1 5539 139 ROLE OF CYSTIC FIBROSIS BRONCHIAL EPITHELIUM IN NEUTROPHIL CHEMOTAXIS. A HALLMARK OF CYSTIC FIBROSIS (CF) CHRONIC RESPIRATORY DISEASE IS AN EXTENSIVE NEUTROPHIL INFILTRATE IN THE MUCOSA FILLING THE BRONCHIAL LUMEN, STARTING EARLY IN LIFE FOR CF INFANTS. THE GENETIC DEFECT OF THE CF TRANSMEMBRANE CONDUCTANCE REGULATOR (CFTR) ION CHANNEL PROMOTES DEHYDRATION OF THE AIRWAY SURFACE LIQUID, ALTERS MUCUS PROPERTIES, AND DECREASES MUCOCILIARY CLEARANCE, FAVORING THE ONSET OF RECURRENT AND, ULTIMATELY, CHRONIC BACTERIAL INFECTION. NEUTROPHIL INFILTRATES ARE UNABLE TO CLEAR BACTERIAL INFECTION AND, AS AN ADVERSE EFFECT, CONTRIBUTE TO MUCOSAL TISSUE DAMAGE BY RELEASING PROTEASES AND REACTIVE OXYGEN SPECIES. MOREOVER, THE RAPID CELLULAR TURNOVER OF LUMENAL NEUTROPHILS RELEASES NUCLEIC ACIDS THAT FURTHER ALTER THE MUCUS VISCOSITY. A PROMINENT ROLE IN THE RECRUITMENT OF NEUTROPHIL IN BRONCHIAL MUCOSA IS PLAYED BY CF BRONCHIAL EPITHELIAL CELLS CARRYING THE DEFECTIVE CFTR PROTEIN AND ARE EXPOSED TO WHOLE BACTERIA AND BACTERIAL PRODUCTS, MAKING PHARMACOLOGICAL APPROACHES TO REGULATE THE EXAGGERATED NEUTROPHIL CHEMOTAXIS IN CF A RELEVANT THERAPEUTIC TARGET. HERE WE REVISE: (A) THE MAJOR RECEPTORS, KINASES, AND TRANSCRIPTION FACTORS LEADING TO THE EXPRESSION, AND RELEASE OF NEUTROPHIL CHEMOKINES IN BRONCHIAL EPITHELIAL CELLS; (B) THE ROLE OF INTRACELLULAR CALCIUM HOMEOSTASIS AND, IN PARTICULAR, THE CALCIUM CROSSTALK BETWEEN ENDOPLASMIC RETICULUM AND MITOCHONDRIA; (C) THE EPIGENETIC REGULATION OF THE KEY CHEMOKINES; (D) THE ROLE OF MUTANT CFTR PROTEIN AS A CO-REGULATOR OF CHEMOKINES TOGETHER WITH THE HOST-PATHOGEN INTERACTIONS; AND (E) DIFFERENT PHARMACOLOGICAL STRATEGIES TO REGULATE THE EXPRESSION OF CHEMOKINES IN CF BRONCHIAL EPITHELIAL CELLS THROUGH NOVEL DRUG DISCOVERY AND DRUG REPURPOSING. 2020 2 4738 30 NOVEL FIBROBLAST PHENOTYPES IN HOMEOSTASIS AND CHRONIC INFLAMMATION: FROM FUNCTIONS TO POTENTIAL REGULATORS. FIBROBLASTS ARE ESSENTIAL COMPONENTS OF THE STROMA, SUSTAINING A VARIETY OF TISSUES AND BEING KEY TO THE PROCESS OF TISSUE REPAIR AFTER INJURY. THEIR ROLE IN TISSUE REPAIR HAS BEEN ATTRIBUTED TO THEIR ABILITY TO ACQUIRE A CONTRACTILE, EXTRACELLULAR MATRIX-PRODUCING PHENOTYPE KNOWN AS MYOFIBROBLASTS. THIS PROPERTY IS PRIMARILY DEPENDENT ON THEIR RESPONSE TO THE PLEIOTROPIC CYTOKINE TRANSFORMING GROWTH FACTOR-BETA1. UNTIL RECENTLY, THE POTENTIAL ROLE OF FIBROBLASTS IN OTHER HOMEOSTATIC AND DISEASE-RELATED PROCESSES WAS LESS WELL UNDERSTOOD. ALTHOUGH IN VITRO STUDIES INDICATED THAT FIBROBLASTS ARE ABLE TO RESPOND TO AND SECRETE INFLAMMATORY MEDIATORS, DEFINITIVE EVIDENCE OF THEIR CONTRIBUTION TO CHRONIC INFLAMMATION WAS LIMITED. HOWEVER, THE EMERGENCE OF TECHNIQUES THAT ALLOW EXPLORATION OF TISSUES AT THE SINGLE CELL LEVEL HAS CHALLENGED THE PREVIOUS PARADIGMS ON FIBROBLAST IDENTITY AND FUNCTIONS, AND HAS LED TO THE DISCOVERY OF SIGNIFICANT DIVERSITY, SHOWING THE PRESENCE OF FIBROBLASTS WITH ALTERNATE TRANSCRIPTIONAL PROFILES IN A VARIETY OF TISSUES. THESE STUDIES HAVE ALSO SUGGESTED POTENTIAL ROLES OF NOVEL FIBROBLAST SUBTYPES AS REGULATORS OF EPITHELIAL HOMEOSTASIS AND RENEWAL, INFLAMMATORY CELL INFILTRATION AND ACTIVATION, AND ANTIGEN PRESENTATION. HERE, WE PROVIDE A COMPREHENSIVE REVIEW OF THE RECENT LITERATURE ON FIBROBLAST DIVERSITY IN THE DIGESTIVE TRACT, SKIN, LUNGS AND JOINTS. WE ALSO REVIEW EVIDENCE OF THEIR CONTRIBUTION TO THE REGULATION OF HOMEOSTASIS AND CHRONIC INFLAMMATION, AS WELL AS THEIR INTERACTIONS WITH OTHER CELLS IN VARIOUS TISSUE COMPARTMENTS. WE DISCUSS EVIDENCE OF DIFFERENT FACTORS INVOLVED IN THE CONTROL OF FIBROBLAST FUNCTION, ADDRESSING THE ROLE OF VARIOUS CYTOKINES, TRANSCRIPTION FACTORS AND EPIGENETIC CHANGES, AS WELL AS MICROENVIRONMENTAL FACTORS, INCLUDING EXTRACELLULAR MATRIX STIFFNESS, HYPOXIA, AND METABOLIC SHIFTS. 2023 3 3921 32 LINKING INFLAMMATION TO CELL CYCLE PROGRESSION. RISK OF GASTROINTESTINAL CANCERS IS CLOSELY RELATED TO INCREASED LEVELS OF OXIDANTS IN THE BALANCE BETWEEN OXIDANT AND ANTI-OXIDANT AGENTS. A POSSIBLE EXPLANATION OF THIS EPIDEMIOLOGICAL OBSERVATION IS THE LOCAL LOSS OF THE EPITHELIAL BARRIER FUNCTION WITH A FOCAL INFLAMMATORY RESPONSE. ACCORDINGLY, CHRONIC INFLAMMATORY DISEASES REPRESENT WELL-KNOWN RISK FACTORS FOR CANCER AND, ON THE OTHER HAND, IT IS KNOWN THAT ANTI-INFLAMMATORY AGENTS, DEMULCENTS AND ANTIOXIDANTS MARKEDLY INHIBIT THE DEVELOPMENT OF COLON CANCER IN ANIMAL MODELS AS WELL IN HUMANS. AT MOLECULAR LEVEL A KEY ROLE IN THE PROCESS THAT LINK INFLAMMATION TO CELLULAR TRANSFORMATION SEEMS TO BE PLAYED BY ACTIVATION OF CYCLOOXYGENASE-2 (COX-2) TOGETHER WITH PRODUCTION OF REACTIVE OXYGEN INTERMEDIATE (ROI). BOTH THESE EVENTS HAVE BEEN STRICTLY LINKED WITH CELL PROLIFERATION AND TRANSFORMATION, ALTHOUGH THE INTRACELLULAR PATHWAYS INVOLVED IN THESE PROCESSES ARE STILL NOT COMPLETELY UNDERSTOOD. THE UNCONTROLLED PROLIFERATION, WHICH IS A LANDMARK OF CELLULAR TRANSFORMATION, IS ACCOMPANIED BY THE DEREGULATION OF PROTEINS INVOLVED IN THE CONTROL OF CELL CYCLE CHECKPOINTS. ALTERED EXPRESSION AND FUNCTION OF CYCLOOXYGENASE AND NITRIC OXIDE SYNTHASE SEEM TO INFLUENCE, AMONG OTHERS, THE EXPRESSION OF PROTEINS INVOLVED IN THE REGULATION OF CELL CYCLE PROGRESSION. SIMILARLY, ANTI-INFLAMMATORY AND ANTIOXIDANT AGENTS MAY ALSO ACT ON THE EXPRESSION AND FUNCTION OF SEVERAL CELL CYCLE REGULATING PROTEINS. UNDERSTANDING THE MECHANISMS BY WHICH CHRONIC INFLAMMATION CONTRIBUTES TO GENETIC AND EPIGENETIC CHANGES INVOLVED IN THE REGULATION OF CRITICAL CELL CYCLE CHECKPOINTS MAY HELP TO DEVELOP MORE AND MORE SPECIFIC TREATMENT STRATEGIES FOR REDUCING MALIGNANT TRANSFORMATION OF THESE INFLAMMATORY DISEASES. 2004 4 6395 29 THE ROLE OF THE MEDIATORS OF INFLAMMATION IN CANCER DEVELOPMENT. EPIGENETIC DISORDERS SUCH AS POINT MUTATIONS IN CELLULAR TUMOR SUPPRESSOR GENES, DNA METHYLATION AND POST-TRANSLATIONAL MODIFICATIONS ARE NEEDED TO TRANSFORMATION OF NORMAL CELLS INTO CANCER CELLS. THESE EVENTS RESULT IN ALTERATIONS IN CRITICAL PATHWAYS RESPONSIBLE FOR MAINTAINING THE NORMAL CELLULAR HOMEOSTASIS, TRIGGERING TO AN INFLAMMATORY RESPONSE WHICH CAN LEAD THE DEVELOPMENT OF CANCER. THE INFLAMMATORY RESPONSE IS A UNIVERSAL DEFENSE MECHANISM ACTIVATED IN RESPONSE TO AN INJURY TISSUE, OF ANY NATURE, THAT INVOLVES BOTH INNATE AND ADAPTIVE IMMUNE RESPONSES, THROUGH THE COLLECTIVE ACTION OF A VARIETY OF SOLUBLE MEDIATORS. MANY INFLAMMATORY SIGNALING PATHWAYS ARE ACTIVATED IN SEVERAL TYPES OF CANCER, LINKING CHRONIC INFLAMMATION TO TUMORIGENESIS PROCESS. THUS, INFLAMMATORY RESPONSES PLAY DECISIVE ROLES AT DIFFERENT STAGES OF TUMOR DEVELOPMENT, INCLUDING INITIATION, PROMOTION, GROWTH, INVASION, AND METASTASIS, AFFECTING ALSO THE IMMUNE SURVEILLANCE. IMMUNE CELLS THAT INFILTRATE TUMORS ENGAGE IN AN EXTENSIVE AND DYNAMIC CROSSTALK WITH CANCER CELLS, AND SOME OF THE MOLECULAR EVENTS THAT MEDIATE THIS DIALOG HAVE BEEN REVEALED. A RANGE OF INFLAMMATION MEDIATORS, INCLUDING CYTOKINES, CHEMOKINES, FREE RADICALS, PROSTAGLANDINS, GROWTH AND TRANSCRIPTION FACTORS, MICRORNAS, AND ENZYMES AS, CYCLOOXYGENASE AND MATRIX METALLOPROTEINASE, COLLECTIVELY ACTS TO CREATE A FAVORABLE MICROENVIRONMENT FOR THE DEVELOPMENT OF TUMORS. IN THIS REVIEW ARE PRESENTED THE MAIN MEDIATORS OF THE INFLAMMATORY RESPONSE AND DISCUSSED THE LIKELY MECHANISMS THROUGH WHICH, THEY INTERACT WITH EACH OTHER TO CREATE A CONDITION FAVORABLE TO DEVELOPMENT OF CANCER. 2015 5 1150 28 CONNECTION BETWEEN INFLAMMATION AND CARCINOGENESIS IN GASTROINTESTINAL TRACT: FOCUS ON TGF-BETA SIGNALING. INFLAMMATION IS A PRIMARY DEFENSE PROCESS AGAINST VARIOUS EXTRACELLULAR STIMULI, SUCH AS VIRUSES, PATHOGENS, FOODS, AND ENVIRONMENTAL POLLUTANTS. WHEN CELLS RESPOND TO STIMULI FOR SHORT PERIODS OF TIME, IT RESULTS IN ACUTE OR PHYSIOLOGICAL INFLAMMATION. HOWEVER, IF THE STIMULATION IS SUSTAINED FOR LONGER TIME OR A PATHOLOGICAL STATE OCCURS, IT IS KNOWN AS CHRONIC OR PATHOLOGICAL INFLAMMATION. SEVERAL STUDIES HAVE SHOWN THAT TUMORIGENESIS IN THE GASTROINTESTINAL (GI) TRACT IS CLOSELY ASSOCIATED WITH CHRONIC INFLAMMATION, FOR WHICH ABNORMAL CELLULAR ALTERATIONS THAT ACCOMPANY CHRONIC INFLAMMATION SUCH AS OXIDATIVE STRESSES, GENE MUTATIONS, EPIGENETIC CHANGES, AND INFLAMMATORY CYTOKINES, ARE SHARED WITH CARCINOGENIC PROCESSES, WHICH FORMS A CRITICAL CROSS-LINK BETWEEN CHRONIC INFLAMMATION AND CARCINOGENESIS. TRANSFORMING GROWTH FACTOR (TGF)-BETA IS A MULTI-POTENT CYTOKINE THAT PLAYS AN IMPORTANT ROLE IN REGULATION OF CELL GROWTH, APOPTOSIS AND DIFFERENTIATION. MOST IMPORTANTLY, TGF-BETA IS A STRONG ANTI-INFLAMMATORY CYTOKINE THAT REGULATES THE DEVELOPMENT OF EFFECTOR CELLS. TGF-BETA HAS A SUPPRESSIVE EFFECT ON CARCINOGENESIS UNDER NORMAL CONDITIONS BY INHIBITING ABNORMAL CELL GROWTH, BUT ON THE OTHER HAND, MANY GI CANCERS ORIGINATE FROM UNCONTROLLED CELL GROWTH AND DIFFERENTIATION BY GENETIC LOSS OF TGF-BETA SIGNALING MOLECULES OR PERTURBATION OF TGF-BETA ADAPTORS. ONCE A TUMOR HAS DEVELOPED, TGF-BETA EXERTS A PROMOTING EFFECT ON THE TUMOR ITSELF AND STROMAL CELLS TO ENHANCE CELL GROWTH, ALTER THE RESPONSIVENESS OF TUMOR CELLS TO STIMULATE INVASION AND METASTASIS, AND INHIBITED IMMUNE SURVEILLANCE. THEREFORE, NOVEL DEVELOPMENT OF THERAPEUTIC AGENTS TO INHIBIT TGF-BETA-INDUCED PROGRESSION OF TUMOR AND TO RETAIN ITS GROWTH INHIBITORY ACTIVITIES, IN ADDITION TO ANTI-INFLAMMATORY ACTIONS, COULD BE USEFUL IN ONCOLOGY. IN THIS REVIEW, WE DISCUSS THE ROLE OF TGF-BETA IN INFLAMMATION AND CARCINOGENESIS OF THE GI TRACT RELATED TO ABNORMAL TGF-BETA SIGNALING. 2010 6 2036 20 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 7 2228 30 EPIGENETIC MODIFICATIONS OF HISTONES IN PERIODONTAL DISEASE. PERIODONTITIS IS A CHRONIC INFECTIOUS DISEASE DRIVEN BY DYSBIOSIS, AN IMBALANCE BETWEEN COMMENSAL BACTERIA AND THE HOST ORGANISM. PERIODONTITIS IS A LEADING CAUSE OF TOOTH LOSS IN ADULTS AND OCCURS IN ABOUT 50% OF THE US POPULATION. IN ADDITION TO THE CLINICAL CHALLENGES ASSOCIATED WITH TREATING PERIODONTITIS, THE PROGRESSION AND CHRONIC NATURE OF THIS DISEASE SERIOUSLY AFFECT HUMAN HEALTH. EMERGING EVIDENCE SUGGESTS THAT PERIODONTITIS IS ASSOCIATED WITH MECHANISMS BEYOND BACTERIA-INDUCED PROTEIN AND TISSUE DEGRADATION. HERE, WE HYPOTHESIZE THAT BACTERIA ARE ABLE TO INDUCE EPIGENETIC MODIFICATIONS IN ORAL EPITHELIAL CELLS MEDIATED BY HISTONE MODIFICATIONS. IN THIS STUDY, WE FOUND THAT DYSBIOSIS IN VIVO LED TO EPIGENETIC MODIFICATIONS, INCLUDING ACETYLATION OF HISTONES AND DOWNREGULATION OF DNA METHYLTRANSFERASE 1. IN ADDITION, IN VITRO EXPOSURE OF ORAL EPITHELIAL CELLS TO LIPOPOLYSACCHARIDES RESULTED IN HISTONE MODIFICATIONS, ACTIVATION OF TRANSCRIPTIONAL COACTIVATORS, SUCH AS P300/CBP, AND ACCUMULATION OF NUCLEAR FACTOR-KAPPAB (NF-KAPPAB). GIVEN THAT ORAL EPITHELIAL CELLS ARE THE FIRST LINE OF DEFENSE FOR THE PERIODONTIUM AGAINST BACTERIA, WE ALSO EVALUATED WHETHER ACTIVATION OF PATHOGEN RECOGNITION RECEPTORS INDUCED HISTONE MODIFICATIONS. WE FOUND THAT ACTIVATION OF THE TOLL-LIKE RECEPTORS 1, 2, AND 4 AND THE NUCLEOTIDE-BINDING OLIGOMERIZATION DOMAIN PROTEIN 1 INDUCED HISTONE ACETYLATION IN ORAL EPITHELIAL CELLS. OUR FINDINGS CORROBORATE THE EMERGING CONCEPT THAT EPIGENETIC MODIFICATIONS PLAY A ROLE IN THE DEVELOPMENT OF PERIODONTITIS. 2016 8 5738 28 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 9 3672 22 INFLAMMATION AND CANCER: AN ANCIENT LINK WITH NOVEL POTENTIALS. INFECTION AND CHRONIC INFLAMMATION CONTRIBUTE TO ABOUT 1 IN 4 OF ALL CANCER CASES. MEDIATORS OF THE INFLAMMATORY RESPONSE, E.G., CYTOKINES, FREE RADICALS, PROSTAGLANDINS AND GROWTH FACTORS, CAN INDUCE GENETIC AND EPIGENETIC CHANGES INCLUDING POINT MUTATIONS IN TUMOR SUPPRESSOR GENES, DNA METHYLATION AND POST-TRANSLATIONAL MODIFICATIONS, CAUSING ALTERATIONS IN CRITICAL PATHWAYS RESPONSIBLE FOR MAINTAINING THE NORMAL CELLULAR HOMEOSTASIS AND LEADING TO THE DEVELOPMENT AND PROGRESSION OF CANCER. RECENT DISCOVERY OF AN INTERACTION BETWEEN MICRORNAS AND INNATE IMMUNITY DURING INFLAMMATION HAS FURTHER STRENGTHENED THE ASSOCIATION BETWEEN INFLAMMATION AND CANCER. 2007 10 5581 29 ROLE OF NF-KAPPAB IN AGEING AND AGE-RELATED DISEASES: LESSONS FROM GENETICALLY MODIFIED MOUSE MODELS. AGEING IS A COMPLEX PROCESS, INDUCED BY MULTIFACETED INTERACTION OF GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS. IT IS MANIFESTED BY A DECLINE IN THE PHYSIOLOGICAL FUNCTIONS OF ORGANISMS AND ASSOCIATED TO THE DEVELOPMENT OF AGE-RELATED CHRONIC DISEASES AND CANCER DEVELOPMENT. IT IS CONSIDERED THAT AGEING FOLLOWS A STRICTLY-REGULATED PROGRAM, IN WHICH SOME SIGNALING PATHWAYS CRITICALLY CONTRIBUTE TO THE ESTABLISHMENT AND MAINTENANCE OF THE AGED STATE. CHRONIC INFLAMMATION IS A MAJOR MECHANISM THAT PROMOTES THE BIOLOGICAL AGEING PROCESS AND COMORBIDITY, WITH THE TRANSCRIPTION FACTOR NF-KAPPAB (NUCLEAR FACTOR KAPPA-LIGHT-CHAIN-ENHANCER OF ACTIVATED B CELLS) AS A CRUCIAL MEDIATOR OF INFLAMMATORY RESPONSES. THIS, TOGETHER WITH THE FINDING THAT THE ACTIVATION OR INHIBITION OF NF-KAPPAB CAN INDUCE OR REVERSE RESPECTIVELY THE MAIN FEATURES OF AGED ORGANISMS, HAS BROUGHT IT UNDER CONSIDERATION AS A KEY TRANSCRIPTION FACTOR THAT ACTS AS A DRIVER OF AGEING. IN THIS REVIEW, WE FOCUSED ON THE DATA OBTAINED ENTIRELY THROUGH THE GENERATION OF KNOCKOUT AND TRANSGENIC MOUSE MODELS OF EITHER PROTEIN INVOLVED IN THE NF-KAPPAB SIGNALING PATHWAY THAT HAVE PROVIDED RELEVANT INFORMATION ABOUT THE INTRICATE PROCESSES OR MOLECULAR MECHANISMS THAT CONTROL AGEING. WE HAVE REVIEWED THE RELATIONSHIP OF NF-KAPPAB AND PREMATURE AGEING; THE DEVELOPMENT OF CANCER ASSOCIATED WITH AGEING AND THE IMPLICATION OF NF-KAPPAB ACTIVATION IN THE DEVELOPMENT OF AGE-RELATED DISEASES, SOME OF WHICH GREATLY INCREASE THE RISK OF DEVELOPING CANCER. 2021 11 4200 33 METABOLIC REQUIREMENTS OF TH17 CELLS AND OF B CELLS: REGULATION AND DEFECTS IN HEALTH AND IN INFLAMMATORY DISEASES. THE IMMUNE SYSTEM PROTECTS FROM INFECTIONS AND CANCER THROUGH COMPLEX CELLULAR NETWORKS. FOR THIS PURPOSE, IMMUNE CELLS REQUIRE WELL-DEVELOPED MECHANISMS OF ENERGY GENERATION. HOWEVER, THE IMMUNE SYSTEM ITSELF CAN ALSO CAUSE DISEASES WHEN DEFECTIVE REGULATION RESULTS IN THE EMERGENCE OF AUTOREACTIVE LYMPHOCYTES. RECENT STUDIES PROVIDE INSIGHTS INTO HOW DIFFERENTIAL PATTERNS OF IMMUNE CELL RESPONSES ARE ASSOCIATED WITH SELECTIVE METABOLIC PATHWAYS. THIS REVIEW WILL EXAMINE THE CHANGING METABOLIC REQUIREMENTS OF TH17 CELLS AND OF B CELLS AT DIFFERENT STAGES OF THEIR DEVELOPMENT AND ACTIVATION. BOTH CELLS PROVIDE PROTECTION BUT CAN ALSO MEDIATE DISEASES THROUGH THE PRODUCTION OF AUTOANTIBODIES AND THE PRODUCTION OF PROINFLAMMATORY MEDIATORS. IN HEALTH, B CELLS PRODUCE ANTIBODIES AND CYTOKINES AND PRESENT ANTIGENS TO T CELLS TO MOUNT SPECIFIC IMMUNITY. TH17 CELLS, ON THE OTHER HAND, PROVIDE PROTECTION AGAINST EXTRA CELLULAR PATHOGENS AT MUCOSAL SURFACES BUT CAN ALSO DRIVE CHRONIC INFLAMMATION. THE LATTER CELLS CAN ALSO PROMOTE THE DIFFERENTIATION OF B CELLS TO PLASMA CELLS TO PRODUCE MORE AUTOANTIBODIES. METABOLISM-REGULATED CHECKPOINTS AT DIFFERENT STAGES OF THEIR DEVELOPMENT ENSURE THE THAT SELF-REACTIVE B CELLS CLONES AND NEEDLESS PRODUCTION OF INTERLEUKIN (IL-)17 ARE LIMITED. THE METABOLIC REGULATION OF THE TWO CELL TYPES HAS SOME SIMILARITIES, E.G. THE UTILITY OF HYPOXIA INDUCED FACTOR (HIF)1ALPHA DURING LOW OXYGEN TENSION, TO PREVENT AUTOIMMUNITY AND REGULATE INFLAMMATION. THERE ARE ALSO CLEAR DIFFERENCES, AS TH17 CELLS ONLY ARE VULNERABLE TO THE LACK OF CERTAIN AMINO ACIDS. B CELLS, UNLIKE TH17 CELLS, ARE ALSO DEPENDENT OF MECHANISTIC TARGET OF RAPAMYCIN 2 (MTORC2) TO FUNCTION. SIGNIFICANT KNOWLEDGE HAS RECENTLY BEEN GAINED, PARTICULARLY ON TH17 CELLS, ON HOW METABOLISM REGULATES THESE CELLS THROUGH INFLUENCING THEIR EPIGENOME. METABOLIC DYSREGULATION OF TH17 CELLS AND B CELLS CAN LEAD TO CHRONIC INFLAMMATION. DISEASE ASSOCIATED ALTERATIONS IN THE GENOME CAN, IN ADDITION, CAUSE DYSREGULATION TO METABOLISM AND, THEREBY, RESULT IN EPIGENETIC ALTERATIONS IN THESE CELLS. RECENT STUDIES HIGHLIGHT HOW PATHOLOGY CAN RESULT FROM THE COOPERATION BETWEEN THE TWO CELL TYPES BUT ONLY FEW HAVE SO FAR ADDRESSED THE KEY METABOLIC ALTERATIONS IN SUCH SETTINGS. KNOWLEDGE OF THE IMPACT OF METABOLIC DYSFUNCTION ON CHRONIC INFLAMMATION AND PATHOLOGY CAN REVEAL NOVEL THERAPEUTIC TARGETS TO TREAT SUCH DISEASES. 2022 12 6359 30 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 13 1864 29 EMERGING AVENUES LINKING INFLAMMATION AND CANCER. THE ROLE OF INFLAMMATION IN CARCINOGENESIS HAS BEEN EXTENSIVELY INVESTIGATED AND WELL DOCUMENTED. MANY BIOCHEMICAL PROCESSES THAT ARE ALTERED DURING CHRONIC INFLAMMATION HAVE BEEN IMPLICATED IN TUMORIGENESIS. THESE INCLUDE SHIFTING CELLULAR REDOX BALANCE TOWARD OXIDATIVE STRESS; INDUCTION OF GENOMIC INSTABILITY; INCREASED DNA DAMAGE; STIMULATION OF CELL PROLIFERATION, METASTASIS, AND ANGIOGENESIS; DEREGULATION OF CELLULAR EPIGENETIC CONTROL OF GENE EXPRESSION; AND INAPPROPRIATE EPITHELIAL-TO-MESENCHYMAL TRANSITION. A WIDE ARRAY OF PROINFLAMMATORY CYTOKINES, PROSTAGLANDINS, NITRIC OXIDE, AND MATRICELLULAR PROTEINS ARE CLOSELY INVOLVED IN PREMALIGNANT AND MALIGNANT CONVERSION OF CELLS IN A BACKGROUND OF CHRONIC INFLAMMATION. INAPPROPRIATE TRANSCRIPTION OF GENES ENCODING INFLAMMATORY MEDIATORS, SURVIVAL FACTORS, AND ANGIOGENIC AND METASTATIC PROTEINS IS THE KEY MOLECULAR EVENT IN LINKING INFLAMMATION AND CANCER. ABERRANT CELL SIGNALING PATHWAYS COMPRISING VARIOUS KINASES AND THEIR DOWNSTREAM TRANSCRIPTION FACTORS HAVE BEEN IDENTIFIED AS THE MAJOR CONTRIBUTORS IN ABNORMAL GENE EXPRESSION ASSOCIATED WITH INFLAMMATION-DRIVEN CARCINOGENESIS. THE POSTTRANSCRIPTIONAL REGULATION OF GENE EXPRESSION BY MICRORNAS ALSO PROVIDES THE MOLECULAR BASIS FOR LINKING INFLAMMATION TO CANCER. THIS REVIEW HIGHLIGHTS THE MULTIFACETED ROLE OF INFLAMMATION IN CARCINOGENESIS IN THE CONTEXT OF ALTERED CELLULAR REDOX SIGNALING. 2012 14 4043 23 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 15 4953 34 PATHOGENESIS OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) INDUCED BY CIGARETTE SMOKE. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS A COMMON RESPIRATORY DISEASE THAT IS CHARACTERIZED BY FUNCTIONAL AND STRUCTURAL ALTERATIONS PRIMARILY CAUSED BY LONG-TERM INHALATION OF HARMFUL PARTICLES. CIGARETTE SMOKE (CS) INDUCES AIRWAY INFLAMMATION IN COPD, WHICH IS KNOWN TO PERSIST EVEN AFTER SMOKING CESSATION. THIS REVIEW DISCUSSES THE BASIC PATHOGENESIS OF COPD, WITH PARTICULAR FOCUS ON AN ENDOGENOUS PROTECTIVE MECHANISM AGAINST OXIDATIVE STRESS VIA NRF2, ALTERED IMMUNE RESPONSE OF THE AIRWAY INFLAMMATORY CELLS, EXAGGERATED CELLULAR SENESCENCE OF THE LUNG STRUCTURAL CELLS, AND CELL DEATH WITH EXPANDED INFLAMMATION. RECENTLY, CS-INDUCED MITOCHONDRIA AUTOPHAGY IS REPORTED TO INITIATE PROGRAMMED NECROSIS (NECROPTOSIS). NECROPTOSIS IS A NEW CONCEPT OF CELL DEATH WHICH IS DRIVEN BY A DEFINED MOLECULAR PATHWAY ALONG WITH EXAGGERATED INFLAMMATION. THIS NEW CELL DEATH MECHANISM IS OF IMPORTANCE DUE TO ITS ABILITY TO PRODUCE MORE INFLAMMATORY SUBSTANCES DURING THE PROCESS OF EPITHELIAL DEATH, CONTRIBUTING TO PERSISTENT AIRWAY INFLAMMATION THAT CANNOT BE EXPLAINED BY APOPTOSIS-DERIVED CELL DEATH. AUTOPHAGY IS AN AUTO-CELL COMPONENT DEGRADATION SYSTEM EXECUTED BY LYSOSOMES THAT CONTROLS PROTEIN AND ORGANELLE DEGRADATION FOR SUCCESSFUL HOMEOSTASIS. AS WELL AS IN THE PROCESS OF NECROPTOSIS, AUTOPHAGY IS ALSO OBSERVED DURING CELLULAR SENESCENCE. AGING OF THE LUNGS RESULTS IN THE ACQUISITION OF SENESCENCE-ASSOCIATED SECRETORY PHENOTYPES (SASP) THAT ARE KNOWN TO SECRETE INFLAMMATORY CYTOKINES, CHEMOKINES, GROWTH FACTORS, AND MATRIX METALLOPROTEINASES RESULTING IN CHRONIC LOW-GRADE INFLAMMATION. IN FUTURE RESEARCH, WE INTEND TO HIGHLIGHT THE GENETIC AND EPIGENETIC APPROACHES THAT CAN FACILITATE THE UNDERSTANDING OF DISEASE SUSCEPTIBILITY. THE GOAL OF PRECISION MEDICINE IS TO ESTABLISH MORE ACCURATE DIAGNOSIS AND TREATMENT METHODS BASED ON THE PATIENT-SPECIFIC PATHOGENIC CHARACTERISTICS. THIS REVIEW PROVIDES INSIGHTS INTO CS-INDUCED COPD PATHOGENESIS, WHICH CONTRIBUTES TO A VERY COMPLEX DISEASE. INVESTIGATING THE MECHANISM OF DEVELOPING COPD, ALONG WITH THE AVAILABILITY OF THE PARTICULAR INHIBITORS, WILL LEAD TO NEW THERAPEUTIC APPROACHES IN COPD TREATMENT. 2019 16 1232 33 CROSSTALK BETWEEN INFLAMMATORY SIGNALING AND METHYLATION IN CANCER. INFLAMMATION IS AN INTRICATE IMMUNE RESPONSE AGAINST INFECTION AND TISSUE DAMAGE. WHILE THE INITIAL IMMUNE RESPONSE IS IMPORTANT FOR PREVENTING TUMORIGENESIS, CHRONIC INFLAMMATION IS IMPLICATED IN CANCER PATHOGENESIS. IT HAS BEEN LINKED TO VARIOUS STAGES OF TUMOR DEVELOPMENT INCLUDING TRANSFORMATION, PROLIFERATION, ANGIOGENESIS, AND METASTASIS. IMMUNE CELLS, THROUGH THE PRODUCTION OF INFLAMMATORY MEDIATORS SUCH AS CYTOKINES, CHEMOKINES, TRANSFORMING GROWTH FACTORS, AND ADHESION MOLECULES CONTRIBUTE TO THE SURVIVAL, GROWTH, AND PROGRESSION OF THE TUMOR IN ITS MICROENVIRONMENT. THE ABERRANT EXPRESSION AND SECRETION OF PRO-INFLAMMATORY AND GROWTH FACTORS BY THE TUMOR CELLS RESULT IN THE RECRUITMENT OF IMMUNE CELLS, THUS CREATING A MUTUAL CROSSTALK. THE RECIPROCAL SIGNALING BETWEEN THE TUMOR CELLS AND THE IMMUNE CELLS CREATES AND MAINTAINS A SUCCESSFUL TUMOR NICHE. MANY INFLAMMATORY FACTORS ARE REGULATED BY EPIGENETIC MECHANISMS INCLUDING DNA METHYLATION AND HISTONE MODIFICATIONS. IN PARTICULAR, DNA AND HISTONE METHYLATION ARE CRUCIAL FORMS OF TRANSCRIPTIONAL REGULATION AND ABERRANT METHYLATION HAS BEEN ASSOCIATED WITH DEREGULATED GENE EXPRESSION IN ONCOGENESIS. SUCH DEREGULATIONS HAVE BEEN REPORTED IN BOTH SOLID TUMORS AND HEMATOLOGICAL MALIGNANCIES. WITH TECHNOLOGICAL ADVANCEMENTS TO STUDY GENOME-WIDE EPIGENETIC LANDSCAPES, IT IS NOW POSSIBLE TO IDENTIFY MOLECULAR MECHANISMS UNDERLYING ALTERED INFLAMMATORY PROFILES IN CANCER. IN THIS REVIEW, WE DISCUSS THE ROLE OF DNA AND HISTONE METHYLATION IN REGULATION OF INFLAMMATORY PATHWAYS IN HUMAN CANCERS AND REVIEW THE MERITS AND CHALLENGES OF TARGETING INFLAMMATORY MEDIATORS AS WELL AS EPIGENETIC REGULATORS IN CANCER. 2021 17 6533 29 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 18 6309 20 THE REGULATION OF MIRNAS IN INFLAMMATION-RELATED CARCINOGENESIS. CHRONIC INFLAMMATION PLAYS IMPORTANT ROLES IN THE INITIATION AND DEVELOPMENT OF VARIOUS CANCERS, PARTICULARLY GASTROINTESTINAL CANCER. CANCER IS CHARACTERIZED BY STEPWISE ACCUMULATION OF GENETIC AND EPIGENETIC ALTERATIONS OF GENES. AS A HIGH RISK FACTOR FOR CANCER, CHRONIC INFLAMMATORY RESPONSE PRODUCES GREAT AMOUNT OF MEDIATORS, INCLUDING CYTOKINES, REACTIVE OXYGEN AND NITROGEN SPECIES, PROTEINASES, WHICH CAN INDUCE GENETIC AND EPIGENETIC CHANGES OF CANCER-ASSOCIATED GENES AND PATHWAYS. FURTHERMORE, INFLAMMATION ALSO MODULATES THE EXPRESSION OF MIRNAS THAT NOT ONLY REGULATE THE EXPRESSION OF TUMOR-RELATED PROTEINS BUT ALSO ENHANCE THE TUMOR-PROMOTING INFLAMMATORY PROCESS. IN THE CURRENT REVIEW, WE SUMMARIZE THE MECHANISMS BY WHICH INFLAMMATORY MEDIATORS AND SIGNALING REGULATE THE BIOSYNTHESIS OF MIRNAS, AS WELL AS THE INVOLVEMENT OF MIRNAS IN THE FEEDBACK LOOPS PROMOTING INFLAMMATION-ASSOCIATED CARCINOGENESIS. 2015 19 2299 32 EPIGENETIC REGULATION OF AIRWAY EPITHELIUM IMMUNE FUNCTIONS IN ASTHMA. ASTHMA IS A CHRONIC INFLAMMATORY DISEASE OF THE RESPIRATORY TRACT CHARACTERIZED BY RECURRENT BREATHING PROBLEMS RESULTING FROM AIRWAY OBSTRUCTION AND HYPERRESPONSIVENESS. HUMAN AIRWAY EPITHELIUM PLAYS AN IMPORTANT ROLE IN THE INITIATION AND CONTROL OF THE IMMUNE RESPONSES TO DIFFERENT TYPES OF ENVIRONMENTAL FACTORS CONTRIBUTING TO ASTHMA PATHOGENESIS. USING PATTERN RECOGNITION RECEPTORS AIRWAY EPITHELIUM SENSES EXTERNAL STIMULI, SUCH AS ALLERGENS, MICROBES, OR POLLUTANTS, AND SUBSEQUENTLY SECRETES ENDOGENOUS DANGER SIGNALING MOLECULES ALARMING AND ACTIVATING DENDRITIC CELLS. HENCE, AIRWAY EPITHELIAL CELLS NOT ONLY MEDIATE INNATE IMMUNE RESPONSES BUT ALSO BRIDGE THEM WITH ADAPTIVE IMMUNE RESPONSES INVOLVING T AND B CELLS THAT PLAY A CRUCIAL ROLE IN THE PATHOGENESIS OF ASTHMA. THE EFFECTS OF ENVIRONMENTAL FACTORS ON THE DEVELOPMENT OF ASTHMA ARE MEDIATED, AT LEAST IN PART, BY EPIGENETIC MECHANISMS. THOSE COMPRISE CLASSICAL EPIGENETICS INCLUDING DNA METHYLATION AND HISTONE MODIFICATIONS AFFECTING TRANSCRIPTION, AS WELL AS MICRORNAS INFLUENCING TRANSLATION. THE COMMON FEATURE OF SUCH MECHANISMS IS THAT THEY REGULATE GENE EXPRESSION WITHOUT AFFECTING THE NUCLEOTIDE SEQUENCE OF THE GENOMIC DNA. EPIGENETIC MECHANISMS PLAY A PIVOTAL ROLE IN THE REGULATION OF DIFFERENT CELL POPULATIONS INVOLVED IN ASTHMA PATHOGENESIS, WITH THE REMARKABLE EXAMPLE OF T CELLS. RECENTLY, HOWEVER, THERE IS INCREASING EVIDENCE THAT EPIGENETIC MECHANISMS ARE ALSO CRUCIAL FOR THE REGULATION OF AIRWAY EPITHELIAL CELLS, ESPECIALLY IN THE CONTEXT OF EPIGENETIC TRANSFER OF ENVIRONMENTAL EFFECTS CONTRIBUTING TO ASTHMA PATHOGENESIS. IN THIS REVIEW, WE SUMMARIZE THE ACCUMULATING EVIDENCE FOR THIS VERY IMPORTANT ASPECT OF AIRWAY EPITHELIAL CELL PATHOBIOLOGY. 2020 20 6428 25 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