1 305 110 AIRWAY WALL REMODELING IN CHILDHOOD ASTHMA-A PERSONALIZED PERSPECTIVE FROM CELL TYPE-SPECIFIC BIOLOGY. AIRWAY WALL REMODELING IS A PATHOLOGY OCCURRING IN CHRONIC INFLAMMATORY LUNG DISEASES INCLUDING ASTHMA, CHRONIC OBSTRUCTIVE PULMONARY DISEASE, AND FIBROSIS. IN 2017, THE AMERICAN THORACIC SOCIETY RELEASED A RESEARCH STATEMENT HIGHLIGHTING THE GAPS IN KNOWLEDGE AND UNDERSTANDING OF AIRWAY WALL REMODELING. THE FOUR MAJOR CHALLENGES ADDRESSED IN THIS STATEMENT WERE: (I) THE LACK OF CONSENSUS TO DEFINE "AIRWAY WALL REMODELING" IN DIFFERENT DISEASES, (II) METHODOLOGIC LIMITATIONS AND INAPPROPRIATE MODELS, (III) THE LACK OF ANTI-REMODELING THERAPIES, AND (IV) THE DIFFICULTY TO DEFINE ENDPOINTS AND OUTCOMES IN RELEVANT STUDIES. THIS REVIEW FOCUSES ON THE IMPORTANCE OF CELL-CELL INTERACTION, ESPECIALLY THE BRONCHIAL EPITHELIUM, IN ASTHMA-ASSOCIATED AIRWAY WALL REMODELING. THE PATHOLOGY OF "AIRWAY WALL REMODELING" SUMMARIZES ALL STRUCTURAL CHANGES OF THE AIRWAY WALL WITHOUT DIFFERENTIATING BETWEEN DIFFERENT PHENO- OR ENDO-TYPES OF ASTHMA. INDICATORS OF AIRWAY WALL REMODELING HAVE BEEN REPORTED IN CHILDHOOD ASTHMA IN THE ABSENCE OF ANY SIGN OF INFLAMMATION; THUS, THE INITIATION EVENT REMAINS UNKNOWN. RECENT STUDIES HAVE IMPLIED THAT THE INTERACTION BETWEEN THE EPITHELIUM WITH IMMUNE CELLS AND SUB-EPITHELIAL MESENCHYMAL CELLS IS MODIFIED IN ASTHMA BY A YET UNKNOWN EPIGENETIC MECHANISM DURING EARLY CHILDHOOD. 2021 2 6005 29 THE AIRWAY EPITHELIUM-A CENTRAL PLAYER IN ASTHMA PATHOGENESIS. ASTHMA IS A CHRONIC INFLAMMATORY AIRWAY DISEASE CHARACTERIZED BY VARIABLE AIRFLOW OBSTRUCTION IN RESPONSE TO A WIDE RANGE OF EXOGENOUS STIMULI. THE AIRWAY EPITHELIUM IS THE FIRST LINE OF DEFENSE AND PLAYS AN IMPORTANT ROLE IN INITIATING HOST DEFENSE AND CONTROLLING IMMUNE RESPONSES. INDEED, INCREASING EVIDENCE INDICATES A RANGE OF ABNORMALITIES IN VARIOUS ASPECTS OF EPITHELIAL BARRIER FUNCTION IN ASTHMA. A CENTRAL PART OF THIS IMPAIRMENT IS A DISRUPTION OF THE AIRWAY EPITHELIAL LAYER, ALLOWING INHALED SUBSTANCES TO PASS MORE EASILY INTO THE SUBMUCOSA WHERE THEY MAY INTERACT WITH IMMUNE CELLS. FURTHERMORE, MANY OF THE IDENTIFIED SUSCEPTIBILITY GENES FOR ASTHMA ARE EXPRESSED IN THE AIRWAY EPITHELIUM. THIS REVIEW FOCUSES ON THE BIOLOGY OF THE AIRWAY EPITHELIUM IN HEALTH AND ITS PATHOBIOLOGY IN ASTHMA. WE WILL SPECIFICALLY DISCUSS EXTERNAL TRIGGERS SUCH AS ALLERGENS, VIRUSES AND ALARMINS AND THE EFFECT OF TYPE 2 INFLAMMATORY RESPONSES ON AIRWAY EPITHELIAL FUNCTION IN ASTHMA. WE WILL ALSO DISCUSS EPIGENETIC MECHANISMS RESPONDING TO EXTERNAL STIMULI ON THE LEVEL OF TRANSCRIPTIONAL AND POSTTRANSCRIPTIONAL REGULATION OF GENE EXPRESSION, AS WELL THE AIRWAY EPITHELIUM AS A POTENTIAL TREATMENT TARGET IN ASTHMA. 2020 3 2330 28 EPIGENETIC REGULATION OF IMMUNE FUNCTION IN ASTHMA. ASTHMA IS A COMMON COMPLEX RESPIRATORY DISEASE CHARACTERIZED BY CHRONIC AIRWAY INFLAMMATION AND PARTIALLY REVERSIBLE AIRFLOW OBSTRUCTION RESULTING FROM GENETIC AND ENVIRONMENTAL DETERMINANTS. BECAUSE EPIGENETIC MARKS INFLUENCE GENE EXPRESSION AND CAN BE MODIFIED BY BOTH ENVIRONMENTAL EXPOSURES AND GENETIC VARIATION, THEY ARE INCREASINGLY RECOGNIZED AS RELEVANT TO THE PATHOGENESIS OF ASTHMA AND MAY BE A KEY LINK BETWEEN ENVIRONMENTAL EXPOSURES AND ASTHMA SUSCEPTIBILITY. UNLIKE CHANGES TO DNA SEQUENCE, EPIGENETIC SIGNATURES ARE DYNAMIC AND REVERSIBLE, CREATING AN OPPORTUNITY FOR NOT ONLY THERAPEUTIC TARGETS BUT MAY SERVE AS BIOMARKERS TO FOLLOW DISEASE COURSE AND IDENTIFY MOLECULAR SUBTYPES IN HETEROGENEOUS DISEASES SUCH AS ASTHMA. IN THIS REVIEW, WE WILL EXAMINE THE RELATIONSHIP BETWEEN ASTHMA AND 3 KEY EPIGENETIC PROCESSES THAT MODIFY GENE EXPRESSION: DNA METHYLATION, MODIFICATION OF HISTONE TAILS, AND NONCODING RNAS. IN ADDITION TO PRESENTING A COMPREHENSIVE ASSESSMENT OF THE EXISTING EPIGENETIC STUDIES FOCUSING ON IMMUNE REGULATION IN ASTHMA, WE WILL DISCUSS FUTURE DIRECTIONS FOR EPIGENETIC INVESTIGATION IN ALLERGIC AIRWAY DISEASE. 2022 4 2531 26 EPIGENETICS IN ASTHMA. PURPOSE OF REVIEW: ASTHMA IS ONE OF THE MOST COMMON CHRONIC RESPIRATORY DISEASES LINKED WITH INCREASED MORBIDITY AND HEALTHCARE UTILIZATION. THE UNDERLYING PATHOPHYSIOLOGICAL PROCESSES AND CAUSAL RELATIONSHIPS OF ASTHMA WITH EPIGENETIC MECHANISMS ARE PARTIALLY UNDERSTOOD. HERE WE REVIEW HUMAN STUDIES OF EPIGENETIC MECHANISMS IN ASTHMA, WITH A SPECIAL FOCUS ON DNA METHYLATION. RECENT FINDINGS: EPIGENETIC STUDIES OF CHILDHOOD ASTHMA HAVE IDENTIFIED SPECIFIC METHYLATION SIGNATURES ASSOCIATED WITH ALLERGIC INFLAMMATION IN THE AIRWAY AND IMMUNE CELLS, DEMONSTRATING A REGULATORY ROLE FOR METHYLATION IN ASTHMA PATHOGENESIS. DESPITE THESE NOVEL FINDINGS, ADDITIONAL RESEARCH IN THE ROLE OF EPIGENETIC MECHANISMS UNDERLYING ASTHMA ENDOTYPES IS NEEDED. SIMILARLY, STUDIES OF HISTONE MODIFICATIONS ARE ALSO LACKING IN ASTHMA. FUTURE STUDIES OF EPIGENETIC MECHANISMS IN ASTHMA WILL BENEFIT FROM DATA INTEGRATION IN WELL PHENOTYPED COHORTS. THIS REVIEW PROVIDES AN OVERVIEW OF THE CURRENT LITERATURE ON EPIGENETIC STUDIES IN HUMAN ASTHMA, WITH SPECIAL EMPHASIS ON METHYLATION AND CHILDHOOD ASTHMA. 2019 5 5534 33 ROLE OF AIRWAY EPITHELIAL CELLS IN THE DEVELOPMENT OF DIFFERENT ASTHMA PHENOTYPES. THE TERM (BRONCHIAL) ASTHMA DESCRIBES A DISORDER SYNDROME THAT COMPRISES SEVERAL DISEASE PHENOTYPES, ALL CHARACTERIZED BY CHRONIC INFLAMMATION IN THE BRONCHIAL EPITHELIUM, WITH A VARIETY OF SUBSEQUENT FUNCTIONAL CONSEQUENCES. THUS, THE EPITHELIUM IN THE CONDUCTING AIRWAYS IS THE MAIN LOCALIZATION OF THE COMPLEX PATHOLOGICAL CHANGES IN THE DISEASE. IN THIS REGARD, BRONCHIAL EPITHELIAL CELLS ARE NOT PASSIVELY AFFECTED BY INFLAMMATORY MECHANISMS INDUCED BY IMMUNOLOGICAL PROCESSES BUT RATHER ACTIVELY INVOLVED IN ALL STEPS OF DISEASE DEVELOPMENT FROM INITIATION AND PERPETUATION TO CHRONIFICATION. IN RECENT YEARS IT TURNED OUT THAT BRONCHIAL EPITHELIAL CELLS SHOW A HIGH LEVEL OF STRUCTURAL AND FUNCTIONAL DIVERSITY AND PLASTICITY WITH EPIGENETIC MECHANISMS PLAYING A CRUCIAL ROLE IN THE REGULATION OF THESE PROCESSES. THUS, IT IS QUITE REASONABLE THAT DIFFERENTIAL FUNCTIONAL ACTIVITIES OF THE BRONCHIAL EPITHELIUM ARE INVOLVED IN THE DEVELOPMENT OF DIFFERENT ASTHMA PHENOTYPES AND/OR STAGES OF DISEASE. THE CURRENT KNOWLEDGE ON THIS TOPIC WILL BE DISCUSSED IN THIS REVIEW ARTICLE. 2020 6 5472 34 RESPIRATORY VIRAL INFECTIONS IN EXACERBATION OF CHRONIC AIRWAY INFLAMMATORY DISEASES: NOVEL MECHANISMS AND INSIGHTS FROM THE UPPER AIRWAY EPITHELIUM. RESPIRATORY VIRUS INFECTION IS ONE OF THE MAJOR SOURCES OF EXACERBATION OF CHRONIC AIRWAY INFLAMMATORY DISEASES. THESE EXACERBATIONS ARE ASSOCIATED WITH HIGH MORBIDITY AND EVEN MORTALITY WORLDWIDE. THE CURRENT UNDERSTANDING ON VIRAL-INDUCED EXACERBATIONS IS THAT VIRAL INFECTION INCREASES AIRWAY INFLAMMATION WHICH AGGRAVATES DISEASE SYMPTOMS. RECENT ADVANCES IN IN VITRO AIR-LIQUID INTERFACE 3D CULTURES, ORGANOID CULTURES AND THE USE OF NOVEL HUMAN AND ANIMAL CHALLENGE MODELS HAVE EVOKED NEW UNDERSTANDINGS AS TO THE MECHANISMS OF VIRAL EXACERBATIONS. IN THIS REVIEW, WE WILL FOCUS ON RECENT NOVEL FINDINGS THAT ELUCIDATE HOW RESPIRATORY VIRAL INFECTIONS ALTER THE EPITHELIAL BARRIER IN THE AIRWAYS, THE UPPER AIRWAY MICROBIAL ENVIRONMENT, EPIGENETIC MODIFICATIONS INCLUDING MIRNA MODULATION, AND OTHER CHANGES IN IMMUNE RESPONSES THROUGHOUT THE UPPER AND LOWER AIRWAYS. FIRST, WE REVIEWED THE PREVALENCE OF DIFFERENT RESPIRATORY VIRAL INFECTIONS IN CAUSING EXACERBATIONS IN CHRONIC AIRWAY INFLAMMATORY DISEASES. SUBSEQUENTLY WE ALSO SUMMARIZED HOW RECENT MODELS HAVE EXPANDED OUR APPRECIATION OF THE MECHANISMS OF VIRAL-INDUCED EXACERBATIONS. FURTHER WE HIGHLIGHTED THE IMPORTANCE OF THE VIROME WITHIN THE AIRWAY MICROBIOME ENVIRONMENT AND ITS IMPACT ON SUBSEQUENT BACTERIAL INFECTION. THIS REVIEW CONSOLIDATES THE UNDERSTANDING OF VIRAL INDUCED EXACERBATION IN CHRONIC AIRWAY INFLAMMATORY DISEASES AND INDICATES PATHWAYS THAT MAY BE TARGETED FOR MORE EFFECTIVE MANAGEMENT OF CHRONIC INFLAMMATORY DISEASES. 2020 7 2775 32 EXTRACELLULAR VESICLES AND ASTHMA-MORE THAN JUST A CO-EXISTENCE. EXTRACELLULAR VESICLES (EVS) ARE MEMBRANOUS STRUCTURES, WHICH ARE SECRETED BY ALMOST EVERY CELL TYPE ANALYZED SO FAR. IN ADDITION TO THEIR IMPORTANCE FOR CELL-CELL COMMUNICATION UNDER PHYSIOLOGICAL CONDITIONS, EVS ARE ALSO RELEASED DURING PATHOGENESIS AND MECHANISTICALLY CONTRIBUTE TO THIS PROCESS. HERE WE SUMMARIZE THEIR FUNCTIONAL RELEVANCE IN ASTHMA, ONE OF THE MOST COMMON CHRONIC NON-COMMUNICABLE DISEASES. ASTHMA IS A COMPLEX PERSISTENT INFLAMMATORY DISORDER OF THE AIRWAYS CHARACTERIZED BY REVERSIBLE AIRFLOW OBSTRUCTION AND, FROM A LONG-TERM PERSPECTIVE, AIRWAY REMODELING. OVERALL, MECHANISTIC STUDIES SUMMARIZED HERE INDICATE THE IMPORTANCE OF DIFFERENT SUBTYPES OF EVS AND THEIR VARIABLE CARGOES IN THE FUNCTIONING OF THE PATHWAYS UNDERLYING ASTHMA, AND SHOW SOME INTERESTING POTENTIAL FOR THE DEVELOPMENT OF FUTURE THERAPEUTIC INTERVENTIONS. ASSOCIATION STUDIES IN TURN DEMONSTRATE A GOOD DIAGNOSTIC POTENTIAL OF EVS IN ASTHMA. 2021 8 3028 24 GENETICS OF COMPLEX AIRWAY DISEASE. THE PAST 3 YEARS HAVE SEEN HIGHLY SIGNIFICANT GENETIC EFFECTS IDENTIFIED FOR A WIDE VARIETY OF COMMON COMPLEX DISEASES, INCLUDING THE AIRWAY DISORDERS OF ASTHMA AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE. IT APPEARS THAT ONLY A PORTION OF THE GENETICALLY MEDIATED SUSCEPTIBILITY TO COMPLEX DISEASES HAS BEEN IDENTIFIED, AND THERE IS MUCH LEFT TO BE DISCOVERED. THIS REVIEW BRIEFLY DESCRIBES THE RESULTS OF THE GENOME-WIDE ASSOCIATION STUDIES OF ASTHMA AND GIVES AN OVERVIEW OF THE PARALLEL AND INCREASINGLY LARGE-SCALE STUDIES THAT ARE TAKING PLACE WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE. THE FUTURE IMPACT IS DISCUSSED OF TECHNOLOGICAL ADVANCES THAT ALLOW INCREASINGLY LARGE-SCALE GENE EXPRESSION STUDIES, NEXT-GENERATION SEQUENCING, AND GENOME-WIDE TESTING FOR EPIGENETIC EFFECTS. THE USE OF GENETIC TECHNOLOGY TO EXAMINE THE AIRWAY MICROBIOTA THAT INTERACT WITH THE MUCOSA IN HEALTH AND DISEASE IS DESCRIBED. 2011 9 5552 26 ROLE OF EPIGENETICS IN THE PATHOGENESIS OF ASTHMA. ASTHMA IS A COMPLEX, HETEROGENEOUS AND CHRONIC AIRWAY INFLAMMATORY DISEASE WITH DIFFERENT CLINICAL PHENOTYPES CAUSED BY DIVERSE TRIGGERS AND PATHOPHYSIOLOGICAL MECHANISMS. ASTHMA HERITABILITY HAS BEEN ESTABLISHED IN MANY GENETIC STUDIES BUT IT IS EVIDENT THAT ONLY GENETIC ELEMENTS ARE NOT RESPONSIBLE FOR THE DEVELOPMENT OF ASTHMA. INCREASING RATE OF ASTHMA INCIDENCE DURING PAST DECADES HAS IMPLICATED THE ROLE OF EPIGENETICS IN DEVELOPMENT OF ASTHMA. ENVIRONMENTAL FACTORS PERFORM AS INITIATOR SIGNALS THROUGH EPIGENETIC MECHANISMS. THREE EPIGENETIC MECHANISMS HAVE BEEN IDENTIFIED, INCLUDING DNA METHYLATION, HISTONE MODIFICATIONS, AND SMALL NONCODING RNAS. THESE MECHANISMS REGULATE THE IMMUNE RESPONSES AND INFLAMMATORY GENES EXPRESSION IN ASTHMA AND ALLERGY. THIS REVIEW EXPLAINS THE ROLE OF EPIGENETIC MODIFICATIONS IN CONTROLLING TH2 RESPONSE AND IGE PRODUCTION IN ASTHMA AND ALSO BRIEFLY OVERVIEWS THE ROLE OF ENVIRONMENTAL FACTORS SUCH AS POLLUTIONS, ALLERGENS, PRENATAL EXPOSURES AND DIET IN DEVELOPING ASTHMA. RECOGNIZING ENVIRONMENTAL RISK FACTORS AND THEIR EFFECTS ON EPIGENETIC MECHANISMS WOULD BE OF GREAT INTEREST FOR PROGNOSTIC AND PREVENTIVE ASPECT IN TREATMENT OF ASTHMA. 2017 10 2059 30 EPIGENETIC CONTROL OF GENE EXPRESSION IN THE LUNG. EPIGENETICS IS TRADITIONALLY DEFINED AS THE STUDY OF HERITABLE CHANGES IN GENE EXPRESSION CAUSED BY MECHANISMS OTHER THAN CHANGES IN THE UNDERLYING DNA SEQUENCE. THERE ARE THREE MAIN CLASSES OF EPIGENETIC MARKS--DNA METHYLATION, MODIFICATIONS OF HISTONE TAILS, AND NONCODING RNAS--EACH OF WHICH MAY BE INFLUENCED BY THE ENVIRONMENT, DIET, DISEASES, AND AGEING. IMPORTANTLY, EPIGENETIC MARKS HAVE BEEN SHOWN TO INFLUENCE IMMUNE CELL MATURATION AND ARE ASSOCIATED WITH THE RISK OF DEVELOPING VARIOUS FORMS OF CANCER, INCLUDING LUNG CANCER. MOREOVER, THERE IS EMERGING EVIDENCE THAT THESE EPIGENETIC MARKS AFFECT GENE EXPRESSION IN THE LUNG AND ARE ASSOCIATED WITH BENIGN LUNG DISEASES, SUCH AS ASTHMA, CHRONIC OBSTRUCTIVE PULMONARY DISEASE, AND INTERSTITIAL LUNG DISEASE. TECHNOLOGICAL ADVANCES HAVE MADE IT FEASIBLE TO STUDY EPIGENETIC MARKS IN THE LUNG, AND IT IS ANTICIPATED THAT THIS KNOWLEDGE WILL ENHANCE OUR UNDERSTANDING OF THE DYNAMIC BIOLOGY IN THE LUNG AND LEAD TO THE DEVELOPMENT OF NOVEL DIAGNOSTIC AND THERAPEUTIC APPROACHES FOR OUR PATIENTS WITH LUNG DISEASE. 2011 11 2279 40 EPIGENETIC REGULATION IN ALLERGIC DISEASES AND RELATED STUDIES. ASTHMA, A CHRONIC INFLAMMATORY DISORDER OF THE AIRWAY, HAS FEATURES OF BOTH HERITABILITY AS WELL AS ENVIRONMENTAL INFLUENCES WHICH CAN BE INTRODUCED IN UTERO EXPOSURES AND MODIFIED THROUGH AGING, AND THE FEATURES MAY ATTRIBUTE TO EPIGENETIC REGULATION. EPIGENETIC REGULATION EXPLAINS THE ASSOCIATION BETWEEN EARLY PRENATAL MATERNAL SMOKING AND LATER ASTHMA-RELATED OUTCOMES. EPIGENETIC MARKS (DNA METHYLATION, MODIFICATIONS OF HISTONE TAILS OR NONCODING RNAS) WORK WITH OTHER COMPONENTS OF THE CELLULAR REGULATORY MACHINERY TO CONTROL THE LEVELS OF EXPRESSED GENES, AND SEVERAL ALLERGY- AND ASTHMA-RELATED GENES HAVE BEEN FOUND TO BE SUSCEPTIBLE TO EPIGENETIC REGULATION, INCLUDING GENES IMPORTANT TO T-EFFECTOR PATHWAYS (IFN-GAMMA, INTERLEUKIN [IL] 4, IL-13, IL-17) AND T-REGULATORY PATHWAYS (FOXP3). THEREFORE, THE MECHANISM BY WHICH EPIGENETIC REGULATION CONTRIBUTES TO ALLERGIC DISEASES IS A CRITICAL ISSUE. IN THE PAST MOST PUBLISHED EXPERIMENTAL WORK, WITH FEW EXCEPTIONS, HAS ONLY COMPRISED SMALL OBSERVATIONAL STUDIES AND MODELS IN CELL SYSTEMS AND ANIMALS. HOWEVER, VERY RECENTLY EXCITING AND ELEGANT EXPERIMENTAL STUDIES AND NOVEL TRANSLATIONAL RESEARCH WORKS WERE PUBLISHED WITH NEW AND ADVANCED TECHNOLOGIES INVESTIGATING EPIGENETIC MARK ON A GENOMIC SCALE AND COMPREHENSIVE APPROACHES TO DATA ANALYSIS. INTERESTINGLY, A POTENTIAL LINK BETWEEN EXPOSURE TO ENVIRONMENTAL POLLUTANTS AND THE OCCURRENCE OF ALLERGIC DISEASES IS REVEALED RECENTLY, PARTICULAR IN DEVELOPED AND INDUSTRIALIZED COUNTRIES, AND ENDOCRINE DISRUPTING CHEMICALS (EDCS) AS ENVIRONMENTAL HORMONE MAY PLAY A KEY ROLE. THIS REVIEW ADDRESSES THE IMPORTANT QUESTION OF HOW EDCS (NONYLPHENOL, 4 OCTYLPHENOL, AND PHTHALATES) INFLUENCES ON ASTHMA-RELATED GENE EXPRESSION VIA EPIGENETIC REGULATION IN IMMUNE CELLS, AND HOW ANTI-ASTHMATIC AGENTS PROHIBIT EXPRESSION OF INFLAMMATORY GENES VIA EPIGENETIC MODIFICATION. THE DISCOVERY AND VALIDATION OF EPIGENETIC BIOMARKERS LINKING EXPOSURE TO ALLERGIC DISEASES MIGHT LEAD TO BETTER EPIGENOTYPING OF RISK, PROGNOSIS, TREATMENT PREDICTION, AND DEVELOPMENT OF NOVEL THERAPIES. 2014 12 6199 29 THE IMPORTANCE OF EPIGENETICS IN THE DEVELOPMENT OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE. IT IS GENERALLY ACCEPTED THAT GENETIC PREDISPOSITION PLAYS A ROLE IN COPD DEVELOPMENT IN SUSCEPTIBLE INDIVIDUALS. THEREFORE, MANY CANDIDATE GENES THAT COULD BE LINKED TO THE DEVELOPMENT OF DISEASE HAVE BEEN EXAMINED IN COPD. HOWEVER, INCONSISTENT RESULTS IN DIFFERENT STUDY POPULATIONS OFTEN LIMIT THIS APPROACH, SUGGESTING THAT NOT ONLY GENETICS, BUT ALSO OTHER FACTORS, MAY BE CONTRIBUTED TO THE SUSCEPTIBILITY TO COPD. EPIGENETIC MECHANISMS CAN AFFECT THE TRANSCRIPTIONAL ACTIVITY OF SPECIFIC GENES, AT DIFFERENT POINTS IN TIME, AND IN DIFFERENT ORGANS. MOREOVER, THESE MECHANISMS CAN HAVE AN EFFECT ON PEOPLE'S HEALTH. RECENTLY, THERE IS EMERGING EVIDENCE SUPPORTING A ROLE OF EPIGENETICS FOR THE REGULATION OF INFLAMMATORY GENES IN DISEASES SUCH AS ASTHMA AND COPD. MOREOVER, RECENT STUDIES SUGGEST THAT THE CURRENTLY USED TREATMENTS INCLUDING CORTICOSTEROIDS MAY WORK THROUGH EPIGENETIC MECHANISMS. EPIGENETIC REGULATION CAN BE REPROGRAMMED, POTENTIALLY AFFECTING THE RISK, AETIOLOGY AND TREATMENT OF VARIOUS DISEASE STATES. THE EPIGENETICALLY INFLUENCED PHENOTYPE COULD BE REVERSED WITH DEMETHYLATING OR DEACETYLATING AGENTS, CONSISTENT WITH EPIGENETIC PLASTICITY. THE POSTNATAL REVERSIBILITY OF THESE METHYLATION OR ACETYLATION EVENTS MAY THEREFORE PROVIDE GOOD OPPORTUNITIES FOR INTERVENTION. THE RECOGNITION OF THE ROLE OF GENETIC AND EPIGENETIC MECHANISMS IN THE DEVELOPMENT OF COPD MAY IDENTIFY NOVEL TARGETS THAT HATCH NEW THERAPIES FOR PATIENTS WITH COPD. 2011 13 3966 32 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 14 2299 34 EPIGENETIC REGULATION OF AIRWAY EPITHELIUM IMMUNE FUNCTIONS IN ASTHMA. ASTHMA IS A CHRONIC INFLAMMATORY DISEASE OF THE RESPIRATORY TRACT CHARACTERIZED BY RECURRENT BREATHING PROBLEMS RESULTING FROM AIRWAY OBSTRUCTION AND HYPERRESPONSIVENESS. HUMAN AIRWAY EPITHELIUM PLAYS AN IMPORTANT ROLE IN THE INITIATION AND CONTROL OF THE IMMUNE RESPONSES TO DIFFERENT TYPES OF ENVIRONMENTAL FACTORS CONTRIBUTING TO ASTHMA PATHOGENESIS. USING PATTERN RECOGNITION RECEPTORS AIRWAY EPITHELIUM SENSES EXTERNAL STIMULI, SUCH AS ALLERGENS, MICROBES, OR POLLUTANTS, AND SUBSEQUENTLY SECRETES ENDOGENOUS DANGER SIGNALING MOLECULES ALARMING AND ACTIVATING DENDRITIC CELLS. HENCE, AIRWAY EPITHELIAL CELLS NOT ONLY MEDIATE INNATE IMMUNE RESPONSES BUT ALSO BRIDGE THEM WITH ADAPTIVE IMMUNE RESPONSES INVOLVING T AND B CELLS THAT PLAY A CRUCIAL ROLE IN THE PATHOGENESIS OF ASTHMA. THE EFFECTS OF ENVIRONMENTAL FACTORS ON THE DEVELOPMENT OF ASTHMA ARE MEDIATED, AT LEAST IN PART, BY EPIGENETIC MECHANISMS. THOSE COMPRISE CLASSICAL EPIGENETICS INCLUDING DNA METHYLATION AND HISTONE MODIFICATIONS AFFECTING TRANSCRIPTION, AS WELL AS MICRORNAS INFLUENCING TRANSLATION. THE COMMON FEATURE OF SUCH MECHANISMS IS THAT THEY REGULATE GENE EXPRESSION WITHOUT AFFECTING THE NUCLEOTIDE SEQUENCE OF THE GENOMIC DNA. EPIGENETIC MECHANISMS PLAY A PIVOTAL ROLE IN THE REGULATION OF DIFFERENT CELL POPULATIONS INVOLVED IN ASTHMA PATHOGENESIS, WITH THE REMARKABLE EXAMPLE OF T CELLS. RECENTLY, HOWEVER, THERE IS INCREASING EVIDENCE THAT EPIGENETIC MECHANISMS ARE ALSO CRUCIAL FOR THE REGULATION OF AIRWAY EPITHELIAL CELLS, ESPECIALLY IN THE CONTEXT OF EPIGENETIC TRANSFER OF ENVIRONMENTAL EFFECTS CONTRIBUTING TO ASTHMA PATHOGENESIS. IN THIS REVIEW, WE SUMMARIZE THE ACCUMULATING EVIDENCE FOR THIS VERY IMPORTANT ASPECT OF AIRWAY EPITHELIAL CELL PATHOBIOLOGY. 2020 15 2984 26 GENETIC DETERMINANTS OF POOR RESPONSE TO TREATMENT IN SEVERE ASTHMA. SEVERE ASTHMA IS A MULTIFACTORIAL DISORDER WITH MARKED PHENOTYPIC HETEROGENEITY AND COMPLEX INTERACTIONS BETWEEN GENETICS AND ENVIRONMENTAL RISK FACTORS, WHICH COULD, AT LEAST IN PART, EXPLAIN WHY DURING STANDARD PHARMACOLOGIC TREATMENT, MANY PATIENTS REMAIN POORLY CONTROLLED AND AT AN INCREASED RISK OF AIRWAY REMODELING AND DISEASE PROGRESSION. THE CONCEPT OF "PRECISION MEDICINE" TO BETTER SUIT INDIVIDUAL UNIQUE NEEDS IS AN EMERGING TREND IN THE MANAGEMENT OF CHRONIC RESPIRATORY DISEASES. OVER THE PAST FEW YEARS, GENOME-WIDE ASSOCIATION STUDIES (GWAS) HAVE REVEALED NOVEL PHARMACOGENETIC VARIANTS RELATED TO RESPONSES TO INHALED CORTICOSTEROIDS AND THE CLINICAL EFFICACY OF BRONCHODILATORS. OPTIMAL CLINICAL RESPONSE TO TREATMENT MAY VARY BETWEEN RACIAL/ETHNIC GROUPS OR INDIVIDUALS DUE TO GENETIC DIFFERENCES. IT IS ALSO PLAUSIBLE TO ASSUME THAT EPIGENETIC FACTORS PLAY A KEY ROLE IN THE MODULATION OF GENE EXPRESSION PATTERNS AND INFLAMMATORY CYTOKINES. REMARKABLY, SPECIFIC GENETIC VARIANTS RELATED TO TREATMENT EFFECTIVENESS MAY INDICATE PROMISING PATHWAYS FOR NOVEL THERAPIES IN SEVERE ASTHMA. IN THIS REVIEW, WE PROVIDE A CONCISE UPDATE OF GENETIC DETERMINANTS OF POOR RESPONSE TO TREATMENT IN SEVERE ASTHMA AND FUTURE DIRECTIONS IN THE FIELD. 2021 16 629 24 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 17 2648 26 EPIGENOMIC TARGETS FOR THE TREATMENT OF RESPIRATORY DISEASE. BACKGROUND: A NUMBER OF PROCESSES LEAD TO EPIGENETIC AND EPIGENOMIC MODIFICATIONS. OBJECTIVE: TO ADDRESS THE IMPORTANCE OF EPIGENOMICS IN RESPIRATORY DISEASE. METHODS: STUDIES OF EPIGENOMICS WERE ANALYSED IN RELATION TO CHRONIC RESPIRATORY DISEASES. RESULTS/CONCLUSION: IN LUNG CANCER AND MESOTHELIOMA, A NUMBER OF GENES INVOLVED IN CARCINOGENESIS HAVE BEEN DEMONSTRATED TO BE HYPERMETHYLATED, IMPLICATING EPIGENOMIC CHANGES IN THE AETIOLOGY OF THESE CANCERS. HYPERMETHYLATED GENES HAVE ALSO BEEN ASSOCIATED WITH LUNG CANCER RECURRENCE, INDICATING EPIGENOMIC REGULATION OF METASTASIS. IN AIRWAY DISEASES, MODULATION OF HISTONE FUNCTION MAY ACTIVATE INFLAMMATORY MECHANISMS IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE PATIENTS AND LEAD TO RELATIVE STEROID RESISTANCE. THERE IS EMERGING EVIDENCE FOR THE ROLE OF EPIGENETIC CHANGES IN CHRONIC LUNG DISEASES SUCH AS ASTHMA, INCLUDING RESPONSES TO ENVIRONMENTAL EXPOSURES IN UTERO AND TO THE EFFECTS OF AIR POLLUTION. INSIGHT INTO EPIGENOMICS WILL LEAD TO THE DEVELOPMENT OF NOVEL BIOMARKERS AND TREATMENT TARGETS IN RESPIRATORY DISEASES. 2009 18 3543 22 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 19 927 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 20 2160 22 EPIGENETIC MECHANISMS IN ASTHMA. ASTHMA AND ALLERGIC DISEASES ARE AMONG THE MOST PREVALENT CHRONIC NONCOMMUNICABLE DISEASES OF CHILDHOOD, BUT THE UNDERLYING PATHOGENETIC MECHANISMS ARE POORLY UNDERSTOOD. BECAUSE EPIGENETIC MECHANISMS LINK GENE REGULATION TO ENVIRONMENTAL CUES AND DEVELOPMENTAL TRAJECTORIES, THEIR CONTRIBUTION TO ASTHMA AND ALLERGY PATHOGENESIS IS UNDER ACTIVE INVESTIGATION. DNA METHYLATION SIGNATURES ASSOCIATED WITH CONCURRENT DISEASE AND WITH THE DEVELOPMENT OF ASTHMA DURING CHILDHOOD ASTHMA HAVE BEEN IDENTIFIED, BUT THEIR SIGNIFICANCE IS NOT EASILY INTERPRETABLE. ON THE OTHER HAND, THE CHARACTERIZATION OF EARLY EPIGENETIC PREDICTORS OF ASTHMA POINTS TO A POTENTIAL ROLE OF EPIGENETIC MECHANISMS IN REGULATING THE INCEPTION OF, AND THE SUSCEPTIBILITY TO, THIS DISEASE. 2016