1 6223 125 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 2 6212 50 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 3 3674 52 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 4 4038 37 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 5 5456 32 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 6 2933 43 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 7 4738 42 NOVEL FIBROBLAST PHENOTYPES IN HOMEOSTASIS AND CHRONIC INFLAMMATION: FROM FUNCTIONS TO POTENTIAL REGULATORS. FIBROBLASTS ARE ESSENTIAL COMPONENTS OF THE STROMA, SUSTAINING A VARIETY OF TISSUES AND BEING KEY TO THE PROCESS OF TISSUE REPAIR AFTER INJURY. THEIR ROLE IN TISSUE REPAIR HAS BEEN ATTRIBUTED TO THEIR ABILITY TO ACQUIRE A CONTRACTILE, EXTRACELLULAR MATRIX-PRODUCING PHENOTYPE KNOWN AS MYOFIBROBLASTS. THIS PROPERTY IS PRIMARILY DEPENDENT ON THEIR RESPONSE TO THE PLEIOTROPIC CYTOKINE TRANSFORMING GROWTH FACTOR-BETA1. UNTIL RECENTLY, THE POTENTIAL ROLE OF FIBROBLASTS IN OTHER HOMEOSTATIC AND DISEASE-RELATED PROCESSES WAS LESS WELL UNDERSTOOD. ALTHOUGH IN VITRO STUDIES INDICATED THAT FIBROBLASTS ARE ABLE TO RESPOND TO AND SECRETE INFLAMMATORY MEDIATORS, DEFINITIVE EVIDENCE OF THEIR CONTRIBUTION TO CHRONIC INFLAMMATION WAS LIMITED. HOWEVER, THE EMERGENCE OF TECHNIQUES THAT ALLOW EXPLORATION OF TISSUES AT THE SINGLE CELL LEVEL HAS CHALLENGED THE PREVIOUS PARADIGMS ON FIBROBLAST IDENTITY AND FUNCTIONS, AND HAS LED TO THE DISCOVERY OF SIGNIFICANT DIVERSITY, SHOWING THE PRESENCE OF FIBROBLASTS WITH ALTERNATE TRANSCRIPTIONAL PROFILES IN A VARIETY OF TISSUES. THESE STUDIES HAVE ALSO SUGGESTED POTENTIAL ROLES OF NOVEL FIBROBLAST SUBTYPES AS REGULATORS OF EPITHELIAL HOMEOSTASIS AND RENEWAL, INFLAMMATORY CELL INFILTRATION AND ACTIVATION, AND ANTIGEN PRESENTATION. HERE, WE PROVIDE A COMPREHENSIVE REVIEW OF THE RECENT LITERATURE ON FIBROBLAST DIVERSITY IN THE DIGESTIVE TRACT, SKIN, LUNGS AND JOINTS. WE ALSO REVIEW EVIDENCE OF THEIR CONTRIBUTION TO THE REGULATION OF HOMEOSTASIS AND CHRONIC INFLAMMATION, AS WELL AS THEIR INTERACTIONS WITH OTHER CELLS IN VARIOUS TISSUE COMPARTMENTS. WE DISCUSS EVIDENCE OF DIFFERENT FACTORS INVOLVED IN THE CONTROL OF FIBROBLAST FUNCTION, ADDRESSING THE ROLE OF VARIOUS CYTOKINES, TRANSCRIPTION FACTORS AND EPIGENETIC CHANGES, AS WELL AS MICROENVIRONMENTAL FACTORS, INCLUDING EXTRACELLULAR MATRIX STIFFNESS, HYPOXIA, AND METABOLIC SHIFTS. 2023 8 5484 52 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 9 6053 40 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 10 4294 38 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 11 2169 36 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 12 5575 47 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 13 5769 40 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 14 1597 35 DNA METHYLATION REGULATED GENE EXPRESSION IN ORGAN FIBROSIS. DNA METHYLATION IS A MAJOR EPIGENETIC MECHANISM TO REGULATE GENE EXPRESSION. EPIGENETIC REGULATION, INCLUDING DNA METHYLATION, HISTONE MODIFICATIONS AND RNA INTERFERENCE, RESULTS IN HERITABLE CHANGES IN GENE EXPRESSION INDEPENDENT OF ALTERATIONS IN DNA SEQUENCE. EPIGENETIC REGULATION OFTEN OCCURS IN RESPONSE TO AGING AND ENVIRONMENT STIMULI, INCLUDING EXPOSURES AND DIET. STUDIES HAVE SHOWN THAT DNA METHYLATION IS CRITICAL IN THE PATHOGENESIS OF FIBROSIS INVOLVING MULTIPLE ORGAN SYSTEMS, CONTRIBUTING TO SIGNIFICANT MORBIDITY AND MORTALITY. ABERRANT DNA METHYLATION CAN SILENCE OR ACTIVATE GENE EXPRESSION PATTERNS THAT DRIVE THE FIBROSIS PROCESS. FIBROSIS IS A PATHOLOGICAL WOUND HEALING PROCESS IN RESPONSE TO CHRONIC INJURY. IT IS CHARACTERIZED BY EXCESSIVE EXTRACELLULAR MATRIX PRODUCTION AND ACCUMULATION, WHICH EVENTUALLY AFFECTS ORGAN ARCHITECTURE AND RESULTS IN ORGAN FAILURE. FIBROSIS CAN AFFECT A WIDE RANGE OF ORGANS, INCLUDING THE HEART AND LUNGS, AND HAVE LIMITED THERAPEUTIC OPTIONS. DNA METHYLATION, LIKE OTHER EPIGENETIC PROCESS, IS REVERSIBLE, THEREFORE REGARDED AS ATTRACTIVE THERAPEUTIC INTERVENTIONS. ALTHOUGH EPIGENETIC MECHANISMS ARE HIGHLY INTERACTIVE AND OFTEN REINFORCING, THIS REVIEW DISCUSSES DNA METHYLATION-DEPENDENT MECHANISMS IN THE PATHOGENESIS OF ORGAN FIBROSIS, WITH FOCUS ON CARDIAC AND PULMONARY FIBROSIS. WE DISCUSS SPECIFIC PRO- AND ANTI-FIBROTIC GENES AND PATHWAYS REGULATED BY DNA METHYLATION IN ORGAN FIBROSIS; WE FURTHER HIGHLIGHT THE POTENTIAL BENEFITS AND SIDE-EFFECTS OF EPIGENETIC THERAPIES IN FIBROTIC DISORDERS. 2017 15 4480 37 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 16 3512 52 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 17 2283 28 EPIGENETIC REGULATION IN FIBROSIS PROGRESS. FIBROSIS, A COMMON PROCESS OF CHRONIC INFLAMMATORY DISEASES, IS DEFINED AS A REPAIR RESPONSE DISORDER WHEN ORGANS UNDERGO CONTINUOUS DAMAGE, ULTIMATELY LEADING TO SCAR FORMATION AND FUNCTIONAL FAILURE. AROUND THE WORLD, FIBROTIC DISEASES CAUSE HIGH MORTALITY, UNFORTUNATELY, WITH LIMITED TREATMENT MEANS IN CLINICAL PRACTICE. WITH THE DEVELOPMENT AND APPLICATION OF DEEP SEQUENCING TECHNOLOGY, COMPREHENSIVELY EXPLORING THE EPIGENETIC MECHANISM IN FIBROSIS HAS BEEN ALLOWED. EXTENSIVE REMODELING OF EPIGENETICS CONTROLLING VARIOUS CELLS PHENOTYPE AND MOLECULAR MECHANISMS INVOLVED IN FIBROGENESIS WAS SUBSEQUENTLY VERIFIED. IN THIS REVIEW, WE SUMMARIZE THE REGULATORY MECHANISMS OF DNA METHYLATION, HISTONE MODIFICATION, NONCODING RNAS (NCRNAS) AND N6-METHYLADENOSINE (M6A) MODIFICATION IN ORGAN FIBROSIS, FOCUSING ON HEART, LIVER, LUNG AND KIDNEY. ADDITIONALLY, WE EMPHASIZE THE DIVERSITY OF EPIGENETICS IN THE CELLULAR AND MOLECULAR MECHANISMS RELATED TO FIBROSIS. FINALLY, THE POTENTIAL AND PROSPECT OF TARGETED THERAPY FOR FIBROSIS BASED ON EPIGENETIC IS DISCUSSED. 2021 18 5258 35 PROGRESSION OF TUBULOINTERSTITIAL FIBROSIS AND THE CHRONIC KIDNEY DISEASE PHENOTYPE - ROLE OF RISK FACTORS AND EPIGENETICS. ALTHOUGH THE KIDNEY HAS CAPACITY TO REPAIR AFTER MILD INJURY, ONGOING OR SEVERE DAMAGE RESULTS IN SCARRING (FIBROSIS) AND AN ASSOCIATED PROGRESSIVE LOSS OF KIDNEY FUNCTION. HOWEVER, DESPITE ITS UNIVERSAL SIGNIFICANCE, EVIDENCE HIGHLIGHTS A POPULATION BASED HETEROGENEITY IN THE TRAJECTORY OF CHRONIC KIDNEY DISEASE (CKD) IN THESE PATIENTS. TO EXPLAIN THE HETEROGENEITY OF THE CKD PHENOTYPE REQUIRES AN UNDERSTANDING OF THE RELEVANT RISK FACTORS FOR FIBROSIS. THESE FACTORS INCLUDE BOTH THE EXTRINSIC NATURE OF INJURY, AND INTRINSIC FACTORS SUCH AS AGE, GENDER, GENETICS, AND PERPETUAL ACTIVATION OF FIBROBLASTS THROUGH PRIMING. IN MANY CASES AN ADDITIONAL LEVEL OF REGULATION IS PROVIDED BY EPIGENETIC MECHANISMS WHICH INTEGRATE THE VARIOUS PRO-FIBROTIC AND ANTI-FIBROTIC TRIGGERS IN FIBROGENESIS. IN THIS REVIEW WE THEREFORE EXAMINE THE VARIOUS MOLECULAR AND STRUCTURAL CHANGES OF FIBROSIS, AND HOW THEY ARE INFLUENCED BY EXTRINSIC AND INTRINSIC FACTORS. OUR AIM IS TO PROVIDE A UNIFYING HYPOTHESIS TO HELP EXPLAIN THE TRANSITION FROM ACUTE TO CKD. 2017 19 1113 37 COMMON PATHWAYS IN IDIOPATHIC PULMONARY FIBROSIS AND CANCER. IDIOPATHIC PULMONARY FIBROSIS (IPF) IS MARKED BY A VERY DISAPPOINTING SURVIVAL RATE AND STILL REPRESENTS A CLINICAL DILEMMA. ACCORDING TO THE CURRENT PATHOGENIC HYPOTHESIS, CHRONIC DAMAGE OF THE ALVEOLAR EPITHELIUM IS FOLLOWED BY ABNORMAL TISSUE REPAIR AND IMPAIRMENT OF THE ALVEOLAR STRUCTURE. THIS PROCESS IS DRIVEN BY PATHOGENIC EVENTS VERY SIMILAR TO CANCER, INCLUDING EPIGENETIC AND GENETIC CHANGES, ALTERED RESPONSE TO REGULATORY SIGNALS, ABNORMAL EXPRESSION OF MICRORNAS AND ACTIVATION OF SPECIFIC SIGNALLING PATHWAYS. IPF ALSO RESEMBLES CANCER WITH REGARD TO ITS POOR RESPONSE TO MEDICAL TREATMENT AND PROGNOSIS, WHICH IS VERY OFTEN WORSE THAN MANY CANCERS. WE HAVE HYPOTHESISED THAT IPF MIGHT BE ASSIMILATED TO A NEOPROLIFERATIVE DISORDER OF THE LUNG. VIEWING IPF AS A CANCER-LIKE DISEASE MAY SATISFY THE NEED FOR A BETTER UNDERSTANDING OF THE PATHOGENESIS OF IPF BY EXPLOITING THE LARGE AMOUNT OF KNOWLEDGE THAT CANCER BIOLOGY EVOKES. THE RECOGNITION OF COMMON PATHOGENIC PATHWAYS BETWEEN THE TWO DISEASES MAY STIMULATE NEW CLINICAL TRIALS WITH CANCER DRUGS, DIFFERENT DRUG COMBINATIONS AND DIFFERENT LINES OF DRUGS, AS ALREADY EXPERIMENTED IN ONCOLOGY. MOREOVER, THE CONCEPT OF IPF AS A CANCER-LIKE DISORDER MAY IMPROVE THE ATTENTION GIVEN TO THIS DREADFUL DISEASE ON A PUBLIC, POLITICAL AND HEALTHCARE LEVEL. 2013 20 763 40 CAUSES OF PULMONARY FIBROSIS IN THE ELDERLY. IDIOPATHIC PULMONARY FIBROSIS (IPF) IS THE MOST COMMON AND MOST LETHAL TYPE OF IDIOPATHIC INTERSTITIAL PNEUMONIA. IT IS A CHRONIC, AGING-ASSOCIATED LUNG DISEASE CHARACTERIZED BY FIBROTIC FOCI AND INFLAMMATORY INFILTRATES, WITH NO CURE AND VERY LIMITED THERAPEUTIC OPTIONS. ALTHOUGH ITS ETIOLOGY IS UNKNOWN, SEVERAL PATHOGENIC PATHWAYS HAVE BEEN DESCRIBED THAT COULD EXPLAIN THIS PROCESS, INVOLVING AGING, ENVIRONMENTAL FACTORS, GENOMIC INSTABILITY, LOSS OF PROTEOSTASIS, TELOMERE ATTRITION, EPIGENETIC CHANGES, MITOCHONDRIAL DYSFUNCTION, CELL SENESCENCE, AND ALTERED INTERCELLULAR COMMUNICATION. ONE OF THE MAIN PROGNOSTIC FACTORS FOR THE DEVELOPMENT OF IPF IN BROAD EPIDEMIOLOGICAL STUDIES IS AGE. THE INCIDENCE INCREASES WITH AGE, MAKING THIS A DISEASE THAT PREDOMINANTLY AFFECTS THE ELDERLY POPULATION, BEING EXCEPTIONAL UNDER 45 YEARS OF AGE. HOWEVER, THE DEGREE TO WHICH EACH OF THESE MECHANISMS IS INVOLVED IN THE ETIOLOGY OF THE UNCONTROLLED FIBROGENESIS THAT DEFINES IPF IS STILL UNKNOWN. CLARIFYING THESE QUESTIONS IS CRUCIAL TO THE DEVELOPMENT OF POINTS OF INTERVENTION IN THE PATHOGENESIS OF THE DISEASE. THIS REVIEW BRIEFLY SUMMARIZES WHAT IS KNOWN ABOUT EACH POSSIBLE ETIOLOGICAL FACTOR, AND THE QUESTIONS THAT MOST URGENTLY NEED TO BE ADDRESSED. 2018