS FIBROBLAST TRANSITION PROLIFERATION AND ACTIVATION, ENDOPLASMIC RETICULUM STRESS, OXIDATIVE STRESS, AND MANY GENETIC AND EPIGENETIC MARKERS THAT PREDISPOSE IPF PATIENTS TO LC DEVELOPMENT. NINTEDANIB, A TYROSINE-KINASE INHIBITOR, WAS FIRSTLY DEVELOPED AS AN ANTICANCER DRUG AND THEN RECOGNIZED AS AN ANTI-FIBROTIC AGENT BASED ON THE COMMON TARGET MOLECULAR PATHWAY. IN THIS REVIEW OUR AIM IS TO DESCRIBE THE UPDATED STUDIES ON COMMON CELLULAR AND MOLECULAR MECHANISMS BETWEEN IPF AND LUNG CANCER, KNOWLEDGE OF WHICH MIGHT HELP TO FIND NOVEL THERAPEUTIC TARGETS FOR THIS DISEASE COMBINATION. 2021 14 5456 30 RESEARCH ADVANCES ON DNA METHYLATION IN IDIOPATHIC PULMONARY FIBROSIS. IDIOPATHIC PULMONARY FIBROSIS (IPF) IS A CHRONIC COMPLEX LUNG DISEASE WITH NO SPECIFIC TREATMENT AND POOR PROGNOSIS, CHARACTERIZED BY THE PULMONARY PROGRESSIVE FIBROSIS AND DYSFUNCTIONS THAT LEAD TO RESPIRATORY FAILURE. SEVERAL FACTORS MAY IMPACT THE PROGRESS OF IPF, INCLUDING AGE, CIGARETTE SMOKING, AND DUSTS, OF WHICH GENETIC AND EPIGENETIC FACTORS MAINLY CONTRIBUTE TO LUNG TISSUE FIBROSIS. DNA METHYLATION IS ONE OF EPIGENETIC PROCESSES THAT OCCUR IN MANY DISEASES AND REGULATE CHROMOSOMAL AND EXTRACHROMOSOMAL DNA FUNCTIONS IN RESPONSE TO ENVIRONMENTAL EXPOSURES. THE METHYLATION PLAYS PIVOTAL ROLES IN REGULATION OF GENE EXPRESSION TO FACILITATE THE FORMATION OF FIBROBLASTIC FOCI AND LUNG FIBROSIS. THIS CHAPTER WILL DESCRIBE ALTERATIONS AND EFFECTS OF THE DNA METHYLATION ON GENE EXPRESSION, THE POTENTIAL APPLICATION OF DNA METHYLATION AS A BIOMARKER, AND SIGNIFICANCE AS THERAPEUTIC TARGETS. THOSE UNDERSTANDING WILL PROVIDE US NEW INSIGHT INTO THE TREATMENT AND PROGNOSIS OF IPF. 2020 15 172 29 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 4038 31 MACROPHAGE IMPLICATION IN IPF: UPDATES ON IMMUNE, EPIGENETIC, AND METABOLIC PATHWAYS. IDIOPATHIC PULMONARY FIBROSIS (IPF) IS A LETHAL INTERSTITIAL LUNG DISEASE OF UNKNOWN ETIOLOGY WITH A POOR PROGNOSIS. IT IS A CHRONIC AND PROGRESSIVE DISEASE THAT HAS A DISTINCT RADIOLOGICAL AND PATHOLOGICAL PATTERN FROM COMMON INTERSTITIAL PNEUMONIA. THE USE OF IMMUNOSUPPRESSIVE MEDICATION WAS SHOWN TO BE COMPLETELY INEFFECTIVE IN CLINICAL TRIALS, RESULTING IN YEARS OF NEGLECT OF THE IMMUNE COMPONENT. HOWEVER, RECENT DEVELOPMENTS IN FUNDAMENTAL AND TRANSLATIONAL SCIENCE DEMONSTRATE THAT IMMUNE CELLS PLAY A SIGNIFICANT REGULATORY ROLE IN IPF, AND MACROPHAGES APPEAR TO BE AMONG THE MOST CRUCIAL. THESE HIGHLY PLASTIC CELLS GENERATE MULTIPLE GROWTH FACTORS AND MEDIATORS THAT HIGHLY AFFECT THE INITIATION AND PROGRESSION OF IPF. IN THIS REVIEW, WE WILL PROVIDE AN UPDATE ON THE ROLE OF MACROPHAGES IN IPF THROUGH A SYSTEMIC DISCUSSION OF VARIOUS REGULATORY MECHANISMS INVOLVING IMMUNE RECEPTORS, CYTOKINES, METABOLISM, AND EPIGENETICS. 2023 17 2933 35 GENESIS OF THE MYOFIBROBLAST IN LUNG INJURY AND FIBROSIS. TISSUE INJURY INCITES A REPAIR RESPONSE WITH A KEY MESENCHYMAL COMPONENT THAT PROVIDES THE ESSENTIAL CONNECTIVE TISSUE FOR SUBSEQUENT REGENERATION OR PATHOLOGICAL FIBROSIS. THE FIBROBLAST IS THE MAJOR MESENCHYMAL CELL TYPE TO BE IMPLICATED IN THIS CONNECTIVE TISSUE RESPONSE, AND IT IS IN ITS ACTIVATED OR DIFFERENTIATED FORM THAT IT PARTICIPATES IN THE REPAIR PROCESS. THE MYOFIBROBLAST REPRESENTS SUCH AN ACTIVATED MESENCHYMAL CELL AND IS A KEY SOURCE OF EXTRACELLULAR MATRIX AND INFLAMMATORY/FIBROGENIC CYTOKINES AS WELL AS PARTICIPATING IN WOUND CONTRACTION. ALTHOUGH SUCCESSFUL HEALING RESULTS IN GRADUAL DISAPPEARANCE OF MYOFIBROBLASTS, THEIR PERSISTENCE IS ASSOCIATED WITH CHRONIC AND PROGRESSIVE FIBROSIS. THUS, ELUCIDATION OF THE MECHANISM INVOLVED IN THE GENESIS OF THE MYOFIBROBLAST SHOULD PROVIDE INSIGHT INTO BOTH PATHOGENESIS OF CHRONIC FIBROTIC DISEASES AND THERAPEUTIC STRATEGIES FOR THEIR MANAGEMENT AND CONTROL. ALTHOUGH THE FIBROBLAST IS A WELL-DOCUMENTED PROGENITOR CELL FOR THE MYOFIBROBLAST, RECENT STUDIES HAVE SUGGESTED ADDITIONAL PRECURSOR CELLS THAT HAVE THE POTENTIAL TO GIVE RISE TO THE MYOFIBROBLAST. MANY OF THE STUDIES FOCUSED ON MECHANISMS AND FACTORS THAT REGULATE INDUCTION OF ALPHA-SMOOTH MUSCLE ACTIN EXPRESSION, A KEY AND COMMONLY USED MARKER OF THE MYOFIBROBLAST. THESE REVEAL COMPLEX AND MULTIFACTORIAL MECHANISMS INVOLVING TRANSCRIPTIONAL AND EPIGENETIC REGULATION AND IMPLICATING DIVERSE CELL-SIGNALING PATHWAYS, INCLUDING THOSE ACTIVATED BY THE POTENT FIBROGENIC CYTOKINE TRANSFORMING GROWTH FACTOR BETA. DESPITE THESE EXTENSIVE STUDIES, MANY ASPECTS REMAIN POORLY UNDERSTOOD, WITH THE SUGGESTION THAT ADDITIONAL NOVEL MECHANISMS REMAIN TO BE DISCOVERED. FUTURE STUDIES WITH THE HELP OF NEWLY DEVELOPED TECHNICAL ADVANCEMENTS SHOULD EXPEDITE DISCOVERY IN THIS DIRECTION. 2012 18 4575 27 MYOFIBROBLASTS. PURPOSE OF REVIEW: INTEREST IN THE MYOFIBROBLAST AS A KEY PLAYER IN PROPAGATION OF CHRONIC PROGRESSIVE FIBROSIS CONTINUES TO ELICIT MANY PUBLICATIONS, WITH FOCUS ON ITS CELLULAR ORIGINS AND THE MECHANISMS UNDERPINNING THEIR DIFFERENTIATION AND/OR TRANSITION. THE OBJECTIVE OF THE REVIEW IS TO HIGHLIGHT THIS RECENT PROGRESS. RECENT FINDINGS: THE EPITHELIAL ORIGIN OF THE MYOFIBROBLAST IN FIBROSIS HAS BEEN CHALLENGED BY RECENT STUDIES, WITH THE PERICYTE SUGGESTED AS A POSSIBLE PRECURSOR INSTEAD. ADDITIONAL SIGNALING PATHWAYS, INCLUDING NOTCH, WNT, AND HEDGEHOG, ARE IMPLICATED IN MYOFIBROBLAST DIFFERENTIATION. THE IMPORTANCE OF NADPH OXIDASE 4 WAS HIGHLIGHTED RECENTLY TO SUGGEST A POTENTIAL LINK BETWEEN CELLULAR/OXIDATIVE STRESS AND THE GENESIS OF THE MYOFIBROBLAST. RECENT OBSERVATIONS ON THE IMPORTANCE OF LYSOPHOSPHATIDIC ACID IN FIBROSIS SUGGEST THAT THIS MAY BE DUE, IN PART, TO ITS ABILITY TO REGULATE MYOFIBROBLAST DIFFERENTIATION. FINALLY, THERE IS INCREASING EVIDENCE FOR THE ROLE OF EPIGENETIC MECHANISMS IN REGULATING MYOFIBROBLAST DIFFERENTIATION, INCLUDING DNA METHYLATION AND MIRNA REGULATION OF GENE EXPRESSION. SUMMARY: THESE RECENT DISCOVERIES OPEN UP A WHOLE NEW ARRAY OF POTENTIAL TARGETS FOR NOVEL ANTIFIBROTIC THERAPIES. THIS IS OF SPECIAL IMPORTANCE GIVEN THE CURRENT BLEAK OUTLOOK FOR CHRONIC PROGRESSIVE FIBROTIC DISEASES, SUCH AS SCLERODERMA, DUE TO LACK OF EFFECTIVE THERAPIES. 2013 19 6212 30 THE INTERPLAY OF THE GENETIC ARCHITECTURE, AGING, AND ENVIRONMENTAL FACTORS IN THE PATHOGENESIS OF IDIOPATHIC PULMONARY FIBROSIS. IDIOPATHIC PULMONARY FIBROSIS (IPF) IS A CHRONIC FIBROSING LUNG DISEASE OF INDETERMINATE ETIOLOGY AND LIMITED THERAPEUTIC OPTIONS. THE INITIATION, DEVELOPMENT, AND PROGRESSION OF IPF ARE INFLUENCED BY GENETIC PREDISPOSITION, AGING, AND HOST AND ENVIRONMENTAL FACTORS, BUT THE MAGNITUDE OF THE CONTRIBUTION OF EACH OF THEM AND THE SEQUENCE OF THE PATHOGENIC EVENTS ARE UNCERTAIN. CURRENT EVIDENCE INDICATES THAT ACCUMULATED ENVIRONMENTAL EXPOSURES IN A GENETICALLY PREDISPOSED INDIVIDUAL, USUALLY OVER 60 YEARS OF AGE, LEADS TO PHENOTYPIC AND FUNCTIONAL ALTERATIONS OF THE LUNG EPITHELIUM. ABERRANT ACTIVATION OF EPITHELIAL CELLS RESULTS, THROUGH A COMPLEX RELEASE OF NUMEROUS MEDIATORS, IN THE LOCAL EXPANSION OF PECULIAR SUBSETS OF AGGRESSIVE FIBROBLASTS AND MYOFIBROBLASTS, WHICH ARE CRUCIAL EFFECTOR CELLS OF FIBROTIC REMODELING AND LOSS OF THE NORMAL LUNG ARCHITECTURE AND FUNCTION. PROGRESSIVE INCREASE OF THE MECHANICAL STIFFNESS ACTIVATES CELL-AUTONOMOUS AND MATRIX-DEPENDENT PROCESSES CONTRIBUTING TO THE PERPETUATION OF THE FIBROTIC RESPONSE. THIS PERSPECTIVE PROVIDES AN INTEGRAL OVERVIEW OF THE MAJOR RISK FACTORS UNDERPINNING THE PATHOGENESIS OF IPF, INCLUDING GENE VARIANTS, AGING ALTERATIONS, ENVIRONMENTAL FACTORS, HOST RISK FACTORS, AND EPIGENETIC REPROGRAMMING. 2021 20 6546 37 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