1   362 139 AMBIENT AIR POLLUTION IMPAIRS REGULATORY T-CELL FUNCTION IN ASTHMA. BACKGROUND: ASTHMA IS THE MOST FREQUENT CHRONIC DISEASE IN CHILDREN, AND CHILDREN ARE AT HIGH RISK FOR ADVERSE HEALTH CONSEQUENCES ASSOCIATED WITH AMBIENT AIR POLLUTION (AAP) EXPOSURE. REGULATORY T (TREG) CELLS ARE SUPPRESSORS OF IMMUNE RESPONSES INVOLVED IN ASTHMA PATHOGENESIS. TREG-CELL IMPAIRMENT IS ASSOCIATED WITH INCREASED DNA METHYLATION OF FORKHEAD BOX TRANSCRIPTION FACTOR 3 (FOXP3), A KEY TRANSCRIPTION FACTOR IN TREG-CELL ACTIVITY. BECAUSE AAP EXPOSURE CAN INDUCE EPIGENETIC CHANGES, WE HYPOTHESIZED THAT TREG-CELL FUNCTION WOULD BE IMPAIRED BY AAP, ALLOWING AMPLIFICATION OF AN INFLAMMATORY RESPONSE. OBJECTIVES: TO ASSESS WHETHER EXPOSURE TO AAP LED TO HYPERMETHYLATION OF THE FOXP3 GENE, CAUSING IMPAIRED TREG-CELL SUPPRESSION AND WORSENED ASTHMA SYMPTOM SCORES. METHODS: CHILDREN WITH AND WITHOUT ASTHMA FROM FRESNO, CALIF (HIGH POLLUTION, FRESNO ASTHMA GROUP [FA], N = 71, AND FRESNO NON ASTHMATIC GROUP, N = 30, RESPECTIVELY), AND FROM STANFORD, CALIF (LOW POLLUTION, STANFORD ASTHMA GROUP, N = 40, AND STANFORD NON ASTHMATIC GROUP, N = 40), WERE ENROLLED IN A CROSS-SECTIONAL STUDY. PERIPHERAL BLOOD TREG CELLS WERE USED IN FUNCTIONAL AND EPIGENETIC STUDIES. ASTHMA OUTCOMES WERE ASSESSED BY GLOBAL INITIATIVE IN ASTHMA SCORE. RESULTS: FRESNO ASTHMA GROUP TREG-CELL SUPPRESSION WAS IMPAIRED AND FA TREG-CELL CHEMOTAXIS WERE REDUCED COMPARED WITH OTHER GROUPS (P </= .05). TREG-CELL DYSFUNCTION WAS ASSOCIATED WITH MORE PRONOUNCED DECREASES IN ASTHMA GLOBAL INITIATIVE IN ASTHMA SCORE IN FA VERSUS THE STANFORD ASTHMA GROUP. FOXP3 WAS DECREASED IN FA COMPARED WITH THE FRESNO NON ASTHMATIC GROUP (P </= .05). FA ALSO CONTAINED SIGNIFICANTLY HIGHER LEVELS OF METHYLATION AT THE FOXP3 LOCUS (P </= .05). CONCLUSION: INCREASED EXPOSURE TO AAP IS ASSOCIATED WITH HYPERMETHYLATION OF THE FOXP3 LOCUS, IMPAIRING TREG-CELL FUNCTION AND INCREASING ASTHMA MORBIDITY. AAP COULD PLAY A ROLE IN MEDIATING EPIGENETIC CHANGES IN TREG CELLS, WHICH MAY WORSEN ASTHMA BY AN IMMUNE MECHANISM.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
2  3709  35 INFLUENCE OF VITAMIN D AND COTININE ON T-REGULATORY CELLS AND ASTHMA SEVERITY IN CHILDREN. ASTHMA IS A COMMON CHRONIC RESPIRATORY DISEASES IN CHILDREN. UNDERSTANDING THE IMMUNE MECHANISMS OF EPIGENETIC FACTORS MAY CONTRIBUTE TO A BETTER CONTROL OF ASTHMA. THIS STUDY SEEKS TO DETERMINE THE EFFECTS OF SERUM VITAMIN D AND URINE COTININE ON ASTHMA SEVERITY AND ON T REGULATORY CELLS (TREGS) AND OTHER IMMUNE-RELATED FACTORS SUCH AS CD3, CD4, CD8, CD19, CD16/56, AND ANTI-CD3 HLA-DR3. THE STUDY INVOLVED 34 CHILDREN WITH ASTHMA. DISEASE SEVERITY WAS ASSESSED WITH THE ASTHMA CONTROL TEST, SPIROMETRY, AND THE FRACTIONAL EXHALED NITRIC OXIDE (FENO). THE CONTROL GROUP CONSISTED OF 18 HEALTHY CHILDREN. WE FOUND A SIGNIFICANTLY LOWER PROPORTION OF TREGS IN THE SERUM OF ASTHMATIC CHILDREN COMPARED WITH THE CONTROL GROUP (P < 0.002). THERE WERE NO SIGNIFICANT DIFFERENCES IN THE OTHER IMMUNOLOGICAL FACTORS INVESTIGATED. NOR WAS THERE ANY APPRECIABLE ASSOCIATION BETWEEN VITAMIN D OR COTININE AND THE COURSE OF ASTHMA, FENO, TREGS, AND THE OTHER IMMUNE FACTORS. HOWEVER, THE PERCENTAGE OF TREGS WAS POSITIVELY ASSOCIATED WITH THE LEVEL OF FENO (P < 0.02). IN CONCLUSION, THE STUDY SHOWS A ROLE OF T REGULATORY CELLS IN THE PATHOGENESIS OF ASTHMA IN CHILDREN, BUT FAILS TO SHOW ANY INFLUENCE OF SERUM VITAMIN D OR URINE COTININE ON DISEASE COURSE.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
3  6247  40 THE METHYLATION PATTERNS OF A DISINTEGRIN AND METALLOPROTEINASE 33 GENE (ADAM33) IN ADULT ASTHMA. BACKGROUND: ASTHMA IS A COMMON CHRONIC INFLAMMATORY RESPIRATORY DISEASE. PREVIOUS STUDIES HAVE SUGGESTED THAT THE PATHOGENESIS OF ASTHMA MAY BE AFFECTED BY EPIGENETIC REGULATION. THE PURPOSE OF THIS STUDY IS TO CHARACTERIZE THE EFFECT OF THE METHYLATION OF EACH CPG SITE IN THE ADAM33 (A DISINTEGRIN AND METALLOPROTEINASE 33) GENE IN ADULT ASTHMA. METHODS: A HUMAN CPG ISLAND MICROARRAY WAS USED TO EXAMINE 4 ASTHMATIC CASES AND 4 HEALTHY CONTROLS, AND THE RESULTS SUGGESTED THAT THERE MIGHT BE DIFFERENCES IN METHYLATION WITHIN EXON 9 OF THE ADAM33 GENE. THEREFORE, WE DESIGNED A CASE-CONTROL STUDY WITH 50 ASTHMATIC PATIENTS AND 50 AGE- AND SEX-MATCHED HEALTHY CONTROLS TO EXAMINE THE RELATIONSHIP BETWEEN THE CPG METHYLATION OF THE ADAM33 GENE AND ASTHMA USING BISULFITE DEOXYRIBONUCLEIC ACID MODIFICATION AND SEQUENCING. RESULTS: BISULFITE SEQUENCING EXPERIMENTS SHOWED THAT THE 14 CPG SITES IN EXON 9 OF THE ADAM33 GENE WERE HIGHLY METHYLATED (100%) IN ALL INDIVIDUALS. THE PROPORTIONS OF METHYLATION OF THE 14 CPG SITES IN ADAM33 IN THE CASE GROUP WERE NOT DIFFERENT FROM THOSE OF THE CONTROL GROUP. THE METHYLATION OF EXON 9 OF THIS LOCUS WAS NOT ASSOCIATED WITH AGE, SEX, IGE LEVELS, OR LUNG FUNCTION. THIS STUDY FOUND NO ASSOCIATION BETWEEN THE METHYLATION OF CPG SITES IN EXON 9 OF THE ADAM33 GENE AND ADULT ASTHMA. CONCLUSIONS: THE 14 CPG SITES WERE HIGHLY METHYLATED IN THE CASE AND CONTROL GROUPS. FURTHER INVESTIGATION OF EXON 9 IN ADAM33 IN A LARGER POPULATION IS NEEDED TO EVALUATE ITS ROLE IN ASTHMA.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
4  3711  26 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
5  5509  38 RHPLD2 INHIBITS AIRWAY INFLAMMATION IN AN ASTHMATIC MURINE MODEL THROUGH INDUCTION OF STABLE CD25(+) FOXP3(+) TREGS. OUR PREVIOUS STUDIES HAVE SHOWN THAT RECOMBINANT HUMAN PHOSPHOLIPASE D2 (RHPLD2) PLAYS A MODULATOR ROLE ON NF-KAPPAB AND PKC SIGNALING PATHWAYS. IT ALSO INHIBITS IL-5-INDUCED INFLAMMATORY RESPONSE IN CHRONIC ASTHMATIC GUINEA PIGS. ADDITIONALLY, INCREASING EVIDENCE ALSO HAS REVEALED THAT THE ADOPTIVE TRANSFER OF INDUCED REGULATORY T CELLS (TREGS) MAY BE A THERAPEUTIC SOLUTION TO AIRWAY ALLERGIC DISEASES. TO INVESTIGATE THE EPIGENETIC, TRANSCRIPTOMIC AND PHENOTYPIC VARIABILITY OF TREG POPULATION IN AN OVALBUMIN (OVA)-INDUCED AIRWAY INFLAMMATION MODEL DERIVED FROM THE INDUCTION OF RHPLD2, OVA-INDUCED ASTHMATIC MURINE MODEL IS USED IN THIS STUDY. THE LUNG INFLAMMATION, EOSINOPHIL INFILTRATION, THE DIFFERENTIATION AND PROLIFERATION OF T HELPER CELLS AND THE AMPLIFICATION OF TREGS WERE EXAMINED IN THIS MOUSE MODEL WITH AND WITHOUT RHPLD2 INDUCTION. OUR DATA SHOWED THAT RHPLD2 ADMINISTRATION IN ASTHMATIC MICE SIGNIFICANTLY INCREASES CD4(+)CD25(+) FOXP3(+) TREG CELL NUMBERS AND ALLEVIATES LUNG INFLAMMATION. THE ADDITION OF RHPLD2 IN VITRO ENHANCED THE DEMETHYLATION OF TREG-SPECIFICDEMETHYLATED REGION (TSDR) IN ITREGS, SUGGESTING THAT RHPLD2 PROTEIN MAY BE INVOLVED IN IMPROVING THE QUALITY AND QUANTITY OF TREG CELLS THAT EVENTUALLY SIGNIFICANTLY REDUCES LUNG INFLAMMATION IN ASTHMATIC MURINE MODEL. THESE RESULTS SUGGEST THAT RHPLD2 COULD HAVE A CLINICAL IMPACT TREATING PATIENTS WITH ALLERGIC AIRWAY INFLAMMATION VIA PROMOTING AND STABILIZING ITREG DIFFERENTIATION AND FUNCTION.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
6  6303  38 THE PUZZLE OF IMMUNE PHENOTYPES OF CHILDHOOD ASTHMA. ASTHMA REPRESENTS THE MOST COMMON CHRONIC CHILDHOOD DISEASE WORLDWIDE. WHEREAS PRESCHOOL CHILDREN PRESENT WITH WHEEZING TRIGGERED BY DIFFERENT FACTORS (MULTITRIGGER AND VIRAL WHEEZE), CLINICAL ASTHMA MANIFESTATION IN SCHOOL CHILDREN HAS PREVIOUSLY BEEN CLASSIFIED AS ALLERGIC AND NON-ALLERGIC ASTHMA. FOR BOTH, THE UNDERLYING IMMUNOLOGICAL MECHANISMS ARE NOT YET UNDERSTOOD IN DEPTH IN CHILDREN. TREATMENT IS STILL PRESCRIBED REGARDLESS OF UNDERLYING MECHANISMS, AND CHILDREN ARE NOT ALWAYS TREATED SUCCESSFULLY. THIS REVIEW SUMMARIZES RECENT KEY FINDINGS ON THE COMPLEX MECHANISMS OF THE DEVELOPMENT AND MANIFESTATION OF CHILDHOOD ASTHMA. WHEREAS TRADITIONAL CLASSIFICATION OF CHILDHOOD ASTHMA IS PRIMARILY BASED ON CLINICAL SYMPTOMS LIKE WHEEZING AND ATOPY, NOVEL APPROACHES TO SPECIFY ASTHMA PHENOTYPES ARE UNDER WAY AND FACE CHALLENGES SUCH AS INCLUDING THE STABILITY OF PHENOTYPES OVER TIME AND TRANSITION INTO ADULTHOOD. EPIDEMIOLOGICAL STUDIES ENCLOSE MORE INFORMATION ON THE PATIENT'S DISEASE HISTORY AND ENVIRONMENTAL INFLUENCES. LATEST STUDIES DEFINE ENDOTYPES BASED ON MOLECULAR AND CELLULAR MECHANISMS, FOR EXAMPLE DEFINING RISK AND PROTECTIVE SINGLE NUCLEOTIDE POLYMORPHISMS (SNPS) AND NEW IMMUNE PHENOTYPES, SHOWING PROMISING RESULTS. ALSO, REGULATORY T CELLS AND RECENTLY DISCOVERED T HELPER CELL SUBTYPES SUCH AS TH9 AND TH17 CELLS WERE SHOWN TO BE IMPORTANT FOR THE DEVELOPMENT OF ASTHMA. INNATE LYMPHOID CELLS (ILC) COULD PLAY A CRITICAL ROLE IN ASTHMA PATIENTS AS THEY PRODUCE DIFFERENT CYTOKINES ASSOCIATED WITH ASTHMA. EPIGENETIC FINDINGS SHOWED DIFFERENT ACETYLATION AND METHYLATION PATTERNS FOR CHILDREN WITH ALLERGIC AND NON-ALLERGIC ASTHMA. ON A POSTTRANSCRIPTIONAL LEVEL, MIRNAS ARE REGULATING FACTORS IDENTIFIED TO DIFFER BETWEEN ASTHMA PATIENTS AND HEALTHY CONTROLS AND ALSO INDICATE DIFFERENCES WITHIN ASTHMA PHENOTYPES. METABOLOMICS IS ANOTHER EXCITING CHAPTER IMPORTANT FOR ENDOTYPING ASTHMATIC CHILDREN. DESPITE THE DEVELOPMENT OF NEW BIOMARKERS AND THE DISCOVERY OF NEW IMMUNOLOGICAL MOLECULES, THE COMPLEX PUZZLE OF CHILDHOOD ASTHMA IS STILL FAR FROM BEING COMPLETED. ADDRESSING THE CURRENT CHALLENGES OF DISTINCT CLINICAL ASTHMA AND WHEEZE PHENOTYPES, INCLUDING THEIR STABILITY AND UNDERLYING ENDOTYPES, INVOLVES ADDRESSING THE INTERPLAY OF INNATE AND ADAPTIVE IMMUNE REGULATORY MECHANISMS IN LARGE, INTERDISCIPLINARY COHORTS.	2016	
                                                                                                                                                                                                                                                                                                                                                        
7  1852  31 ELECTRONIC CIGARETTES: THEIR CONSTITUENTS AND POTENTIAL LINKS TO ASTHMA. PURPOSE OF REVIEW: VAPING IS GAINING POPULARITY IN THE USA, PARTICULARLY AMONG TEENS AND YOUNG ADULTS. WHILE E-CIGS ARE COMMONLY REPRESENTED AS SAFER ALTERNATIVES TO TOBACCO CIGARETTES, LITTLE IS KNOWN REGARDING THE HEALTH EFFECTS OF THEIR SHORT- OR LONG-TERM USE, ESPECIALLY IN INDIVIDUALS WITH PRE-EXISTING RESPIRATORY DISEASES SUCH AS ASTHMA. FLAVORED E-CIG LIQUIDS (E-LIQUIDS) AND E-CIG AEROSOLS CONTAIN AIRWAY IRRITANTS AND TOXICANTS THAT HAVE BEEN IMPLICATED IN THE PATHOGENESIS AND WORSENING OF LUNG DISEASES. IN THIS REVIEW, WE WILL SUMMARIZE EXISTING DATA ON POTENTIAL HEALTH EFFECTS OF COMPONENTS PRESENT IN E-CIG AEROSOLS, SUCH AS PROPYLENE GLYCOL, VEGETABLE GLYCERIN, NICOTINE, AND FLAVORINGS, AND DISCUSS THEIR RELEVANCE IN THE CONTEXT OF ASTHMA. RECENT FINDINGS: RECENT SURVEY DATA INDICATE THAT ADOLESCENTS WITH ASTHMA HAD A HIGHER PREVALENCE OF CURRENT E-CIG USE (12.4%) COMPARED TO THEIR NON-ASTHMATICS PEERS (10.2%) AND CONVEYED POSITIVE BELIEFS ABOUT TOBACCO PRODUCTS, ESPECIALLY E-CIGS. SIMILARLY, A STUDY CONDUCTED AMONG HIGH SCHOOL STUDENTS FROM ONTARIO, CANADA, INDICATED A GREATER LIKELIHOOD OF E-CIG USE IN ASTHMATICS AS COMPARED TO THEIR NON-ASTHMATIC PEERS. AVAILABILITY OF DIFFERENT FLAVORINGS IS OFTEN CITED AS THE MAIN REASON AMONG YOUTH/ADOLESCENTS FOR TRYING E-CIGS OR SWITCHING FROM CIGARETTES TO E-CIGS. OCCUPATIONAL INHALATION OF SOME COMMON FOOD-SAFE FLAVORING AGENTS IS REPORTED TO CAUSE OCCUPATIONAL ASTHMA AND WORSEN ASTHMATIC SYMPTOMS. MOREOVER, WORKPLACE INHALATION EXPOSURES TO THE FLAVORING AGENT DIACETYL HAVE CAUSED IRREVERSIBLE OBSTRUCTIVE AIRWAY DISEASE IN HEALTHY WORKERS. ADDITIONALLY, RECENT STUDIES REPORT THAT THERMAL DECOMPOSITION OF PROPYLENE GLYCOL (PG) AND VEGETABLE GLYCERIN (VG), THE BASE CONSTITUENTS OF E-LIQUIDS, PRODUCES REACTIVE CARBONYLS, INCLUDING ACROLEIN, FORMALDEHYDE, AND ACETALDEHYDE, WHICH HAVE KNOWN RESPIRATORY TOXICITIES. FURTHERMORE, RECENT NICOTINE STUDIES IN RODENTS REVEAL THAT PRENATAL NICOTINE EXPOSURES LEAD TO EPIGENETIC REPROGRAMMING IN THE OFFSPRING, ABNORMAL LUNG DEVELOPMENT, AND MULTIGENERATIONAL TRANSMISSION OF ASTHMATIC-LIKE SYMPTOMS. COMPARISONS OF THE TOXICITY AND HEALTH EFFECTS OF E-CIGS AND CONVENTIONAL CIGARETTES OFTEN FOCUS ON TOXICANTS KNOWN TO BE PRESENT IN CIGARETTE SMOKE (CS) (I.E., FORMALDEHYDE, NITROSAMINES, ETC.), AS WELL AS SMOKING-ASSOCIATED CLINICAL ENDPOINTS, SUCH AS CANCER, BRONCHITIS, AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). HOWEVER, THIS APPROACH DISREGARDS POTENTIAL TOXICITY OF COMPONENTS UNIQUE TO FLAVORED E-CIGS, SUCH AS PG, VG, AND THE MANY DIFFERENT FLAVORING CHEMICALS, WHICH LIKELY INDUCE RESPIRATORY EFFECTS NOT USUALLY OBSERVED IN CIGARETTE SMOKERS.	2017	

8   517  41 ASSOCIATION STUDY OF FOXO3A SINGLE-NUCLEOTIDE POLYMORPHISM AND BRONCHIAL ASTHMA IN EGYPTIAN CHILDREN. ASTHMA IS THE MOST COMMON CHRONIC ILLNESS IN CHILDREN AND IS A LEADING CAUSE OF CHILDHOOD HOSPITALIZATION AND SCHOOL ABSENTEEISM. ASTHMA PRESENTS WITH DIFFERENT PHENOTYPES DEPENDING ON AGE, GENDER, GENETIC BACKGROUND, ENVIRONMENTAL EXPOSURES AND EPIGENETIC FACTORS. FORKHEAD BOX O3 (FOXO3) IS A TRANSCRIPTION FACTOR INVOLVED IN THE PATHOGENESIS OF A NUMBER OF INFLAMMATORY AND RESPIRATORY DISEASES. THE STUDY AIMS TO INVESTIGATE THE ASSOCIATION BETWEEN THE SNP RS13217795 IN FOXO3 GENE AND PEDIATRIC ONSET ASTHMA IN THE EGYPTIAN POPULATION. NINETY ASTHMATICS AND 160 HEALTHY CONTROLS WERE SUBJECTED TO GENOTYPING OF FOXO3 SNP (RS13217795) USING THE PCR-RFLP METHOD. THE PROPORTION OF HOMOZYGOUS (CC) AND HETEROZYGOUS (CT) GENOTYPES WAS LOWER IN THE ASTHMATIC GROUP COMPARED TO THE CONTROL GROUP BUT STATISTICALLY INSIGNIFICANT; P > 0.05. ON THE OTHER HAND THE PROPORTION OF THE MUTANT HOMOZYGOUS (TT) GENOTYPE IN ASTHMATIC GROUP WAS HIGHER; 30 (33.3%) THAN THE CONTROL GROUP; 28(17.5%), THE DIFFERENCE WAS SIGNIFICANT IN RECESSIVE MODEL OF DISEASE PENETRANCE WITH ODDS RATIO OR (95% CI) OF 2.4(1 - 5.49) AND P=0.039. THIS ASSOCIATION WAS MORE PRONOUNCED IN MALE GENDER; OR AND 95% CI OF 5.3 (1.4- 19.3) AND P=0.01. IN CONCLUSIONS, EGYPTIAN CHILDREN CARRYING THE MUTANT (TT) GENOTYPE WERE AT HIGHER RISK TO DEVELOP ASTHMA WITH A HIGHER RISK IN MALE GENDER.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
9  6161  23 THE GENETICS OF ASTHMA: ADAM33 AS AN EXAMPLE OF A SUSCEPTIBILITY GENE. THE ABILITY TO IDENTIFY NOVEL DISEASE GENES BY POSITIONAL CLONING LED TO THE IDENTIFICATION OF A DISINTEGRIN AND METALLOPROTEASE (ADAM)33 GENE ON CHROMOSOME 20P13 AS A SUSCEPTIBILITY GENE FOR ASTHMA. CASE-CONTROL AND FAMILY-BASED ASSOCIATION STUDIES HAVE MOSTLY CONFIRMED A LINK BETWEEN ADAM33 AND ASTHMA. ITS RESTRICTED EXPRESSION TO MESENCHYMAL CELLS AS WELL AS ITS ASSOCIATION WITH BRONCHIAL HYPERRESPONSIVENESS AND ACCELERATED DECLINE IN LUNG FUNCTION OVER TIME POINT STRONGLY TO ITS INVOLVEMENT IN THE STRUCTURAL AIRWAY COMPONENTS OF ASTHMA, SUCH AS REMODELING. EXTENSIVE ALTERNATIVE SPLICING, EXPRESSION DURING BRANCHING MORPHOGENSIS IN THE DEVELOPING FETUS, IMPAIRED LUNG FUNCTION IN CHILDHOOD, THE PRODUCTION OF A SOLUBLE FORM LINKED TO CHRONIC ASTHMA, AND TIGHT EPIGENETIC REGULATION INDICATE A LEVEL OF COMPLEXITY IN THE WAY ADAM33 INFLUENCES DISEASE PHENOTYPE. ITS RECENT ASSOCIATION WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE AS WELL AS WITH ASTHMA AND LUNG DEVELOPMENT POINTS TO FUNCTIONS RELATING TO AIRWAY WALL MODELING AND REMODELING AS A GENERAL MORPHOGENETIC REPAIR GENE RATHER THAN BEING RESTRICTED TO ASTHMA.	2006	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
10  6071  46 THE DNA METHYLATION INHIBITOR 5-AZACYTIDINE INCREASES REGULATORY T CELLS AND ALLEVIATES AIRWAY INFLAMMATION IN OVALBUMIN-SENSITIZED MICE. BACKGROUND: ASTHMA IS CHARACTERIZED AS A CHRONIC INFLAMMATORY DISORDER OF THE AIRWAYS ASSOCIATED WITH AN ENHANCED TH2 RESPONSE TO INHALED ALLERGENS. CD4+ T REGULATORY (TREG) CELLS ARE CONTROLLED BY THE MASTER TRANSCRIPTION FACTOR FOXP3 AND STRICTLY MAINTAIN PERIPHERAL IMMUNOTOLERANCE. EPIGENETIC REGULATION OF FOXP3 BY DNA METHYLTRANSFERASE INHIBITORS, SUCH AS 5-AZACYTIDINE (AZA), CAN GENERATE A STEADY SUPPLY OF FUNCTIONAL TREG CELLS. THEREFORE, WE PROPOSE THAT AZA CAN AUGMENT TREG CELLS IN VIVO TO PREVENT THE PATHOGENESIS OF ASTHMA. METHODS: BALB/C MICE WERE SENSITIZED WITH CHICKEN OVALBUMIN (OVA) AND TREATED WITH DIFFERENT DOSES OF AZA. AIRWAY HYPERRESPONSIVENESS TO METHACHOLINE, EOSINOPHILIA IN BRONCHOALVEOLAR LAVAGE FLUID, CIRCULATING TITERS OF OVA-SPECIFIC IGG1 AND IGE, AND STIMULATING LEVELS OF TH2 CYTOKINES FROM SPLENOCYTES WERE THEN DETERMINED. CELLULAR POPULATIONS WERE EXAMINED BY FLOW CYTOMETRY. PC61 ANTIBODY, WHICH DEPLETES CD25+ CELLS, WAS USED TO VERIFY THE ROLE OF CD25+ CELLS IN AZA-INDUCED TOLERANCE. RESULTS: ADMINISTRATION OF AZA TO OVA-SENSITIZED MICE DIMINISHED AIRWAY HYPERREACTIVITY, PULMONARY EOSINOPHILIA, LEVELS OF OVA-SPECIFIC IGG1 AND IGE IN SERUM, AND SECRETION OF TH2 CYTOKINES FROM OVA-STIMULATED SPLENOCYTES IN A DOSE-DEPENDENT MANNER. PERCENTAGES OF CD25+ AND FOXP3+ CELLS IN THE CD4+ CELL POPULATION WERE NOTABLY INCREASED IN AZA-TREATED MICE COMPARED TO SENSITIZED CONTROL MICE. FURTHERMORE, THE MAJOR SYMPTOMS OF ASTHMA WERE EXACERBATED BY DEPLETING CD25+ CELLS IN AZA-TREATED MICE. CONCLUSIONS: AZA MAY HAVE APPLICATIONS AS A NOVEL CLINICAL STRATEGY TO INCREASE THE PRODUCTION OF TREG CELLS IN ORDER TO MODULATE THE AIRWAY INFLAMMATION ASSOCIATED WITH ASTHMA.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
11  5398  33 REDUCED MOUSE ALLERGEN IS ASSOCIATED WITH EPIGENETIC CHANGES IN REGULATORY GENES, BUT NOT MOUSE SENSITIZATION, IN ASTHMATIC CHILDREN. CHRONIC EXPOSURE TO MOUSE ALLERGEN MAY CONTRIBUTE GREATLY TO THE INNER-CITY ASTHMA BURDEN. WE HYPOTHESIZED THAT REDUCING MOUSE ALLERGEN EXPOSURE MAY MODULATE THE IMMUNOPATHOLOGY UNDERLYING SYMPTOMATIC PEDIATRIC ALLERGIC ASTHMA, AND THAT THIS OCCURS THROUGH EPIGENETIC REGULATION. TO TEST THIS HYPOTHESIS, WE STUDIED A COHORT OF MOUSE SENSITIZED, PERSISTENT ASTHMATIC INNER-CITY CHILDREN UNDERGOING MOUSE ALLERGEN-TARGETED INTEGRATED PEST MANAGEMENT (IPM) VS EDUCATION IN A RANDOMIZED CONTROLLED INTERVENTION TRIAL. WE FOUND THAT DECREASING MOUSE ALLERGEN EXPOSURE, BUT NOT COCKROACH, WAS ASSOCIATED WITH REDUCED FOXP3 BUCCAL DNA PROMOTER METHYLATION, BUT THIS WAS UNRELATED TO MOUSE SPECIFIC IGE PRODUCTION. THIS FINDING SUGGESTS THAT THE ENVIRONMENTAL EPIGENETIC REGULATION OF AN IMMUNOMODULATORY GENE MAY OCCUR FOLLOWING CHANGING ALLERGEN EXPOSURES IN SOME HIGHLY EXPOSED COHORTS. GIVEN THE CLINICAL AND PUBLIC HEALTH IMPORTANCE OF INNER-CITY PEDIATRIC ASTHMA AND THE POTENTIAL IMPACT OF ENVIRONMENTAL INTERVENTIONS, FURTHER STUDIES WILL BE NEEDED TO CORROBORATE CHANGES IN EPIGENETIC REGULATION FOLLOWING CHANGING EXPOSURES OVER TIME, AND DETERMINE THEIR IMPACT ON ASTHMA MORBIDITY IN SUSCEPTIBLE CHILDREN.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
12  3993  31 LONGITUDINAL FOLLOW-UP OF THE ASTHMA STATUS IN A FRENCH-CANADIAN COHORT. ASTHMA AFFECTS 340 MILLION PEOPLE WORLDWIDE AND VARIES IN TIME. TWENTY YEARS AGO, IN CANADA, THE SAGUENAY-LAC-SAINT-JEAN ASTHMA FAMILY COHORT WAS CREATED TO STUDY THE GENETIC AND ENVIRONMENTAL COMPONENTS OF ASTHMA. THIS STUDY IS A FOLLOW-UP OF 125 PARTICIPANTS OF THIS COHORT TO EXPLORE THE APPEARANCE, PERSISTENCE, AND PROGRESSION OF ASTHMA OVER 10-20 YEARS. PARTICIPANTS ANSWERED A CLINICAL STANDARDIZED QUESTIONNAIRE. LUNG FUNCTION WAS ASSESSED (FORCED EXPIRATORY VOLUME IN 1 S, FORCED VITAL CAPACITY, BRONCHIAL REVERSIBILITY, AND METHACHOLINE BRONCHOPROVOCATION), SKIN ALLERGY TESTING WAS PERFORMED, BLOOD SAMPLES WERE OBTAINED (IMMUNOGLOBULIN E, WHITE BLOOD CELL COUNTS) AND PHENOTYPES WERE COMPARED BETWEEN RECRUITMENT AND FOLLOW-UP. FROM THE PARTICIPANTS WITHOUT ASTHMA AT RECRUITMENT, 12% DEVELOPED A PHENOTYPE OF ADULT-ONSET ASTHMA WITH THE PRESENCE OF RISK FACTORS, SUCH AS ATOPY, HIGH BODY MASS INDEX, AND EXPOSURE TO SMOKING. A DECREASE OF PC(20) VALUES IN THIS GROUP WAS OBSERVED AND A DECREASE IN THE FEV(1)/FVC RATIO IN ALL GROUPS. ALSO, 7% OF INDIVIDUALS WITH ASTHMA AT RECRUITMENT DEVELOPED CHRONIC OBSTRUCTIVE PULMONARY DISEASE, PRESENTING RISK FACTORS AT RECRUITMENT, SUCH AS MODERATE-TO-SEVERE BRONCHIAL HYPERRESPONSIVENESS, EXPOSURE TO SMOKING, AND ASTHMA. THIS STUDY ALLOWED A BETTER INTERPRETATION OF THE EVOLUTION OF ASTHMA. FINE PHENOTYPIC CHARACTERIZATION IS THE FIRST STEP FOR MEANINGFUL GENETIC AND EPIGENETIC STUDIES.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
13  1694  36 DUST MITE ALLERGEN-SPECIFIC IMMUNOTHERAPY INCREASES IL4 DNA METHYLATION AND INDUCES DER P-SPECIFIC T CELL TOLERANCE IN CHILDREN WITH ALLERGIC ASTHMA. ALLERGEN-SPECIFIC IMMUNOTHERAPY (ALLERGEN-SIT) IS A HIGHLY EFFECTIVE TREATMENT FOR CHILDREN WITH ALLERGIC ASTHMA (AA), AN IMMUNE-MEDIATED CHRONIC DISEASE LEADING TO BRONCHIAL MUSCLE HYPERTROPHY AND AIRWAY OBSTRUCTION IN RESPONSE TO SPECIFIC ALLERGENS. T HELPER CELLS AND SECRETED CYTOKINES PLAY IMPORTANT ROLES IN THE PATHOGENESIS OF ASTHMA, AND EPIGENETIC MODULATION CONTROLS GENES IMPORTANT FOR T CELL DEVELOPMENT AND CYTOKINE EXPRESSION. THIS STUDY EVALUATED T HELPER CELL-SECRETED CYTOKINES AND DNA METHYLATION PATTERNS IN CHILDREN TREATED WITH DERMATOPHAGOIDES PTERONYSSINUS (DER P) ALLERGEN-SIT. OUR RESULTS SHOWED THAT AFTER DER P CHALLENGE, PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) FROM THE SIT GROUP, COMPARED WITH THE NON-SIT AA GROUP, PRODUCED LOWER LEVELS OF IL-4, IL-5 AND IL-2. THE SIT GROUP, COMPARED WITH THE AA GROUP, EXHIBITED DECREASED SENSITIVITY TO THE DER P ALLERGEN, CONCURRENT WITH IL-4 DOWN-MODULATION DUE TO INCREASED PROMOTER DNA METHYLATION, AS ESTIMATED IN PBMCS. OUR RESULTS SHOWED THAT SIT DECREASED IL-4 AND IL-5, AND INHIBITED T CELL PROLIFERATION, BY INHIBITING IL-2 PRODUCTION AFTER THE SPECIFIC ALLERGEN CHALLENGE. THESE RESULTS SUGGEST THAT DECREASED IL-2 PRODUCTION AND INCREASED IL-4 CYTOKINE PROMOTER METHYLATION IS A POTENTIAL MECHANISM OF DER P-SPECIFIC ALLERGEN DESENSITIZATION IMMUNOTHERAPY.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
14  2369  35 EPIGENETIC REGULATION OF T-HELPER CELL DIFFERENTIATION, MEMORY, AND PLASTICITY IN ALLERGIC ASTHMA. AN ESTIMATED 300 MILLION PEOPLE CURRENTLY SUFFER FROM ASTHMA, WHICH CAUSES APPROXIMATELY 250 000 DEATHS A YEAR. ALLERGEN-SPECIFIC T-HELPER (TH) CELLS PRODUCE CYTOKINES THAT INDUCE MANY OF THE HALLMARK FEATURES OF ASTHMA INCLUDING AIRWAYS HYPERREACTIVITY, EOSINOPHILIC AND NEUTROPHILIC INFLAMMATION, MUCUS HYPERSECRETION, AND AIRWAY REMODELING. CYTOKINE-PRODUCING TH SUBSETS INCLUDING TH1 (IFN-GAMMA), TH2 (IL-4, IL-5, IL-13), TH9 (IL-9), TH17 (IL-17), TH22 (IL-22), AND T REGULATORY (IL-10) CELLS HAVE ALL BEEN SUGGESTED TO PLAY A ROLE IN THE DEVELOPMENT OF ASTHMA. TH DIFFERENTIATION INVOLVES GENETIC REGULATION OF GENE EXPRESSION THROUGH THE CONCERTED ACTION OF CYTOKINES, TRANSCRIPTION FACTORS, AND EPIGENETIC REGULATORS. WE DESCRIBE HOW TH DIFFERENTIATION AND PLASTICITY IS REGULATED BY EPIGENETIC HISTONE AND DNA MODIFICATIONS, WITH A FOCUS ON THE REGULATION OF HISTONE METHYLATION BY MEMBERS OF THE POLYCOMB AND TRITHORAX COMPLEXES. IN ADDITION, WE OUTLINE ENVIRONMENTAL INFLUENCES THAT COULD INFLUENCE EPIGENETIC REGULATION OF TH CELLS AND DISCUSS THE POTENTIAL TO REGULATE TH PLASTICITY AND FUNCTION THROUGH DRUGS TARGETING THE EPIGENETIC MACHINERY. IT IS ALSO BECOMING APPARENT THAT EPIGENETIC REGULATION OF ALLERGEN-SPECIFIC MEMORY TH CELLS MAY BE IMPORTANT IN THE DEVELOPMENT AND PERSISTENCE OF CHRONIC ALLERGIES. FINALLY, WE DESCRIBE HOW EPIGENETIC MODIFIERS REGULATE CYTOKINE MEMORY IN TH CELLS AND DESCRIBE RECENTLY IDENTIFIED HYBRID, PLASTIC, AND PATHOGENIC MEMORY TH SUBSETS THE CONTEXT OF ALLERGIC ASTHMA.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
15  3563  39 IMPACT OF FRAILTY IN ELDERLY PATIENTS WITH MODERATE TO SEVERE ASTHMA. FRAILTY ASSESSMENT HAS BEEN IDENTIFIED AS CRITICAL APPROACH IN CHRONIC RESPIRATORY DISEASES WITH SUBSTANTIAL IMPACT IN THE HEALTH STATUS AND FUNCTIONALITY IN LATER LIFE. AGING MODIFIES THE IMMUNE RESPONSE LEADING TO A CHRONIC PRO-INFLAMMATORY STATE AND INCREASED SUSCEPTIBILITY TO AIRWAY INFECTIONS. SINCE EPIGENETIC CHANGES, AIRWAY EPITHELIUM DYSFUNCTION AND INFLAMMATORY CYTOKINE ACTIVITY SEEM TO BE MORE PRONOUNCED IN THE IMMUNOSENESCENCE, ELDERLY ASTHMATICS ARE AT HIGHER RISK OF POOR CLINICAL OUTCOMES. THEREFORE, WE HYPOTHESIZE THAT FRAILTY WOULD BE ASSOCIATED WITH THE DEGREE OF ASTHMA CONTROL IN ELDERLY PATIENTS WITH MODERATE TO SEVERE ASTHMA. THE AIMS OF THIS STUDY ARE TO INVESTIGATE ASSOCIATION BETWEEN FRAILTY AND ASTHMA CONTROL IN PATIENTS OVER 60 YEARS OLD TO ESTIMATE THE PREVALENCE OF FRAILTY IN THIS STUDY POPULATION. WE PLAN TO CONDUCT A CROSS-SECTIONAL STUDY WITH AT LEAST 120 PATIENTS ABOVE 60 YEARS OLD WITH DIAGNOSTIC OF MODERATE TO SEVERE ASTHMA ACCORDING TO GLOBAL INITIATIVE FOR ASTHMA (GINA) GUIDELINES, TREATED AT A REFERRAL OUTPATIENT CLINIC. WE DEFINED ASTHMA CONTROL BY THE SIX-DOMAIN ASTHMA CONTROL QUESTIONNAIRE (ACQ-6) AND FRAILTY PHENOTYPE IN ACCORDANCE WITH FRIED SCALE AND VISUAL SCALE OF FRAILTY (VS-FRAILTY). WE HOPE TO ANALYZE THE MULTIDIMENSIONAL RELATIONSHIPS BETWEEN FRAILTY AND ASTHMA AND CONTRIBUTE TO INNOVATIVE THERAPEUTIC PLANS IN GERIATRIC ASTHMA.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
16  5138  29 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
17  2022  49 EPIGENETIC CHANGES ASSOCIATED WITH DISEASE PROGRESSION IN A MOUSE MODEL OF CHILDHOOD ALLERGIC ASTHMA. DEVELOPMENT OF ASTHMA IN CHILDHOOD IS LINKED TO VIRAL INFECTIONS OF THE LOWER RESPIRATORY TRACT IN EARLY LIFE, WITH SUBSEQUENT CHRONIC EXPOSURE TO ALLERGENS. PROGRESSION TO PERSISTENT ASTHMA IS ASSOCIATED WITH A TH2-BIASED IMMUNOLOGICAL RESPONSE AND STRUCTURAL REMODELLING OF THE AIRWAYS. THE UNDERLYING MECHANISMS ARE UNCLEAR, BUT COULD INVOLVE EPIGENETIC CHANGES. TO INVESTIGATE THIS, WE EMPLOYED A RECENTLY DEVELOPED MOUSE MODEL IN WHICH SELF-LIMITED NEONATAL INFECTION WITH A PNEUMOVIRUS, FOLLOWED BY SENSITISATION TO OVALBUMIN VIA THE RESPIRATORY TRACT AND LOW-LEVEL CHRONIC CHALLENGE WITH AEROSOLISED ANTIGEN, LEADS TO DEVELOPMENT OF AN ASTHMATIC PHENOTYPE. WE ASSESSED EXPRESSION OF MICRORNA BY CELLS IN THE PROXIMAL AIRWAYS, COMPARING CHANGES OVER THE PERIOD OF DISEASE PROGRESSION, AND USED TARGET PREDICTION DATABASES TO IDENTIFY GENES LIKELY TO BE UP- OR DOWNREGULATED AS A CONSEQUENCE OF ALTERED REGULATION OF MICRORNA. IN PARALLEL, WE ASSESSED DNA METHYLATION IN PULMONARY CD4(+) T CELLS. WE FOUND THAT A LIMITED NUMBER OF MICRORNAS EXHIBITED MARKED UP- OR DOWNREGULATION FOLLOWING EARLY-LIFE INFECTION AND SENSITISATION, FOR MANY OF WHICH THE LEVELS OF EXPRESSION WERE FURTHER CHANGED FOLLOWING CHRONIC CHALLENGE WITH THE SENSITIZING ANTIGEN. TARGETS OF THESE MICRORNAS INCLUDED GENES INVOLVED IN IMMUNE OR INFLAMMATORY RESPONSES (E.G. GATA3, KITL) AND IN TISSUE REMODELLING (E.G. IGF1, TGFBR1), AS WELL AS GENES FOR VARIOUS TRANSCRIPTION FACTORS AND SIGNALLING PROTEINS. IN PULMONARY CD4(+) T CELLS, THERE WAS SIGNIFICANT DEMETHYLATION AT PROMOTER SITES FOR INTERLEUKIN-4 AND INTERFERON-GAMMA, THE LATTER INCREASING FOLLOWING CHRONIC CHALLENGE. WE CONCLUDE THAT, IN THIS MODEL, PROGRESSION TO AN ASTHMATIC PHENOTYPE IS LINKED TO EPIGENETIC REGULATION OF GENES ASSOCIATED WITH INFLAMMATION AND STRUCTURAL REMODELLING, AND WITH T-CELL COMMITMENT TO A TH2 IMMUNOLOGICAL RESPONSE. EPIGENETIC CHANGES ASSOCIATED WITH THIS PATTERN OF GENE ACTIVATION MIGHT PLAY A ROLE IN THE DEVELOPMENT OF CHILDHOOD ASTHMA.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
18  6005  36 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
19   305  25 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
20  2519  38 EPIGENETICS AND THE ENVIRONMENT IN AIRWAY DISEASE: ASTHMA AND ALLERGIC RHINITIS. ASTHMA AND RHINITIS ARE COMPLEX, HETEROGENEOUS DISEASES CHARACTERIZED BY CHRONIC INFLAMMATION OF THE UPPER AND LOWER AIRWAYS. WHILE GENOME-WIDE ASSOCIATION STUDIES (GWAS) HAVE IDENTIFIED A NUMBER OF SUSCEPTIBLE LOCI AND CANDIDATE GENES ASSOCIATED WITH THE PATHOGENESIS OF ASTHMA AND ALLERGIC RHINITIS (AR), THE RISK-ASSOCIATED ALLELES ACCOUNT FOR ONLY A VERY SMALL PERCENT OF THE GENETIC RISK. IN ALLERGIC AIRWAY AND OTHER COMPLEX DISEASES, IT IS THOUGHT THAT EPIGENETIC MODIFICATIONS, INCLUDING DNA METHYLATION, HISTONE MODIFICATIONS, AND NON-CODING MICRORNAS, CAUSED BY COMPLEX INTERACTIONS BETWEEN THE UNDERLYING GENOME AND THE ENVIRONMENT MAY ACCOUNT FOR SOME OF THIS "MISSING HERITABILITY" AND MAY EXPLAIN THE HIGH DEGREE OF PLASTICITY IN IMMUNE RESPONSES. IN THIS CHAPTER, WE WILL FOCUS ON THE CURRENT KNOWLEDGE OF CLASSICAL EPIGENETIC MODIFICATIONS, DNA METHYLATION AND HISTONE MODIFICATIONS, AND THEIR POTENTIAL ROLE IN ASTHMA AND AR. IN PARTICULAR, WE WILL REVIEW EPIGENETIC VARIATIONS ASSOCIATED WITH MATERNAL AIRWAY DISEASE, DEMOGRAPHICS, ENVIRONMENT, AND NON-SPECIFIC ASSOCIATIONS. THE ROLE OF SPECIFIC GENETIC HAPLOTYPES IN ENVIRONMENTALLY INDUCED EPIGENETIC CHANGES ARE ALSO DISCUSSED. A MAJOR LIMITATION OF MANY OF THE CURRENT STUDIES OF ASTHMA EPIGENETICS IS THAT THEY EVALUATE EPIGENETIC MODIFICATIONS IN BOTH ALLERGIC AND NON-ALLERGIC ASTHMA, MAKING IT DIFFICULT TO DISTINGUISH THOSE EPIGENETIC MODIFICATIONS THAT MEDIATE ALLERGIC ASTHMA FROM THOSE THAT MEDIATE NON-ALLERGIC ASTHMA. ADDITIONALLY, MOST DNA METHYLATION STUDIES IN ASTHMA USE PERIPHERAL OR CORD BLOOD DUE TO POOR ACCESSIBILITY OF AIRWAY CELLS OR TISSUE. UNLIKE DNA SEQUENCES, EPIGENETIC ALTERATIONS ARE QUITE CELL- AND TISSUE-SPECIFIC, AND EPIGENETIC CHANGES FOUND IN AIRWAY TISSUE OR CELLS MAY BE DISCORDANT FROM THAT OF CIRCULATING BLOOD. THESE TWO CONFOUNDING FACTORS SHOULD BE CONSIDERED WHEN REVIEWING EPIGENETIC STUDIES IN ALLERGIC AIRWAY DISEASE.	2020