1 1244 105 CURRENT CONCEPTS ON OXIDATIVE/CARBONYL STRESS, INFLAMMATION AND EPIGENETICS IN PATHOGENESIS OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS A GLOBAL HEALTH PROBLEM. THE CURRENT THERAPIES FOR COPD ARE POORLY EFFECTIVE AND THE MAINSTAYS OF PHARMACOTHERAPY ARE BRONCHODILATORS. A BETTER UNDERSTANDING OF THE PATHOBIOLOGY OF COPD IS CRITICAL FOR THE DEVELOPMENT OF NOVEL THERAPIES. IN THE PRESENT REVIEW, WE HAVE DISCUSSED THE ROLES OF OXIDATIVE/ALDEHYDE STRESS, INFLAMMATION/IMMUNITY, AND CHROMATIN REMODELING IN THE PATHOGENESIS OF COPD. AN IMBALANCE OF OXIDANTS/ANTIOXIDANTS CAUSED BY CIGARETTE SMOKE AND OTHER POLLUTANTS/BIOMASS FUELS PLAYS AN IMPORTANT ROLE IN THE PATHOGENESIS OF COPD BY REGULATING REDOX-SENSITIVE TRANSCRIPTION FACTORS (E.G., NF-KAPPAB), AUTOPHAGY AND UNFOLDED PROTEIN RESPONSE LEADING TO CHRONIC LUNG INFLAMMATORY RESPONSE. CIGARETTE SMOKE ALSO ACTIVATES CANONICAL/ALTERNATIVE NF-KAPPAB PATHWAYS AND THEIR UPSTREAM KINASES LEADING TO SUSTAINED INFLAMMATORY RESPONSE IN LUNGS. RECENTLY, EPIGENETIC REGULATION HAS BEEN SHOWN TO BE CRITICAL FOR THE DEVELOPMENT OF COPD BECAUSE THE EXPRESSION/ACTIVITY OF ENZYMES THAT REGULATE THESE EPIGENETIC MODIFICATIONS HAVE BEEN REPORTED TO BE ABNORMAL IN AIRWAYS OF COPD PATIENTS. HENCE, THE SIGNIFICANT ADVANCES MADE IN UNDERSTANDING THE PATHOPHYSIOLOGY OF COPD AS DESCRIBED HEREIN WILL IDENTIFY NOVEL THERAPEUTIC TARGETS FOR INTERVENTION IN COPD. 2011 2 4658 33 NEW ANTI-INFLAMMATORY TARGETS FOR CHRONIC OBSTRUCTIVE PULMONARY DISEASE. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS ASSOCIATED WITH CHRONIC INFLAMMATION OF THE PERIPHERAL AIRWAYS AND LUNG PARENCHYMA, WHICH LEADS TO PROGRESSIVE OBSTRUCTION OF THE AIRWAYS. CURRENT MANAGEMENT WITH LONG-ACTING BRONCHODILATORS DOES NOT REDUCE DISEASE PROGRESSION, AND THERE ARE NO TREATMENTS THAT EFFECTIVELY SUPPRESS CHRONIC INFLAMMATION IN COPD. AN INCREASED UNDERSTANDING OF THE INFLAMMATORY PROCESSES THAT ARE INVOLVED IN THE PATHOPHYSIOLOGY OF COPD HAS IDENTIFIED SEVERAL NEW THERAPEUTIC TARGETS. THIS REVIEW DISCUSSES SOME OF THE MOST PROMISING OF THESE TARGETS, INCLUDING NEW ANTIOXIDANTS, KINASE INHIBITORS AND DRUGS THAT TARGET CELLULAR SENESCENCE, MICROBIAL COLONIZATION, EPIGENETIC REGULATION OF INFLAMMATORY GENE EXPRESSION AND CORTICOSTEROID RESISTANCE. 2013 3 1245 47 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 4 3966 40 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 5 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 6 4026 34 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 7 2212 34 EPIGENETIC MODIFICATIONS AND THERAPY IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD): AN UPDATE REVIEW. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) THAT IS ONE OF THE MOST PREVALENT CHRONIC ADULT DISEASES AND THE THIRD LEADING CAUSE OF FATALITY UNTIL 2020. ELASTASE/ANTI-ELASTASE HYPOTHESIS, CHRONIC INFLAMMATION, APOPTOSIS, OXIDANT-ANTIOXIDANT BALANCE AND INFECTIVE REPAIR CAUSE PATHOGENESIS OF COPD ARE AMONG THE FACTORS AT PLAY. EPIGENETIC CHANGES ARE POST-TRANSLATIONAL MODIFICATIONS IN HISTONE PROTEINS AND DNA SUCH AS METHYLATION AND ACETYLATION AS WELL AS DYSREGULATION OF MIRNAS EXPRESSION. IN THIS UPDATE REVIEW, WE HAVE EXAMINED RECENT STUDIES ON THE UPREGULATION OR DOWNREGULATION OF METHYLATION IN DIFFERENT GENES ASSOCIATED WITH COPD. DYSREGULATION OF HDAC ACTIVITY WHICH IS CAUSED BY SOME FACTORS AND MIRNAS PLAYS A KEY ROLE IN THE SUPPRESSION AND REDUCTION OF COPD DEVELOPMENT. ALSO, SOME THERAPEUTIC APPROACHES ARE PROPOSED AGAINST COPD BY TARGETING HDAC2 AND MIRNAS, WHICH HAVE THERAPEUTIC EFFECTS. 2020 8 2161 37 EPIGENETIC MECHANISMS IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE. EPIGENETIC MODIFICATION MAY AFFECT THE EXPRESSION OF MULTIPLE INFLAMMATORY GENES IN LUNGS OF PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). MAJOR EPIGENETIC EVENTS INCLUDE DNA METHYLATION AND VARIOUS POST-TRANSLATIONAL MODIFICATIONS OF HISTONES, SUCH AS HISTONE METHYLATION, ACETYLATION, PHOSPHORYLATION, UBIQUITINATION, AND SUMOYLATION. ENZYMES WHICH REGULATE THESE EPIGENETIC MODIFICATIONS CAN BE ACTIVATED BY SMOKING. BOTH ENVIRONMENTAL AND GENETIC FACTORS PLAY SIGNIFICANT EFFECT IN DEVELOPMENT OF COPD WHICH HAVE BEEN REPORTED BY MOST REFERENCES; HOWEVER, LITTLE IS KNOWN ABOUT THE EPIGENETIC PATHWAYS INVOLVED IN THE DISEASE. UNDERSTANDING THE EPIGENETIC MECHANISMS CAN HELP US CLARIFY THE PATHOGENESIS OF COPD AND IDENTIFY NOVEL TARGETS FOR DEVELOPING NEW THERAPIES FOR PATIENTS WITH COPD. 2015 9 6799 24 [EPIGENETIC AND CURRENT TREATMENT APPROACHES IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE]. EPIGENETICS MECHANISMS SUCH AS DNA METHYLATION, HISTONE ACETYLATION AND NON-CODING RNAS MAY PLAY ARE A ROLE IN THE PATHOGENESIS OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). RESEARCHS WITH REGARD EPIGENETIC IN COPD CAN SHED LIGHT ON PATHOGENES AND MAY BE RELEVANT IN THE DEVELOPMENT OF NOVEL TARGETED THERAPIES. THE AIM OF THIS ARTICLE IS TO REVIEW EPIGENETIC MECHANISMS NEW TREATMENTS APPROACHES IN COPD. 2016 10 2357 42 EPIGENETIC REGULATION OF PULMONARY INFLAMMATION. PULMONARY DISEASE SUCH AS CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD), ASTHMA, PULMONARY FIBROSIS AND PULMONARY HYPERTENSION ARE THE LEADING CAUSE OF DEATHS. MORE IMPORTANTLY, LUNG DISEASES ARE ON THE RISE AND ENVIRONMENTAL FACTORS INDUCED EPIGENETIC MODIFICATIONS ARE MAJOR PLAYERS ON THIS INCREASED PREVALENCE. IT HAS BEEN REPORTED THAT DYSREGULATION OF GENES INVOLVED IN EPIGENETIC REGULATION SUCH AS THE HISTONE DEACETYLASE (HDACS) AND HISTONE ACETYLTRANSFERASE (HATS) PLAY IMPORTANT ROLE IN LUNG HEALTH AND PULMONARY DISEASE PATHOGENESIS. INFLAMMATION IS AN ESSENTIAL COMPONENT OF RESPIRATORY DISEASES. INJURY AND INFLAMMATION TRIGGER RELEASE OF EXTRACELLULAR VESICLES THAT CAN ACT AS EPIGENETIC MODIFIERS THROUGH TRANSFER OF EPIGENETIC REGULATORS SUCH AS MICRORNAS (MIRNAS), LONG NON-CODING RNAS (LNCRNAS), PROTEINS AND LIPIDS, FROM ONE CELL TO ANOTHER. THE IMMUNE DYSREGULATIONS CAUSED BY THE CARGO CONTENTS ARE IMPORTANT CONTRIBUTORS OF RESPIRATORY DISEASE PATHOGENESIS. N6 METHYLATION OF RNA IS ALSO EMERGING TO BE A CRITICAL MECHANISM OF EPIGENETIC ALTERATION AND UPREGULATION OF IMMUNE RESPONSES TO ENVIRONMENTAL STRESSORS. EPIGENETIC CHANGES SUCH AS DNA METHYLATION ARE STABLE AND OFTEN LONG TERM AND CAUSE ONSET OF CHRONIC LUNG CONDITIONS. THESE EPIGENETIC PATHWAYS ARE ALSO BEING UTILIZED FOR THERAPEUTIC INTERVENTION IN SEVERAL LUNG CONDITIONS. 2023 11 4953 46 PATHOGENESIS OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) INDUCED BY CIGARETTE SMOKE. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS A COMMON RESPIRATORY DISEASE THAT IS CHARACTERIZED BY FUNCTIONAL AND STRUCTURAL ALTERATIONS PRIMARILY CAUSED BY LONG-TERM INHALATION OF HARMFUL PARTICLES. CIGARETTE SMOKE (CS) INDUCES AIRWAY INFLAMMATION IN COPD, WHICH IS KNOWN TO PERSIST EVEN AFTER SMOKING CESSATION. THIS REVIEW DISCUSSES THE BASIC PATHOGENESIS OF COPD, WITH PARTICULAR FOCUS ON AN ENDOGENOUS PROTECTIVE MECHANISM AGAINST OXIDATIVE STRESS VIA NRF2, ALTERED IMMUNE RESPONSE OF THE AIRWAY INFLAMMATORY CELLS, EXAGGERATED CELLULAR SENESCENCE OF THE LUNG STRUCTURAL CELLS, AND CELL DEATH WITH EXPANDED INFLAMMATION. RECENTLY, CS-INDUCED MITOCHONDRIA AUTOPHAGY IS REPORTED TO INITIATE PROGRAMMED NECROSIS (NECROPTOSIS). NECROPTOSIS IS A NEW CONCEPT OF CELL DEATH WHICH IS DRIVEN BY A DEFINED MOLECULAR PATHWAY ALONG WITH EXAGGERATED INFLAMMATION. THIS NEW CELL DEATH MECHANISM IS OF IMPORTANCE DUE TO ITS ABILITY TO PRODUCE MORE INFLAMMATORY SUBSTANCES DURING THE PROCESS OF EPITHELIAL DEATH, CONTRIBUTING TO PERSISTENT AIRWAY INFLAMMATION THAT CANNOT BE EXPLAINED BY APOPTOSIS-DERIVED CELL DEATH. AUTOPHAGY IS AN AUTO-CELL COMPONENT DEGRADATION SYSTEM EXECUTED BY LYSOSOMES THAT CONTROLS PROTEIN AND ORGANELLE DEGRADATION FOR SUCCESSFUL HOMEOSTASIS. AS WELL AS IN THE PROCESS OF NECROPTOSIS, AUTOPHAGY IS ALSO OBSERVED DURING CELLULAR SENESCENCE. AGING OF THE LUNGS RESULTS IN THE ACQUISITION OF SENESCENCE-ASSOCIATED SECRETORY PHENOTYPES (SASP) THAT ARE KNOWN TO SECRETE INFLAMMATORY CYTOKINES, CHEMOKINES, GROWTH FACTORS, AND MATRIX METALLOPROTEINASES RESULTING IN CHRONIC LOW-GRADE INFLAMMATION. IN FUTURE RESEARCH, WE INTEND TO HIGHLIGHT THE GENETIC AND EPIGENETIC APPROACHES THAT CAN FACILITATE THE UNDERSTANDING OF DISEASE SUSCEPTIBILITY. THE GOAL OF PRECISION MEDICINE IS TO ESTABLISH MORE ACCURATE DIAGNOSIS AND TREATMENT METHODS BASED ON THE PATIENT-SPECIFIC PATHOGENIC CHARACTERISTICS. THIS REVIEW PROVIDES INSIGHTS INTO CS-INDUCED COPD PATHOGENESIS, WHICH CONTRIBUTES TO A VERY COMPLEX DISEASE. INVESTIGATING THE MECHANISM OF DEVELOPING COPD, ALONG WITH THE AVAILABILITY OF THE PARTICULAR INHIBITORS, WILL LEAD TO NEW THERAPEUTIC APPROACHES IN COPD TREATMENT. 2019 12 970 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 13 1539 29 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 14 5560 43 ROLE OF HISTONE DEACETYLASE 2 IN EPIGENETICS AND CELLULAR SENESCENCE: IMPLICATIONS IN LUNG INFLAMMAGING AND COPD. HISTONE DEACETYLASE 2 (HDAC2) IS A CLASS I HISTONE DEACETYLASE THAT REGULATES VARIOUS CELLULAR PROCESSES, SUCH AS CELL CYCLE, SENESCENCE, PROLIFERATION, DIFFERENTIATION, DEVELOPMENT, APOPTOSIS, AND GLUCOCORTICOID FUNCTION IN INHIBITING INFLAMMATORY RESPONSE. HDAC2 HAS BEEN SHOWN TO PROTECT AGAINST DNA DAMAGE RESPONSE AND CELLULAR SENESCENCE/PREMATURE AGING VIA AN EPIGENETIC MECHANISM IN RESPONSE TO OXIDATIVE STRESS. THESE PHENOMENA ARE OBSERVED IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). HDAC2 IS POSTTRANSLATIONALLY MODIFIED BY OXIDATIVE/CARBONYL STRESS IMPOSED BY CIGARETTE SMOKE AND OXIDANTS, LEADING TO ITS REDUCTION VIA AN UBIQUITINATION-PROTEASOME DEPENDENT DEGRADATION IN LUNGS OF PATIENTS WITH COPD. IN THIS PERSPECTIVE, WE HAVE DISCUSSED THE ROLE OF HDAC2 POSTTRANSLATIONAL MODIFICATIONS AND ITS ROLE IN REGULATION OF INFLAMMATION, HISTONE/DNA EPIGENETIC MODIFICATIONS, DNA DAMAGE RESPONSE, AND CELLULAR SENESCENCE, PARTICULARLY IN INFLAMMAGING, AND DURING THE DEVELOPMENT OF COPD. WE HAVE ALSO DISCUSSED THE POTENTIAL DIRECTIONS FOR FUTURE TRANSLATIONAL RESEARCH AVENUES IN MODULATING LUNG INFLAMMAGING AND CELLULAR SENESCENCE BASED ON EPIGENETIC CHROMATIN MODIFICATIONS IN DISEASES ASSOCIATED WITH INCREASED OXIDATIVE STRESS. 2012 15 4901 28 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 16 927 34 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 17 2162 36 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 18 6281 32 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 19 3535 31 IMMUNE AND GENETIC MECHANISMS IN COPD: POSSIBLE TARGETS FOR THERAPEUTIC INTERVENTIONS. GENETIC, IMMUNE AND ENVIRONMENTAL INTERACTIONS ARE KEY ELEMENTS FOR THE DEVELOPMENT OF COPD. CIGARETTE SMOKING IS CONSIDERED THE PRIMARY RISK FACTOR INITIATING INFLAMMATORY CASCADES IN GENETICALLY SUSCEPTIBLE INDIVIDUALS. THE "DANGER SIGNALS" ELICITED BY THE INJURED CELLS OF NON-SPECIFIC IMMUNITY INDUCE THE DOWNSTREAM ACTIVATION OF PROINFLAMMATORY CASCADES AND ANTIGEN-SPECIFIC ADAPTIVE IMMUNE RESPONSES. THE PRODUCED OXIDATIVE STRESS FURTHER DAMAGES THE LUNG LEADING TO ACQUIRED GENETIC CHANGES (HISTONE DEACETYLATION, MICROSATELLITE DNA INSTABILITY, DNA METHYLATION, TELOMERE SHORTENING, MIRNA ALTERATIONS) DUE TO AN INEFFICIENT DNA REPAIR MACHINERY. ON THE OTHER HAND, AUGMENTED APOPTOSIS, IMPAIRED EFFEROCYTOSIS AND ABNORMAL TISSUE REMODELING CONTRIBUTE TO THE CHRONIC INFLAMMATORY RESPONSE AND TISSUE DESTRUCTION IN COPD. THIS REVIEW FOCUSES ON THE ROLE OF GENETIC, EPIGENETIC AND IMMUNE MECHANISMS IN THE DEVELOPMENT OF COPD IN ORDER TO PUT FORWARD POSSIBLE PROGNOSTIC AND THERAPEUTIC TARGETS. 2013 20 629 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