1 3711 128 INHALED DRUG DELIVERY FOR THE TARGETED TREATMENT OF ASTHMA. ASTHMA IS A CHRONIC LUNG DISEASE AFFECTING MILLIONS WORLDWIDE. WHILE CLASSICALLY ACKNOWLEDGED TO RESULT FROM ALLERGEN-DRIVEN TYPE 2 INFLAMMATORY RESPONSES LEADING TO IGE AND CYTOKINE PRODUCTION AND THE INFLUX OF IMMUNE CELLS SUCH AS MAST CELLS AND EOSINOPHILS, THE WIDE RANGE IN ASTHMATIC PATHOBIOLOGICAL SUBTYPES LEAD TO HIGHLY VARIABLE RESPONSES TO ANTI-INFLAMMATORY THERAPIES. THUS, THERE IS A NEED TO DEVELOP PATIENT-SPECIFIC THERAPIES CAPABLE OF ADDRESSING THE FULL SPECTRUM OF ASTHMATIC LUNG DISEASE. MOREOVER, DELIVERY OF TARGETED TREATMENTS FOR ASTHMA DIRECTLY TO THE LUNG MAY HELP TO MAXIMIZE THERAPEUTIC BENEFIT, BUT CHALLENGES REMAIN IN DESIGN OF EFFECTIVE FORMULATIONS FOR THE INHALED ROUTE. IN THIS REVIEW, WE DISCUSS THE CURRENT UNDERSTANDING OF ASTHMATIC DISEASE PROGRESSION AS WELL AS GENETIC AND EPIGENETIC DISEASE MODIFIERS ASSOCIATED WITH ASTHMA SEVERITY AND EXACERBATION OF DISEASE. WE ALSO OVERVIEW THE LIMITATIONS OF CLINICALLY AVAILABLE TREATMENTS FOR ASTHMA AND DISCUSS PRE-CLINICAL MODELS OF ASTHMA USED TO EVALUATE NEW THERAPIES. BASED ON THE SHORTCOMINGS OF EXISTING TREATMENTS, WE HIGHLIGHT RECENT ADVANCES AND NEW APPROACHES TO TREAT ASTHMA VIA INHALATION FOR MONOCLONAL ANTIBODY DELIVERY, MUCOLYTIC THERAPY TO TARGET AIRWAY MUCUS HYPERSECRETION AND GENE THERAPIES TO ADDRESS UNDERLYING DRIVERS OF DISEASE. FINALLY, WE CONCLUDE WITH DISCUSSION ON THE PROSPECTS FOR AN INHALED VACCINE TO PREVENT ASTHMA. 2023 2 2455 39 EPIGENETIC TARGETS FOR NOVEL THERAPIES OF LUNG DISEASES. IN SPITE OF SUBSTANTIAL ADVANCES IN DEFINING THE IMMUNOBIOLOGY AND FUNCTION OF STRUCTURAL CELLS IN LUNG DISEASES THERE IS STILL INSUFFICIENT KNOWLEDGE TO DEVELOP FUNDAMENTALLY NEW CLASSES OF DRUGS TO TREAT MANY LUNG DISEASES. FOR EXAMPLE, THERE IS A COMPELLING NEED FOR NEW THERAPEUTIC APPROACHES TO ADDRESS SEVERE PERSISTENT ASTHMA THAT IS INSENSITIVE TO INHALED CORTICOSTEROIDS. ALTHOUGH THE PREVALENCE OF STEROID-RESISTANT ASTHMA IS 5-10%, SEVERE ASTHMATICS REQUIRE A DISPROPORTIONATE LEVEL OF HEALTH CARE SPENDING AND CONSTITUTE A MAJORITY OF FATAL ASTHMA EPISODES. NONE OF THE ESTABLISHED DRUG THERAPIES INCLUDING LONG-ACTING BETA AGONISTS OR INHALED CORTICOSTEROIDS REVERSE ESTABLISHED AIRWAY REMODELING. OBSTRUCTIVE AIRWAYS REMODELING IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD), RESTRICTIVE REMODELING IN IDIOPATHIC PULMONARY FIBROSIS (IPF) AND OCCLUSIVE VASCULAR REMODELING IN PULMONARY HYPERTENSION ARE SIMILARLY UNRESPONSIVE TO CURRENT DRUG THERAPY. THEREFORE, DRUGS ARE NEEDED TO ACHIEVE LONG-ACTING SUPPRESSION AND REVERSAL OF PATHOLOGICAL AIRWAY AND VASCULAR REMODELING. NOVEL DRUG CLASSES ARE EMERGING FROM ADVANCES IN EPIGENETICS. NOVEL MECHANISMS ARE EMERGING BY WHICH CELLS ADAPT TO ENVIRONMENTAL CUES, WHICH INCLUDE CHANGES IN DNA METHYLATION, HISTONE MODIFICATIONS AND REGULATION OF TRANSCRIPTION AND TRANSLATION BY NONCODING RNAS. IN THIS REVIEW WE WILL SUMMARIZE CURRENT EPIGENETIC APPROACHES BEING APPLIED TO PRECLINICAL DRUG DEVELOPMENT ADDRESSING IMPORTANT THERAPEUTIC CHALLENGES IN LUNG DISEASES. THESE CHALLENGES ARE BEING ADDRESSED BY ADVANCES IN LUNG DELIVERY OF OLIGONUCLEOTIDES AND SMALL MOLECULES THAT MODIFY THE HISTONE CODE, DNA METHYLATION PATTERNS AND MIRNA FUNCTION. 2015 3 2984 34 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 4 3028 26 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 5 2330 33 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 6 485 29 ARTIFICIAL AIRWAYS FOR THE STUDY OF RESPIRATORY DISEASE. THIS REVIEW WILL FOCUS ON HUMAN CELL-BASED EXPERIMENTAL MODELS TO STUDY RESPIRATORY DISEASES, IN PARTICULAR MODELS OF THE LARGE AIRWAYS RELEVANT TO ASTHMA AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE. SUCH MODELS HAVE THE ADVANTAGE OF INCORPORATING CELLS THAT CAN BE DERIVED FROM DISEASE-RELEVANT TISSUE AND SO HAVE RETAINED IMPORTANT GENETIC AND EPIGENETIC FEATURES THAT CONTRIBUTE TO THE HUMAN DISEASE. THESE MODELS CAN BE USED FOR MECHANISTIC STUDIES, TARGET IDENTIFICATION AND VALIDATION AND TOXICOLOGICAL TESTING. WHILE MANY MODELS HAVE BEEN DEVELOPED TO VARYING DEGREES OF SOPHISTICATION, THE CHALLENGE REMAINS TO DEVELOP AN INTEGRATED SYSTEM THAT RECAPITULATES THE COMPLEX CELL-CELL AND CELL-MATRIX INTERACTIONS THAT OCCUR IN VIVO AND TO PROVIDE THESE WITH A 'CIRCULATION' TO STUDY THE DYNAMICS OF IMMUNE AND INFLAMMATORY CELL INFLUX AND EFFLUX. 2011 7 5552 31 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 8 2859 32 FROM SMOKING TO COPD--CURRENT APPROACHES. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) REMAINS A LEADING CAUSE OF DEATH ALL OVER THE WORLD. EVEN THOUGH IT IS THE MOST INTENSELY STUDIED DISEASE INDUCED BY CIGARETTE SMOKING THERE ARE STILL INCOMPLETE RESEARCHES CONCERNING ITS PATHOPHYSIOLOGY AND TREATMENT. SO FAR IT HAS BEEN DETERMINED THE DELETERIOUS EFFECTS OF THE SECRETED MOLECULES DIVERSITY AND SOME FEASIBLE THERAPIES FOR THEIR DIMINUTION. ACCORDING TO CURRENT STUDIES MORE RELEVANCE GAINS THE POSSIBLE AUTOIMMUNE ORIGIN OF COPD AND THE EPIGENETIC MODIFICATIONS. THE IDEA OF AUTOIMMUNITY IN SMOKING INDUCED COPD BEGAN TO BE SPECULATED WITH THE DISCOVERY OF AUTOANTIBODIES IN PATIENT'S SERUM, BUT THERE ARE SOME STUDIES WHO CONSIDER ANTIBODY COMPLEXES THAT RESIDE IN THE LUNG TISSUE AS MORE RELEVANT FOR FUTURE RESEARCH. BY DEVELOPING THE AUTOIMMUNE ASPECT OF COPD IT WILL BECOME POSSIBLE TO SELECT MORE PRECISE TREATMENT STRATEGIES. THE IMPORTANCE OF EPIGENETIC CHANGES IN THIS FIELD MIGHT BE APPRECIATED STARTING WITH THE FACT OF AN EXISTING CONNECTION BETWEEN EPIGENETIC MODIFICATIONS INDUCED BY MATERNAL SMOKING AND LATTER COPD DEVELOPMENT. THIS EXPLAINS THE TENDENCY TOWARD DIFFERENT DRUGS CAPABLE OF RESTORING THESE TRANSFORMATIONS SUCH AS DEACETYLATION AGENTS EXPECTED ALSO TO PREVENT STEROID RESISTANCE. NEVERTHELESS SMOKING CESSATION REMAINS AS THE INDISPENSABLE APPROACH FOR COPD TREATMENT AND PREVENTION. 2016 9 5138 32 POTENTIAL METABOLIC BIOMARKERS IN ADULT ASTHMATICS. ASTHMA IS THE MOST COMMON CHRONIC AIRWAY INFLAMMATION, WITH MULTIPLE PHENOTYPES CAUSED BY COMPLICATED INTERACTIONS OF GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS. TO DATE, VARIOUS DETERMINANTS HAVE BEEN SUGGESTED FOR ASTHMA PATHOGENESIS BY A NEW TECHNOLOGY TERMED OMICS, INCLUDING GENOMICS, TRANSCRIPTOMICS, PROTEOMICS, AND METABOLOMICS. IN PARTICULAR, THE SYSTEMATIC ANALYSIS OF ALL METABOLITES IN A BIOLOGICAL SYSTEM, SUCH AS CARBOHYDRATES, AMINO ACIDS, AND LIPIDS, HAS HELPED IDENTIFY A NOVEL PATHWAY RELATED TO COMPLEX DISEASES. THESE METABOLITES ARE INVOLVED IN THE REGULATION OF HYPERMETHYLATION, RESPONSE TO HYPOXIA, AND IMMUNE REACTIONS IN THE PATHOGENESIS OF ASTHMA. AMONG THEM, LIPID METABOLISM HAS BEEN SUGGESTED TO BE RELATED TO LUNG DYSFUNCTION IN MILD-TO-MODERATE ASTHMA. SPHINGOLIPID METABOLITES ARE AN IMPORTANT MEDIATOR CONTRIBUTING TO AIRWAY INFLAMMATION IN OBESE ASTHMA AND ASPIRIN-EXACERBATED RESPIRATORY DISEASE. ALTHOUGH HOW THESE MOLECULAR VARIANTS IMPACT THE DISEASE HAS NOT BEEN COMPLETELY DETERMINED, IDENTIFICATION OF NEW CAUSATIVE FACTORS MAY POSSIBLY LEAD TO MORE-PERSONALIZED AND PRECISE PATHWAY-SPECIFIC APPROACHES FOR BETTER DIAGNOSIS AND TREATMENT OF ASTHMA. IN THIS REVIEW, PERSPECTIVES OF METABOLITES RELATED TO ASTHMA AND CLINICAL IMPLICATIONS HAVE BEEN HIGHLIGHTED ACCORDING TO VARIOUS PHENOTYPES. 2021 10 3421 36 HUMAN MATTERS IN ASTHMA: CONSIDERING THE MICROBIOME IN PULMONARY HEALTH. MICROBIAL COMMUNITIES FORM AN IMPORTANT SYMBIOTIC ECOSYSTEM WITHIN HUMANS AND HAVE DIRECT EFFECTS ON HEALTH AND WELL-BEING. NUMEROUS EXOGENOUS FACTORS INCLUDING AIRBORNE TRIGGERS, DIET, AND DRUGS IMPACT THESE ESTABLISHED, BUT FRAGILE COMMUNITIES ACROSS THE HUMAN LIFESPAN. CROSSTALK BETWEEN THE MUCOSAL MICROBIOTA AND THE IMMUNE SYSTEM AS WELL AS THE GUT-LUNG AXIS HAVE DIRECT CORRELATIONS TO IMMUNE BIAS THAT MAY PROMOTE CHRONIC DISEASES LIKE ASTHMA. ASTHMA INITIATION AND PATHOGENESIS ARE MULTIFACETED AND COMPLEX WITH INPUT FROM GENETIC, EPIGENETIC, AND ENVIRONMENTAL COMPONENTS. IN THIS REVIEW, WE SUMMARIZE AND DISCUSS THE ROLE OF THE AIRWAY MICROBIOME IN ASTHMA, AND HOW THE ENVIRONMENT, DIET AND THERAPEUTICS IMPACT THIS LOW BIOMASS COMMUNITY OF MICROORGANISMS. WE ALSO FOCUS THIS REVIEW ON THE PEDIATRIC AND BLACK POPULATIONS AS HIGH-RISK GROUPS REQUIRING SPECIAL ATTENTION, EMPHASIZING THAT THE WHOLE PATIENT MUST BE CONSIDERED DURING TREATMENT. ALTHOUGH NEW CULTURE-INDEPENDENT TECHNIQUES HAVE BEEN DEVELOPED AND ARE MORE ACCESSIBLE TO RESEARCHERS, THE EXACT CONTRIBUTION THE AIRWAY MICROBIOME MAKES IN ASTHMA PATHOGENESIS IS NOT WELL UNDERSTOOD. UNDERSTANDING HOW THE AIRWAY MICROBIOME, AS A LIVING ENTITY IN THE RESPIRATORY TRACT, PARTICIPATES IN LUNG IMMUNITY DURING THE DEVELOPMENT AND PROGRESSION OF ASTHMA MAY LEAD TO CRITICAL NEW TREATMENTS FOR ASTHMA, INCLUDING POPULATION-TARGETED INTERVENTIONS, OR EVEN MORE EFFECTIVE ADMINISTRATION OF CURRENTLY AVAILABLE THERAPEUTICS. 2022 11 2531 32 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 12 6005 40 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 13 5472 37 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 14 2581 31 EPIGENETICS OF MUCUS HYPERSECRETION IN CHRONIC RESPIRATORY DISEASES. ASTHMA, CHRONIC OBSTRUCTIVE PULMONARY DISEASE, AND CYSTIC FIBROSIS ARE THREE CHRONIC PULMONARY DISEASES THAT AFFECT AN ESTIMATED 420 MILLION INDIVIDUALS ACROSS THE GLOBE. A KEY FACTOR CONTRIBUTING TO EACH OF THESE CONDITIONS IS MUCUS HYPERSECRETION. ALTHOUGH MANAGEMENT OF THESE DISEASES IS VASTLY STUDIED, RESEARCHERS HAVE ONLY BEGUN TO SCRATCH THE SURFACE OF THE MECHANISMS CONTRIBUTING TO MUCUS HYPERSECRETION. EPIGENETIC REGULATION OF MUCUS HYPERSECRETION, OTHER THAN MICRORNA POST-TRANSLATIONAL MODIFICATION, IS EVEN MORE SCARCELY RESEARCHED. DETAILED STUDY OF EPIGENETIC MECHANISMS, SUCH AS DNA METHYLATION AND HISTONE MODIFICATION, COULD NOT ONLY HELP TO BETTER THE UNDERSTANDING OF THESE RESPIRATORY CONDITIONS BUT ALSO REVEAL NEW TREATMENTS FOR THEM. BECAUSE MUCUS HYPERSECRETION IS SUCH A COMPLEX EVENT, THERE ARE INNUMERABLE GENES INVOLVED IN THE PROCESS, WHICH ARE BEYOND THE SCOPE OF A SINGLE REVIEW. THEREFORE, THE PURPOSE OF THIS REVIEW IS TO NARROW THE FOCUS AND SUMMARIZE SPECIFIC EPIGENETIC RESEARCH THAT HAS BEEN CONDUCTED ON A FEW ASPECTS OF MUCUS HYPERSECRETION IN ASTHMA, CHRONIC OBSTRUCTIVE PULMONARY DISEASE, CYSTIC FIBROSIS, AND SOME CANCERS. SPECIFICALLY, THIS REVIEW EMPHASIZES THE CONTRIBUTION OF DNA METHYLATION AND HISTONE MODIFICATION OF PARTICULAR GENES INVOLVED IN MUCUS HYPERSECRETION TO IDENTIFY POSSIBLE TARGETS FOR THE DEVELOPMENT OF FUTURE THERAPIES FOR THESE CONDITIONS. ELUCIDATING THE ROLE OF EPIGENETICS IN THESE RESPIRATORY DISEASES MAY PROVIDE A BREATH OF FRESH AIR TO MILLIONS OF AFFECTED INDIVIDUALS AROUND THE WORLD. 2018 15 6735 32 WHAT HAVE MECHANISTIC STUDIES TAUGHT US ABOUT CHILDHOOD ASTHMA? CHILDHOOD ASTHMA IS A CHRONIC HETEROGENEOUS SYNDROME CONSISTING OF DIFFERENT DISEASE ENTITIES OR PHENOTYPES. THE IMMUNOLOGIC AND CELLULAR PROCESSES THAT OCCUR DURING ASTHMA DEVELOPMENT ARE STILL NOT FULLY UNDERSTOOD BUT REPRESENT DISTINCT ENDOTYPES. MECHANISTIC STUDIES HAVE EXAMINED THE ROLE OF GENE EXPRESSION, PROTEIN LEVELS, AND CELL TYPES IN EARLY LIFE DEVELOPMENT AND THE MANIFESTATION OF ASTHMA, MANY UNDER THE INFLUENCE OF ENVIRONMENTAL STIMULI, WHICH CAN BE BOTH PROTECTIVE AND RISK FACTORS FOR ASTHMA. GENETIC VARIANTS CAN REGULATE GENE EXPRESSION, CONTROLLED PARTLY BY DIFFERENT EPIGENETIC MECHANISMS. IN ADDITION, ENVIRONMENTAL FACTORS, SUCH AS LIVING SPACE, NUTRITION, AND SMOKING, CAN CONTRIBUTE TO THESE MECHANISMS. ALL OF THESE FACTORS PRODUCE MODIFICATIONS IN GENE EXPRESSION THAT CAN ALTER THE DEVELOPMENT AND FUNCTION OF IMMUNE AND EPITHELIAL CELLS AND SUBSEQUENTLY DIFFERENT TRAJECTORIES OF CHILDHOOD ASTHMA. THESE EARLY CHANGES IN A PARTIALLY IMMATURE IMMUNE SYSTEM CAN HAVE DRAMATIC EFFECTS (E.G., CAUSING DYSREGULATION), WHICH IN TURN CONTRIBUTE TO DIFFERENT DISEASE ENDOTYPES AND MAY HELP TO EXPLAIN DIFFERENTIAL RESPONSIVENESS TO ASTHMA TREATMENT. IN THIS REVIEW, WE SUMMARIZE PUBLISHED STUDIES THAT HAVE AIMED TO UNCOVER DISTINCT MECHANISMS IN CHILDHOOD ASTHMA, CONSIDERING GENETICS, EPIGENETICS, AND ENVIRONMENT. MOREOVER, A DISCUSSION OF NEW, POWERFUL TOOLS FOR SINGLE-CELL IMMUNOLOGIC ASSAYS FOR PHENOTYPIC AND FUNCTIONAL ANALYSIS IS INCLUDED, WHICH PROMISE NEW MECHANISTIC INSIGHTS INTO CHILDHOOD ASTHMA DEVELOPMENT AND THERAPEUTIC AND PREVENTIVE STRATEGIES. 2023 16 2333 37 EPIGENETIC REGULATION OF INFLAMMATION: THE METABOLOMICS CONNECTION. EPIGENETIC FACTORS ARE CONSIDERED THE REGULATOR OF COMPLEX MACHINERY BEHIND INFLAMMATORY DISORDERS AND SIGNIFICANTLY CONTRIBUTED TO THE EXPRESSION OF INFLAMMATION-ASSOCIATED GENES. EPIGENETIC MODIFICATIONS MODULATE VARIATION IN THE EXPRESSION PATTERN OF TARGET GENES WITHOUT AFFECTING THE DNA SEQUENCE. THE CURRENT KNOWLEDGE OF EPIGENETIC RESEARCH FOCUSED ON THEIR ROLE IN THE PATHOGENESIS OF VARIOUS INFLAMMATORY DISEASES THAT CAUSES MORBIDITY AND MORTALITY WORLDWIDE. INFLAMMATORY DISEASES ARE CATEGORIZED AS ACUTE AND CHRONIC BASED ON THE DISEASE SEVERITY AND ARE REGULATED BY THE EXPRESSION PATTERN OF VARIOUS GENES. HENCE, UNDERSTANDING THE ROLE OF EPIGENETIC MODIFICATIONS DURING INFLAMMATION PROGRESSION WILL CONTRIBUTE TO THE DISEASE OUTCOMES AND THERAPEUTIC APPROACHES. THIS REVIEW ALSO FOCUSES ON THE METABOLOMICS APPROACH ASSOCIATED WITH THE STUDY OF INFLAMMATORY DISORDERS. INFLAMMATORY RESPONSES AND METABOLIC REGULATION ARE HIGHLY INTEGRATED AND VARIOUS ADVANCED TECHNIQUES ARE ADOPTED TO STUDY THE METABOLIC SIGNATURE MOLECULES. HERE WE DISCUSS SEVERAL METABOLOMICS APPROACHES USED TO LINK INFLAMMATORY DISORDERS AND EPIGENETIC CHANGES. WE PROPOSED THAT DECIPHERING THE MECHANISM BEHIND THE INFLAMMATION-METABOLISM LOOP MAY HAVE IMMENSE IMPORTANCE IN BIOMARKERS RESEARCH AND MAY ACT AS A PRINCIPAL COMPONENT IN DRUG DISCOVERY AS WELL AS THERAPEUTIC APPLICATIONS. 2022 17 874 27 CHRONIC ALLERGY SIGNALING: IS IT ALL STRESSED-OUT MITOCHONDRIA? ALLERGIC DISEASES IN GENERAL, AND CHRONIC ALLERGIC INFLAMMATION IN PARTICULAR, ARE ON THE RISE IN THE UNITED STATES AND OTHER DEVELOPED COUNTRIES. THE IDEA OF CHRONIC ALLERGIC DISEASE AS A CHRONIC TYPE 2 IMMUNE RESPONSE HAS BEEN AROUND FOR SEVERAL DECADES. HOWEVER, DATA SUGGEST THAT OTHER MECHANISMS MAY BE IMPORTANT IN CHRONIC DISEASE. THEREFORE, WE BELIEVE IT IS TIME FOR A PARADIGM SHIFT IN UNDERSTANDING THE MECHANISTIC CAUSES OF DISEASE SYMPTOMS IN THESE DISEASES. IN THIS REVIEW, WE HAVE AVOIDED THE CLASSIC CANONICAL PATHWAYS AND FOCUSED ON THE EMERGING IDEA THAT OXIDATIVE STRESS, CHANGES IN IMMUNO-METABOLISM, MITOCHONDRIAL DYSFUNCTION, AND EPIGENETIC CHANGES (PARTICULARLY MICRORNA PROFILE) MAY BE WORKING CONCURRENTLY OR SYNERGISTICALLY TO POTENTIATE ALLERGIC DISEASE SYMPTOMS. FURTHERMORE, WE HAVE ADDRESSED HOW THE EPIDEMIC OF OBESITY EXACERBATES ALLERGIC DISEASE VIA THE DYSREGULATION OF THE AFOREMENTIONED FACTORS. 2022 18 4445 30 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 19 3966 33 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 20 5026 37 PERSONALIZED MEDICINE IN IDIOPATHIC PULMONARY FIBROSIS: FACTS AND PROMISES. PURPOSE OF REVIEW: IN THIS ARTICLE, WE SUMMARIZE AND DISCUSS THE MOST RECENT LITERATURE ON PERSONALIZED MEDICINE IN IDIOPATHIC PULMONARY FIBROSIS (IPF), A CHRONIC PROGRESSIVE AND ALMOST INVARIABLY LETHAL DISEASE OF UNKNOWN CAUSE. THIS REVIEW IS TIMELY AS MAJOR ADVANCES IN OUR UNDERSTANDING OF DISEASE PATHOBIOLOGY AND IMPROVEMENTS IN MOLECULAR TECHNIQUES HAVE RECENTLY LED TO THE IDENTIFICATION OF POTENTIAL SURROGATES OF DIAGNOSIS, PROGNOSIS AND RESPONSE TO TREATMENT. RECENT FINDINGS: THE MOST PROMISING AND ADVANCED CANDIDATE BIOMARKERS ARE PRESENTED BASED ON THEIR PROPOSED MECHANISTIC PATHWAYS (E.G. ALVEOLAR EPITHELIAL CELL DYSFUNCTION, IMMUNE DYSREGULATION, MICROBIOME, EXTRACELLULAR MATRIX REMODELING AND FIBROPROLIFERATION, EPIGENETIC MARKERS AND METABOLOMICS). RECENT DATA SUGGEST THAT COMPONENTS OF THE IMMUNE SYSTEM MAY CONTRIBUTE TO THE DEVELOPMENT OF IPF. A POTENTIAL ROLE FOR INFECTIONS AS A COFACTOR IN DISEASE DEVELOPMENT AND PROGRESSION OR AS A TRIGGER IN DISEASE EXACERBATION HAS ALSO RECENTLY BEEN PROPOSED. SUMMARY: CLINICAL MANAGEMENT OF IPF IS UNSATISFACTORY BECAUSE OF LIMITED AVAILABILITY OF TRULY EFFECTIVE THERAPIES, LACK OF ACCURATE PREDICTORS OF DISEASE BEHAVIOR AND ABSENCE OF SIMPLE SHORT-TERM MEASURES OF THERAPEUTIC RESPONSE. A NUMBER OF PUTATIVE BIOMARKERS HAVE BEEN IDENTIFIED IN PATIENTS WITH IPF, ALTHOUGH NONE HAS BEEN VALIDATED TO THE STANDARD NECESSARY FOR THEIR USE IN EITHER THERAPEUTIC TRIALS OR CLINICAL PRACTICE. CURRENTLY, ONGOING PROSPECTIVE LONGITUDINAL STUDIES WILL HOPEFULLY PERMIT SUCH VALIDATION. 2015