1 3329 119 HISTONE DEACETYLASE 6-MEDIATED SELECTIVE AUTOPHAGY REGULATES COPD-ASSOCIATED CILIA DYSFUNCTION. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) INVOLVES ABERRANT AIRWAY INFLAMMATORY RESPONSES TO CIGARETTE SMOKE (CS) THAT ARE ASSOCIATED WITH EPITHELIAL CELL DYSFUNCTION, CILIA SHORTENING, AND MUCOCILIARY CLEARANCE DISRUPTION. EXPOSURE TO CS REDUCED CILIA LENGTH AND INDUCED AUTOPHAGY IN VIVO AND IN DIFFERENTIATED MOUSE TRACHEAL EPITHELIAL CELLS (MTECS). AUTOPHAGY-IMPAIRED (BECN1+/- OR MAP1LC3B-/-) MICE AND MTECS RESISTED CS-INDUCED CILIA SHORTENING. FURTHERMORE, CS INCREASED THE AUTOPHAGIC TURNOVER OF CILIARY PROTEINS, INDICATING THAT AUTOPHAGY MAY REGULATE CILIA HOMEOSTASIS. WE IDENTIFIED CYTOSOLIC DEACETYLASE HDAC6 AS A CRITICAL REGULATOR OF AUTOPHAGY-MEDIATED CILIA SHORTENING DURING CS EXPOSURE. MICE BEARING AN X CHROMOSOME DELETION OF HDAC6 (HDAC6-/Y) AND MTECS FROM THESE MICE HAD REDUCED AUTOPHAGY AND WERE PROTECTED FROM CS-INDUCED CILIA SHORTENING. AUTOPHAGY-IMPAIRED BECN1-/-, MAP1LC3B-/-, AND HDAC6-/Y MICE OR MICE INJECTED WITH AN HDAC6 INHIBITOR WERE PROTECTED FROM CS-INDUCED MUCOCILIARY CLEARANCE (MCC) DISRUPTION. MCC WAS PRESERVED IN MICE GIVEN THE CHEMICAL CHAPERONE 4-PHENYLBUTYRIC ACID, BUT WAS DISRUPTED IN MICE LACKING THE TRANSCRIPTION FACTOR NRF2, SUGGESTING THAT OXIDATIVE STRESS AND ALTERED PROTEOSTASIS CONTRIBUTE TO THE DISRUPTION OF MCC. ANALYSIS OF HUMAN COPD SPECIMENS REVEALED EPIGENETIC DEREGULATION OF HDAC6 BY HYPOMETHYLATION AND INCREASED PROTEIN EXPRESSION IN THE AIRWAYS. WE CONCLUDE THAT AN AUTOPHAGY-DEPENDENT PATHWAY REGULATES CILIA LENGTH DURING CS EXPOSURE AND HAS POTENTIAL AS A THERAPEUTIC TARGET FOR COPD. 2013 2 453 29 APPLICATIONS OF CRISPR SYSTEMS IN RESPIRATORY HEALTH: ENTERING A NEW 'RED PEN' ERA IN GENOME EDITING. RESPIRATORY DISEASES, SUCH AS INFLUENZA INFECTION, ACUTE TRACHEAL BRONCHITIS, PNEUMONIA, TUBERCULOSIS, CHRONIC OBSTRUCTIVE PULMONARY DISEASE, ASTHMA, LUNG CANCER AND NASOPHARYNGEAL CARCINOMA, CONTINUE TO SIGNIFICANTLY IMPACT HUMAN HEALTH. DISEASES OF THE LUNG AND RESPIRATORY TRACT ARE INFLUENCED BY ENVIRONMENTAL CONDITIONS AND SOCIO-ECONOMIC FACTORS; HOWEVER, MANY OF THESE SERIOUS RESPIRATORY DISORDERS ARE ALSO ROOTED IN GENETIC OR EPIGENETIC CAUSES. CLUSTERED REGULARLY INTERSPACED PALINDROMIC REPEATS (CRISPR) AND CRISPR-ASSOCIATED (CAS) PROTEINS, ISOLATED FROM THE IMMUNE SYSTEM OF PROKARYOTES, PROVIDE A TOOL TO MANIPULATE GENE SEQUENCES AND GENE EXPRESSION WITH SIGNIFICANT IMPLICATIONS FOR RESPIRATORY RESEARCH. CRISPR/CAS SYSTEMS ALLOW PRECLINICAL MODELLING OF CAUSAL FACTORS INVOLVED IN MANY RESPIRATORY DISEASES, PROVIDING NEW INSIGHTS INTO THEIR UNDERLYING MECHANISMS. CRISPR CAN ALSO BE USED TO SCREEN FOR GENES INVOLVED IN RESPIRATORY PROCESSES, DEVELOPMENT AND PATHOLOGY, IDENTIFYING NOVEL DISEASE DRIVERS OR DRUG TARGETS. FINALLY, CRISPR/CAS SYSTEMS CAN POTENTIALLY CORRECT GENETIC MUTATIONS AND EDIT EPIGENETIC MARKS THAT CONTRIBUTE TO RESPIRATORY DISORDERS, PROVIDING A FORM OF PERSONALIZED MEDICINE THAT COULD BE USED IN CONJUNCTION WITH OTHER TECHNOLOGIES SUCH AS STEM CELL REPROGRAMMING AND TRANSPLANTATION. CRISPR GENE EDITING IS A YOUNG FIELD OF RESEARCH, AND CONCERNS REGARDING ITS SPECIFICITY, AS WELL AS THE NEED FOR EFFICIENT AND SAFE DELIVERY METHODS, NEED TO BE ADDRESSED FURTHER. HOWEVER, CRISPR/CAS SYSTEMS REPRESENT A SIGNIFICANT STEP FORWARD FOR RESEARCH AND THERAPY IN RESPIRATORY HEALTH, AND IT IS LIKELY WE WILL SEE THE BREAKTHROUGHS GENERATED FROM THIS TECHNOLOGY CONTINUE. 2019 3 3767 39 INTEGRATIVE EPIGENOMIC ANALYSIS IN DIFFERENTIATED HUMAN PRIMARY BRONCHIAL EPITHELIAL CELLS EXPOSED TO CIGARETTE SMOKE. CIGARETTE SMOKE (CS) IS ONE OF THE MAJOR RISK FACTORS FOR MANY PULMONARY DISEASES, INCLUDING CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) AND LUNG CANCER. THE FIRST LINE OF DEFENSE FOR CS EXPOSURE IS THE BRONCHIAL EPITHELIAL CELLS. ELUCIDATION OF THE EPIGENETIC CHANGES DURING CS EXPOSURE IS KEY TO GAINING A MECHANISTIC UNDERSTANDING INTO HOW MATURE AND DIFFERENTIATED BRONCHIAL EPITHELIAL CELLS RESPOND TO CS. THEREFORE, WE PERFORMED EPIGENOMIC PROFILING IN CONJUNCTION WITH TRANSCRIPTIONAL PROFILING IN WELL-DIFFERENTIATED HUMAN BRONCHIAL EPITHELIAL (HBE) CELLS CULTURED IN AIR-LIQUID INTERFACE (ALI) EXPOSED TO THE VAPOR PHASE OF CS. THE GENOME-WIDE ENRICHMENT OF HISTONE 3 LYSINE 27 ACETYLATION WAS DETECTED BY CHROMATIN IMMUNOPRECIPITATION FOLLOWED BY NEXT GENERATION SEQUENCING (CHIP-SEQ) IN HBE CELLS AND SUGGESTED THE PLAUSIBLE BINDING OF SPECIFIC TRANSCRIPTION FACTORS RELATED TO CS EXPOSURE. ADDITIONALLY, INTERROGATION OF CHIP-SEQ DATA WITH GENE EXPRESSION PROFILING OF HBE CELLS AFTER CS EXPOSURE FOR DIFFERENT DURATIONS (3 HOURS, 2 DAYS, 4 DAYS) SUGGESTED THAT EARLIER EPIGENETIC CHANGES (3 HOURS AFTER CS EXPOSURE) MAY BE ASSOCIATED WITH LATER GENE EXPRESSION CHANGES INDUCED BY CS EXPOSURE (4 DAYS). THE INTEGRATION OF EPIGENETICS AND GENE EXPRESSION DATA REVEALED SIGNALING PATHWAYS RELATED TO CS-INDUCED EPIGENETIC CHANGES IN HBE CELLS THAT MAY IDENTIFY NOVEL REGULATORY PATHWAYS RELATED TO CS-INDUCED COPD. 2018 4 1012 38 CIGARETTE SMOKE INDUCES DISTINCT HISTONE MODIFICATIONS IN LUNG CELLS: IMPLICATIONS FOR THE PATHOGENESIS OF COPD AND LUNG CANCER. CIGARETTE SMOKE (CS)-MEDIATED OXIDATIVE STRESS INDUCES SEVERAL SIGNALING CASCADES, INCLUDING KINASES, WHICH RESULTS IN CHROMATIN MODIFICATIONS (HISTONE ACETYLATION/DEACETYLATION AND HISTONE METHYLATION/DEMETHYLATION). WE HAVE PREVIOUSLY REPORTED THAT CS INDUCES CHROMATIN REMODELING IN PRO-INFLAMMATORY GENE PROMOTERS; HOWEVER, THE UNDERLYING SITE-SPECIFIC HISTONE MARKS FORMED IN HISTONES H3 AND H4 DURING CS EXPOSURE IN LUNGS IN VIVO AND IN LUNG CELLS IN VITRO, WHICH CAN EITHER DRIVE GENE EXPRESSION OR REPRESSION, ARE NOT KNOWN. WE HYPOTHESIZE THAT CS EXPOSURE IN MOUSE AND HUMAN BRONCHIAL EPITHELIAL CELLS (H292) CAN CAUSE SITE-SPECIFIC POSTTRANSLATIONAL HISTONE MODIFICATIONS (PTMS) THAT MAY PLAY AN IMPORTANT ROLE IN THE PATHOGENESIS OF CS-INDUCED CHRONIC LUNG DISEASES. WE USED A BOTTOM-UP MASS SPECTROMETRY APPROACH TO IDENTIFY SOME POTENTIALLY NOVEL HISTONE MARKS, INCLUDING ACETYLATION, MONOMETHYLATION, AND DIMETHYLATION, IN SPECIFIC LYSINE AND ARGININE RESIDUES OF HISTONES H3 AND H4 IN MOUSE LUNGS AND H292 CELLS. WE FOUND THAT CS-INDUCED DISTINCT POSTTRANSLATIONAL HISTONE MODIFICATION PATTERNS IN HISTONE H3 AND HISTONE H4 IN LUNG CELLS, WHICH MAY BE CONSIDERED AS USABLE BIOMARKERS FOR CS-INDUCED CHRONIC LUNG DISEASES. THESE IDENTIFIED HISTONE MARKS (HISTONE H3 AND HISTONE H4) MAY PLAY AN IMPORTANT ROLE IN THE EPIGENETIC STATE DURING THE PATHOGENESIS OF SMOKING-INDUCED CHRONIC LUNG DISEASES, SUCH AS CHRONIC OBSTRUCTIVE PULMONARY DISEASE AND LUNG CANCER. 2014 5 2910 41 GENE EXPRESSION PROFILING OF EPIGENETIC CHROMATIN MODIFICATION ENZYMES AND HISTONE MARKS BY CIGARETTE SMOKE: IMPLICATIONS FOR COPD AND LUNG CANCER. CHROMATIN-MODIFYING ENZYMES MEDIATE DNA METHYLATION AND HISTONE MODIFICATIONS ON RECRUITMENT TO SPECIFIC TARGET GENE LOCI IN RESPONSE TO VARIOUS STIMULI. THE KEY ENZYMES THAT REGULATE CHROMATIN ACCESSIBILITY FOR MAINTENANCE OF MODIFICATIONS IN DNA AND HISTONES, AND FOR MODULATION OF GENE EXPRESSION PATTERNS IN RESPONSE TO CIGARETTE SMOKE (CS), ARE NOT KNOWN. WE HYPOTHESIZE THAT CS EXPOSURE ALTERS THE GENE EXPRESSION PATTERNS OF CHROMATIN-MODIFYING ENZYMES, WHICH THEN AFFECTS MULTIPLE DOWNSTREAM PATHWAYS INVOLVED IN THE RESPONSE TO CS. WE HAVE, THEREFORE, ANALYZED CHROMATIN-MODIFYING ENZYME PROFILES AND VALIDATED BY QUANTITATIVE REAL-TIME PCR (QPCR). WE ALSO PERFORMED IMMUNOBLOT ANALYSIS OF TARGETED HISTONE MARKS IN C57BL/6J MICE EXPOSED TO ACUTE AND SUBCHRONIC CS, AND OF LUNGS FROM NONSMOKERS, SMOKERS, AND PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). WE FOUND A SIGNIFICANT INCREASE IN EXPRESSION OF SEVERAL CHROMATIN MODIFICATION ENZYMES, INCLUDING DNA METHYLTRANSFERASES, HISTONE ACETYLTRANSFERASES, HISTONE METHYLTRANSFERASES, AND SET DOMAIN PROTEINS, HISTONE KINASES, AND UBIQUITINASES. OUR QPCR VALIDATION DATA REVEALED A SIGNIFICANT DOWNREGULATION OF DNMT1, DNMT3A, DNMT3B, HDAC2, HDAC4, HAT1, PRMT1, AND AURKB WE IDENTIFIED TARGETED CHROMATIN HISTONE MARKS (H3K56AC AND H4K12AC), WHICH ARE INDUCED BY CS. THUS CS-INDUCED GENOTOXIC STRESS DIFFERENTIALLY AFFECTS THE EXPRESSION OF EPIGENETIC MODULATORS THAT REGULATE TRANSCRIPTION OF TARGET GENES VIA DNA METHYLATION AND SITE-SPECIFIC HISTONE MODIFICATIONS. THIS MAY HAVE IMPLICATIONS IN DEVISING EPIGENETIC-BASED THERAPIES FOR COPD AND LUNG CANCER. 2016 6 3447 35 HYPERMETHYLATION OF MITOCHONDRIAL TRANSCRIPTION FACTOR A INDUCED BY CIGARETTE SMOKE IS ASSOCIATED WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE. PURPOSE OF THE STUDY: CIGARETTE SMOKING IS A LEADING ENVIRONMENTAL CONTRIBUTOR TO CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD), BUT ITS EPIGENETIC REGULATION OF MTTFA GENE REMAINS ELUSIVE. THIS STUDY AIMS TO EXPLORE THE RELATIONSHIP OF DNA METHYLATION OF MTTFA AND CIGARETTE SMOKING IN COPD. MATERIALS AND METHODS: WE ANALYZED DNA METHYLATION ON MTTFA PROMOTERS IN CLINICAL SAMPLES FROM COPD PATIENTS AND SUBJECTS WITH NORMAL PULMONARY FUNCTION. EXPRESSION OF MTTFA MRNA IN THE CLINICAL SAMPLES AND MTTFA MRNA AND PROTEIN IN HUMAN UMBILICAL VEIN ENDOTHELIAL CELLS(HUVECS) TREATED WITH CIGARETTE SMOKE EXTRACT (CSE) WAS EVALUATED. MTTFA MRNA AND PROTEIN LEVELS WERE MEASURED TO DETERMINE EFFECTS OF DEMETHYLATION AGENTS ON CSE-TREATED HUVECS. RESULTS: THE DNA METHYLATION LEVEL OF THE MTTFA PROMOTER WAS SIGNIFICANTLY INCREASED IN COPD GROUP. EXPRESSION OF MTTFA MRNA WAS DOWNREGULATED IN THE LUNGS AS A CONSEQUENCE OF HYPERMETHYLATION OF MTTFA PROMOTER. EXPRESSION OF MTTFA MRNA AND PROTEIN WAS DOWNREGULATED IN CSE-TREATED HUVECS AS A CONSEQUENCE OF HYPERMETHYLATION OF THE MTTFA PROMOTER. MTTFA EXPRESSION IN CSE-TREATED HUVECS WAS RESTORED BY THE METHYLATION INHIBITOR, 5-AZA-2'-DEOXYCYTIDINE(AZA). CONCLUSIONS: CIGARETTE SMOKE-INDUCED HYPERMETHYLATION OF THE MTTFA PROMOTER IS RELATED TO THE INITIATION AND PROGRESSION OF COPD. OUR FINDING MAY PROVIDE A NEW STRATEGY FOR THE INTERVENTION OF COPD BY DEVELOPING DEMETHYLATION AGENTS TARGETING MTTFA HYPERMETHYLATION. 2019 7 4116 44 MECHANISMS OF AIRWAY EPITHELIAL INJURY AND ABNORMAL REPAIR IN ASTHMA AND COPD. THE AIRWAY EPITHELIUM COMPRISES OF DIFFERENT CELL TYPES AND ACTS AS A PHYSICAL BARRIER PREVENTING PATHOGENS, INCLUDING INHALED PARTICLES AND MICROBES, FROM ENTERING THE LUNGS. GOBLET CELLS AND SUBMUCOSAL GLANDS PRODUCE MUCUS THAT TRAPS PATHOGENS, WHICH ARE EXPELLED FROM THE RESPIRATORY TRACT BY CILIATED CELLS. BASAL CELLS ACT AS PROGENITOR CELLS, DIFFERENTIATING INTO DIFFERENT EPITHELIAL CELL TYPES, TO MAINTAIN HOMEOSTASIS FOLLOWING INJURY. ADHERENS AND TIGHT JUNCTIONS BETWEEN CELLS MAINTAIN THE EPITHELIAL BARRIER FUNCTION AND REGULATE THE MOVEMENT OF MOLECULES ACROSS IT. IN THIS REVIEW WE DISCUSS HOW ABNORMAL EPITHELIAL STRUCTURE AND FUNCTION, CAUSED BY CHRONIC INJURY AND ABNORMAL REPAIR, DRIVES AIRWAY DISEASE AND SPECIFICALLY ASTHMA AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). IN BOTH DISEASES, INHALED ALLERGENS, POLLUTANTS AND MICROBES DISRUPT JUNCTIONAL COMPLEXES AND PROMOTE CELL DEATH, IMPAIRING THE BARRIER FUNCTION AND LEADING TO INCREASED PENETRATION OF PATHOGENS AND A CONSTANT AIRWAY IMMUNE RESPONSE. IN ASTHMA, THE INFLAMMATORY RESPONSE PRECIPITATES THE EPITHELIAL INJURY AND DRIVES ABNORMAL BASAL CELL DIFFERENTIATION. THIS LEADS TO REDUCED CILIATED CELLS, GOBLET CELL HYPERPLASIA AND INCREASED EPITHELIAL MESENCHYMAL TRANSITION, WHICH CONTRIBUTE TO IMPAIRED MUCOCILIARY CLEARANCE AND AIRWAY REMODELLING. IN COPD, CHRONIC OXIDATIVE STRESS AND INFLAMMATION TRIGGER PREMATURE EPITHELIAL CELL SENESCENCE, WHICH CONTRIBUTES TO LOSS OF EPITHELIAL INTEGRITY AND AIRWAY INFLAMMATION AND REMODELLING. INCREASED NUMBERS OF BASAL CELLS SHOWING DEREGULATED DIFFERENTIATION, CONTRIBUTES TO CILIARY DYSFUNCTION AND MUCOUS HYPERPRODUCTION IN COPD AIRWAYS. DEFECTIVE ANTIOXIDANT, ANTIVIRAL AND DAMAGE REPAIR MECHANISMS, POSSIBLY DUE TO GENETIC OR EPIGENETIC FACTORS, MAY CONFER SUSCEPTIBILITY TO AIRWAY EPITHELIAL DYSFUNCTION IN THESE DISEASES. THE CURRENT EVIDENCE SUGGESTS THAT A CONSTANT CYCLE OF INJURY AND ABNORMAL REPAIR OF THE EPITHELIUM DRIVES CHRONIC AIRWAY INFLAMMATION AND REMODELLING IN ASTHMA AND COPD. MECHANISTIC UNDERSTANDING OF INJURY SUSCEPTIBILITY AND DAMAGE RESPONSE MAY LEAD TO IMPROVED THERAPIES FOR THESE DISEASES. 2023 8 4889 37 OXIDATIVE STRESS AND CHROMATIN REMODELING IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE AND SMOKING-RELATED DISEASES. SIGNIFICANCE: CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS PREDOMINANTLY A TOBACCO SMOKE-TRIGGERED DISEASE WITH FEATURES OF CHRONIC LOW-GRADE SYSTEMIC INFLAMMATION AND AGING (INFLAMMAGING) OF THE LUNG ASSOCIATED WITH STEROID RESISTANCE INDUCED BY CIGARETTE SMOKE (CS)-MEDIATED OXIDATIVE STRESS. OXIDATIVE STRESS INDUCES VARIOUS KINASE SIGNALING PATHWAYS LEADING TO CHROMATIN MODIFICATIONS (HISTONE ACETYLATION/DEACETYLATION AND HISTONE METHYLATION/DEMETHYLATION) IN INFLAMMATION, SENESCENCE, AND STEROID RESISTANCE. RECENT ADVANCES: HISTONE MONO-, DI-, OR TRI-METHYLATION AT LYSINE RESIDUES RESULT IN EITHER GENE ACTIVATION (H3K4, H3K36, AND H3K79) OR REPRESSION (H3K9, H3K27, AND H3K20). CROSS-TALK OCCURS BETWEEN VARIOUS EPIGENETIC MARKS ON HISTONES AND DNA METHYLATION. BOTH CS AND OXIDANTS ALTER HISTONE ACETYLATION/DEACETYLATION AND METHYLATION/DEMETHYLATION LEADING TO ENHANCED PROINFLAMMATORY GENE EXPRESSION. CHROMATIN MODIFICATIONS OCCUR IN LUNGS OF PATIENTS WITH COPD. HISTONE DEACETYLASE 2 (HDAC2) REDUCTION (LEVELS AND ACTIVITY) IS ASSOCIATED WITH STEROID RESISTANCE IN RESPONSE TO OXIDATIVE STRESS. CRITICAL ISSUES: HISTONE MODIFICATIONS ARE ASSOCIATED WITH DNA DAMAGE/REPAIR AND EPIGENOMIC INSTABILITY AS WELL AS PREMATURE LUNG AGING, WHICH HAVE IMPLICATIONS IN THE PATHOGENESIS OF COPD. HDAC2/SIRTUIN1 (SIRT1)-DEPENDENT CHROMATIN MODIFICATIONS ARE ASSOCIATED WITH DNA DAMAGE-INDUCED INFLAMMATION AND SENESCENCE IN RESPONSE TO CS-MEDIATED OXIDATIVE STRESS. FUTURE DIRECTIONS: UNDERSTANDING CS/OXIDATIVE STRESS-MEDIATED CHROMATIN MODIFICATIONS AND THE CROSS-TALK BETWEEN HISTONE ACETYLATION AND METHYLATION WILL DEMONSTRATE THE INVOLVEMENT OF EPIGENETIC REGULATION OF CHROMATIN REMODELING IN INFLAMMAGING. THIS WILL LEAD TO IDENTIFICATION OF NOVEL EPIGENETIC-BASED THERAPIES AGAINST COPD AND OTHER SMOKING-RELATED LUNG DISEASES. PHARMACOLOGICAL ACTIVATION OF HDAC2/SIRT1 OR REVERSAL OF THEIR OXIDATIVE POST-TRANSLATIONAL MODIFICATIONS MAY OFFER THERAPIES FOR TREATMENT OF COPD AND CS-RELATED DISEASES BASED ON EPIGENETIC HISTONE MODIFICATIONS. 2013 9 5916 28 TARGETING AGING PATHWAYS IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) HAS BECOME A GLOBAL EPIDEMIC AND IS THE THIRD LEADING CAUSE OF DEATH WORLDWIDE. COPD IS CHARACTERIZED BY CHRONIC AIRWAY INFLAMMATION, LOSS OF ALVEOLAR-CAPILLARY UNITS, AND PROGRESSIVE DECLINE IN LUNG FUNCTION. MAJOR RISK FACTORS FOR COPD ARE CIGARETTE SMOKING AND AGING. COPD-ASSOCIATED PATHOMECHANISMS INCLUDE MULTIPLE AGING PATHWAYS SUCH AS TELOMERE ATTRITION, EPIGENETIC ALTERATIONS, ALTERED NUTRIENT SENSING, MITOCHONDRIAL DYSFUNCTION, CELL SENESCENCE, STEM CELL EXHAUSTION AND CHRONIC INFLAMMATION. IN THIS REVIEW, WE WILL HIGHLIGHT THE CURRENT LITERATURE THAT FOCUSES ON THE ROLE OF AGE AND AGING-ASSOCIATED SIGNALING PATHWAYS AS WELL AS THEIR IMPACT ON CURRENT TREATMENT STRATEGIES IN THE PATHOGENESIS OF COPD. FURTHERMORE, WE WILL DISCUSS ESTABLISHED AND EXPERIMENTAL COPD TREATMENTS INCLUDING SENOLYTIC AND ANTI-AGING THERAPIES AND THEIR POTENTIAL USE AS NOVEL TREATMENT STRATEGIES IN COPD. 2020 10 1244 36 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 11 1245 32 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 12 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 13 6330 27 THE ROLE OF CIGARETTE SMOKE-INDUCED PULMONARY VASCULAR ENDOTHELIAL CELL APOPTOSIS IN COPD. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS ONE OF THE MOST COMMON CHRONIC RESPIRATORY DISEASES WITH HIGH MORBIDITY AND MORTALITY. IT HAS BECOME THE FIFTH MOST BURDENED AND THE THIRD MOST DEADLY DISEASE IN THE GLOBAL ECONOMY AND INCREASES YEAR BY YEAR. THE PREVENTION AND TREATMENT OF COPD ARE URGENT. SMOKING IS THE MAIN AND MOST COMMON RISK FACTOR FOR COPD. CIGARETTE SMOKE (CS) CONTAINS A LARGE NUMBER OF TOXIC SUBSTANCES, CAN CAUSE A SERIES OF CHANGES IN THE TRACHEA, LUNG TISSUE, PULMONARY BLOOD VESSELS, AND PROMOTES THE OCCURRENCE AND DEVELOPMENT OF COPD. IN RECENT YEARS, THE DEVELOPMENT OF EPIGENETICS AND MOLECULAR BIOLOGY HAVE PROVIDED NEW GUIDANCE FOR REVEALING THE PATHOGENESIS, DIAGNOSIS, AND TREATMENT OF DISEASES. THE LATEST RESEARCH INDICATES THAT PULMONARY VASCULAR ENDOTHELIAL CELL APOPTOSIS INITIATES AND PARTICIPATES IN THE PATHOGENESIS OF COPD. IN THIS REVIEW, WE SUMMARIZE THE CURRENT RESEARCH ON THE EPIGENETIC MECHANISMS AND MOLECULAR BIOLOGY OF CS-INDUCED PULMONARY VASCULAR ENDOTHELIAL CELL APOPTOSIS IN COPD, PROVIDING A NEW RESEARCH DIRECTION FOR PATHOGENESIS OF COPD AND A NEW TARGET FOR THE DIAGNOSIS, TREATMENT, AND PREVENTION OF COPD. 2021 14 5910 34 TARGETED EPIGENETIC EDITING OF SPDEF REDUCES MUCUS PRODUCTION IN LUNG EPITHELIAL CELLS. AIRWAY MUCUS HYPERSECRETION CONTRIBUTES TO THE MORBIDITY AND MORTALITY IN PATIENTS WITH CHRONIC INFLAMMATORY LUNG DISEASES. REDUCING MUCUS PRODUCTION IS CRUCIAL FOR IMPROVING PATIENTS' QUALITY OF LIFE. THE TRANSCRIPTION FACTOR SAM-POINTED DOMAIN-CONTAINING ETS-LIKE FACTOR (SPDEF) PLAYS A CRITICAL ROLE IN THE REGULATION OF MUCUS PRODUCTION AND, THEREFORE, REPRESENTS A POTENTIAL THERAPEUTIC TARGET. THIS STUDY AIMS TO REDUCE LUNG EPITHELIAL MUCUS PRODUCTION BY TARGETED SILENCING SPDEF USING THE NOVEL STRATEGY, EPIGENETIC EDITING. ZINC FINGERS AND CRISPR/DCAS PLATFORMS WERE ENGINEERED TO TARGET REPRESSORS (KRAB, DNA METHYLTRANSFERASES, HISTONE METHYLTRANSFERASES) TO THE SPDEF PROMOTER. ALL CONSTRUCTS WERE ABLE TO EFFECTIVELY SUPPRESS BOTH SPDEF MRNA AND PROTEIN EXPRESSION, WHICH WAS ACCOMPANIED BY INHIBITION OF DOWNSTREAM MUCUS-RELATED GENES [ANTERIOR GRADIENT 2 (AGR2), MUCIN 5AC (MUC5AC)]. FOR THE HISTONE METHYLTRANSFERASE G9A, AND NOT ITS MUTANT OR OTHER EFFECTORS, THE OBTAINED SILENCING WAS MITOTICALLY STABLE. THESE RESULTS INDICATE EFFICIENT SPDEF SILENCING AND DOWNREGULATION OF MUCUS-RELATED GENE EXPRESSION BY EPIGENETIC EDITING, IN HUMAN LUNG EPITHELIAL CELLS. THIS OPENS AVENUES FOR EPIGENETIC EDITING AS A NOVEL THERAPEUTIC STRATEGY TO INDUCE LONG-LASTING MUCUS INHIBITION. 2017 15 4493 37 MORAXELLA CATARRHALIS INDUCES INFLAMMATORY RESPONSE OF BRONCHIAL EPITHELIAL CELLS VIA MAPK AND NF-KAPPAB ACTIVATION AND HISTONE DEACETYLASE ACTIVITY REDUCTION. MORAXELLA CATARRHALIS IS A MAJOR CAUSE OF INFECTIOUS EXACERBATIONS OF CHRONIC OBSTRUCTIVE LUNG DISEASE (COPD) AND MAY ALSO CONTRIBUTE TO THE PATHOGENESIS OF COPD. LITTLE IS KNOWN ABOUT M. CATARRHALIS-BRONCHIAL EPITHELIUM INTERACTION. WE INVESTIGATED ACTIVATION OF M. CATARRHALIS INFECTED BRONCHIAL EPITHELIAL CELLS AND CHARACTERIZED THE SIGNAL TRANSDUCTION PATHWAYS. MOREOVER, WE TESTED THE HYPOTHESIS THAT THE M. CATARRHALIS-INDUCED CYTOKINE EXPRESSION IS REGULATED BY ACETYLATION OF HISTONE RESIDUES AND CONTROLLED BY HISTONE DEACETYLASE ACTIVITY (HDAC). WE DEMONSTRATED THAT M. CATARRHALIS INDUCED A STRONG TIME- AND DOSE-DEPENDENT INFLAMMATORY RESPONSE IN THE BRONCHIAL EPITHELIAL CELL LINE (BEAS-2B), CHARACTERIZED BY THE RELEASE OF IL-8 AND GM-CSF. FOR THIS CYTOKINE LIBERATION ACTIVATION OF THE ERK AND P38 MITOGEN-ACTIVATED PROTEIN (MAP) KINASES AND TRANSCRIPTION FACTOR NF-KAPPAB WAS REQUIRED. FURTHERMORE, M. CATARRHALIS-INFECTED BRONCHIAL EPITHELIAL CELLS SHOWED AN ENHANCED ACETYLATION OF HISTONE H3 AND H4 GLOBALLY AND AT THE PROMOTER OF THE IL8 GENE. PREVENTING HISTONE DEACETYLATION BY THE HISTONE DEACETYLASE INHIBITOR TRICHOSTATIN A AUGMENTED THE M. CATARRHALIS-INDUCED IL-8 RESPONSE. AFTER EXPOSURE TO M. CATARRHALIS, WE FOUND A DECREASE IN GLOBAL HISTONE DEACETYLASE EXPRESSION AND ACTIVITY. OUR FINDINGS SUGGEST THAT M. CATARRHALIS-INDUCED ACTIVATION OF IL8 GENE TRANSCRIPTION WAS CAUSED BY INTERFERENCE WITH EPIGENETIC MECHANISMS REGULATING IL8 GENE ACCESSIBILITY. OUR FINDINGS PROVIDE INSIGHT INTO IMPORTANT MOLECULAR AND CELLULAR MECHANISMS OF M. CATARRHALIS-INDUCED ACTIVATION OF HUMAN BRONCHIAL EPITHELIUM. 2006 16 1251 33 CURRENT PERSPECTIVES ON ROLE OF CHROMATIN MODIFICATIONS AND DEACETYLASES IN LUNG INFLAMMATION IN COPD. CHROMATIN MODIFICATIONS AND EPIGENETIC REGULATION ARE CRITICAL FOR SUSTAINED AND ABNORMAL INFLAMMATORY RESPONSE SEEN IN LUNGS OF PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) BECAUSE THE ACTIVITIES OF ENZYMES THAT REGULATE THESE EPIGENETIC MODIFICATIONS ARE ALTERED IN RESPONSE TO CIGARETTE SMOKE. CIGARETTE SMOKE INDUCES CHROMATIN MODIFICATIONS AND EPIGENETIC CHANGES BY CAUSING POST-TRANSLATIONAL MODIFICATIONS OF HISTONE ACETYLTRANSFERASES, AND HISTONE/NON-HISTONE DEACETYLASES (HDACS), SUCH AS HDAC2 AND SIRTUIN 1 (SIRT1), WHICH LEADS TO CHROMATIN REMODELING. IN THIS REVIEW, WE DISCUSSED THE CURRENT KNOWLEDGE ON CIGARETTE SMOKE/OXIDANTS-INDUCED POST-TRANSLATIONAL MODIFICATIONS OF DEACETYLASES (HDAC2 AND SIRT1), DISRUPTION OF HDAC2/SIRT1-RELA/P65 COREPRESSOR COMPLEX ASSOCIATED WITH ACETYLATION OF RELA/P65, AND CHROMATIN MODIFICATIONS (HISTONE H3 PHOSPHO-ACETYLATION) LEADING TO SUSTAINED PRO-INFLAMMATORY GENE TRANSCRIPTION. KNOWLEDGE ON MOLECULAR MECHANISMS OF EPIGENETIC CHANGES IN ABNORMAL LUNG INFLAMMATION WILL HELP IN UNDERSTANDING THE PATHOPHYSIOLOGY OF COPD WHICH MAY LEAD TO THE DEVELOPMENT OF NOVEL EPIGENETIC THERAPIES IN THE NEAR FUTURE. 2009 17 5334 37 QUADRICEPS MUSCLE WEAKNESS AND ATROPHY ARE ASSOCIATED WITH A DIFFERENTIAL EPIGENETIC PROFILE IN ADVANCED COPD. EPIGENETIC MECHANISMS REGULATE MUSCLE MASS AND FUNCTION IN MODELS OF MUSCLE DYSFUNCTION AND ATROPHY. WE ASSESSED WHETHER QUADRICEPS MUSCLE WEAKNESS AND ATROPHY ARE ASSOCIATED WITH A DIFFERENTIAL EXPRESSION PROFILE OF EPIGENETIC EVENTS IN PATIENTS WITH ADVANCED COPD (CHRONIC OBSTRUCTIVE PULMONARY DISEASE). IN VASTUS LATERALIS (VL) OF SEDENTARY SEVERE COPD PATIENTS (N=41), WHO WERE FURTHER SUBDIVIDED INTO THOSE WITH (N=25) AND WITHOUT (N=16) MUSCLE WEAKNESS AND HEALTHY CONTROLS (N=19), EXPRESSION OF MUSCLE-ENRICHED MIRNAS, HISTONE ACETYLTRANSFERASES (HATS) AND DEACETYLASES (HDACS), GROWTH AND ATROPHY SIGNALLING MARKERS, TOTAL PROTEIN AND HISTONE ACETYLATION, TRANSCRIPTION FACTORS, SMALL UBIQUITIN-RELATED MODIFIER (SUMO) LIGASES AND MUSCLE STRUCTURE WERE EXPLORED. ALL SUBJECTS WERE CLINICALLY EVALUATED. COMPARED WITH CONTROLS, IN VL OF ALL COPD TOGETHER AND IN MUSCLE-WEAKNESS PATIENTS, EXPRESSION OF MIR-1, MIR-206 AND MIR-27A, LEVELS OF LYSINE-ACETYLATED PROTEINS AND HISTONES AND ACETYLATED HISTONE 3 WERE INCREASED, WHEREAS EXPRESSION OF HDAC3, HDAC4, SIRTUIN-1 (SIRT-1), IGF-1 (INSULIN-LIKE GROWTH FACTOR-1) WERE DECREASED, AKT (V-AKT MURINE THYMOMA VIRAL ONCOGENE HOMOLOGUE 1) EXPRESSION DID NOT DIFFER, FOLLISTATIN EXPRESSION WAS GREATER, WHEREAS MYOSTATIN EXPRESSION WAS LOWER, SERUM REPONSE FACTOR (SRF) EXPRESSION WAS INCREASED AND FIBRE SIZE OF FAST-TWITCH FIBRES WAS SIGNIFICANTLY REDUCED. IN VL OF SEVERE COPD PATIENTS WITH MUSCLE WEAKNESS AND ATROPHY, EPIGENETIC EVENTS REGULATE MUSCLE DIFFERENTIATION RATHER THAN PROLIFERATION AND MUSCLE GROWTH AND ATROPHY SIGNALLING, PROBABLY AS FEEDBACK MECHANISMS TO PREVENT THOSE MUSCLES FROM UNDERGOING FURTHER ATROPHY. LYSINE-HYPERACETYLATION OF HISTONES MAY DRIVE ENHANCED PROTEIN CATABOLISM IN THOSE MUSCLES. THESE FINDINGS MAY HELP DESIGN NOVEL THERAPEUTIC STRATEGIES (ENHANCERS OF MIRNAS PROMOTING MYOGENESIS AND ACETYLATION INHIBITORS) TO SELECTIVELY TARGET MUSCLE WEAKNESS AND ATROPHY IN SEVERE COPD. 2015 18 5479 34 RESVERATROL ATTENUATES CIGARETTE SMOKE EXTRACT INDUCED CELLULAR SENESCENCE IN HUMAN AIRWAY EPITHELIAL CELLS BY REGULATING THE MIR-34A/SIRT1/NF-KAPPAB PATHWAY. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS CHARACTERIZED BY ACCELERATED LUNG AGING. SMOKING IS THE CRITICAL RISK FACTOR FOR COPD. CELLULAR SENESCENCE OF AIRWAY EPITHELIAL CELLS IS THE CYTOLOGICAL BASIS OF ACCELERATED LUNG AGING IN COPD, AND THE REGULATION OF MICRORNAS (MIRNAS) IS THE CENTRAL EPIGENETIC MECHANISM OF CELLULAR SENESCENCE. RESVERATROL (RES) IS A POLYPHENOL WITH ANTI-AGING PROPERTIES. THIS STUDY INVESTIGATED WHETHER RES ATTENUATES CIGARETTE SMOKE EXTRACT (CSE)-INDUCED CELLULAR SENESCENCE IN HUMAN AIRWAY EPITHELIAL CELLS (BEAS-2B) THROUGH THE MIR-34A/SIRT1/NUCLEAR FACTOR-KAPPAB (NF-KAPPAB) PATHWAY. BEAS-2B CELLS WERE TREATED WITH RES, CSE AND TRANSFECTED WITH MIR-34A-5P MIMICS. CELLULAR SENESCENCE WAS EVALUATED BY SENESCENCE -RELATED BETA-GALACTOSIDASE (SA-BETA-GAL) STAINING AND EXPRESSION OF SENESCENCE-RELATED GENES (P16, P21, AND P53). THE EXPRESSIONS OF MIR-34A-5P, SIRT1, AND NF-KAPPAB P65 WERE EXAMINED USING QUANTITATIVE REAL TIME POLYMERASE CHAIN REACTION AND WESTERN BLOTTING. THE SENESCENCE-ASSOCIATED SECRETORY PHENOTYPE (SASP) CYTOKINES (IL-1BETA, IL-6, IL-8, TNF-ALPHA) WERE ASSESSED BY ENZYME-LINKED IMMUNOSORBENT ASSAY. THE BINDING BETWEEN MIR-34A-5P AND SIRT1 WAS CONFIRMED BY DUAL-LUCIFERASE REPORTER ASSAY. THE RESULTS SHOWED THAT CSE DOSE-DEPENDENTLY DECREASED CELL VIABILITY AND ELEVATED CELLULAR SENESCENCE, CHARACTERIZED BY INCREASED SA-BETA-GAL STAINING AND SENESCENCE-RELATED GENE EXPRESSIONS (P16, P21, AND P53). FURTHER, CSE DOSE-DEPENDENTLY INCREASED THE EXPRESSION OF MIR-34A-5P AND SASP CYTOKINES (IL-1BETA, IL-6, IL-8, TNF-ALPHA) IN BEAS-2B CELLS. PRETREATMENT WITH RES INHIBITED CSE-INDUCED CELLULAR SENESCENCE AND SECRETION OF SASP CYTOKINES (IL-1BETA, IL-6, IL-8, TNF-ALPHA) IN A DOSE-DEPENDENT MANNER. MOREOVER, RES REVERSED THE CSE-INDUCED DOWN-REGULATION OF SIRT1 AND UP-REGULATION OF MIR-34A-5P AND NF-KAPPAB P65. SIRT1 IS A TARGET OF MIR-34A-5P. OVEREXPRESSION OF MIR-34A-5P VIA TRANSFECTION WITH MIR-34A-5P MIMIC IN BEAS-2B CELLS ATTENUATED THE INHIBITORY EFFECT OF RES ON CELLULAR SENESCENCE, ACCOMPANIED BY REVERSING THE EXPRESSION OF SIRT1 AND NF-KAPPAB P65. IN CONCLUSION, RES ATTENUATED CSE-INDUCED CELLULAR SENESCENCE IN BEAS-2B CELLS BY REGULATING THE MIR-34A/SIRT1/NF-KAPPAB PATHWAY, WHICH MAY PROVIDE A NEW APPROACH FOR COPD TREATMENT. 2022 19 756 38 CARM1 REGULATES SENESCENCE DURING AIRWAY EPITHELIAL CELL INJURY IN COPD PATHOGENESIS. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS A LIFE-THREATENING LUNG DISEASE. ALTHOUGH CIGARETTE SMOKE WAS CONSIDERED THE MAIN CAUSE OF DEVELOPMENT, THE HETEROGENEOUS NATURE OF THE DISEASE LEAVES IT UNCLEAR WHETHER OTHER FACTORS CONTRIBUTE TO THE PREDISPOSITION OR IMPAIRED REGENERATION RESPONSE OBSERVED. RECENTLY, EPIGENETIC MODIFICATION HAS EMERGED TO BE A KEY PLAYER IN THE PATHOGENESIS OF COPD. THE ADDITION OF METHYL GROUPS TO ARGININE RESIDUES IN BOTH HISTONE AND NONHISTONE PROTEINS BY PROTEIN ARGININE METHYLTRANSFERASES (PRMTS) IS AN IMPORTANT POSTTRANSLATIONAL EPIGENETIC MODIFICATION EVENT REGULATING CELLULAR PROLIFERATION, DIFFERENTIATION, APOPTOSIS, AND SENESCENCE. HERE, WE HYPOTHESIZE THAT COACTIVATOR-ASSOCIATED ARGININE METHYLTRANSFERASE-1 (CARM1) REGULATES AIRWAY EPITHELIAL CELL INJURY IN COPD PATHOGENESIS BY CONTROLLING CELLULAR SENESCENCE. USING THE NAPHTHALENE (NA)-INDUCED MOUSE MODEL OF AIRWAY EPITHELIAL DAMAGE, WE DEMONSTRATE THAT LOSS OF CC10-POSITIVE CLUB CELLS IS ACCOMPANIED BY A REDUCTION IN CARM1-EXPRESSING CELLS OF THE AIRWAY EPITHELIUM. FURTHERMORE, CARM1 HAPLOINSUFFFICENT MICE SHOWED PERTURBED CLUB CELL REGENERATION FOLLOWING NA TREATMENT. IN ADDITION, CARM1 REDUCTION LED TO DECREASED NUMBERS OF ANTISENESCENT SIRTUIN 1-EXPRESSING CELLS ACCOMPANIED BY HIGHER P21, P16, AND BETA-GALACTOSIDASE-POSITIVE SENESCENT CELLS IN THE MOUSE AIRWAY FOLLOWING NA TREATMENT. IMPORTANTLY, CARM1-SILENCED HUMAN BRONCHIAL EPITHELIAL CELLS SHOWED IMPAIRED WOUND HEALING AND HIGHER BETA-GALACTOSIDASE ACTIVITY. THESE RESULTS DEMONSTRATE THAT CARM1 CONTRIBUTES TO AIRWAY REPAIR AND REGENERATION BY REGULATING AIRWAY EPITHELIAL CELL SENESCENCE. 2019 20 4658 30 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