1 3543 94 IMMUNOLOGY, GENETICS AND MICROBIOTA IN THE COPD PATHOPHYSIOLOGY: POTENTIAL SCOPE FOR PATIENT STRATIFICATION. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS CHARACTERIZED BY SUSTAINED INFLAMMATION OF THE AIRWAYS, LEADING TO DESTRUCTION OF LUNG TISSUE AND DECLINING PULMONARY FUNCTION. ALTHOUGH SMOKING IS THE MOST OBVIOUS RISK FACTOR FOR COPD, ONLY ABOUT 20% OF SMOKERS DEVELOP COPD AND SMOKING CESSATION DOES NOT REVERSE PROGRESSION OF COPD, INDICATING THAT WHILE SMOKING IS AN IMPORTANT CAUSE OR INITIATING FACTOR, IT IS NOT THE ONLY DRIVER OF ONGOING CHRONIC INFLAMMATION AND DISEASE PROGRESSION IN COPD PATIENTS. WE HYPOTHESIZE THAT SMOKING-INDUCED CHANGES IN LUNG MICROBIOTA, EPITHELIAL INTEGRITY AND EPIGENETIC CONTROL OF GENE EXPRESSION RESULT IN AUTOANTIGEN INDUCTION AND PERTURBED IMMUNE REGULATION IN GENETICALLY VUNERABLE INDIVIDUALS. IN OUR VIEW, COPD PATIENTS MAY BE STRATIFIED ACCORDING TO THEIR IMMUNOLOGICAL AND INFLAMMATORY STATUS RELATED TO SPECIFIC CHANGES IN THE LUNG MICROBIOTA (INNATE AND ADAPTIVE IMMUNITY), PRESENCE OF AUTOANTIGENS (ADAPTIVE IMMUNITY: TH1-B-CELL AXIS) AND EPIGENETIC MODIFICATIONS (INFLAMMATION AND STRUCTURAL CHANGES). 2015 2 629 27 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 3 6628 26 UNDERSTANDING THE GENETICS OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE, ALPHA1-ANTITRYPSIN DEFICIENCY, AND IMPLICATIONS FOR CLINICAL PRACTICE. CIGARETTE SMOKING AND POOR AIR QUALITY ARE THE GREATEST RISK FACTORS FOR DEVELOPING CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD), BUT GROWING EVIDENCE INDICATES THAT GENETIC FACTORS ALSO AFFECT PREDISPOSITION TO AND CLINICAL EXPRESSION OF DISEASE. WITH THE EXCEPTION OF ALPHA1-ANTITRYPSIN DEFICIENCY (AATD), A RARE AUTOSOMAL RECESSIVE DISORDER THAT IS PRESENT IN 1-3% OF INDIVIDUALS WITH COPD, NO SINGLE GENE IS ASSOCIATED WITH THE DEVELOPMENT OF OBSTRUCTIVE LUNG DISEASE. INSTEAD, A COMPLEX INTERPLAY OF GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS IS THE BASIS FOR PERSISTENT INFLAMMATORY RESPONSES, ACCELERATED CELL AGING, CELL DEATH, AND FIBROSIS, LEADING TO THE CLINICAL SYMPTOMS OF COPD AND DIFFERENT PHENOTYPIC PRESENTATIONS. IN THIS BRIEF REVIEW, WE DISCUSS CURRENT UNDERSTANDING OF THE GENETICS OF COPD, PATHOGENETICS OF AATD, EPIGENETIC INFLUENCES ON THE DEVELOPMENT OF OBSTRUCTIVE LUNG DISEASE, AND HOW CLASSIFYING COPD BY PHENOTYPE CAN INFLUENCE CLINICAL TREATMENT AND PATIENT OUTCOMES. 2021 4 927 32 CHRONIC INFLAMMATION, CHRONIC OBSTRUCTIVE PULMONARY DISEASE, AND LUNG CANCER. PURPOSE OF REVIEW: SMOKING IS A MAJOR RISK FACTOR FOR LUNG CANCER, WHICH IS THE LEADING CAUSE OF CANCER-RELATED DEATHS BOTH IN THE USA AND WORLDWIDE. CHRONIC OBSTRUCTIVE PULMONARY DISEASE AND EMPHYSEMA ARE COMORBID CONDITIONS OFTEN FOUND IN LUNG CANCER PATIENTS. THE INFLAMMATORY PATHWAYS THAT LINK CHRONIC OBSTRUCTIVE PULMONARY DISEASE, EMPHYSEMA, AND LUNG CANCER LIKELY INVOLVE GENETIC AND EPIGENETIC MODULATIONS DUE TO CHRONIC TISSUE INJURY AND ABNORMAL TUMOR IMMUNITY IN SUSCEPTIBLE HOSTS. RECENT FINDINGS: CHRONIC AIRWAY INFLAMMATION CONTRIBUTES TO ALTERATIONS IN THE BRONCHIAL EPITHELIUM AND LUNG MICROENVIRONMENT, PROVOKING A MILIEU CONDUCIVE TO PULMONARY CARCINOGENESIS. FOR EXAMPLE, INFLAMMATION-INDUCIBLE CYCLOOXYGENASE-2 IS UPREGULATED IN NONSMALL CELL LUNG CANCER AND ALSO PLAYS AN IMPORTANT ROLE IN PROMOTING EPITHELIAL-TO-MESENCHYMAL TRANSITION. GENETIC CHANGES IN THE AIRWAY EPITHELIUM OF SMOKERS MAY HELP PREDICT OR IDENTIFY INDIVIDUALS AT RISK FOR LUNG CANCER. FINALLY, RADIOGRAPHIC FINDINGS OF EMPHYSEMA HAVE BEEN ESTABLISHED AS INDEPENDENT RISK FACTORS FOR LUNG CANCER. SUMMARY: THE RELATIONSHIPS BETWEEN INFLAMMATION, AIRFLOW OBSTRUCTION, AND LUNG CANCER ARE COMPLEX. DEREGULATED INFLAMMATION IS COMPLICIT IN THE PATHOGENESIS OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE AND LUNG CANCER, BUT THE OVERLAP OF SIGNALING EVENTS IS NOT YET FULLY UNDERSTOOD. TOBACCO EXPOSURE IS AN IMPORTANT RISK FACTOR THAT CONFERS LONG-TERM RISK OF LUNG DISEASE. DIAGNOSTIC SENSITIVITY OF DETECTING LUNG CANCER MAY IMPROVE WITH THE UTILIZATION OF GENETIC PROFILING IN COMBINATION WITH PATHOLOGIC EVALUATION OF AIRWAY EPITHELIUM. ADDITIONAL RESEARCH IS REQUIRED TO UNDERSTAND THE ROLE OF EPITHELIAL-TO-MESENCHYMAL TRANSITION IN CHRONIC INFLAMMATORY LUNG DISEASES AND LUNG CARCINOGENESIS. 2009 5 1245 27 CURRENT CONCEPTS ON THE ROLE OF INFLAMMATION IN COPD AND LUNG CANCER. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) AND LUNG CANCER ARE LEADING CAUSE OF DEATH, AND BOTH ARE ASSOCIATED WITH CIGARETTE SMOKE EXPOSURE. IT HAS BEEN SHOWN THAT 50-70% OF PATIENTS DIAGNOSED WITH LUNG CANCER SUFFER FROM COPD, AND REDUCED LUNG FUNCTION IS AN IMPORTANT EVENT IN LUNG CANCER SUGGESTING AN ASSOCIATION BETWEEN COPD AND LUNG CANCER. HOWEVER, A CAUSAL RELATIONSHIP BETWEEN COPD AND LUNG TUMORIGENESIS IS NOT YET FULLY UNDERSTOOD. RECENT STUDIES HAVE SUGGESTED A CENTRAL ROLE OF CHRONIC INFLAMMATION IN THE PATHOGENESIS OF BOTH THE DISEASES. FOR EXAMPLE, IMMUNE DYSFUNCTION, ABNORMAL ACTIVATION OF NF-KAPPAB, EPITHELIAL-TO-MESENCHYMAL TRANSITION, ALTERED ADHESION SIGNALING PATHWAYS, AND EXTRACELLULAR MATRIX DEGRADATION/ALTERED SIGNALING ARE THE KEY UNDERLYING MECHANISMS IN BOTH COPD AND LUNG CANCER. THESE PARAMETERS ALONG WITH OTHER PROCESSES, SUCH AS CHROMATIN MODIFICATIONS/EPIGENETIC CHANGES, ANGIOGENESIS, AND AUTOPHAGY/APOPTOSIS ARE ALTERED BY CIGARETTE SMOKE, ARE CRUCIAL IN THE DEVELOPMENT OF COPD AND LUNG CANCER. UNDERSTANDING THE CELLULAR AND MOLECULAR MECHANISMS UNDERLYING THESE PROCESSES WILL PROVIDE NOVEL AVENUES FOR HALTING THE CHRONIC INFLAMMATION IN COPD AND DEVISING THERAPEUTIC STRATEGIES AGAINST LUNG CANCER. 2009 6 1188 32 COPD: A MULTIFACTORIAL SYSTEMIC DISEASE. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) HAS TRADITIONALLY BEEN CONSIDERED A DISEASE OF THE LUNGS SECONDARY TO CIGARETTE SMOKING AND CHARACTERIZED BY AIRFLOW OBSTRUCTION DUE TO ABNORMALITIES OF BOTH AIRWAY (BRONCHITIS) AND LUNG PARENCHYMA (EMPHYSEMA). IT IS NOW WELL KNOWN THAT COPD IS ASSOCIATED WITH SIGNIFICANT SYSTEMIC ABNORMALITIES, SUCH AS RENAL AND HORMONAL ABNORMALITIES, MALNUTRITION, MUSCLE WASTING, OSTEOPOROSIS, AND ANEMIA. HOWEVER, IT IS STILL UNCLEAR WHETHER THEY REPRESENT CONSEQUENCES OF THE PULMONARY DISORDER, OR WHETHER COPD SHOULD BE CONSIDERED AS A SYSTEMIC DISEASE. THESE SYSTEMIC ABNORMALITIES HAVE BEEN ATTRIBUTED TO AN INCREASED LEVEL OF SYSTEMIC INFLAMMATION. CHRONIC INFLAMMATION, HOWEVER, MAY NOT BE THE ONLY CAUSE OF THE SYSTEMIC EFFECTS OF COPD. RECENT DATA FROM HUMANS AND ANIMAL MODELS SUPPORT THE VIEW THAT EMPHYSEMA MAY BE A VASCULAR DISEASE. OTHER STUDIES HAVE HIGHLIGHTED THE ROLE OF REPAIR FAILURE, BONE MARROW ABNORMALITY, GENETIC AND EPIGENETIC FACTORS, IMMUNOLOGICAL DISORDERS AND INFECTIONS AS POTENTIAL CAUSES OF COPD SYSTEMIC MANIFESTATIONS. BASED ON THIS NEW EVIDENCE, IT IS REASONABLE TO CONSIDER COPD, AND EMPHYSEMA IN PARTICULAR, AS 'A DISEASE WITH A SIGNIFICANT SYSTEMIC COMPONENT' IF NOT A 'SYSTEMIC DISEASE' PER SE. THE AIM OF THIS REVIEW IS TO GIVE AN OVERVIEW OF THE MOST RELEVANT AND INNOVATIVE HYPOTHESIS ABOUT THE EXTRAPULMONARY MANIFESTATIONS OF COPD. 2011 7 1539 19 DNA METHYLATION IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS A LUNG DISEASE AFFECTED BY BOTH GENETIC AND ENVIRONMENTAL FACTORS. THEREFORE, THE ROLE OF EPIGENETICS IN THE PATHOGENESIS OF COPD HAS ATTRACTED MUCH ATTENTION. AS ONE OF THE THREE EPIGENETIC MECHANISMS, DNA METHYLATION HAS BEEN EXTENSIVELY STUDIED IN COPD. THE PRESENT REVIEW AIMS AT OVERVIEWING THE EFFECT OF DNA METHYLATION ON ETIOLOGY, PATHOGENESIS, PATHOPHYSIOLOGICAL CHANGES, AND COMPLICATIONS OF COPD. THE CLARIFICATION OF ABERRANT METHYLATION OF TARGET GENES, WHICH PLAY IMPORTANT ROLES IN THE INITIATION AND PROGRESSION OF COPD, WILL PROVIDE NEW DISEASE-SPECIFIC BIOMARKER AND TARGETS FOR EARLY DIAGNOSIS AND THERAPY. 2020 8 4445 31 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 9 970 22 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 10 4028 32 LUNG TUMORS, COPD AND IMMUNE RESPONSE: IS EPIGENETICS THE BOTTOM LINE? NSCLC IS A HETEROGENEOUS DISORDER CONSISTING OF DISTINCT MOLECULAR SUBTYPES WHICH CAN BE TREATED BY USING SPECIFIC DRUGS TARGETED TO DISTINCT GENETIC LESIONS. IT IS WELL KNOWN THAT NSCLS INCIDENCE IS HIGHER IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) PATIENTS BECAUSE THEY SHARE A COMMON RISK FACTOR (CIGARETTE SMOKING) AND IT IS BELIEVED THAT THE TYPICAL INFLAMMATORY MICROENVIRONMENT OBSERVED IN COPD MAY INFLUENCE THE MOLECULAR MECHANISMS RESPONSIBLE OF CARCINOGENESIS. IN THE LAST YEARS, THE ROLE OF EPIGENETIC PROCESSES IN CELL BIOLOGY AND TISSUE PATHOLOGY HAS BEEN EXTENSIVELY STUDIED BOTH IN COPD AND NSCLC. THE RECENT PAPER BY WAUTERS ET AL. SHOWED A SPECIFIC PATTERN OF DRIVER MUTATIONS AND MOLECULAR FEATURES IN NSCLC RAISING IN THE CONTEXT OF COPD. ALL THESE FINDINGS HAVE SHOWN FOR THE FIRST TIME THAT LUNG TUMORS FOUND IN COPD PATIENTS DIFFER FROM THOSE OBSERVED IN PATIENT WITHOUT COPD DUE TO THE PRESENCE OF A SPECIFIC TUMOR MICROENVIRONMENT WHICH IS CHARACTERIZED BY REDUCED CD4+ TREG CELLS. ON THIS BASIS, THE PRESENT WORK AIMS AT DISCUSSING AND ANALYZING THE CONTEXT-SPECIFIC MECHANISMS OF CLONAL SELECTION AND EVOLUTION MAINLY FOCUSING ON THE EPIGENETIC ALTERATIONS AND AT POINTING OUT THE POTENTIAL THERAPEUTIC IMPLICATIONS. 2016 11 4112 34 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 12 4026 22 LUNG CANCER AND ITS ASSOCIATION WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE: UPDATE ON NEXUS OF EPIGENETICS. PURPOSE OF REVIEW: CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) AND LUNG CANCER ARE THE LEADING CAUSES OF MORBIDITY AND MORTALITY WORLDWIDE. THE CURRENT RESEARCH IS FOCUSED ON IDENTIFYING THE COMMON AND DISPARATE EVENTS INVOLVED IN EPIGENETIC MODIFICATIONS THAT CONCURRENTLY OCCUR DURING THE PATHOGENESIS OF COPD AND LUNG CANCER. THE PURPOSE OF THIS REVIEW IS TO DESCRIBE THE CURRENT KNOWLEDGE AND UNDERSTANDING OF EPIGENETIC MODIFICATIONS IN PATHOGENESIS OF COPD AND LUNG CANCER. RECENT FINDINGS: THIS REVIEW PROVIDES AN UPDATE ON ADVANCES OF HOW EPIGENETIC MODIFICATIONS ARE LINKED TO COPD AND LUNG CANCER, AND THEIR COMMONALITIES AND DISPARITIES. THE KEY EPIGENETIC MODIFICATION ENZYMES (E.G. DNA METHYLTRANSFERASES -- CPG METHYLATION, HISTONE ACETYLASES/DEACETYLASES AND HISTONE METHYLTRANSFERASES/DEMETHYLASES) THAT ARE IDENTIFIED TO PLAY AN IMPORTANT ROLE IN COPD AND LUNG TUMORIGENESIS AND PROGRESSION ARE DESCRIBED IN THIS REVIEW. SUMMARY: DISTINCT DNA METHYLTRANSFERASES AND HISTONE MODIFICATION ENZYMES ARE DIFFERENTIALLY INVOLVED IN PATHOGENESIS OF LUNG CANCER AND COPD, ALTHOUGH SOME OF THE MODIFICATIONS ARE COMMON. UNDERSTANDING THE EPIGENETIC MODIFICATIONS INVOLVED IN PATHOGENESIS OF LUNG CANCER OR COPD WITH RESPECT TO COMMON AND DISPARATE MECHANISMS WILL LEAD TO TARGETING OF EPIGENETIC THERAPIES AGAINST THESE DISORDERS. 2011 13 971 29 CHRONIC OBSTRUCTIVE PULMONARY DISEASE AND THE HALLMARKS OF AGING. AGING IS CHARACTERIZED BY PROGRESSIVE DETERIORATION OF PHYSIOLOGICAL INTEGRITY, DECLINE IN HOMEOSTASIS, AND DEGENERATION OF THE TISSUES THAT OCCURS AFTER THE REPRODUCTIVE PHASE OF LIFE IS COMPLETE, LEADING TO IMPAIRED FUNCTION. THIS DETERIORATION IS AN IMPORTANT RISK FACTOR FOR CHRONIC LUNG PATHOLOGIES SUCH AS CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). COPD IS A DISEASE THAT DEVELOPS GRADUALLY. EMPHYSEMATOUS CHANGES IN THE LUNG TAKE YEARS TO DEVELOP AFTER EXPOSURE TO CIGARETTE SMOKE; HENCE, THE VAST MAJORITY OF PATIENTS ARE ELDERLY. THERE HAS BEEN A DRAMATIC INCREASE IN THE LIFE EXPECTANCY OF THE GENERAL POPULATION, RESULTING IN AN INCREASED BURDEN OF CHRONIC LUNG DISEASES. THERE IS GROWING EVIDENCE THAT MOLECULAR MECHANISMS INVOLVED IN AGING MAY ALSO PLAY A ROLE IN COPD PATHOGENESIS. RECENTLY, THE NINE HALLMARKS OF AGING WERE IDENTIFIED. IN THIS ARTICLE, WE WILL REVIEW THE NINE HALLMARKS OF AGING AND HOW EACH HALLMARK CONTRIBUTES TO THE PATHOGENESIS OF COPD. 2018 14 2162 32 EPIGENETIC MECHANISMS IN COPD: IMPLICATIONS FOR PATHOGENESIS AND DRUG DISCOVERY. INTRODUCTION: CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS THE FOURTH LEADING CAUSE OF DEATH WORLDWIDE. THE GROWING BURDEN OF COPD IS DUE TO CONTINUOUS TOBACCO USE, WHICH IS THE MOST IMPORTANT RISK FACTOR OF THE DISEASE, INDOOR FUMES, OCCUPATIONAL EXPOSURES AND ALSO AGING OF THE WORLD'S POPULATION. EPIGENETIC MECHANISMS SIGNIFICANTLY CONTRIBUTE TO COPD PATHOPHYSIOLOGY. AREAS COVERED: THIS REVIEW FOCUSES ON DISEASE-RELEVANT CHANGES IN DNA MODIFICATION, HISTONE MODIFICATION AND NON-CODING RNA EXPRESSION IN COPD, AND PROVIDES INSIGHT INTO NOVEL THERAPEUTIC APPROACHES MODULATING EPIGENETIC MECHANISMS. RECENT FINDINGS REVEALED, AMONG OTHERS, GLOBALLY CHANGED DNA METHYLATION PATTERNS, DECREASED LEVELS OF HISTONE DEACETYLASES AND REDUCED MICRORNAS LEVELS IN COPD. THE AUTHORS ALSO DISCUSS A POTENTIAL ROLE OF THE CHROMATIN SILENCING POLYCOMB GROUP OF PROTEINS IN COPD. EXPERT OPINION: COPD IS A HIGHLY COMPLEX DISEASE AND THERAPY DEVELOPMENT IS COMPLICATED BY THE FACT THAT MANY SMOKERS DEVELOP BOTH COPD AND LUNG CANCER. OF INTEREST, COMBINATION THERAPIES INVOLVING DNA METHYLTRANSFERASE INHIBITORS AND ANTI-INFLAMMATORY DRUGS PROVIDE A PROMISING APPROACH, AS THEY MIGHT BE THERAPEUTIC FOR BOTH COPD AND CANCER. ALTHOUGH THE FIELD OF EPIGENETIC RESEARCH HAS VIRTUALLY EXPLODED OVER THE LAST 10 YEARS, PARTICULAR EFFORTS ARE REQUIRED TO ENHANCE OUR KNOWLEDGE OF THE COPD EPIGENOME IN ORDER TO SUCCESSFULLY ESTABLISH EPIGENETIC-BASED THERAPIES FOR THIS WIDESPREAD DISEASE. 2014 15 2059 28 EPIGENETIC CONTROL OF GENE EXPRESSION IN THE LUNG. EPIGENETICS IS TRADITIONALLY DEFINED AS THE STUDY OF HERITABLE CHANGES IN GENE EXPRESSION CAUSED BY MECHANISMS OTHER THAN CHANGES IN THE UNDERLYING DNA SEQUENCE. THERE ARE THREE MAIN CLASSES OF EPIGENETIC MARKS--DNA METHYLATION, MODIFICATIONS OF HISTONE TAILS, AND NONCODING RNAS--EACH OF WHICH MAY BE INFLUENCED BY THE ENVIRONMENT, DIET, DISEASES, AND AGEING. IMPORTANTLY, EPIGENETIC MARKS HAVE BEEN SHOWN TO INFLUENCE IMMUNE CELL MATURATION AND ARE ASSOCIATED WITH THE RISK OF DEVELOPING VARIOUS FORMS OF CANCER, INCLUDING LUNG CANCER. MOREOVER, THERE IS EMERGING EVIDENCE THAT THESE EPIGENETIC MARKS AFFECT GENE EXPRESSION IN THE LUNG AND ARE ASSOCIATED WITH BENIGN LUNG DISEASES, SUCH AS ASTHMA, CHRONIC OBSTRUCTIVE PULMONARY DISEASE, AND INTERSTITIAL LUNG DISEASE. TECHNOLOGICAL ADVANCES HAVE MADE IT FEASIBLE TO STUDY EPIGENETIC MARKS IN THE LUNG, AND IT IS ANTICIPATED THAT THIS KNOWLEDGE WILL ENHANCE OUR UNDERSTANDING OF THE DYNAMIC BIOLOGY IN THE LUNG AND LEAD TO THE DEVELOPMENT OF NOVEL DIAGNOSTIC AND THERAPEUTIC APPROACHES FOR OUR PATIENTS WITH LUNG DISEASE. 2011 16 6440 21 THERAPEUTIC APPROACHES FOR CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) EXACERBATIONS. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS A PROGRESSIVE PULMONARY DISORDER UNDERPINNED BY POORLY REVERSIBLE AIRFLOW RESULTING FROM CHRONIC BRONCHITIS OR EMPHYSEMA. THE PREVALENCE AND MORTALITY OF COPD CONTINUE TO INCREASE. PHARMACOTHERAPY FOR PATIENTS WITH COPD HAS INCLUDED ANTIBIOTICS, BRONCHODILATORS, AND ANTI-INFLAMMATORY CORTICOSTEROIDS (BUT WITH LITTLE SUCCESS). ORAL DISEASES HAVE LONG BEEN ESTABLISHED AS CLINICAL RISK FACTORS FOR DEVELOPING RESPIRATORY DISEASES. THE ESTABLISHMENT OF A VERY SIMILAR MICROBIOME IN THE MOUTH AND THE LUNG CONFIRMS THE ORAL-LUNG CONNECTION. THE ASPIRATION OF PATHOGENIC MICROBES FROM THE ORAL CAVITY HAS BEEN IMPLICATED IN SEVERAL RESPIRATORY DISEASES, INCLUDING PNEUMONIA AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). THIS REVIEW FOCUSES ON CURRENT AND FUTURE PHARMACOTHERAPEUTIC APPROACHES FOR COPD EXACERBATION INCLUDING ANTIMICROBIALS, MUCOREGULATORS, THE USE OF BRONCHODILATORS AND ANTI-INFLAMMATORY DRUGS, MODIFYING EPIGENETIC MARKS, AND MODULATING DYSBIOSIS OF THE MICROBIOME. 2022 17 6281 28 THE POTENTIAL FOR TARGETED REWRITING OF EPIGENETIC MARKS IN COPD AS A NEW THERAPEUTIC APPROACH. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS AN AGE AND SMOKING RELATED PROGRESSIVE, PULMONARY DISORDER PRESENTING WITH POORLY REVERSIBLE AIRFLOW LIMITATION AS A RESULT OF CHRONIC BRONCHITIS AND EMPHYSEMA. THE PREVALENCE, DISEASE BURDEN FOR THE INDIVIDUAL, AND MORTALITY OF COPD CONTINUES TO INCREASE, WHEREAS NO EFFECTIVE TREATMENT STRATEGIES ARE AVAILABLE. FOR MANY YEARS NOW, A COMBINATION OF BRONCHODILATORS AND ANTI-INFLAMMATORY CORTICOSTEROIDS HAS BEEN MOST WIDELY USED FOR THERAPEUTIC MANAGEMENT OF PATIENTS WITH PERSISTENT COPD. HOWEVER, THIS APPROACH HAS HAD DISAPPOINTING RESULTS AS A LARGE NUMBER OF COPD PATIENTS ARE CORTICOSTEROID RESISTANT. IN PATIENTS WITH COPD, THERE IS EMERGING EVIDENCE SHOWING ABERRANT EXPRESSION OF EPIGENETIC MARKS SUCH AS DNA METHYLATION, HISTONE MODIFICATIONS AND MICRORNAS IN BLOOD, SPUTUM AND LUNG TISSUE. THEREFORE, NOVEL THERAPEUTIC APPROACHES MAY EXIST USING EPIGENETIC THERAPY. THIS REVIEW AIMS TO DESCRIBE AND SUMMARIZE CURRENT KNOWLEDGE OF ABERRANT EXPRESSION OF EPIGENETIC MARKS IN COPD. IN ADDITION, TOOLS AVAILABLE FOR RESTORATION OF EPIGENETIC MARKS ARE DESCRIBED, AS WELL AS DELIVERY MECHANISMS OF EPIGENETIC EDITORS TO CELLS. TARGETING EPIGENETIC MARKS MIGHT BE A VERY PROMISING TOOL FOR TREATMENT AND LUNG REGENERATION IN COPD IN THE FUTURE. 2018 18 6199 30 THE IMPORTANCE OF EPIGENETICS IN THE DEVELOPMENT OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE. IT IS GENERALLY ACCEPTED THAT GENETIC PREDISPOSITION PLAYS A ROLE IN COPD DEVELOPMENT IN SUSCEPTIBLE INDIVIDUALS. THEREFORE, MANY CANDIDATE GENES THAT COULD BE LINKED TO THE DEVELOPMENT OF DISEASE HAVE BEEN EXAMINED IN COPD. HOWEVER, INCONSISTENT RESULTS IN DIFFERENT STUDY POPULATIONS OFTEN LIMIT THIS APPROACH, SUGGESTING THAT NOT ONLY GENETICS, BUT ALSO OTHER FACTORS, MAY BE CONTRIBUTED TO THE SUSCEPTIBILITY TO COPD. EPIGENETIC MECHANISMS CAN AFFECT THE TRANSCRIPTIONAL ACTIVITY OF SPECIFIC GENES, AT DIFFERENT POINTS IN TIME, AND IN DIFFERENT ORGANS. MOREOVER, THESE MECHANISMS CAN HAVE AN EFFECT ON PEOPLE'S HEALTH. RECENTLY, THERE IS EMERGING EVIDENCE SUPPORTING A ROLE OF EPIGENETICS FOR THE REGULATION OF INFLAMMATORY GENES IN DISEASES SUCH AS ASTHMA AND COPD. MOREOVER, RECENT STUDIES SUGGEST THAT THE CURRENTLY USED TREATMENTS INCLUDING CORTICOSTEROIDS MAY WORK THROUGH EPIGENETIC MECHANISMS. EPIGENETIC REGULATION CAN BE REPROGRAMMED, POTENTIALLY AFFECTING THE RISK, AETIOLOGY AND TREATMENT OF VARIOUS DISEASE STATES. THE EPIGENETICALLY INFLUENCED PHENOTYPE COULD BE REVERSED WITH DEMETHYLATING OR DEACETYLATING AGENTS, CONSISTENT WITH EPIGENETIC PLASTICITY. THE POSTNATAL REVERSIBILITY OF THESE METHYLATION OR ACETYLATION EVENTS MAY THEREFORE PROVIDE GOOD OPPORTUNITIES FOR INTERVENTION. THE RECOGNITION OF THE ROLE OF GENETIC AND EPIGENETIC MECHANISMS IN THE DEVELOPMENT OF COPD MAY IDENTIFY NOVEL TARGETS THAT HATCH NEW THERAPIES FOR PATIENTS WITH COPD. 2011 19 3966 28 LONG NONCODING TRANSCRIPTOME IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE. CHRONIC AIRWAY INFLAMMATION FROM RECURRING EXPOSURES TO NOXIOUS ENVIRONMENTAL STIMULI RESULTS IN A PROGRESSIVE AND IRREVERSIBLE AIRFLOW LIMITATION AND THE LUNG PARENCHYMAL DAMAGE THAT CHARACTERIZES CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). THE LARGE VARIABILITY OBSERVED IN THE ONSET AND PROGRESSION OF COPD IS PRIMARILY DRIVEN BY COMPLEX GENE-ENVIRONMENT INTERACTIONS. THE TRANSCRIPTOMIC AND EPIGENETIC MEMORY POTENTIAL OF LUNG EPITHELIAL AND INNATE IMMUNE CELLS DRIVE RESPONSES, SUCH AS MUCUS HYPERREACTIVITY AND AIRWAY REMODELING, THAT ARE TIGHTLY REGULATED BY VARIOUS MOLECULAR MECHANISMS, FOR WHICH SEVERAL CANDIDATE SUSCEPTIBILITY GENES HAVE BEEN DESCRIBED. HOWEVER, THE RECENTLY DESCRIBED NONCODING RNA SPECIES, IN PARTICULAR THE LONG NONCODING RNAS, MAY ALSO HAVE AN IMPORTANT ROLE IN MODULATING PULMONARY RESPONSES TO CHRONIC INHALATION OF TOXIC SUBSTANCES AND THE DEVELOPMENT OF COPD. THIS REVIEW OUTLINES THE FEATURES OF LONG NONCODING RNAS THAT HAVE BEEN IMPLICATED IN REGULATING THE AIRWAY INFLAMMATORY RESPONSES TO CIGARETTE SMOKE EXPOSURE AND THEIR POSSIBLE ASSOCIATION WITH COPD PATHOGENESIS. AS COPD CONTINUES TO DEBILITATE THE INCREASINGLY AGING POPULATION AND CONTRIBUTE TO HIGHER MORBIDITY AND MORTALITY RATES WORLDWIDE, THE SEARCH FOR BETTER BIOMARKERS AND ALTERNATIVE THERAPEUTIC OPTIONS IS PIVOTAL. 2019 20 1143 28 CONCISE REVIEW: CLINICAL PROSPECTS FOR TREATING CHRONIC OBSTRUCTIVE PULMONARY DISEASE WITH REGENERATIVE APPROACHES. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS BECOMING A MAJOR CAUSE OF DEATH WORLDWIDE. COPD IS CHARACTERIZED BY A PROGRESSIVE AND NOT FULLY REVERSIBLE AIRFLOW LIMITATION CAUSED BY CHRONIC SMALL AIRWAY DISEASE AND LUNG PARENCHYMAL DESTRUCTION. CLINICALLY AVAILABLE DRUGS IMPROVE AIRFLOW OBSTRUCTION AND RESPIRATORY SYMPTOMS BUT CANNOT CURE THE DISEASE. SLOWING THE PROGRESSIVE LUNG DESTRUCTION OR REBUILDING THE DESTROYED LUNG STRUCTURE IS A PROMISING STRATEGY TO CURE COPD. IN CONTRAST TO SMALL ANIMAL MODELS, PHARMACOLOGICAL LUNG REGENERATION IS DIFFICULT IN HUMAN COPD. MATURATION, AGING, AND SENESCENCE IN COPD LUNG CELLS, INCLUDING ENDOGENOUS STEM CELLS, MAY AFFECT THE REGENERATIVE CAPACITY FOLLOWING PHARMACOLOGICAL THERAPY. THE LUNG IS A COMPLEX ORGAN COMPOSED OF MORE THAN 40 DIFFERENT CELL TYPES; THEREFORE, DETAILED ANALYSES, SUCH AS EPIGENETIC MODIFICATION ANALYSIS, IN EACH SPECIFIC CELL TYPE HAVE NOT BEEN PERFORMED IN LUNGS WITH COPD. RECENTLY, A METHOD FOR THE DIRECT ISOLATION OF INDIVIDUAL CELL TYPES FROM HUMAN LUNG HAS BEEN DEVELOPED, AND FINGERPRINTS OF EACH CELL TYPE IN COPD LUNGS CAN BE ANALYZED. RESEARCH USING THIS TECHNIQUE COMBINED WITH THE RECENTLY DISCOVERED LUNG ENDOGENOUS STEM-PROGENITOR POPULATIONS WILL GIVE A BETTER UNDERSTANDING ABOUT THE FATE OF COPD LUNG CELLS AND PROVIDE A FUTURE FOR CELL-BASED THERAPY TO TREAT THIS INTRACTABLE DISEASE. 2012