1 4450 123 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 2 4480 49 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 3 5575 43 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 4 5456 37 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 5 4038 34 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 6 1113 36 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 7 6223 44 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 8 6212 36 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 9 763 39 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 10 2527 32 EPIGENETICS APPROACHES TOWARD PRECISION MEDICINE FOR IDIOPATHIC PULMONARY FIBROSIS: FOCUS ON DNA METHYLATION. GENETIC INFORMATION IS NOT TRANSMITTED SOLELY BY DNA BUT BY THE EPIGENETICS PROCESS. EPIGENETICS DESCRIBES MOLECULAR MISSING LINK PATHWAYS THAT COULD BRIDGE THE GAP BETWEEN THE GENETIC BACKGROUND AND ENVIRONMENTAL RISK FACTORS THAT CONTRIBUTE TO THE PATHOGENESIS OF PULMONARY FIBROSIS. SPECIFIC EPIGENETIC PATTERNS, ESPECIALLY DNA METHYLATION, HISTONE MODIFICATIONS, LONG NON-CODING, AND MICRORNA (MIRNAS), AFFECT THE ENDOPHENOTYPES UNDERLYING THE DEVELOPMENT OF IDIOPATHIC PULMONARY FIBROSIS (IPF). AMONG ALL THE EPIGENETIC MARKS, DNA METHYLATION MODIFICATIONS HAVE BEEN THE MOST WIDELY STUDIED IN IPF. THIS REVIEW SUMMARIZES THE CURRENT KNOWLEDGE CONCERNING DNA METHYLATION CHANGES IN PULMONARY FIBROSIS AND DEMONSTRATES A PROMISING NOVEL EPIGENETICS-BASED PRECISION MEDICINE. 2023 11 2169 40 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 5769 37 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 13 6475 47 TOBACCO, INFLAMMATION, AND RESPIRATORY TRACT CANCER. CIGARETTE SMOKING IS THE MOST RECOGNIZED RISK FACTOR FOR MANY INFLAMMATORY DISEASES SUCH AS CARDIOVASCULAR DISEASES, CHRONIC OBSTRUCTIVE PULMONARY DISEASE AND FOR A NUMBER OF MALIGNANCES SUCH AS LUNG CANCER. LUNG CANCER IS CURRENTLY CONSIDERED THE LEADING CAUSE OF CANCER-RELATED DEATHS BECAUSE ITS AGGRESSIVE NATURE AND THE LACK OF EFFECTIVE THERAPEUTIC OPTIONS. RECENT ADVANCES IN MOLECULAR BIOLOGY AND IMMUNOLOGY HAVE IMPROVED THE KNOWLEDGE ON DIFFERENT MECHANISMS IMPLICATED IN LUNG CELL MALIGNANT TRANSFORMATION, PROGRESSION AND METASTASIS, THUS PRESENTING AN EXCITING NEW ERA FOR LUNG ANTICANCER THERAPIES. THE WAY BY WHICH CIGARETTE SMOKE MAY INDUCE LUNG MALIGNANCY INCLUDES A LARGE NUMBER OF DIFFERENT MECHANISMS AND SUBSTANCES, MOST OF THEM CURRENTLY UNKNOWN. THUS, IDENTIFIED CARCINOGENIC COMPOUNDS OF CIGARETTE SMOKE MAY INDUCE THEMSELVES A DIRECT CYTOTOXICITY AND MUTAGENIC ACTION ON LUNG EPITHELIAL CELLS BY MEANS OF GENERATION OF SOMATIC MUTATIONS, EPIGENETIC EVENTS, EPITHELIAL CELL TO MESENCHYMAL CELL TRANSFORMATIONS, AS WELL AS BY CHRONIC CELL DAMAGE. HOWEVER, THE FACT THAT THERE IS A RELATIVE HIGH PREVALENCE OF EX-SMOKER WHO MAY DEVELOP LUNG CANCER AFTER YEARS OF SMOKING CESSATION SUGGEST THAT OTHER CAUSES ARE ALSO IMPLICATED. THUS CIGARETTE SMOKE-INDUCED CHRONIC LUNG INFLAMMATORY MICROENVIRONMENT, OXIDATIVE STRESS AND CELL STRUCTURAL ALTERATIONS SUCH AS THE INCREASE OF CELL PROLIFERATION, ANGIOGENESIS AND APOPTOSIS ARREST ARE IRREVERSIBLE PROCESSES THAT HAVE A HIGH INFLUENCE IN LUNG TUMOR GROWTH. IN THIS REVIEW WE FOCUSED IN CURRENT KNOWLEDGE ON THE MECHANISMS IMPLICATED IN CIGARETTE SMOKE-INDUCED LUNG CHRONIC INFLAMMATORY PROCESSES LEADING TO LUNG CARCINOGENESIS, AS WELL AS IN CURRENT THERAPIES BASED ON NOVEL MOLECULAR ADVANCES. 2012 14 4445 44 MOLECULAR LINKS BETWEEN COPD AND LUNG CANCER: NEW TARGETS FOR DRUG DISCOVERY? COPD AND LUNG CANCER ARE LEADING CAUSES OF MORBIDITY AND MORTALITY WORLDWIDE, AND THEY SHARE A COMMON ENVIRONMENTAL RISK FACTOR IN CIGARETTE SMOKE EXPOSURE AND A GENETIC PREDISPOSITION REPRESENTED BY THEIR INCIDENCE IN ONLY A FRACTION OF SMOKERS. THIS REFLECTS THE ABILITY OF CIGARETTE SMOKE TO INDUCE AN INFLAMMATORY RESPONSE IN THE AIRWAYS OF SUSCEPTIBLE SMOKERS. MOREOVER, COPD COULD BE A DRIVING FACTOR IN LUNG CANCER, BY INCREASING OXIDATIVE STRESS AND THE RESULTING DNA DAMAGE AND REPRESSION OF THE DNA REPAIR MECHANISMS, CHRONIC EXPOSURE TO PRO-INFLAMMATORY CYTOKINES, REPRESSION OF INNATE IMMUNITY AND INCREASED CELLULAR PROLIFERATION. AREAS COVERED: WE HAVE FOCUSED OUR REVIEW ON THE POTENTIAL PATHOGENIC MOLECULAR LINKS BETWEEN TOBACCO SMOKING-RELATED COPD AND LUNG CANCER AND THE POTENTIAL MOLECULAR TARGETS FOR NEW DRUG DEVELOPMENT BY UNDERSTANDING THE COMMON SIGNALING PATHWAYS INVOLVED IN COPD AND LUNG CANCER. EXPERT COMMENTARY: RESEARCH IN THIS FIELD IS MOSTLY LIMITED TO ANIMAL MODELS OR SMALL CLINICAL TRIALS. LARGE CLINICAL TRIALS ARE NEEDED BUT MOSTLY COMBINED MODELS OF COPD AND LUNG CANCER ARE NECESSARY TO INVESTIGATE THE PROCESSES CAUSED BY CHRONIC INFLAMMATION, INCLUDING GENETIC AND EPIGENETIC ALTERATION, AND THE EXPRESSION OF INFLAMMATORY MEDIATORS THAT LINK COPD AND LUNG CANCER, TO IDENTIFY NEW MOLECULAR THERAPEUTIC TARGETS. 2019 15 970 31 CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) AND LUNG CANCER: COMMON PATHWAYS FOR PATHOGENESIS. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) AND LUNG CANCER COMPRISE THE LEADING CAUSES OF LUNG DISEASE-RELATED MORTALITY WORLDWIDE. EXPOSURE TO TOBACCO SMOKE IS A MUTUAL AETIOLOGY UNDERLYING THE TWO DISEASES, ACCOUNTING FOR ALMOST 90% OF CASES. THERE IS ACCUMULATING EVIDENCE SUPPORTING THE ROLE OF IMMUNE DYSFUNCTION, THE LUNG MICROBIOME, EXTRACELLULAR VESICLES AND UNDERLYING GENETIC SUSCEPTIBILITY IN THE DEVELOPMENT OF COPD AND LUNG CANCER. FURTHER, EPIGENETIC FACTORS, INVOLVING DNA METHYLATION AND MICRORNA EXPRESSION, HAVE BEEN IMPLICATED IN BOTH DISEASES. CHRONIC INFLAMMATION IS A KEY FEATURE OF COPD AND COULD BE A POTENTIAL DRIVER OF LUNG CANCER DEVELOPMENT. USING NEXT GENERATION TECHNOLOGIES, FURTHER STUDIES INVESTIGATING THE GENOMICS, EPIGENETICS AND GENE-ENVIRONMENT INTERACTION IN KEY MOLECULAR PATHWAYS WILL CONTINUE TO ELUCIDATE THE PATHOGENIC MECHANISMS UNDERLYING THE DEVELOPMENT OF COPD AND LUNG CANCER, AND CONTRIBUTE TO THE DEVELOPMENT OF NOVEL DIAGNOSTIC AND PROGNOSTIC TOOLS FOR EARLY INTERVENTION AND PERSONALISED THERAPEUTIC STRATEGIES. 2019 16 5026 42 PERSONALIZED MEDICINE IN IDIOPATHIC PULMONARY FIBROSIS: FACTS AND PROMISES. PURPOSE OF REVIEW: IN THIS ARTICLE, WE SUMMARIZE AND DISCUSS THE MOST RECENT LITERATURE ON PERSONALIZED MEDICINE IN IDIOPATHIC PULMONARY FIBROSIS (IPF), A CHRONIC PROGRESSIVE AND ALMOST INVARIABLY LETHAL DISEASE OF UNKNOWN CAUSE. THIS REVIEW IS TIMELY AS MAJOR ADVANCES IN OUR UNDERSTANDING OF DISEASE PATHOBIOLOGY AND IMPROVEMENTS IN MOLECULAR TECHNIQUES HAVE RECENTLY LED TO THE IDENTIFICATION OF POTENTIAL SURROGATES OF DIAGNOSIS, PROGNOSIS AND RESPONSE TO TREATMENT. RECENT FINDINGS: THE MOST PROMISING AND ADVANCED CANDIDATE BIOMARKERS ARE PRESENTED BASED ON THEIR PROPOSED MECHANISTIC PATHWAYS (E.G. ALVEOLAR EPITHELIAL CELL DYSFUNCTION, IMMUNE DYSREGULATION, MICROBIOME, EXTRACELLULAR MATRIX REMODELING AND FIBROPROLIFERATION, EPIGENETIC MARKERS AND METABOLOMICS). RECENT DATA SUGGEST THAT COMPONENTS OF THE IMMUNE SYSTEM MAY CONTRIBUTE TO THE DEVELOPMENT OF IPF. A POTENTIAL ROLE FOR INFECTIONS AS A COFACTOR IN DISEASE DEVELOPMENT AND PROGRESSION OR AS A TRIGGER IN DISEASE EXACERBATION HAS ALSO RECENTLY BEEN PROPOSED. SUMMARY: CLINICAL MANAGEMENT OF IPF IS UNSATISFACTORY BECAUSE OF LIMITED AVAILABILITY OF TRULY EFFECTIVE THERAPIES, LACK OF ACCURATE PREDICTORS OF DISEASE BEHAVIOR AND ABSENCE OF SIMPLE SHORT-TERM MEASURES OF THERAPEUTIC RESPONSE. A NUMBER OF PUTATIVE BIOMARKERS HAVE BEEN IDENTIFIED IN PATIENTS WITH IPF, ALTHOUGH NONE HAS BEEN VALIDATED TO THE STANDARD NECESSARY FOR THEIR USE IN EITHER THERAPEUTIC TRIALS OR CLINICAL PRACTICE. CURRENTLY, ONGOING PROSPECTIVE LONGITUDINAL STUDIES WILL HOPEFULLY PERMIT SUCH VALIDATION. 2015 17 629 36 BIOLOGICAL AND GENETIC MECHANISMS OF COPD, ITS DIAGNOSIS, TREATMENT, AND RELATIONSHIP WITH LUNG CANCER. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS ONE OF THE MOST PREVALENT CHRONIC ADULT DISEASES, WITH SIGNIFICANT WORLDWIDE MORBIDITY AND MORTALITY. ALTHOUGH LONG-TERM TOBACCO SMOKING IS A CRITICAL RISK FACTOR FOR THIS GLOBAL HEALTH PROBLEM, ITS MOLECULAR MECHANISMS REMAIN UNCLEAR. SEVERAL PHENOMENA ARE THOUGHT TO BE INVOLVED IN THE EVOLUTION OF EMPHYSEMA, INCLUDING AIRWAY INFLAMMATION, PROTEINASE/ANTI-PROTEINASE IMBALANCE, OXIDATIVE STRESS, AND GENETIC/EPIGENETIC MODIFICATIONS. FURTHERMORE, COPD IS ONE MAIN RISK FOR LUNG CANCER (LC), THE DEADLIEST FORM OF HUMAN TUMOR; FORMATION AND CHRONIC INFLAMMATION ACCOMPANYING COPD CAN BE A POTENTIAL DRIVER OF MALIGNANCY MATURATION (0.8-1.7% OF COPD CASES DEVELOP CANCER/PER YEAR). RECENTLY, THE DEVELOPMENT OF MORE RESEARCH BASED ON COPD AND LUNG CANCER MOLECULAR ANALYSIS HAS PROVIDED NEW LIGHT FOR UNDERSTANDING THEIR PATHOGENESIS, IMPROVING THE DIAGNOSIS AND TREATMENTS, AND ELUCIDATING MANY CONNECTIONS BETWEEN THESE DISEASES. OUR REVIEW EMPHASIZES THE BIOLOGICAL FACTORS INVOLVED IN COPD AND LUNG CANCER, THE ADVANCES IN THEIR MOLECULAR MECHANISMS' RESEARCH, AND THE STATE OF THE ART OF DIAGNOSIS AND TREATMENTS. THIS WORK COMBINES MANY BIOLOGICAL AND GENETIC ELEMENTS INTO A SINGLE WHOLE AND STRONGLY LINKS COPD WITH LUNG TUMOR FEATURES. 2023 18 4294 35 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 19 4112 39 MECHANISMS CONTRIBUTING TO THE COMORBIDITY OF COPD AND LUNG CANCER. LUNG CANCER AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) OFTEN CO-OCCUR, AND INDIVIDUALS WITH COPD ARE AT A HIGHER RISK OF DEVELOPING LUNG CANCER. WHILE THE UNDERLYING MECHANISM FOR THIS RISK IS NOT WELL UNDERSTOOD, ITS MAJOR CONTRIBUTING FACTORS HAVE BEEN PROPOSED TO INCLUDE GENOMIC, IMMUNE, AND MICROENVIRONMENT DYSREGULATION. HERE, WE REVIEW THE EVIDENCE AND SIGNIFICANT STUDIES THAT EXPLORE THE MECHANISMS UNDERLYING THE HEIGHTENED LUNG CANCER RISK IN PEOPLE WITH COPD. GENETIC AND EPIGENETIC CHANGES, AS WELL AS THE ABERRANT EXPRESSION OF NON-CODING RNAS, PREDISPOSE THE LUNG EPITHELIUM TO CARCINOGENESIS BY ALTERING THE EXPRESSION OF CANCER- AND IMMUNE-RELATED GENES. OXIDATIVE STRESS GENERATED BY TOBACCO SMOKING PLAYS A ROLE IN REDUCING GENOMIC INTEGRITY, PROMOTING EPITHELIAL-MESENCHYMAL-TRANSITION, AND GENERATING A CHRONIC INFLAMMATORY ENVIRONMENT. THIS LEADS TO ABNORMAL IMMUNE RESPONSES THAT PROMOTE CANCER DEVELOPMENT, THOUGH NOT ALL SMOKERS DEVELOP LUNG CANCER. SEX DIFFERENCES IN THE METABOLISM OF TOBACCO SMOKE PREDISPOSE FEMALES TO DEVELOPING COPD AND ACCUMULATING DAMAGE FROM OXIDATIVE STRESS THAT POSES A RISK FOR THE DEVELOPMENT OF LUNG CANCER. DYSREGULATION OF THE LUNG MICROENVIRONMENT AND MICROBIOME CONTRIBUTES TO CHRONIC INFLAMMATION, WHICH IS OBSERVED IN COPD AND KNOWN TO FACILITATE CANCER INITIATION IN VARIOUS TUMOR TYPES. FURTHER, THERE IS A NEED TO BETTER CHARACTERIZE AND IDENTIFY THE PROPORTION OF INDIVIDUALS WITH COPD WHO ARE AT A HIGH RISK FOR DEVELOPING LUNG CANCER. WE EVALUATE POSSIBLE NOVEL AND INDIVIDUALIZED SCREENING STRATEGIES, INCLUDING BIOMARKERS IDENTIFIED IN GENETIC STUDIES AND EXHALED BREATH CONDENSATE ANALYSIS. WE ALSO DISCUSS THE USE OF CORTICOSTEROIDS AND STATINS AS CHEMOPREVENTIVE AGENTS TO PREVENT LUNG CANCER. IT IS CRUCIAL THAT WE OPTIMIZE THE CURRENT METHODS FOR THE EARLY DETECTION AND MANAGEMENT OF LUNG CANCER AND COPD IN ORDER TO IMPROVE THE HEALTH OUTCOMES FOR A LARGE AFFECTED POPULATION. 2023 20 2540 33 EPIGENETICS IN IDIOPATHIC PULMONARY FIBROSIS. IDIOPATHIC PULMONARY FIBROSIS (IPF) IS A LETHAL CHRONIC LUNG DISORDER WITH NO EFFECTIVE TREATMENT AND A PROGNOSIS WORSE THAN THAT OF LUNG CANCER. DESPITE EXTENSIVE RESEARCH EFFORTS, ITS ETIOLOGY AND PATHOGENESIS STILL REMAIN LARGELY UNKNOWN. CURRENT EXPERIMENTAL EVIDENCE HAS SHIFTED THE DISEASE PARADIGM FROM CHRONIC INFLAMMATION TOWARDS THE PREMISE OF ABNORMAL EPITHELIAL WOUND REPAIR IN RESPONSE TO REPEATED EPIGENETIC INJURIOUS STIMULI IN GENETICALLY PREDISPOSED INDIVIDUALS. EPIGENETICS IS DEFINED AS THE STUDY OF HERITABLE CHANGES IN GENE FUNCTION BY FACTORS OTHER THAN AN INDIVIDUAL'S DNA SEQUENCE, PROVIDING VALUABLE INFORMATION REGARDING ADAPTION OF GENES TO ENVIRONMENTAL CHANGES. ALTHOUGH CANCER IS THE MOST STUDIED DISEASE WITH RELEVANCE TO EPIGENETIC MODIFICATIONS, RECENT DATA SUPPORT THE IDEA THAT EPIGENOMIC ALTERATIONS MAY LEAD TO VARIABLE DISEASE PHENOTYPES, INCLUDING FIBROPROLIFERATIVE LUNG DISORDERS SUCH AS IPF. THIS REVIEW ARTICLE SUMMARIZES THE LATEST EXPERIMENTAL AND TRANSLATIONAL EPIGENETIC STUDIES IN THE RESEARCH FIELD OF CHRONIC LUNG DISORDERS, MAINLY FOCUSING ON IPF, HIGHLIGHTS CURRENT METHODOLOGY LIMITATIONS, AND UNDERLINES FUTURE DIRECTIONS AND PERSPECTIVES. 2015