1 4112 150 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 2 4445 39 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 3 629 37 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 4 970 40 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 5 927 51 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 6 6475 49 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 7 5738 47 SMOKING AND LUNG CANCER: THE ROLE OF INFLAMMATION. WORLDWIDE OVER 1 MILLION PEOPLE DIE DUE TO LUNG CANCER EACH YEAR. IT IS ESTIMATED THAT CIGARETTE SMOKING EXPLAINS ALMOST 90% OF LUNG CANCER RISK IN MEN AND 70 TO 80% IN WOMEN. CLINICALLY EVIDENT LUNG CANCERS HAVE MULTIPLE GENETIC AND EPIGENETIC ABNORMALITIES. THESE ABNORMALITIES MAY RESULT IN ACTIVATION OF ONCOGENES AND INACTIVATION OF TUMOR-SUPPRESSOR GENES. CHRONIC INFLAMMATION, WHICH IS KNOWN TO PROMOTE CANCER, MAY RESULT BOTH FROM SMOKING AND FROM GENETIC ABNORMALITIES. THESE MEDIATORS IN TURN MAY BE RESPONSIBLE FOR INCREASED MACROPHAGE RECRUITMENT, DELAYED NEUTROPHIL CLEARANCE, AND INCREASE IN REACTIVE OXYGEN SPECIES (ROS). THUS, THE PULMONARY ENVIRONMENT PRESENTS A UNIQUE MILIEU IN WHICH LUNG CARCINOGENESIS PROCEEDS IN COMPLICITY WITH THE HOST CELLULAR NETWORK. THE PULMONARY DISEASES THAT ARE ASSOCIATED WITH THE GREATEST RISK FOR LUNG CANCER ARE CHARACTERIZED BY ABUNDANT AND DEREGULATED INFLAMMATION. PULMONARY DISORDERS SUCH AS CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD)/EMPHYSEMA ARE CHARACTERIZED BY PROFOUND ABNORMALITIES IN INFLAMMATORY AND FIBROTIC PATHWAYS. THE CYTOKINES AND GROWTH FACTORS ABERRANTLY PRODUCED IN COPD AND THE DEVELOPING TUMOR MICROENVIRONMENT HAVE BEEN FOUND TO HAVE DELETERIOUS PROPERTIES THAT SIMULTANEOUSLY PAVE THE WAY FOR BOTH EPITHELIAL-MESENCHYMAL TRANSITION (EMT) AND DESTRUCTION OF SPECIFIC HOST CELL-MEDIATED IMMUNE RESPONSES. FULL DEFINITION OF THESE PATHWAYS WILL AFFORD THE OPPORTUNITY TO INTERVENE IN SPECIFIC INFLAMMATORY EVENTS MEDIATING LUNG TUMORIGENESIS AND RESISTANCE TO THERAPY. 2008 8 3100 46 GENOMIC IMPACT OF CIGARETTE SMOKE, WITH APPLICATION TO THREE SMOKING-RELATED DISEASES. THERE IS CONSIDERABLE EVIDENCE THAT INHALED TOXICANTS SUCH AS CIGARETTE SMOKE CAN CAUSE BOTH IRREVERSIBLE CHANGES TO THE GENETIC MATERIAL (DNA MUTATIONS) AND PUTATIVELY REVERSIBLE CHANGES TO THE EPIGENETIC LANDSCAPE (CHANGES IN THE DNA METHYLATION AND CHROMATIN MODIFICATION STATE). THE DISEASES THAT ARE BELIEVED TO INVOLVE GENETIC AND EPIGENETIC PERTURBATIONS INCLUDE LUNG CANCER, CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD), AND CARDIOVASCULAR DISEASE (CVD), ALL OF WHICH ARE STRONGLY LINKED EPIDEMIOLOGICALLY TO CIGARETTE SMOKING. IN THIS REVIEW, WE HIGHLIGHT THE SIGNIFICANCE OF GENOMICS AND EPIGENOMICS IN THESE MAJOR SMOKING-RELATED DISEASES. WE ALSO SUMMARIZE THE IN VITRO AND IN VIVO FINDINGS ON THE SPECIFIC PERTURBATIONS THAT SMOKE AND ITS CONSTITUENT COMPOUNDS CAN INFLICT UPON THE GENOME, PARTICULARLY ON THE PULMONARY SYSTEM. FINALLY, WE REVIEW STATE-OF-THE-ART GENOMICS AND NEW TECHNIQUES SUCH AS HIGH-THROUGHPUT SEQUENCING AND GENOME-WIDE CHROMATIN ASSAYS, RAPIDLY EVOLVING TECHNIQUES WHICH HAVE ALLOWED EPIGENETIC CHANGES TO BE CHARACTERIZED AT THE GENOME LEVEL. THESE TECHNIQUES HAVE THE POTENTIAL TO SIGNIFICANTLY IMPROVE OUR UNDERSTANDING OF THE SPECIFIC MECHANISMS BY WHICH EXPOSURE TO ENVIRONMENTAL CHEMICALS CAUSES DISEASE. SUCH MECHANISTIC KNOWLEDGE PROVIDES A VARIETY OF OPPORTUNITIES FOR ENHANCED PRODUCT SAFETY ASSESSMENT AND THE DISCOVERY OF NOVEL THERAPEUTIC INTERVENTIONS. 2012 9 6199 49 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 10 971 37 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 11 2648 36 EPIGENOMIC TARGETS FOR THE TREATMENT OF RESPIRATORY DISEASE. BACKGROUND: A NUMBER OF PROCESSES LEAD TO EPIGENETIC AND EPIGENOMIC MODIFICATIONS. OBJECTIVE: TO ADDRESS THE IMPORTANCE OF EPIGENOMICS IN RESPIRATORY DISEASE. METHODS: STUDIES OF EPIGENOMICS WERE ANALYSED IN RELATION TO CHRONIC RESPIRATORY DISEASES. RESULTS/CONCLUSION: IN LUNG CANCER AND MESOTHELIOMA, A NUMBER OF GENES INVOLVED IN CARCINOGENESIS HAVE BEEN DEMONSTRATED TO BE HYPERMETHYLATED, IMPLICATING EPIGENOMIC CHANGES IN THE AETIOLOGY OF THESE CANCERS. HYPERMETHYLATED GENES HAVE ALSO BEEN ASSOCIATED WITH LUNG CANCER RECURRENCE, INDICATING EPIGENOMIC REGULATION OF METASTASIS. IN AIRWAY DISEASES, MODULATION OF HISTONE FUNCTION MAY ACTIVATE INFLAMMATORY MECHANISMS IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE PATIENTS AND LEAD TO RELATIVE STEROID RESISTANCE. THERE IS EMERGING EVIDENCE FOR THE ROLE OF EPIGENETIC CHANGES IN CHRONIC LUNG DISEASES SUCH AS ASTHMA, INCLUDING RESPONSES TO ENVIRONMENTAL EXPOSURES IN UTERO AND TO THE EFFECTS OF AIR POLLUTION. INSIGHT INTO EPIGENOMICS WILL LEAD TO THE DEVELOPMENT OF NOVEL BIOMARKERS AND TREATMENT TARGETS IN RESPIRATORY DISEASES. 2009 12 4901 32 OXIDATIVE, INFLAMMATORY, GENETIC, AND EPIGENETIC BIOMARKERS ASSOCIATED WITH CHRONIC OBSTRUCTIVE PULMONARY DISORDER. A LARGE BODY OF EVIDENCE INDICATES THAT CHRONIC OBSTRUCTIVE PULMONARY DISORDER (COPD) IS ACCOMPANIED BY OXIDATIVE STRESS AND INFLAMMATORY AND GENETIC PATHWAYS. EPIDEMIOLOGICAL STUDIES INDICATE THAT COPD IS A MAJOR CAUSE OF MORTALITY AND MORBIDITY IN THE WORLD. RECENT RESEARCH DEVELOPMENT IN COPD FOCUSES ON ACCELERATED AGING AND VARIOUS OXIDATIVE STRESS BIOMARKERS. IT INVOLVES THE CLINICAL MANIFESTATION OF THE DISEASE PROCESS AND MAY ALSO CONTAIN BIOCHEMICAL, IMMUNOLOGICAL, PHYSIOLOGICAL, MORPHOLOGICAL, AND GENETIC ASPECTS THAT ADD TO THE PROGRESSIVENESS OF THE DISEASE. HEREIN, WE SUMMARIZE FINDINGS THAT HIGHLIGHT THE ROLE OF DIMENSIONS OF COPD IN THE INVESTIGATION OF OXIDATIVE STRESS, INFLAMMATORY RESPONSES, GENETIC AND EPIGENETIC STUDIES, AND PHARMACOLOGICAL AND DIETARY ANTIOXIDANT INTERVENTION. 2019 13 6834 36 [IMMUNOPATHOLOGY OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE]. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS A COMMON, PREVENTABLE AND TREATABLE CONDITION THAT HAS A COMPLEX PATHOPHYSIOLOGY AND AN EVEN MORE COMPLEX IMMUNOPATHOLOGICAL PROCESS. THE PURPOSE OF THIS REVIEW WAS TO ANALYZE COPD IMMUNOPATHOLOGICAL ASPECTS, WHICH WAS ADDRESSED BY UNDERTAKING A LITERATURE SEARCH FOR THE MOST RELEVANT DOCUMENTS INDEXED IN THE PUBMED DATABASE OVER THE LAST 10 YEARS. DIFFERENT CONCLUSIONS COULD BE DRAWN: IN COPD IMMUNOPATHOLOGY THERE ARE IMMUNE AND NON-IMMUNE INFLAMMATORY CHANGES WITH OXIDATIVE STRESS IMBALANCE, THERE ARE ALTERATIONS IN THE PROTEASE/ANTI-PROTEASE RATIO CAUSED BY DIRECT AND INDIRECT GENETIC AND EPIGENETIC-ENVIRONMENTAL DEFECTS; COPD PRODUCES IRREVERSIBLE TISSUE DAMAGE AND CHRONIC INFLAMMATION WITH TISSUE REPAIR ALTERATION, WHICH INDUCES CHRONIC OBSTRUCTION OF THE AIRWAY, BRONCHITIS AND SYSTEMIC DAMAGE. MOST COMMON RESULTING COMORBIDITIES INCLUDE CARDIOVASCULAR DISEASE, METABOLIC SYNDROME, OSTEOPOROSIS, DEPRESSION, MUSCULOSKELETAL DYSFUNCTION, INCREASED BIOLOGICAL AGE, LUNG CANCER AND OTHER TYPES OF MALIGNANCIES. IN THE CONCEPTION OF COPD, RECOGNIZING THAT IT IS A NON-TRANSMITTABLE AND PREVENTABLE DISEASE IS INDISPENSABLE. 2017 14 2162 41 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 6281 35 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 16 5742 37 SMOKING MOLECULAR DAMAGE IN BRONCHIAL EPITHELIUM. OUR UNDERSTANDING OF THE MOLECULAR PATHOLOGY OF LUNG CANCER IS ADVANCING RAPIDLY WITH SEVERAL SPECIFIC GENES AND CHROMOSOMAL REGIONS BEING IDENTIFIED. LUNG CANCER APPEARS TO REQUIRE MANY MUTATIONS IN BOTH DOMINANT AND RECESSIVE ONCOGENES TO POSSESS MALIGNANT PHENOTYPES. SEVERAL GENETIC AND EPIGENETIC CHANGES ARE COMMON TO ALL LUNG CANCER HISTOLOGIC TYPES, WHILE OTHERS APPEAR TO BE CELL TYPE SPECIFIC. HOWEVER, SPECIFIC ROLES OF THE GENES UNDERGOING MUTATIONS AND THE ORDER OF CUMULATIVE MOLECULAR CHANGES THAT LEAD TO THE DEVELOPMENT OF EACH LUNG TUMOR HISTOLOGIC TYPE REMAIN TO BE FULLY ELUCIDATED. RECENT FINDINGS OF MOLECULAR ABNORMALITIES IN NORMAL APPEARING AND PRENEOPLASTIC BRONCHIAL EPITHELIUM FROM PATIENTS WITH LUNG CANCER AND CHRONIC SMOKERS SUGGEST THAT GENETIC CHANGES MAY SERVE AS BIOMARKERS FOR EARLY DIAGNOSIS, RISK ASSESSMENT AND MONITORING RESPONSE TO CHEMOPREVENTION. 2002 17 1188 37 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 18 3966 49 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 19 1539 32 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 20 4026 25 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