1 5946 124 TARGETING THE EPIGENOME IN THE TREATMENT OF ASTHMA AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE. EPIGENETIC MODIFICATION OF GENE EXPRESSION BY METHYLATION OF DNA AND VARIOUS POST-TRANSLATIONAL MODIFICATIONS OF HISTONES MAY AFFECT THE EXPRESSION OF MULTIPLE INFLAMMATORY GENES. ACETYLATION OF HISTONES BY HISTONE ACETYLTRANSFERASES ACTIVATES INFLAMMATORY GENES, WHEREAS HISTONE DEACETYLATION RESULTS IN INFLAMMATORY GENE REPRESSION. CORTICOSTEROIDS EXERT THEIR ANTIINFLAMMATORY EFFECTS PARTLY BY INDUCING ACETYLATION OF ANTIINFLAMMATORY GENES, BUT MAINLY BY RECRUITING HISTONE DEACETYLASE-2 (HDAC2) TO ACTIVATED INFLAMMATORY GENES. HDAC2 DEACETYLATES ACETYLATED GLUCOCORTICOID RECEPTORS SO THAT THEY CAN SUPPRESS ACTIVATED INFLAMMATORY GENES IN ASTHMA. IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD), THERE IS RESISTANCE TO THE ANTIINFLAMMATORY ACTIONS OF CORTICOSTEROIDS, WHICH IS EXPLAINED BY REDUCED ACTIVITY AND EXPRESSION OF HDAC2. THIS CAN BE REVERSED BY A PLASMID VECTOR, WHICH RESTORES HDAC2 LEVELS, BUT MAY ALSO BE ACHIEVED BY LOW CONCENTRATIONS OF THEOPHYLLINE. OXIDATIVE STRESS CAUSES CORTICOSTEROID RESISTANCE BY REDUCING HDAC2 ACTIVITY AND EXPRESSION BY ACTIVATION OF PHOSPHOINOSITIDE-3-KINASE-DELTA, RESULTING IN HDAC2 PHOSPHORYLATION VIA A CASCADE OF KINASES. THEOPHYLLINE REVERSES CORTICOSTEROID RESISTANCE BY DIRECTLY INHIBITING OXIDANT-ACTIVATED PI3KDELTA AND IS MIMICKED BY PI3KDELTA KNOCKOUT OR BY SELECTIVE INHIBITORS. OTHER TREATMENTS MAY ALSO INTERACT IN THIS PATHWAY, MAKING IT POSSIBLE TO REVERSE CORTICOSTEROID RESISTANCE IN PATIENTS WITH COPD, AS WELL AS IN SMOKERS WITH ASTHMA AND SOME PATIENTS WITH SEVERE ASTHMA IN WHOM SIMILAR MECHANISMS OPERATE. OTHER HISTONE MODIFICATIONS, INCLUDING METHYLATION, TYROSINE NITRATION, AND UBIQUITINATION MAY ALSO AFFECT HISTONE FUNCTION AND INFLAMMATORY GENE EXPRESSION, AND BETTER UNDERSTANDING OF THESE EPIGENETIC PATHWAYS COULD LED TO NOVEL ANTIINFLAMMATORY THERAPIES, PARTICULARLY IN CORTICOSTEROID-RESISTANT INFLAMMATION. 2009 2 973 28 CHRONIC OBSTRUCTIVE PULMONARY DISEASE: AN UPDATE ON NUCLEAR SIGNALING RELATED TO INFLAMMATION AND ANTI-INFLAMMATORY TREATMENT. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS ONE OF THE MOST FREQUENT DISEASES WORLDWIDE. CIGARETTE SMOKE IS CONSIDERED THE MAIN PATHOLOGICAL CAUSE OF THE DISORDER, ALTHOUGH EVIDENCE IS GROWING CONCERNING OTHER ETIOLOGICAL FACTORS, SUCH AS ENVIRONMENTAL POLLUTION, BIOMASS COMBUSTION, INFECTIONS, GENETIC PREDISPOSITION, WHICH MAY EXPLAIN WHY SOME INDIVIDUALS DEVELOP COPD WITH NO HISTORY OF SMOKING. CHRONIC INFLAMMATION AND REMODELING OF THE SMALL AIRWAYS CHARACTERIZE THE DISEASE AT THE CELLULAR LEVEL, AND OXIDATIVE STRESS IS CONSIDERED THE MAIN DRIVING FORCE THAT STANDS BEHIND COPD INFLAMMATION. RECENTLY, CHROMATIN REMODELING AND EPIGENETIC CHANGES HAVE BEEN FOUND TO UNDERLIE DISEASE PATHOLOGY AND PROGRESSION. IN THIS REVIEW, THE AUTHORS GAVE A SHORT UPDATE ON THE RECENT HYPOTHESIS AND FINDINGS THAT MAY IMPLY NOVEL APPROACH TO PHARMACOTHERAPY OF THE DISEASE, FOCUSING ON THE ROLE OF GLUCOCORTICOSTEROIDS, THEOPHYLLINE, AND ANTIOXIDANTS. 2008 3 1753 35 EARLY LIFE STRESS TRIGGERS SUSTAINED CHANGES IN HISTONE DEACETYLASE EXPRESSION AND HISTONE H4 MODIFICATIONS THAT ALTER RESPONSIVENESS TO ADOLESCENT ANTIDEPRESSANT TREATMENT. EARLY LIFE STRESS CAN ELICIT LONG-LASTING CHANGES IN GENE EXPRESSION AND BEHAVIOR. RECENT STUDIES ON RODENTS SUGGEST THAT THESE LASTING EFFECTS DEPEND ON THE GENETIC BACKGROUND. WHETHER EPIGENETIC FACTORS ALSO PLAY A ROLE REMAINS TO BE INVESTIGATED. HERE WE EXPOSED THE STRESS-SUSCEPTIBLE MOUSE STRAIN BALB/C AND THE MORE RESILIENT STRAIN C57BL/6 TO A POWERFUL EARLY LIFE STRESS PARADIGM, INFANT MATERNAL SEPARATION. IN BALB/C MICE, INFANT MATERNAL SEPARATION LED TO DECREASED EXPRESSION OF MRNA ENCODING THE HISTONE DEACETYLASES (HDACS) 1, 3, 7, 8, AND 10 IN THE FOREBRAIN NEOCORTEX IN ADULTHOOD, AN EFFECT ACCOMPANIED BY INCREASED EXPRESSION OF ACETYLATED HISTONE H4 PROTEINS, ESPECIALLY ACETYLATED H4K12 PROTEIN. THESE CHANGES IN HDAC EXPRESSION AND HISTONE MODIFICATIONS WERE NOT DETECTED IN C57BL/6 MICE EXPOSED TO EARLY LIFE STRESS. MOREOVER, A REVERSAL OF THE H4K12 HYPERACETYLATION DETECTED IN INFANT MATERNALLY SEPARATED BALB/C MICE (ACHIEVED WITH CHRONIC ADOLESCENT TREATMENT WITH A LOW DOSE OF THEOPHYLLINE THAT ONLY ACTIVATES HDACS) WORSENED THE ABNORMAL EMOTIONAL PHENOTYPE RESULTING FROM THIS EARLY LIFE STRESS EXPOSURE. IN CONTRAST, FLUOXETINE, A DRUG WITH POTENT ANTIDEPRESSANT EFFICACY IN INFANT MATERNALLY SEPARATED BALB/C MICE, POTENTIATED ALL HISTONE MODIFICATIONS TRIGGERED BY EARLY LIFE STRESS. MOREOVER, IN NON-STRESSED BALB/C MICE, CO-ADMINISTRATION OF AN HDAC INHIBITOR AND FLUOXETINE, BUT NOT FLUOXETINE ALONE, ELICITED ANTIDEPRESSANT EFFECTS AND ALSO TRIGGERED CHANGES IN HISTONE H4 EXPRESSION THAT WERE SIMILAR TO THOSE PROVOKED BY FLUOXETINE TREATMENT OF MICE EXPOSED TO EARLY LIFE STRESS. THESE RESULTS SUGGEST THAT BALB/C MICE DEVELOP EPIGENETIC MODIFICATIONS AFTER EARLY LIFE STRESS EXPOSURE THAT, IN TERMS OF THE EMOTIVE PHENOTYPE, ARE OF ADAPTIVE NATURE, AND THAT ENHANCE THE EFFICACY OF ANTIDEPRESSANT DRUGS. 2012 4 4704 37 NITRATION OF DISTINCT TYROSINE RESIDUES CAUSES INACTIVATION OF HISTONE DEACETYLASE 2. HISTONE DEACETYLASES (HDACS) ARE KEY MOLECULES INVOLVED IN EPIGENETIC REGULATION OF GENE EXPRESSION. WE HAVE PREVIOUSLY DEMONSTRATED THAT OXIDATIVE STRESS CAUSED A REDUCTION IN HDAC2, RESULTING IN AMPLIFIED INFLAMMATION AND REDUCED CORTICOSTEROID RESPONSIVENESS. HERE WE SHOWED NITRATIVE/OXIDATIVE STRESS REDUCED HDAC2 EXPRESSION VIA NITRATION OF DISTINCT TYROSINE RESIDUES. PEROXYNITRITE, HYDROGEN PEROXIDE AND CIGARETTE SMOKE-CONDITIONED MEDIUM REDUCED HDAC2 EXPRESSION IN A549 EPITHELIAL CELLS IN VITRO. THIS REDUCTION WAS DUE TO INCREASED PROTEASOMAL DEGRADATION FOLLOWING UBIQUITINATION RATHER THAN REDUCTION OF MRNA EXPRESSION OR STABILITY. HDAC2 WAS NITRATED UNDER NITRATIVE/OXIDATIVE STRESS AND IN THE PERIPHERAL LUNG TISSUES OF SMOKERS AND PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE. MUTAGENESIS STUDIES REPLACING TYROSINE (Y) RESIDUES WITH ALANINE REVEALED THAT Y253 IS AT LEAST PARTLY RESPONSIBLE FOR THE PROTEASOMAL DEGRADATION OF HDAC2 UNDER NITRATIVE STRESS. THUS, NITRATION OF DISTINCT TYROSINE RESIDUES MODIFIES BOTH THE EXPRESSION AND ACTIVITY OF HDAC2, HAVING AN IMPACT ON EPIGENETIC REGULATION. 2009 5 4135 27 MECHANISMS OF LUNG DAMAGE AND DEVELOPMENT OF COPD DUE TO HOUSEHOLD BIOMASS-SMOKE EXPOSURE: INFLAMMATION, OXIDATIVE STRESS, MICRORNAS, AND GENE POLYMORPHISMS. CHRONIC EXPOSURE TO INDOOR BIOMASS SMOKE FROM THE COMBUSTION OF SOLID ORGANIC FUELS IS A MAJOR CAUSE OF DISEASE BURDEN WORLDWIDE. ALMOST 3 BILLION PEOPLE USE SOLID FUELS SUCH AS WOOD, CHARCOAL, AND CROP RESIDUES FOR INDOOR COOKING AND HEATING, ACCOUNTING FOR APPROXIMATELY 50% OF ALL HOUSEHOLDS AND 90% OF RURAL HOUSEHOLDS GLOBALLY. BIOMASS SMOKE CONTAINS MANY HAZARDOUS POLLUTANTS, RESULTING IN HOUSEHOLD AIR POLLUTION (HAP) EXPOSURE THAT OFTEN EXCEEDS INTERNATIONAL STANDARDS. LONG-TERM BIOMASS-SMOKE EXPOSURE IS ASSOCIATED WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IN ADULTS, A LEADING CAUSE OF MORBIDITY AND MORTALITY WORLDWIDE, CHRONIC BRONCHITIS, AND OTHER LUNG CONDITIONS. BIOMASS SMOKE-ASSOCIATED COPD DIFFERS FROM THE BEST-KNOWN CIGARETTE SMOKE-INDUCED COPD IN SEVERAL ASPECTS, SUCH AS A SLOWER DECLINE IN LUNG FUNCTION, GREATER AIRWAY INVOLVEMENT, AND LESS EMPHYSEMA, WHICH SUGGESTS A DIFFERENT PHENOTYPE AND PATHOPHYSIOLOGY. DESPITE THE HIGH BURDEN OF BIOMASS-ASSOCIATED COPD, THE MOLECULAR, GENETIC, AND EPIGENETIC MECHANISMS UNDERLYING ITS PATHOGENESIS ARE POORLY UNDERSTOOD. THIS REVIEW DESCRIBES THE PATHOGENIC MECHANISMS POTENTIALLY INVOLVED IN LUNG DAMAGE, THE DEVELOPMENT OF COPD ASSOCIATED WITH WOOD-DERIVED SMOKE EXPOSURE, AND THE INFLUENCE OF GENETIC AND EPIGENETIC FACTORS ON THE DEVELOPMENT OF THIS DISEASE. 2022 6 2737 29 EXPOSING A DEADLY ALLIANCE: NOVEL INSIGHTS INTO THE BIOLOGICAL LINKS BETWEEN COPD AND LUNG CANCER. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) AFFECTS MORE THAN 200 MILLION PEOPLE WORLDWIDE AND IS EXPECTED TO BECOME THE THIRD LEADING CAUSE OF DEATH IN 2020. COPD IS CHARACTERIZED BY PROGRESSIVE AIRFLOW LIMITATION, DUE TO A COMBINATION OF CHRONIC INFLAMMATION AND REMODELING OF THE SMALL AIRWAYS (BRONCHIOLITIS) AND LOSS OF ELASTIC RECOIL CAUSED BY DESTRUCTION OF THE ALVEOLAR WALLS (EMPHYSEMA). LUNG CANCER IS THE MOST IMPORTANT CAUSE OF CANCER-RELATED DEATH IN THE WORLD. (CIGARETTE) SMOKING IS THE PRINCIPAL CULPRIT CAUSING BOTH COPD AND LUNG CANCER; IN ADDITION, EXPOSURE TO ENVIRONMENTAL TOBACCO SMOKE, BIOMASS FUEL SMOKE, COAL SMOKE AND OUTDOOR AIR POLLUTION HAVE ALSO BEEN ASSOCIATED WITH AN INCREASED INCIDENCE OF BOTH DISEASES. IMPORTANTLY, SMOKERS WITH COPD--DEFINED AS EITHER NOT FULLY REVERSIBLE AIRFLOW LIMITATION OR EMPHYSEMA--HAVE A TWO- TO FOUR-FOLD INCREASED RISK TO DEVELOP LUNG CANCER. IN THIS REVIEW, WE HIGHLIGHT SEVERAL OF THE GENETIC, EPIGENETIC AND INFLAMMATORY MECHANISMS, WHICH LINK COPD AND CARCINOGENESIS IN THE LUNGS. ELUCIDATING THE BIOLOGICAL PATHWAYS AND NETWORKS, WHICH UNDERLIE THE INCREASED SUSCEPTIBILITY OF LUNG CANCER IN PATIENTS WITH COPD, HAS IMPORTANT IMPLICATIONS FOR SCREENING, PREVENTION, DIAGNOSIS AND TREATMENT OF THESE TWO DEVASTATING PULMONARY DISEASES. 2013 7 1251 35 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 8 4954 23 PATHOGENESIS OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE. THE PATHOGENESIS OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) ENCOMPASSES A NUMBER OF INJURIOUS PROCESSES, INCLUDING AN ABNORMAL INFLAMMATORY RESPONSE IN THE LUNGS TO INHALED PARTICLES AND GASES. OTHER PROCESSES, SUCH AS FAILURE TO RESOLVE INFLAMMATION, ABNORMAL CELL REPAIR, APOPTOSIS, ABNORMAL CELLULAR MAINTENANCE PROGRAMS, EXTRACELLULAR MATRIX DESTRUCTION (PROTEASE/ANTIPROTEASE IMBALANCE), AND OXIDATIVE STRESS (OXIDANT/ANTIOXIDANT IMBALANCE) ALSO HAVE A ROLE. THE INFLAMMATORY RESPONSES TO THE INHALATION OF ACTIVE AND PASSIVE TOBACCO SMOKE AND URBAN AND RURAL AIR POLLUTION ARE MODIFIED BY GENETIC AND EPIGENETIC FACTORS. THE SUBSEQUENT CHRONIC INFLAMMATORY RESPONSES LEAD TO MUCUS HYPERSECRETION, AIRWAY REMODELING, AND ALVEOLAR DESTRUCTION. THIS ARTICLE PROVIDES AN UPDATE ON THE CELLULAR AND MOLECULAR MECHANISMS OF THESE PROCESSES IN THE PATHOGENESIS OF COPD. 2007 9 4889 50 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 10 6285 37 THE POTENTIAL OF LIPID-POLYMER NANOPARTICLES AS EPIGENETIC AND ROS CONTROL APPROACHES FOR COPD. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS A LUNG DISEASE CAUSED BY AN INFLAMMATORY RESPONSE TO VARIOUS INHALED TOXINS, ESPECIALLY CIGARETTE SMOKE. REACTIVE OXYGEN SPECIES (ROS) AND EPIGENETIC ABNORMALITY ARE INTIMATELY RELATED TO THE PATHOLOGY OF COPD, AND THE OVERPRODUCTION OF ROS RESULTS IN A DECREASE OF HISTONE DEACETYLASE 2 (HDAC2), LEADING TO GLUCOCORTICOID RESISTANCE. THEREFORE, A NOVEL TREATMENT THAT SIMULTANEOUSLY REDUCES ROS LEVEL AND GLUCOCORTICOID RESISTANCE IS URGENTLY NEEDED. IN THIS STUDY, WE DEVELOPED A CODELIVERY SYSTEM USING CORE-SHELL TYPE LIPID-POLYMER NANOPARTICLES (LPNS) COMPOSED OF A POLY(LACTIC ACID) (PLA) CORE ENCAPSULATING A POTENT ANTIOXIDANT MN-PORPHYRIN DIMER (MNPD) AND A CATIONIC LIPID (DOTAP) SHELL THAT BINDS HDAC2-ENCODING PLASMID DNA (PHDAC2), AS A NEW THERAPEUTIC APPROACH TOWARD COPD. THE TRANSFECTION OF PHDAC2 COMBINED WITH THE ELIMINATION OF ROS BY MNPD EXHIBITED A SIGNIFICANT ENHANCEMENT OF INTRACELLULAR HDAC2 EXPRESSION LEVELS, SUGGESTING THAT THE MULTI-ANTIOXIDATIVE ACTIVITY OF MNPD PLAYS A CRUCIAL ROLE IN THE EXPRESSION OF HDAC2. MOREOVER, TREATMENT WITH LPNS EFFICIENTLY AMELIORATED THE STEROID RESISTANCE IN COPD MODELS IN VITRO AS EVIDENCED BY THE LOWERED EXPRESSION LEVELS OF IL-8. RECOVERY FROM MITOCHONDRIAL DYSFUNCTION MAY BE THE MECHANISM UNDERLYING THE ACTION OF LPNS. THE PLA-MNPD/DOTAP/PHDAC2 SYSTEM PROPOSED OFFERS A NEW THERAPEUTIC APPROACH FOR COPD BASED ON THE SYNERGISM OF ROS ELIMINATION AND HDAC2 EXPRESSION. 2020 11 6440 26 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 12 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 13 2212 38 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 14 1244 34 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 15 1259 30 CURRENT VIEWS IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE PATHOGENESIS AND MANAGEMENT. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS A PROGRESSIVE LUNG DYSFUNCTION CAUSED MAINLY BY INHALING TOXIC PARTICLES AND CIGARETTE SMOKING (CS). THE CONTINUOUS EXPOSURE TO RUINOUS MOLECULES CAN LEAD TO ABNORMAL INFLAMMATORY RESPONSES, PERMANENT DAMAGES TO THE RESPIRATORY SYSTEM, AND IRREVERSIBLE PATHOLOGICAL CHANGES. OTHER FACTORS, SUCH AS GENETICS AND AGING, INFLUENCE THE DEVELOPMENT OF COPD. IN THE LAST DECADE, ACCUMULATING EVIDENCE SUGGESTED THAT MITOCHONDRIAL ALTERATION, INCLUDING MITOCHONDRIAL DNA DAMAGE, INCREASED MITOCHONDRIAL REACTIVE OXYGEN SPECIES (ROS), ABNORMAL AUTOPHAGY, AND APOPTOSIS, HAVE BEEN IMPLICATED IN THE PATHOGENESIS OF COPD. THE ALTERATION CAN ALSO EXTEND TO EPIGENETICS, NAMELY DNA METHYLATION, HISTONE MODIFICATION, AND NON-CODING RNA. THIS REVIEW WILL DISCUSS THE RECENT PROGRESSIONS IN COPD PATHOLOGY, PATHOPHYSIOLOGY, AND MOLECULAR PATHWAYS. MORE FOCUS WILL BE SHED ON MITOCHONDRIAL AND EPIGENETIC VARIATIONS RELATED TO COPD DEVELOPMENT AND THE ROLE OF NANOMEDICINE AS A POTENTIAL TOOL FOR THE PREVENTION AND TREATMENT OF THIS DISEASE. 2021 16 6799 27 [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 17 1012 35 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 18 5560 38 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 19 6915 20 [VULNERABILITY OF WOMEN TO TOBACCO: THE BRONCHO-PULMONARY CONSEQUENCES (ASTHMA, COPD)]. SMOKING REMAINS COMMON, WITH AN EXPOSURE THAT BEGINS EARLY DURING PREGNANCY. IT INDUCES EPIGENETIC CHANGES, WITH A TRANS-GENERATIONAL TRANSMISSION. SMOKING INCREASES THE RISK OF UNCONTROLLED ASTHMA DURING CHILDHOOD AND ADULT LIFE. ASTHMA IS ALSO ASSOCIATED WITH INCREASED RISK OF A DECLINE OF LUNG FUNCTION AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). WOMEN ARE MORE AT RISK OF DEVELOPING EARLY AND SEVERE COPD. THE MECHANISMS ARE CURRENTLY POORLY KNOWN. 2019 20 2161 41 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