1 2737 126 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 2 1245 41 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 3 927 53 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 4 6440 34 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 5 1143 40 CONCISE REVIEW: CLINICAL PROSPECTS FOR TREATING CHRONIC OBSTRUCTIVE PULMONARY DISEASE WITH REGENERATIVE APPROACHES. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS BECOMING A MAJOR CAUSE OF DEATH WORLDWIDE. COPD IS CHARACTERIZED BY A PROGRESSIVE AND NOT FULLY REVERSIBLE AIRFLOW LIMITATION CAUSED BY CHRONIC SMALL AIRWAY DISEASE AND LUNG PARENCHYMAL DESTRUCTION. CLINICALLY AVAILABLE DRUGS IMPROVE AIRFLOW OBSTRUCTION AND RESPIRATORY SYMPTOMS BUT CANNOT CURE THE DISEASE. SLOWING THE PROGRESSIVE LUNG DESTRUCTION OR REBUILDING THE DESTROYED LUNG STRUCTURE IS A PROMISING STRATEGY TO CURE COPD. IN CONTRAST TO SMALL ANIMAL MODELS, PHARMACOLOGICAL LUNG REGENERATION IS DIFFICULT IN HUMAN COPD. MATURATION, AGING, AND SENESCENCE IN COPD LUNG CELLS, INCLUDING ENDOGENOUS STEM CELLS, MAY AFFECT THE REGENERATIVE CAPACITY FOLLOWING PHARMACOLOGICAL THERAPY. THE LUNG IS A COMPLEX ORGAN COMPOSED OF MORE THAN 40 DIFFERENT CELL TYPES; THEREFORE, DETAILED ANALYSES, SUCH AS EPIGENETIC MODIFICATION ANALYSIS, IN EACH SPECIFIC CELL TYPE HAVE NOT BEEN PERFORMED IN LUNGS WITH COPD. RECENTLY, A METHOD FOR THE DIRECT ISOLATION OF INDIVIDUAL CELL TYPES FROM HUMAN LUNG HAS BEEN DEVELOPED, AND FINGERPRINTS OF EACH CELL TYPE IN COPD LUNGS CAN BE ANALYZED. RESEARCH USING THIS TECHNIQUE COMBINED WITH THE RECENTLY DISCOVERED LUNG ENDOGENOUS STEM-PROGENITOR POPULATIONS WILL GIVE A BETTER UNDERSTANDING ABOUT THE FATE OF COPD LUNG CELLS AND PROVIDE A FUTURE FOR CELL-BASED THERAPY TO TREAT THIS INTRACTABLE DISEASE. 2012 6 6330 36 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 7 4954 30 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 8 970 34 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 9 5916 38 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 37 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 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 12 3966 43 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 13 2169 31 EPIGENETIC MECHANISMS IN PARENCHYMAL LUNG DISEASES: BYSTANDERS OR THERAPEUTIC TARGETS? EPIGENETIC RESPONSES DUE TO ENVIRONMENTAL CHANGES ALTER CHROMATIN STRUCTURE, WHICH IN TURN MODIFIES THE PHENOTYPE, GENE EXPRESSION PROFILE, AND ACTIVITY OF EACH CELL TYPE THAT HAS A ROLE IN THE PATHOPHYSIOLOGY OF A DISEASE. PULMONARY DISEASES ARE ONE OF THE MAJOR CAUSES OF DEATH IN THE WORLD, INCLUDING LUNG CANCER, IDIOPATHIC PULMONARY FIBROSIS (IPF), CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD), PULMONARY HYPERTENSION (PH), LUNG TUBERCULOSIS, PULMONARY EMBOLISM, AND ASTHMA. SEVERAL LINES OF EVIDENCE INDICATE THAT EPIGENETIC MODIFICATIONS MAY BE ONE OF THE MAIN FACTORS TO EXPLAIN THE INCREASING INCIDENCE AND PREVALENCE OF LUNG DISEASES INCLUDING IPF AND COPD. INTERESTINGLY, ISOLATED FIBROBLASTS AND SMOOTH MUSCLE CELLS FROM PATIENTS WITH PULMONARY DISEASES SUCH AS IPF AND PH THAT WERE CULTURED EX VIVO MAINTAINED THE DISEASE PHENOTYPE. THE CELLS OFTEN SHOW A HYPER-PROLIFERATIVE, APOPTOSIS-RESISTANT PHENOTYPE WITH INCREASED EXPRESSION OF EXTRACELLULAR MATRIX (ECM) AND ACTIVATED FOCAL ADHESIONS SUGGESTING THE PRESENCE OF AN EPIGENETICALLY IMPRINTED PHENOTYPE. MOREOVER, MANY ABNORMALITIES OBSERVED IN MOLECULAR PROCESSES IN IPF PATIENTS ARE SHOWN TO BE EPIGENETICALLY REGULATED, SUCH AS INNATE IMMUNITY, CELLULAR SENESCENCE, AND APOPTOTIC CELL DEATH. DNA METHYLATION, HISTONE MODIFICATION, AND MICRORNA REGULATION CONSTITUTE THE MOST COMMON EPIGENETIC MODIFICATION MECHANISMS. 2022 14 3543 33 IMMUNOLOGY, GENETICS AND MICROBIOTA IN THE COPD PATHOPHYSIOLOGY: POTENTIAL SCOPE FOR PATIENT STRATIFICATION. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS CHARACTERIZED BY SUSTAINED INFLAMMATION OF THE AIRWAYS, LEADING TO DESTRUCTION OF LUNG TISSUE AND DECLINING PULMONARY FUNCTION. ALTHOUGH SMOKING IS THE MOST OBVIOUS RISK FACTOR FOR COPD, ONLY ABOUT 20% OF SMOKERS DEVELOP COPD AND SMOKING CESSATION DOES NOT REVERSE PROGRESSION OF COPD, INDICATING THAT WHILE SMOKING IS AN IMPORTANT CAUSE OR INITIATING FACTOR, IT IS NOT THE ONLY DRIVER OF ONGOING CHRONIC INFLAMMATION AND DISEASE PROGRESSION IN COPD PATIENTS. WE HYPOTHESIZE THAT SMOKING-INDUCED CHANGES IN LUNG MICROBIOTA, EPITHELIAL INTEGRITY AND EPIGENETIC CONTROL OF GENE EXPRESSION RESULT IN AUTOANTIGEN INDUCTION AND PERTURBED IMMUNE REGULATION IN GENETICALLY VUNERABLE INDIVIDUALS. IN OUR VIEW, COPD PATIENTS MAY BE STRATIFIED ACCORDING TO THEIR IMMUNOLOGICAL AND INFLAMMATORY STATUS RELATED TO SPECIFIC CHANGES IN THE LUNG MICROBIOTA (INNATE AND ADAPTIVE IMMUNITY), PRESENCE OF AUTOANTIGENS (ADAPTIVE IMMUNITY: TH1-B-CELL AXIS) AND EPIGENETIC MODIFICATIONS (INFLAMMATION AND STRUCTURAL CHANGES). 2015 15 5422 41 REGULATION OF LUNG EPITHELIAL CELL SENESCENCE IN SMOKING-INDUCED COPD/EMPHYSEMA BY MICROR-125A-5P VIA SP1 MEDIATION OF SIRT1/HIF-1A. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) AFFECTS THE HEALTH OF MORE THAN 300 MILLION PEOPLE WORLDWIDE; AT PRESENT, THERE IS NO EFFECTIVE DRUG TO TREAT COPD. SMOKING IS THE MOST IMPORTANT RISK FACTOR, BUT THE MOLECULAR MECHANISM BY WHICH SMOKING CAUSES THE DISEASE IS UNCLEAR. THE SENESCENCE OF LUNG EPITHELIAL CELLS IS RELATED TO DEVELOPMENT OF COPD. REGULATION OF MIRNAS IS THE MAIN EPIGENETIC MECHANISM RELATED TO AGING. BETA-GALACTOSE STAINING SHOWED THAT THE LUNG TISSUES OF SMOKERS HAVE A HIGHER DEGREE OF CELLULAR SENESCENCE, AND THE EXPRESSION OF MIR-125A-5P IS HIGH. THIS EFFECT IS OBVIOUS FOR SMOKERS WITH COPD/EMPHYSEMA, AND THERE IS A NEGATIVE CORRELATION BETWEEN MIR-125A-5P LEVELS AND VALUES FOR FORCED EXPIRATORY VOLUME IN ONE SECOND (FEV1)/FORCED VITAL CAPACITY (FVC). AFTER BALB/C MICE WERE CHRONICALLY EXPOSED TO VARIOUS CONCENTRATIONS OF CIGARETTE SMOKE (CS), PLETHYSMOGRAPHY SHOWED THAT LUNG FUNCTION WAS IMPAIRED, LUNG TISSUE SENESCENCE WAS INCREASED, AND THE SENESCENCE-ASSOCIATED SECRETORY PHENOTYPE (SASP) IN BRONCHOALVEOLAR LAVAGE FLUID WAS INCREASED. FOR MOUSE LUNG EPITHELIAL (MLE)-12 CELLS TREATED WITH CIGARETTE SMOKE EXTRACT (CSE), SP1 AND SIRT1 LEVELS WERE LOW, HIF-1ALPHA ACETYLATION LEVELS WERE HIGH, AND CELL SENESCENCE AND SECRETION OF SASP FACTORS WERE ELEVATED. DOWN-REGULATION OF MIR-125A-5P OR UP-REGULATION OF SP1 REVERSED THESE EFFECTS. IN ADDITION, COMPARED WITH MICE EXPOSED TO CS, KNOCKDOWN OF MIR-125A-5P REDUCED LUNG EPITHELIAL CELL SENESCENCE AND COPD/EMPHYSEMA. THEREFORE, IN SMOKING-INDUCED COPD, ELEVATED MIR-125A-5P PARTICIPATES IN THE SENESCENCE OF LUNG EPITHELIAL CELLS THROUGH SP1/SIRT1/HIF-1ALPHA. THESE FINDINGS PROVIDE EVIDENCE RELATED TO THE PATHOGENESIS OF COPD/EMPHYSEMA CAUSED BY CHRONIC SMOKING. 2022 16 1539 28 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 17 4445 42 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 18 4450 42 MOLECULAR MECHANISMS AND CELLULAR CONTRIBUTION FROM LUNG FIBROSIS TO LUNG CANCER DEVELOPMENT. IDIOPATHIC PULMONARY FIBROSIS (IPF) IS A CHRONIC, PROGRESSIVE, FIBROSING INTERSTITIAL LUNG DISEASE (ILD) OF UNKNOWN AETIOLOGY, WITH A MEDIAN SURVIVAL OF 2-4 YEARS FROM THE TIME OF DIAGNOSIS. ALTHOUGH IPF HAS UNKNOWN AETIOLOGY BY DEFINITION, THERE HAVE BEEN IDENTIFIED SEVERAL RISKS FACTORS INCREASING THE PROBABILITY OF THE ONSET AND PROGRESSION OF THE DISEASE IN IPF PATIENTS SUCH AS CIGARETTE SMOKING AND ENVIRONMENTAL RISK FACTORS ASSOCIATED WITH DOMESTIC AND OCCUPATIONAL EXPOSURE. AMONG THEM, CIGARETTE SMOKING TOGETHER WITH CONCOMITANT EMPHYSEMA MIGHT PREDISPOSE IPF PATIENTS TO LUNG CANCER (LC), MOSTLY TO NON-SMALL CELL LUNG CANCER (NSCLC), INCREASING THE RISK OF LUNG CANCER DEVELOPMENT. TO THIS PURPOSE, IPF AND LC SHARE SEVERAL CELLULAR AND MOLECULAR PROCESSES DRIVING THE PROGRESSION OF BOTH PATHOLOGIES SUCH AS FIBROBLAST TRANSITION PROLIFERATION AND ACTIVATION, ENDOPLASMIC RETICULUM STRESS, OXIDATIVE STRESS, AND MANY GENETIC AND EPIGENETIC MARKERS THAT PREDISPOSE IPF PATIENTS TO LC DEVELOPMENT. NINTEDANIB, A TYROSINE-KINASE INHIBITOR, WAS FIRSTLY DEVELOPED AS AN ANTICANCER DRUG AND THEN RECOGNIZED AS AN ANTI-FIBROTIC AGENT BASED ON THE COMMON TARGET MOLECULAR PATHWAY. IN THIS REVIEW OUR AIM IS TO DESCRIBE THE UPDATED STUDIES ON COMMON CELLULAR AND MOLECULAR MECHANISMS BETWEEN IPF AND LUNG CANCER, KNOWLEDGE OF WHICH MIGHT HELP TO FIND NOVEL THERAPEUTIC TARGETS FOR THIS DISEASE COMBINATION. 2021 19 1551 37 DNA METHYLATION IS GLOBALLY DISRUPTED AND ASSOCIATED WITH EXPRESSION CHANGES IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE SMALL AIRWAYS. DNA METHYLATION IS AN EPIGENETIC MODIFICATION THAT IS HIGHLY DISRUPTED IN RESPONSE TO CIGARETTE SMOKE AND INVOLVED IN A WIDE SPECTRUM OF MALIGNANT AND NONMALIGNANT DISEASES, BUT SURPRISINGLY NOT PREVIOUSLY ASSESSED IN SMALL AIRWAYS OF PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). SMALL AIRWAYS ARE THE PRIMARY SITES OF AIRFLOW OBSTRUCTION IN COPD. WE SOUGHT TO DETERMINE WHETHER DNA METHYLATION PATTERNS ARE DISRUPTED IN SMALL AIRWAY EPITHELIA OF PATIENTS WITH COPD, AND EVALUATE WHETHER CHANGES IN GENE EXPRESSION ARE ASSOCIATED WITH THESE DISRUPTIONS. GENOME-WIDE METHYLATION AND GENE EXPRESSION ANALYSIS WERE PERFORMED ON SMALL AIRWAY EPITHELIAL DNA AND RNA OBTAINED FROM THE SAME PATIENT DURING BRONCHOSCOPY, USING ILLUMINA'S INFINIUM HM27 AND AFFYMETRIX'S GENECHIP HUMAN GENE 1.0 ST ARRAYS. TO CONTROL FOR KNOWN EFFECTS OF CIGARETTE SMOKING ON DNA METHYLATION, METHYLATION AND GENE EXPRESSION PROFILES WERE COMPARED BETWEEN FORMER SMOKERS WITH AND WITHOUT COPD MATCHED FOR AGE, PACK-YEARS, AND YEARS OF SMOKING CESSATION. OUR RESULTS INDICATE THAT ABERRANT DNA METHYLATION IS (1) A GENOME-WIDE PHENOMENON IN SMALL AIRWAYS OF PATIENTS WITH COPD, AND (2) ASSOCIATED WITH ALTERED EXPRESSION OF GENES AND PATHWAYS IMPORTANT TO COPD, SUCH AS THE NF-E2-RELATED FACTOR 2 OXIDATIVE RESPONSE PATHWAY. DNA METHYLATION IS LIKELY AN IMPORTANT MECHANISM CONTRIBUTING TO MODULATION OF GENES IMPORTANT TO COPD PATHOLOGY. BECAUSE THESE METHYLATION EVENTS MAY UNDERLIE DISEASE-SPECIFIC GENE EXPRESSION CHANGES, THEIR CHARACTERIZATION IS A CRITICAL FIRST STEP TOWARD THE DEVELOPMENT OF EPIGENETIC MARKERS AND AN OPPORTUNITY FOR DEVELOPING NOVEL EPIGENETIC THERAPEUTIC INTERVENTIONS FOR COPD. 2014 20 4026 26 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