1 6269 135 THE NEXT CHALLENGE IN PEDIATRIC CHOLESTASIS: DECIPHERING THE PATHOGENESIS OF BILIARY ATRESIA. CHOLESTASIS IS A COMMON PRESENTING SYMPTOM OF LIVER DISEASE IN INFANTS. CHIEF AMONG DISEASES PRESENTING AS NEONATAL CHOLESTASIS IS BILIARY ATRESIA, THE MOST COMMON CAUSE OF CHRONIC LIVER DISEASE IN CHILDREN, BUT LITTLE IS KNOWN ABOUT THE PATHOGENESIS OF THIS DISEASE. IN SEARCH FOR THE MOLECULAR BASIS OF BILIARY ATRESIA, WE BEGAN TWO AREAS OF INVESTIGATION. IN THE FIRST, WE INTERROGATED THE HEPATIC TRANSCRIPTOME OF CHILDREN WITH BILIARY ATRESIA AND FOUND AN INTERFERON-GAMMA (IFNGAMMA)-RICH PROINFLAMMATORY FOOTPRINT AT THE TIME OF DIAGNOSIS. TO DIRECTLY EXPLORE IF IFNGAMMA PLAYS AN IMPORTANT ROLE IN BILIARY INJURY AND OBSTRUCTION, WE USED A MOUSE MODEL OF EXPERIMENTAL BILIARY ATRESIA AND FOUND THAT INACTIVATION OF THE MURINE IFNGAMMA GENE DECREASES THE TROPISM OF LYMPHOCYTES TO NEONATAL BILE DUCTS AND PREVENTS THE INFLAMMATORY OBSTRUCTION OF THE DUCT LUMEN. FURTHER ANALYSIS OF THE EXTRAHEPATIC BILIARY TRACT ALSO OUTLINED A BROADER NETWORK OF PROINFLAMMATORY GENES AT THE ONSET AND DURING PROGRESSION TO DUCT OBSTRUCTION, WITH THE TIME-SPECIFIC ACTIVATION OF IFNGAMMA-, APOPTOSIS-, AND COMPLEMENT-DRIVEN NETWORKS. IN THE SECOND APPROACH, WE SEARCHED FOR MOLECULAR PROFILES THAT DIFFERENTIATE CLINICAL FORMS OF BILIARY ATRESIA BY ANALYZING THE HEPATIC TRANSCRIPTOME OF AGE-MATCHED SUBJECTS AT THE TIME OF DIAGNOSIS. WE FOUND A PRELIMINARY PROFILE THAT DIFFERENTIATES THE EMBRYONIC FROM THE PERINATAL FORMS OF BILIARY ATRESIA. THE PROFILE CONTAINED THE DIFFERENTIAL ACTIVATION OF GENES INVOLVED IN EPIGENETIC MECHANISMS OF DISEASE. COLLECTIVELY, THESE STUDIES PROVIDE NEW INSIGHT INTO PATHOGENESIS OF BILIARY ATRESIA AND IDENTIFY POTENTIAL THERAPEUTIC TARGETS TO FOSTER LONG-TERM OUTCOME WITH THE NATIVE LIVER. 2006 2 6650 33 UPDATE ON ETIOLOGY AND PATHOGENESIS OF BILIARY ATRESIA. BILIARY ATRESIA IS A RARE INFLAMMATORY SCLEROSING OBSTRUCTIVE CHOLANGIOPATHY THAT INITIATES IN INFANCY AS COMPLETE CHOLEDOCHAL BLOCKAGE AND PROGRESSES TO THE INVOLVEMENT OF INTRAHEPATIC BILIARY EPITHELIUM. GROWING EVIDENCE SHOWS THAT BILIARY ATRESIA IS NOT A SINGLE ENTITY WITH A SINGLE ETIOLOGY BUT A PHENOTYPE RESULTING FROM MULTIFACTORIAL EVENTS WHOSE COMMON PATH IS OBLITERATIVE CHOLANGIOPATHY. THE ETIOLOGY OF BILIARY ATRESIA HAS BEEN EXPLAINED AS RESULTING FROM GENETIC VARIANTS, TOXINS, VIRAL INFECTION, CHRONIC INFLAMMATION OR BILE DUCT LESIONS MEDIATED BY AUTOIMMUNITY, ABNORMALITIES IN THE DEVELOPMENT OF THE BILE DUCTS, AND DEFECTS IN EMBRYOGENESIS, ABNORMAL FETAL OR PRENATAL CIRCULATION AND SUSCEPTIBILITY FACTORS. IT IS INCREASINGLY EVIDENT THAT THE GENETIC AND EPIGENETIC PREDISPOSITION COMBINED WITH THE ENVIRONMENTAL FACTORS TO WHICH THE MOTHER IS EXPOSED ARE POTENTIAL TRIGGERS FOR BILIARY ATRESIA. THERE IS ALSO AN INDICATION THAT A PROGRESSIVE THICKENING OF THE ARTERIAL MIDDLE LAYER OCCURS IN THIS DISEASE, SUGGESTIVE OF VASCULAR REMODELING AND DISAPPEARANCE OF THE INTERLOBULAR BILE DUCTS. IT IS SUGGESTED THAT THE HYPOXIA/ISCHEMIA PROCESS CAN AFFECT PORTAL STRUCTURES IN BILIARY ATRESIA AND IS ASSOCIATED WITH BOTH THE EXTENT OF BILIARY PROLIFERATION AND THE THICKENING OF THE MEDIAL LAYER. 2022 3 4472 38 MOLECULAR PATHOGENESIS OF CHOLANGIOCARCINOMA. BACKGROUND: CHOLANGIOCARCINOMAS ARE A HETEROGENEOUS GROUP OF MALIGNANCIES ARISING FROM A NUMBER OF CELLS OF ORIGIN ALONG THE BILIARY TREE. ALTHOUGH MOST CASES IN WESTERN COUNTRIES ARE SPORADIC, LARGE POPULATION-BASED STUDIES HAVE IDENTIFIED A NUMBER OF RISK FACTORS. THIS REVIEW SUMMARISES THE EVIDENCE BEHIND REPORTED RISK FACTORS AND CURRENT UNDERSTANDING OF THE MOLECULAR PATHOGENESIS OF CHOLANGIOCARCINOMA, WITH A FOCUS ON INFLAMMATION AND CHOLESTASIS AS THE DRIVING FORCES IN CHOLANGIOCARCINOMA DEVELOPMENT. RISK FACTORS FOR CHOLANGIOCARCINOGENESIS: CHOLESTATIC LIVER DISEASES (E.G. PRIMARY SCLEROSING CHOLANGITIS AND FIBROPOLYCYSTIC LIVER DISEASES), LIVER CIRRHOSIS, AND BILIARY STONE DISEASE ALL INCREASE THE RISK OF CHOLANGIOCARCINOMA. CERTAIN BACTERIAL, VIRAL OR PARASITIC INFECTIONS SUCH AS HEPATITIS B AND C AND LIVER FLUKES ALSO INCREASE CHOLANGIOCARCINOMA RISK. OTHER RISK FACTORS INCLUDE INFLAMMATORY DISORDERS (SUCH AS INFLAMMATORY BOWEL DISEASE AND CHRONIC PANCREATITIS), TOXINS (E.G. ALCOHOL AND TOBACCO), METABOLIC CONDITIONS (DIABETES, OBESITY AND NON-ALCOHOLIC FATTY LIVER DISEASE) AND A NUMBER OF GENETIC DISORDERS. MOLECULAR PATHOGENESIS OF CHOLANGIOCARCINOMA: REGARDLESS OF AETIOLOGY, MOST RISK FACTORS CAUSE CHRONIC INFLAMMATION OR CHOLESTASIS. CHRONIC INFLAMMATION LEADS TO INCREASED EXPOSURE OF CHOLANGIOCYTES TO THE INFLAMMATORY MEDIATORS INTERLEUKIN-6, TUMOUR NECROSIS FACTOR-A, CYCLO-OXYGENASE-2 AND WNT, RESULTING IN PROGRESSIVE MUTATIONS IN TUMOUR SUPPRESSOR GENES, PROTO-ONCOGENES AND DNA MISMATCH-REPAIR GENES. ACCUMULATING BILE ACIDS FROM CHOLESTASIS LEAD TO REDUCED PH, INCREASED APOPTOSIS AND ACTIVATION OF ERK1/2, AKT AND NF-KAPPAB PATHWAYS THAT ENCOURAGE CELL PROLIFERATION, MIGRATION AND SURVIVAL. OTHER MEDIATORS UPREGULATED IN CHOLANGIOCARCINOMA INCLUDE TRANSFORMING GROWTH FACTOR-BETA, VASCULAR ENDOTHELIAL GROWTH FACTOR, HEPATOCYTE GROWTH FACTOR AND SEVERAL MICRORNAS. INCREASED EXPRESSION OF THE CELL SURFACE RECEPTOR C-MET, THE GLUCOSE TRANSPORTER GLUT-1 AND THE SODIUM IODIDE SYMPORTER LEAD TO TUMOUR GROWTH, ANGIOGENESIS AND CELL MIGRATION. STROMAL CHANGES ARE ALSO OBSERVED, RESULTING IN ALTERATIONS TO THE EXTRACELLULAR MATRIX COMPOSITION AND RECRUITMENT OF FIBROBLASTS AND MACROPHAGES THAT CREATE A MICROENVIRONMENT PROMOTING CELL SURVIVAL, INVASION AND METASTASIS. CONCLUSION: REGARDLESS OF AETIOLOGY, MOST RISK FACTORS FOR CHOLANGIOCARCINOMA CAUSE CHRONIC INFLAMMATION AND/OR CHOLESTASIS, LEADING TO THE ACTIVATION OF COMMON INTRACELLULAR PATHWAYS THAT RESULT IN REACTIVE CELL PROLIFERATION, GENETIC/EPIGENETIC MUTATIONS AND CHOLANGIOCARCINOGENESIS. AN UNDERSTANDING OF THE MOLECULAR PATHOGENESIS OF CHOLANGIOCARCINOMA IS VITAL WHEN DEVELOPING NEW DIAGNOSTIC BIOMARKERS AND TARGETED THERAPIES FOR THIS DISEASE. 2019 4 2588 32 EPIGENETICS OF PRIMARY BILIARY CHOLANGITIS. PRIMARY BILIARY CHOLANGITIS (PBC) IS A CHRONIC CHOLESTATIC LIVER DISEASE WITH NON-SUPPURATIVE DESTRUCTION OF THE INTRAHEPATIC BILE DUCTS. THE INTERPLAY OF GENETICS AND ENVIRONMENTAL TRIGGERS CONTRIBUTES TO THE ONSET OF THE DISEASE AND SUBSEQUENTLY RESULTS IN CHOLESTASIS AND PROGRESSIVE FIBROSIS. RECENTLY, GENOME-WIDE ASSOCIATION STUDIES (GWAS) HAVE IDENTIFIED MULTIPLE GENES INFLUENCING THE SUSCEPTIBILITY TO PBC IN HLA AND NON-HLA LOCI. HOWEVER, IT IS ESTIMATED THAT THE KNOWN RISK VARIANTS MERELY ACCOUNT FOR NO MORE THAN 20% OF THE HERITABILITY OF PBC AND CAUSES OF THE REMAINING HERITABILITY REMAIN UNCERTAIN. INCREASING EVIDENCE SUGGESTS THAT THE PRESENCE OF EPIGENETIC ABNORMALITIES MAY EXPLAIN THE "MISSING HERITABILITY" THAT CANNOT BE CAPTURED BY GWAS. AMONG THESE EPIGENETIC MECHANISMS, DNA METHYLATION, HISTONE MODIFICATION, AND NONCODING RNAS (I.E. MIRNA AND LNCRNA) ARE INVOLVED IN THE PATHOGENESIS OF PBC. ADDITIONALLY, TELOMERE DYSREGULATION IN BILIARY EPITHELIAL CELLS (BECS) MAY PLAY A ROLE IN DISEASE ONSET, WHEREAS A DEFICIENCY IN SEX CHROMOSOME AND SKEWED GENE EXPRESSION IN THE X CHROMOSOME MAY TO SOME EXTENT EXPLAIN THE FEMALE DOMINANCE IN PBC. 2020 5 5738 29 SMOKING AND LUNG CANCER: THE ROLE OF INFLAMMATION. WORLDWIDE OVER 1 MILLION PEOPLE DIE DUE TO LUNG CANCER EACH YEAR. IT IS ESTIMATED THAT CIGARETTE SMOKING EXPLAINS ALMOST 90% OF LUNG CANCER RISK IN MEN AND 70 TO 80% IN WOMEN. CLINICALLY EVIDENT LUNG CANCERS HAVE MULTIPLE GENETIC AND EPIGENETIC ABNORMALITIES. THESE ABNORMALITIES MAY RESULT IN ACTIVATION OF ONCOGENES AND INACTIVATION OF TUMOR-SUPPRESSOR GENES. CHRONIC INFLAMMATION, WHICH IS KNOWN TO PROMOTE CANCER, MAY RESULT BOTH FROM SMOKING AND FROM GENETIC ABNORMALITIES. THESE MEDIATORS IN TURN MAY BE RESPONSIBLE FOR INCREASED MACROPHAGE RECRUITMENT, DELAYED NEUTROPHIL CLEARANCE, AND INCREASE IN REACTIVE OXYGEN SPECIES (ROS). THUS, THE PULMONARY ENVIRONMENT PRESENTS A UNIQUE MILIEU IN WHICH LUNG CARCINOGENESIS PROCEEDS IN COMPLICITY WITH THE HOST CELLULAR NETWORK. THE PULMONARY DISEASES THAT ARE ASSOCIATED WITH THE GREATEST RISK FOR LUNG CANCER ARE CHARACTERIZED BY ABUNDANT AND DEREGULATED INFLAMMATION. PULMONARY DISORDERS SUCH AS CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD)/EMPHYSEMA ARE CHARACTERIZED BY PROFOUND ABNORMALITIES IN INFLAMMATORY AND FIBROTIC PATHWAYS. THE CYTOKINES AND GROWTH FACTORS ABERRANTLY PRODUCED IN COPD AND THE DEVELOPING TUMOR MICROENVIRONMENT HAVE BEEN FOUND TO HAVE DELETERIOUS PROPERTIES THAT SIMULTANEOUSLY PAVE THE WAY FOR BOTH EPITHELIAL-MESENCHYMAL TRANSITION (EMT) AND DESTRUCTION OF SPECIFIC HOST CELL-MEDIATED IMMUNE RESPONSES. FULL DEFINITION OF THESE PATHWAYS WILL AFFORD THE OPPORTUNITY TO INTERVENE IN SPECIFIC INFLAMMATORY EVENTS MEDIATING LUNG TUMORIGENESIS AND RESISTANCE TO THERAPY. 2008 6 4228 27 METHYLATION OF INFLAMMATORY CELLS IN LUNG DISEASES. THIS CHAPTER OVERVIEWS ROLES OF DNA METHYLATION IN INFLAMMATORY CELL BIOLOGY WITH THE FOCUSES ON LYMPHOCYTES AND MACROPHAGES/MONOCYTES IN LUNG DISEASES, ALTHOUGH THE MOLECULAR MECHANISMS BY WHICH TARGET GENES ARE METHYLATED AND REGULATED IN LUNG DISEASES REMAIN UNCLEAR. MOST OF EPIGENETIC STUDIES ON DNA METHYLATION OF TARGET GENES IN LUNG DISEASES MAINLY DEMONSTRATED THE CORRELATION OF DNA METHYLATION OF TARGET GENES WITH THE LEVELS OF OTHER CORRESPONDING FACTORS, WITH THE SPECIFICITY OF CLINICAL PHENOMES, AND WITH THE SEVERITY OF LUNG DISEASES. THERE IS AN URGENT NEED TO IDENTIFY AND VALIDATE THE SPECIFICITY AND REGULATORY MECHANISMS OF INFLAMMATORY CELL EPIGENETICS IN DEPTH. THE EPIGENETIC HETEROGENEITY AMONG DIFFERENT SUBSETS OF T CELLS AND AMONG PROMOTERS OR NON-PROMOTERS OF TARGET GENES SHOULD BE FURTHERMORE CLARIFIED IN ACUTE OR CHRONIC LUNG DISEASES AND CANCERS. THE HYPER/HYPO-METHYLATION AND MODIFICATIONS OF CHROMOSOL AND EXTRACHROMOSOMAL DNA MAY RESULT IN ALTERNATIONS IN PROTEINS WITHIN INFLAMMATORY CELLS, WHICH CAN BE IDENTIFIED AS DISEASE-SPECIFIC BIOMARKERS AND THERAPEUTIC TARGETS. 2020 7 2512 40 EPIGENETICS AND PRIMARY BILIARY CIRRHOSIS: A COMPREHENSIVE REVIEW AND IMPLICATIONS FOR AUTOIMMUNITY. PRIMARY BILIARY CIRRHOSIS (PBC) IS A CHRONIC INFLAMMATORY AUTOIMMUNE DISEASE THAT DEVELOPS BASED UPON THE INTERACTION OF GENETIC AND ENVIRONMENTAL FACTORS. RECENT GENOME-WIDE ASSOCIATION STUDIES (GWAS) HAVE IDENTIFIED DOZENS OF PREDISPOSING VARIANTS INCLUDING HLA, IL12A, AND CTLA4 BUT HAVE BEEN DISAPPOINTED IN IDENTIFYING A "SMOKING GUN." THESE DISCOVERIES HIGHLIGHT THE IMPORTANCE OF THE GENETIC BACKGROUND INVOLVED IN IMMUNOLOGICAL DYSREGULATION. ALTHOUGH CONCORDANCE RATE OF PBC IN MONOZYGOTIC (MZ) TWINS IS AMONG THE HIGHEST REPORTED IN AUTOIMMUNE DISORDERS, INCOMPLETE DISEASE CONCORDANCE IN TWINS ASSOCIATED WITH DIFFERENTIALLY EXPRESSED GENES HAS BEEN DEMONSTRATED. HOWEVER, LITTLE IS UNDERSTOOD ABOUT HOW ENVIRONMENTAL ASPECTS CONTRIBUTE TO THE DISEASE AND WHY MIDDLE-AGED WOMEN ARE MORE SUSCEPTIBLE. AS A RESULT, EPIGENETIC FACTORS, WHICH CONVERT SIGNALS INDICATING ENVIRONMENTAL CHANGES INTO DYNAMIC AND HERITABLE ALTERATIONS OF TRANSCRIPTIONAL POTENTIAL, ARE GETTING INCREASED ATTENTION BY RESEARCHERS IN BOTH BASIC AND CLINICAL STUDIES. AMONG EPIGENETIC MECHANISMS, THE INSTABILITY AND SKEWED GENE EXPRESSION IN THE X CHROMOSOME MAY ACCOUNT FOR THE FEMALE PREPONDERANCE IN PBC. IN ADDITION, TRANSCRIPTIONAL REGULATION OF HISTONE MODIFICATION AND DNA METHYLATION UNDERSCORES POTENTIAL INVOLVEMENT IN DISEASE PATHOGENESIS. HIGH-THROUGHPUT TECHNIQUES ARE BEING USED TO IDENTIFY EPIGENETIC REGULATORS. IN THIS REVIEW, WE ATTEMPT TO OUTLINE RECENT PROGRESS REGARDING EPIGENETICS IN PBC AND OTHER AUTOIMMUNE DISEASES. 2016 8 4043 29 MACROPHAGES IN CHRONIC LIVER FAILURE: DIVERSITY, PLASTICITY AND THERAPEUTIC TARGETING. CHRONIC LIVER INJURY RESULTS IN IMMUNE-DRIVEN PROGRESSIVE FIBROSIS, WITH RISK OF CIRRHOSIS DEVELOPMENT AND IMPACT ON MORBIDITY AND MORTALITY. PERSISTENT LIVER CELL DAMAGE AND DEATH CAUSES IMMUNE CELL ACTIVATION AND INFLAMMATION. PATIENTS WITH ADVANCED CIRRHOSIS ADDITIONALLY EXPERIENCE PATHOLOGICAL BACTERIAL TRANSLOCATION, EXPOSURE TO MICROBIAL PRODUCTS AND CHRONIC ENGAGEMENT OF THE IMMUNE SYSTEM. BACTERIAL INFECTIONS HAVE A HIGH INCIDENCE IN CIRRHOSIS, WITH SPONTANEOUS BACTERIAL PERITONITIS BEING THE MOST COMMON, WHILE THE SUBSEQUENT SYSTEMIC INFLAMMATION, ORGAN FAILURE AND IMMUNE DYSREGULATION INCREASE THE MORTALITY RISK. TISSUE-RESIDENT AND RECRUITED MACROPHAGES PLAY A CENTRAL PART IN THE DEVELOPMENT OF INFLAMMATION AND FIBROSIS PROGRESSION. IN THE LIVER, ADIPOSE TISSUE, PERITONEUM AND INTESTINES, DIVERSE MACROPHAGE POPULATIONS EXHIBIT GREAT PHENOTYPIC AND FUNCTIONAL PLASTICITY DETERMINED BY THEIR ONTOGENY, EPIGENETIC PROGRAMMING AND LOCAL MICROENVIRONMENT. THESE CHANGES CAN, AT DIFFERENT TIMES, PROMOTE OR AMELIORATE DISEASE STATES AND THEREFORE REPRESENT POTENTIAL TARGETS FOR MACROPHAGE-DIRECTED THERAPIES. IN THIS REVIEW, WE DISCUSS THE EVIDENCE FOR MACROPHAGE PHENOTYPIC AND FUNCTIONAL ALTERATIONS IN TISSUE COMPARTMENTS DURING THE DEVELOPMENT AND PROGRESSION OF CHRONIC LIVER FAILURE IN DIFFERENT AETIOLOGIES AND HIGHLIGHT THE POTENTIAL OF MACROPHAGE MODULATION AS A THERAPEUTIC STRATEGY FOR LIVER DISEASE. 2021 9 6359 27 THE ROLE OF INFLAMMATION IN THE PATHOGENESIS OF LUNG CANCER. INTRODUCTION: IT IS REPORTED THAT CANCER MAY ARISE IN CHRONICALLY INFLAMED TISSUE. THERE IS MOUNTING EVIDENCE SUGGESTING THAT THE CONNECTION BETWEEN INFLAMMATION AND LUNG CANCER IS NOT COINCIDENTAL BUT MAY INDEED BE CAUSAL. THE INFLAMMATORY MOLECULES MAY BE RESPONSIBLE FOR AUGMENTED MACROPHAGE RECRUITMENT, DELAYED NEUTROPHIL CLEARANCE AND AN INCREASE IN REACTIVE OXYGEN SPECIES. THE CYTOKINES AND GROWTH FACTORS UNUSUALLY PRODUCED IN CHRONIC PULMONARY DISORDERS HAVE BEEN FOUND TO HAVE HARMFUL PROPERTIES THAT PAVE THE WAY FOR EPITHELIAL-TO-MESENCHYMAL TRANSITION AND TUMOR MICROENVIRONMENT. HOWEVER, THE ROLE OF INFLAMMATION IN LUNG CANCER IS NOT YET FULLY UNDERSTOOD. AREAS COVERED: THE ROLE OF CHRONIC INFLAMMATION IN THE PATHOGENESIS OF LUNG CANCER AND SOME OF THE POSSIBLE MECHANISMS INVOLVED, WITH PARTICULAR FOCUS ON INFLAMMATORY MEDIATORS, GENETIC AND EPIGENETIC ALTERATIONS, INFLAMMATORY MARKERS, TUMOR MICROENVIRONMENT AND ANTI-INFLAMMATORY DRUGS ARE DISCUSSED. A FRAMEWORK FOR UNDERSTANDING THE CONNECTION BETWEEN INFLAMMATION AND LUNG CANCER IS PROVIDED, WHICH MAY AFFORD THE OPPORTUNITY TO INTERCEDE IN SPECIFIC INFLAMMATORY DAMAGE MEDIATING LUNG CARCINOGENESIS AND THERAPEUTIC RESISTANCE. EXPERT OPINION: ADVANCES IN TUMOR IMMUNOLOGY SUPPORT THE CLINICAL IMPLEMENTATION OF IMMUNOTHERAPIES FOR LUNG CANCER. ALONG WITH THERAPEUTIC BENEFITS, IMMUNOTHERAPY PRESENTS THE CHALLENGES OF DRUG-RELATED TOXICITIES. GENE MODIFICATION OF IMMUNOCYTOKINE MAY LOWER THE ASSOCIATED TOXIC EFFECTS. 2011 10 5742 18 SMOKING MOLECULAR DAMAGE IN BRONCHIAL EPITHELIUM. OUR UNDERSTANDING OF THE MOLECULAR PATHOLOGY OF LUNG CANCER IS ADVANCING RAPIDLY WITH SEVERAL SPECIFIC GENES AND CHROMOSOMAL REGIONS BEING IDENTIFIED. LUNG CANCER APPEARS TO REQUIRE MANY MUTATIONS IN BOTH DOMINANT AND RECESSIVE ONCOGENES TO POSSESS MALIGNANT PHENOTYPES. SEVERAL GENETIC AND EPIGENETIC CHANGES ARE COMMON TO ALL LUNG CANCER HISTOLOGIC TYPES, WHILE OTHERS APPEAR TO BE CELL TYPE SPECIFIC. HOWEVER, SPECIFIC ROLES OF THE GENES UNDERGOING MUTATIONS AND THE ORDER OF CUMULATIVE MOLECULAR CHANGES THAT LEAD TO THE DEVELOPMENT OF EACH LUNG TUMOR HISTOLOGIC TYPE REMAIN TO BE FULLY ELUCIDATED. RECENT FINDINGS OF MOLECULAR ABNORMALITIES IN NORMAL APPEARING AND PRENEOPLASTIC BRONCHIAL EPITHELIUM FROM PATIENTS WITH LUNG CANCER AND CHRONIC SMOKERS SUGGEST THAT GENETIC CHANGES MAY SERVE AS BIOMARKERS FOR EARLY DIAGNOSIS, RISK ASSESSMENT AND MONITORING RESPONSE TO CHEMOPREVENTION. 2002 11 733 25 CANCER EPIGENETICS: LINKING BASIC BIOLOGY TO CLINICAL MEDICINE. CANCER EVOLUTION AT ALL STAGES IS DRIVEN BY BOTH EPIGENETIC ABNORMALITIES AS WELL AS GENETIC ALTERATIONS. DYSREGULATION OF EPIGENETIC CONTROL EVENTS MAY LEAD TO ABNORMAL PATTERNS OF DNA METHYLATION AND CHROMATIN CONFIGURATIONS, BOTH OF WHICH ARE CRITICAL CONTRIBUTORS TO THE PATHOGENESIS OF CANCER. THESE EPIGENETIC ABNORMALITIES ARE SET AND MAINTAINED BY MULTIPLE PROTEIN COMPLEXES AND THE INTERPLAY BETWEEN THEIR INDIVIDUAL COMPONENTS INCLUDING DNA METHYLATION MACHINERY, HISTONE MODIFIERS, PARTICULARLY, POLYCOMB (PCG) PROTEINS, AND CHROMATIN REMODELING PROTEINS. RECENT ADVANCES IN GENOME-WIDE TECHNOLOGY HAVE REVEALED THAT THE INVOLVEMENT OF THESE DYSREGULATED EPIGENETIC COMPONENTS APPEARS TO BE EXTENSIVE. MOREOVER, THERE IS A GROWING CONNECTION BETWEEN EPIGENETIC ABNORMALITIES IN CANCER AND CONCEPTS CONCERNING STEM-LIKE CELL SUBPOPULATIONS AS A DRIVING FORCE FOR CANCER. EMERGING DATA SUGGEST THAT ASPECTS OF THE EPIGENETIC LANDSCAPE INHERENT TO NORMAL EMBRYONIC AND ADULT STEM/PROGENITOR CELLS MAY HELP FOSTER, UNDER THE STRESS OF CHRONIC INFLAMMATION OR ACCUMULATING REACTIVE OXYGEN SPECIES, EVOLUTION OF MALIGNANT SUBPOPULATIONS. FINALLY, UNDERSTANDING MOLECULAR MECHANISMS INVOLVED IN INITIATION AND MAINTENANCE OF EPIGENETIC ABNORMALITIES IN ALL TYPES OF CANCER HAS GREAT POTENTIAL FOR TRANSLATIONAL PURPOSES. THIS IS ALREADY EVIDENT FOR EPIGENETIC BIOMARKER DEVELOPMENT, AND FOR PHARMACOLOGICAL TARGETING AIMED AT REVERSING CANCER-SPECIFIC EPIGENETIC ALTERATIONS. 2011 12 6244 32 THE MECHANISMS OF HSC ACTIVATION AND EPIGENETIC REGULATION OF HSCS PHENOTYPES. EPIGENETICS IS A DYNAMICALLY EXPANDING FIELD OF SCIENCE ENTAILING NUMEROUS REGULATORY MECHANISMS CONTROLLING CHANGES OF GENE EXPRESSION IN RESPONSE TO ENVIRONMENTAL FACTORS. OVER THE RECENT YEARS THERE HAS BEEN A GREAT INTEREST IN EPIGENETIC MARKS AS A POTENTIAL DIAGNOSTIC AND PROGNOSTIC TOOL OR FUTURE TARGET FOR TREATMENT OF VARIOUS HUMAN DISEASES. THERE IS AN INCREASING BODY OF PUBLISHED RESEARCH TO SUGGEST THAT EPIGENETIC EVENTS REGULATE PROGRESSION OF CHRONIC LIVER DISEASE. EXPERIMENTAL MANIPULATION OF EPIGENETIC SIGNATURES SUCH AS DNA METHYLATION, HISTONE ACETYLATION / METHYLATION AND THE ACTIVITIES OF PROTEINS THAT EITHER ANNOTATE OR INTERPRET THESE EPIGENETIC MARKS CAN HAVE PROFOUND EFFECTS ON THE ACTIVATION AND PHENOTYPE OF HSC, KEY CELLS RESPONSIBLE FOR ONSET AND PROGRESSION OF LIVER FIBROSIS. THIS REVIEW PRESENTS RECENT ADVANCES IN EPIGENETIC ALTERATIONS, WHICH COULD PROVIDE MECHANISTIC INSIGHT INTO THE PATHOGENESIS OF CHRONIC LIVER DISEASE AND PROVIDE NOVEL CLINICAL APPLICATIONS. 2014 13 6428 28 THE TUMOR MICROENVIRONMENT AND METASTATIC DISEASE. THE MICROENVIRONMENT OF SOLID TUMORS IS A HETEROGENEOUS, COMPLEX MILIEU FOR TUMOR GROWTH AND SURVIVAL THAT INCLUDES FEATURES SUCH AS ACIDIC PH, LOW NUTRIENT LEVELS, ELEVATED INTERSTITIAL FLUID PRESSURE (IFP) AND CHRONIC AND FLUCTUATING LEVELS OF OXYGENATION THAT RELATE TO THE ABNORMAL VASCULAR NETWORK THAT EXISTS IN TUMORS. THE METASTATIC POTENTIAL OF TUMOR CELLS IS BELIEVED TO BE REGULATED BY INTERACTIONS BETWEEN THE TUMOR CELLS AND THEIR EXTRACELLULAR ENVIRONMENT (EXTRACELLULAR MATRIX (ECM)). THESE INTERACTIONS CAN BE MODIFIED BY THE ACCUMULATION OF GENETIC CHANGES AND BY THE TRANSIENT ALTERATIONS IN GENE EXPRESSION INDUCED BY THE LOCAL TUMOR MICROENVIRONMENT. CLINICAL AND EXPERIMENTAL EVIDENCE SUGGESTS THAT ALTERED GENE EXPRESSION IN RESPONSE TO THE HYPOXIC MICROENVIRONMENT IS A CONTRIBUTING FACTOR TO INCREASED METASTATIC EFFICIENCY. A NUMBER OF GENES THAT HAVE BEEN IMPLICATED IN THE METASTATIC PROCESS, INVOLVING ANGIOGENESIS, INTRA/EXTRAVASATION, SURVIVAL AND GROWTH, HAVE BEEN FOUND TO BE HYPOXIA-RESPONSIVE. THE VARIOUS METASTATIC DETERMINANTS, GENETIC AND EPIGENETIC, SOMATIC AND INHERITED MAY SERVE AS PRECEDENTS FOR THE FUTURE IDENTIFICATION OF MORE GENES THAT ARE INVOLVED IN METASTASIS. MUCH RESEARCH HAS FOCUSED ON GENETIC AND MOLECULAR PROPERTIES OF THE TUMOR CELLS THEMSELVES. IN THE PRESENT REVIEW WE DISCUSS THE EPIGENETIC AND PHYSIOLOGICAL REGULATION OF METASTASIS AND EMPHASIZE THE NEED FOR FURTHER STUDIES ON THE INTERACTIONS BETWEEN THE PATHOPHYSIOLOGIC TUMOR MICROENVIRONMENT AND THE TUMOR EXTRACELLULAR MATRIX. 2009 14 551 34 AUTOIMMUNITY AS AN ETIOLOGICAL FACTOR OF CANCER: THE TRANSFORMATIVE POTENTIAL OF CHRONIC TYPE 2 INFLAMMATION. RECENT EPIDEMIOLOGICAL STUDIES HAVE FOUND AN ALARMING TREND OF INCREASED CANCER INCIDENCE IN ADULTS YOUNGER THAN 50 YEARS OF AGE AND PROJECTED A SUBSTANTIAL RISE IN CANCER INCIDENCE OVER THE NEXT 10 YEARS IN THIS AGE GROUP. THIS TREND WAS EXEMPLIFIED IN THE INCIDENCE OF NON-CARDIA GASTRIC CANCER AND ITS DISPROPORTIONATE IMPACT ON NON-HISPANIC WHITE FEMALES UNDER THE AGE OF 50. THE TREND IS CONCURRENT WITH THE INCREASING INCIDENCE OF AUTOIMMUNE DISEASES IN INDUSTRIALIZED COUNTRIES, SUGGESTING A CAUSAL LINK BETWEEN THE TWO. WHILE AUTOIMMUNITY HAS BEEN SUSPECTED TO BE A RISK FACTOR FOR SOME CANCERS, THE EXACT MECHANISMS UNDERLYING THE CONNECTION BETWEEN AUTOIMMUNITY AND CANCER REMAIN UNCLEAR AND ARE OFTEN CONTROVERSIAL. THE LINK HAS BEEN ATTRIBUTED TO SEVERAL MEDIATORS SUCH AS IMMUNE SUPPRESSION, INFECTION, DIET, ENVIRONMENT, OR, PERHAPS MOST PLAUSIBLY, CHRONIC INFLAMMATION BECAUSE OF ITS WELL-RECOGNIZED ROLE IN TUMORIGENESIS. IN THAT REGARD, AUTOIMMUNE CONDITIONS ARE COMMON CAUSES OF CHRONIC INFLAMMATION AND MAY TRIGGER REPETITIVE CYCLES OF ANTIGEN-SPECIFIC CELL DAMAGE, TISSUE REGENERATION, AND WOUND HEALING. ILLUSTRATING THE CONNECTION BETWEEN AUTOIMMUNE DISEASES AND CANCER ARE PATIENTS WHO HAVE AN INCREASED RISK OF CANCER DEVELOPMENT ASSOCIATED WITH GENETICALLY PREDISPOSED INSUFFICIENCY OF CYTOTOXIC T LYMPHOCYTE-ASSOCIATED PROTEIN 4 (CTLA4), A PROTOTYPICAL IMMUNE CHECKPOINT AGAINST AUTOIMMUNITY AND ONE OF THE MAIN TARGETS OF CANCER IMMUNE THERAPY. THE TUMORIGENIC PROCESS TRIGGERED BY CTLA4 INSUFFICIENCY HAS BEEN SHOWN IN A MOUSE MODEL TO BE DEPENDENT ON THE TYPE 2 CYTOKINES INTERLEUKIN-4 (IL4) AND INTERLEUKIN-13 (IL13). IN THIS TYPE 2 INFLAMMATORY MILIEU, CROSSTALK WITH TYPE 2 IMMUNE CELLS MAY INITIATE EPIGENETIC REPROGRAMMING OF EPITHELIAL CELLS, LEADING TO A METAPLASTIC DIFFERENTIATION AND EVENTUALLY MALIGNANT TRANSFORMATION EVEN IN THE ABSENCE OF CLASSICAL ONCOGENIC MUTATIONS. THOSE FINDINGS COMPLEMENT A LARGE BODY OF EVIDENCE FOR TYPE 1, TYPE 3, OR OTHER INFLAMMATORY MEDIATORS IN INFLAMMATORY TUMORIGENESIS. THIS REVIEW ADDRESSES THE POTENTIAL OF AUTOIMMUNITY AS A CAUSAL FACTOR FOR TUMORIGENESIS, THE UNDERLYING INFLAMMATORY MECHANISMS THAT MAY VARY DEPENDING ON HOST-ENVIRONMENT VARIATIONS, AND IMPLICATIONS TO CANCER PREVENTION AND IMMUNOTHERAPY. 2021 15 3697 27 INFLAMMATORY MARKERS IN CANCER: POTENTIAL RESOURCES. CANCER IS A LEADING CAUSE OF DEATH WORLDWIDE AND A MAJOR BURDEN ON DEVELOPING AND LESS DEVELOPED COUNTRIES OF THE WORLD WITH LIMITED RESOURCES FOR PREVENTION AND EFFECTIVE TREATMENT OF CANCER. ALTHOUGH CANCER IS MULTIFACTORIAL IN ORIGIN, VARIOUS EPIDEMIOLOGICAL AND EXPERIMENTAL STUDIES SUGGEST THAT CHRONIC INFLAMMATION HAS AN IMPORTANT ROLE IN ALL STAGES OF CANCER, FROM INITIATION TO PROGRESSION AND EVEN SURVIVAL OF THE PATIENT. INFLAMMATORY PRODUCTS LIKE CYTOKINES, CHEMOKINES, LEUCOCYTES, PROSTAGLANDINS, CYCLOOXYGENASE, REACTIVE OXYGEN AND NITROGEN SPECIES, METALLOPROTEINASE INDUCE GENETIC AND EPIGENETIC CHANGES IN NORMAL CELLS DAMAGING ITS DNA, INHIBITING ITS REPAIR, ALTERING TRANSCRIPTION FACTORS, PREVENTING APOPTOSIS, AND STIMULATING ANGIOGENESIS, AND THUS RESULTING IN CARCINOGENESIS. THUS, THESE INFLAMMATORY MEDIATORS HAVE A POTENTIAL ROLE TO BECOME CANCER BIOMARKERS FOR ALL STAGES OF CANCER AS MANY OF THEM CAN BE MEASURED IN A COST-EFFECTIVE MANNER. HOWEVER, LARGE SCALE PROSPECTIVE TRIALS ARE REQUIRED TO VALIDATE THESE POTENTIAL CANCER BIOMARKERS. NONETHELESS, A TRANSITION FROM POTENTIAL TO PRACTICAL UTILIZATION OF THESE MARKERS WILL BE AN EFFECTIVE TOOL FOR THE AMELIORATION OF CANCER BURDEN AND MORTALITY IN A RESOURCE LIMITED SETTING. 2020 16 3038 33 GENOME ENGINEERING FOR OSTEOARTHRITIS: FROM DESIGNER CELLS TO DISEASE-MODIFYING DRUGS. BACKGROUND: OSTEOARTHRITIS (OA) IS A HIGHLY PREVALENT DEGENERATIVE JOINT DISEASE INVOLVING JOINT CARTILAGE AND ITS SURROUNDING TISSUES. OA IS THE LEADING CAUSE OF PAIN AND DISABILITY WORLDWIDE. AT PRESENT, THERE ARE NO DISEASE-MODIFYING OA DRUGS, AND THE PRIMARY THERAPIES INCLUDE EXERCISE AND NONSTEROIDAL ANTI-INFLAMMATORY DRUGS UNTIL TOTAL JOINT REPLACEMENT AT THE END-STAGE OF THE DISEASE. METHODS: IN THIS REVIEW, WE SUMMARIZED THE CURRENT STATE OF KNOWLEDGE IN GENETIC AND EPIGENETIC ASSOCIATIONS AND RISK FACTORS FOR OA AND THEIR POTENTIAL DIAGNOSTIC AND THERAPEUTIC APPLICATIONS. RESULTS: GENOME-WIDE ASSOCIATION STUDIES AND ANALYSIS OF EPIGENETIC MODIFICATIONS (SUCH AS MIRNA EXPRESSION, DNA METHYLATION AND HISTONE MODIFICATIONS) CONDUCTED ACROSS VARIOUS POPULATIONS SUPPORT THE NOTION THAT THERE IS A GENETIC BASIS FOR CERTAIN SUBSETS OF OA PATHOGENESIS. CONCLUSION: WITH RECENT ADVANCES IN THE DEVELOPMENT OF GENOME EDITING TECHNOLOGIES SUCH AS THE CRISPR-CAS9 SYSTEM, THESE GENETIC AND EPIGENETIC ALTERNATIONS IN OA CAN BE USED AS PLATFORMS FROM WHICH POTENTIAL BIOMARKERS FOR THE DIAGNOSIS, PROGNOSIS, DRUG RESPONSE, AND DEVELOPMENT OF POTENTIAL PERSONALIZED THERAPEUTIC TARGETS FOR OA CAN BE APPROACHED. FURTHERMORE, GENOME EDITING HAS ALLOWED THE DEVELOPMENT OF "DESIGNER" CELLS, WHEREBY THE RECEPTORS, GENE REGULATORY NETWORKS, OR TRANSGENES CAN BE MODIFIED AS A BASIS FOR NEW CELL-BASED THERAPIES. 2019 17 2036 23 EPIGENETIC CHANGES OF THE IMMUNE SYSTEM WITH ROLE IN TUMOR DEVELOPMENT. TUMOR DEVELOPMENT IS CLOSELY RELATED TO CHRONIC INFLAMMATION AND TO EVASION OF IMMUNE DEFENSE MECHANISMS BY NEOPLASTIC CELLS. THE MEDIATORS OF THE INFLAMMATORY PROCESS AS WELL AS PROTEINS INVOLVED IN IMMUNE RESPONSE OR IMMUNE RESPONSE EVASION CAN BE SUBJECT TO VARIOUS EPIGENETIC CHANGES SUCH AS METHYLATION, ACETYLATION, OR PHOSPHORYLATION. SOME OF THESE, SUCH AS CYTOKINE SUPPRESSORS, ARE UNDERGOING REPRESSION THROUGH EPIGENETIC CHANGES, AND OTHERS SUCH AS CYTOKINES OR CHEMOKINES ARE UNDERGOING ACTIVATION THROUGH EPIGENETIC CHANGES, BOTH MODIFICATIONS HAVING AS A RESULT TUMOR PROGRESSION. THE ACTIVATING CHANGES CAN AFFECT THE RECEPTOR MOLECULES INVOLVED IN IMMUNE RESPONSE AND THESE PROMOTE INFLAMMATION AND SUBSEQUENTLY TUMOR DEVELOPMENT WHILE THE INACTIVATING CHANGES SEEM TO BE RELATED TO THE TUMOR REGRESSION PROCESS. THE PROTEINS INVOLVED IN ANTIGEN PRESENTATION, AND, THEREFORE IN IMMUNE RESPONSE ESCAPE, SUCH AS CLASSICAL HLA PROTEINS AND RELATED APM (ANTIGEN PRESENTATION MACHINERY) WITH THEIR EPIGENETIC CHANGES CONTRIBUTE TO THE TUMOR DEVELOPMENT PROCESS, EITHER TO TUMOR PROGRESSION OR REGRESSION, DEPENDING ON THE IMMUNE EFFECTOR CELLS THAT ARE IN PLAY. 2018 18 6533 33 TRANSCRIPTIONAL REGULATION OF INFLAMMATORY GENES ASSOCIATED WITH SEVERE ASTHMA. THE 10% OF PATIENTS WITH THE MOST SEVERE ASTHMA ARE RESPONSIBLE FOR A LARGE PART OF HEALTHCARE EXPENDITURE AND MORBIDITY. UNDERSTANDING THE PROCESSES INVOLVED IS KEY IF NEW THERAPEUTIC APPROACHES ARE TO BE DEVELOPED. EVIDENCE IS ACCUMULATING THAT CHRONIC DISEASES SUCH AS ASTHMA ARE ASSOCIATED WITH TEMPORAL AND SPATIAL ALTERATIONS IN THE PATTERN OF INFLAMMATORY GENE EXPRESSION WITHIN THE AIRWAYS. EXPRESSION OF THESE GENES CAN BE REGULATED BY TRANSCRIPTIONAL, POSTTRANSCRIPTIONAL, TRANSLATIONAL AND EPIGENETIC MECHANISMS. IT IS WELL ESTABLISHED THAT BINDING OF ACTIVATED TRANSCRIPTION FACTORS TO SPECIFIC INDUCIBLE GENE PROMOTER SITES IS TIGHTLY CONTROLLED BY CHROMATIN STATE AS A RESULT OF HISTONE MODIFICATIONS, PARTICULARLY THE BALANCE BETWEEN HISTONE ACETYLATION AND DEACETYLATION [1]. THE INTERACTION BETWEEN TRANSCRIPTION FACTORS AND THE PROMOTER IS KEY TO THE DIVERSIFICATION OF GENE EXPRESSION IN A TIME DEPENDENT MANNER LEADING TO ALTERED GENE EXPRESSION PROFILES. ALTERATIONS OF THE ACCESSIBILITY OF TRANSCRIPTION FACTORS TO THE DNA CAN HAVE RESIDING EFFECTS UPON GENE TRANSCRIPTION. THIS REVIEW WILL FOCUS ON THE REGULATION OF SEVERAL GROUPS OF KEY GENES WHICH ARE INVOLVED IN CHRONIC AIRWAY INFLAMMATION AND REMODELLING IN ASTHMA DRAWING MAINLY FROM OUR EXPERIENCE OF STUDYING THESE PROCESSES IN AIRWAY SMOOTH MUSCLE CELLS. AN OVERVIEW IS SHOWN IN FIGURE 1. 2011 19 6199 40 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 20 1606 28 DNA METHYLATION, BACTERIA AND AIRWAY INFLAMMATION: LATEST INSIGHTS. PURPOSE OF REVIEW: DNA METHYLATION IS AN EPIGENETIC MECHANISM THAT HAS BEEN IMPLICATED IN THE PATHOGENESIS OF CHRONIC INFLAMMATORY DISEASES BY REGULATING DIFFERENTIATION, PROLIFERATION, APOPTOSIS, AND ACTIVATION OF IMMUNE CELLS. CHANGES IN THE METHYLATION STATUS OF RELEVANT GENES HAVE BEEN LINKED TO THE ORIGIN, PERPETUATION, AND SEVERITY OF AIRWAY DISEASES. THE DNA METHYLATION PROFILE CAN BE ALSO MODIFIED BY THE ACTION OF VIRAL AND BACTERIAL COLONIZATION. BACTERIA AND SPECIALLY STAPHYLOCOCCUS AUREUS TOXINS ARE RECOGNIZED INFLAMMATORY AMPLIFYING FACTORS IN BOTH LOWER AND UPPER AIRWAY CHRONIC DISEASES. THIS REVIEW SUMMARIZES THE EXISTENT KNOWLEDGE ABOUT THE ROLE OF DNA METHYLATION CHANGES IN CHRONIC AIRWAY DISEASES AND THE CONTRIBUTION OF BACTERIAL INFECTION ON THIS EVENT. RECENT FINDINGS: IT HAS BEEN DEMONSTRATED THAT CHANGES IN DNA METHYLATION, EITHER INTRINSIC OR INDUCED BY ALLERGEN OR INFECTION, MAY BE LINKED TO THE PATHOGENESIS OF ASTHMA AND ALLERGY. THESE CHANGES IN METHYLATION MAY SUPPRESS THE PRODUCTION OF ANTI-INFLAMMATORY MEDIATORS AND INCREASE THE SURVIVAL AND ACTIVATION OF PRO-INFLAMMATORY CELLS, AS WELL AS MODIFY THE IMMUNE RESPONSE IN RESPONSE TO BACTERIAL INFECTION, INCREASING THEIR SURVIVAL AND PATHOGENICITY WITHIN THE INFECTED ORGANISM. SUMMARY: UNDERSTANDING THE INTRINSIC EPIGENETIC MECHANISMS, AS WELL AS THE EFFECT OF ENVIRONMENT -FOR EXAMPLE, BACTERIAL INFECTION IN THE PATHOGENESIS OF AIRWAYS DISEASES - WILL GREATLY IMPROVE THE MANAGEMENT AND THE DIAGNOSIS OF THESE DISEASES. 2015