1 5472 114 RESPIRATORY VIRAL INFECTIONS IN EXACERBATION OF CHRONIC AIRWAY INFLAMMATORY DISEASES: NOVEL MECHANISMS AND INSIGHTS FROM THE UPPER AIRWAY EPITHELIUM. RESPIRATORY VIRUS INFECTION IS ONE OF THE MAJOR SOURCES OF EXACERBATION OF CHRONIC AIRWAY INFLAMMATORY DISEASES. THESE EXACERBATIONS ARE ASSOCIATED WITH HIGH MORBIDITY AND EVEN MORTALITY WORLDWIDE. THE CURRENT UNDERSTANDING ON VIRAL-INDUCED EXACERBATIONS IS THAT VIRAL INFECTION INCREASES AIRWAY INFLAMMATION WHICH AGGRAVATES DISEASE SYMPTOMS. RECENT ADVANCES IN IN VITRO AIR-LIQUID INTERFACE 3D CULTURES, ORGANOID CULTURES AND THE USE OF NOVEL HUMAN AND ANIMAL CHALLENGE MODELS HAVE EVOKED NEW UNDERSTANDINGS AS TO THE MECHANISMS OF VIRAL EXACERBATIONS. IN THIS REVIEW, WE WILL FOCUS ON RECENT NOVEL FINDINGS THAT ELUCIDATE HOW RESPIRATORY VIRAL INFECTIONS ALTER THE EPITHELIAL BARRIER IN THE AIRWAYS, THE UPPER AIRWAY MICROBIAL ENVIRONMENT, EPIGENETIC MODIFICATIONS INCLUDING MIRNA MODULATION, AND OTHER CHANGES IN IMMUNE RESPONSES THROUGHOUT THE UPPER AND LOWER AIRWAYS. FIRST, WE REVIEWED THE PREVALENCE OF DIFFERENT RESPIRATORY VIRAL INFECTIONS IN CAUSING EXACERBATIONS IN CHRONIC AIRWAY INFLAMMATORY DISEASES. SUBSEQUENTLY WE ALSO SUMMARIZED HOW RECENT MODELS HAVE EXPANDED OUR APPRECIATION OF THE MECHANISMS OF VIRAL-INDUCED EXACERBATIONS. FURTHER WE HIGHLIGHTED THE IMPORTANCE OF THE VIROME WITHIN THE AIRWAY MICROBIOME ENVIRONMENT AND ITS IMPACT ON SUBSEQUENT BACTERIAL INFECTION. THIS REVIEW CONSOLIDATES THE UNDERSTANDING OF VIRAL INDUCED EXACERBATION IN CHRONIC AIRWAY INFLAMMATORY DISEASES AND INDICATES PATHWAYS THAT MAY BE TARGETED FOR MORE EFFECTIVE MANAGEMENT OF CHRONIC INFLAMMATORY DISEASES. 2020 2 4954 22 PATHOGENESIS OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE. THE PATHOGENESIS OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) ENCOMPASSES A NUMBER OF INJURIOUS PROCESSES, INCLUDING AN ABNORMAL INFLAMMATORY RESPONSE IN THE LUNGS TO INHALED PARTICLES AND GASES. OTHER PROCESSES, SUCH AS FAILURE TO RESOLVE INFLAMMATION, ABNORMAL CELL REPAIR, APOPTOSIS, ABNORMAL CELLULAR MAINTENANCE PROGRAMS, EXTRACELLULAR MATRIX DESTRUCTION (PROTEASE/ANTIPROTEASE IMBALANCE), AND OXIDATIVE STRESS (OXIDANT/ANTIOXIDANT IMBALANCE) ALSO HAVE A ROLE. THE INFLAMMATORY RESPONSES TO THE INHALATION OF ACTIVE AND PASSIVE TOBACCO SMOKE AND URBAN AND RURAL AIR POLLUTION ARE MODIFIED BY GENETIC AND EPIGENETIC FACTORS. THE SUBSEQUENT CHRONIC INFLAMMATORY RESPONSES LEAD TO MUCUS HYPERSECRETION, AIRWAY REMODELING, AND ALVEOLAR DESTRUCTION. THIS ARTICLE PROVIDES AN UPDATE ON THE CELLULAR AND MOLECULAR MECHANISMS OF THESE PROCESSES IN THE PATHOGENESIS OF COPD. 2007 3 5541 33 ROLE OF DIETARY PHENOLS IN MITIGATING MICROGLIA-MEDIATED NEUROINFLAMMATION. CHRONIC NEUROINFLAMMATION IS A PATHOLOGICAL FEATURE OF A NUMBER OF CENTRAL NERVOUS SYSTEM (CNS) DISEASES AND IS MEDIATED BY SUSTAINED ACTIVATION OF MICROGLIAL CELLS, THE INNATE IMMUNE CELLS OF THE CNS. STUDIES HAVE MAINLY FOCUSED ON IDENTIFYING THE MOLECULAR AND EPIGENETIC MECHANISMS OF MICROGLIAL ACTIVATION. THIS IS CRUCIAL IN DESIGNING THERAPEUTIC STRATEGIES FOR NEUROPATHOLOGIES IN WHICH PROLONGED MICROGLIAL ACTIVATION IS KNOWN TO EXACERBATE DISEASE CONDITION. IN RECENT YEARS, INCREASING EVIDENCE SHOW THAT NATURALLY OCCURRING COMPOUNDS PRESENT IN REGULAR DIET COULD FUNCTION AS "NUTRACEUTICALS," ARRESTING MICROGLIAL ACTIVATION, AND THUS CONFERRING NEUROPROTECTION. THIS REVIEW SUMMARIZES OUR UNDERSTANDING OF THE ROLE OF DIETARY PHENOLIC NUTRACEUTICALS IN MITIGATING MICROGLIA-MEDIATED NEUROINFLAMMATION. STUDIES SHOW THAT THESE NATURAL PHENOLS INHIBIT KEY SIGNALING PATHWAYS IN ACTIVATED MICROGLIA SUCH AS THE NFKAPPAB, MAPK AND JAK-STAT THAT TRIGGER MICROGLIA-MEDIATED INFLAMMATION IN VARIOUS NEUROPATHOLOGICAL CONDITIONS SUCH AS INJURY, INFECTION, STROKE, AUTISM AND NEURODEGENERATIVE DISEASES, I.E., ALZHEIMER'S DISEASE AND PARKINSON'S DISEASE. THE ANTI-INFLAMMATORY AND ANTIOXIDANT EFFECT EXERTED BY THESE NATURAL PHENOLS HAVE SHOWN CONSIDERABLE SUCCESS IN IMPROVING DISEASE CONDITION IN ANIMAL MODELS OF NEUROPATHOLOGIES, AND THUS SEEM TO BE SUITABLE CANDIDATES FOR DEVELOPING THERAPEUTIC STRATEGIES. 2016 4 4953 40 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 5 4543 28 MUSCLE DYSFUNCTION IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE: UPDATE ON CAUSES AND BIOLOGICAL FINDINGS. RESPIRATORY AND/OR LIMB MUSCLE DYSFUNCTION, WHICH ARE FREQUENTLY OBSERVED IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) PATIENTS, CONTRIBUTE TO THEIR DISEASE PROGNOSIS IRRESPECTIVE OF THE LUNG FUNCTION. MUSCLE DYSFUNCTION IS CAUSED BY THE INTERACTION OF LOCAL AND SYSTEMIC FACTORS. THE KEY DELETERIOUS ETIOLOGIC FACTORS ARE PULMONARY HYPERINFLATION FOR THE RESPIRATORY MUSCLES AND DECONDITIONING SECONDARY TO REDUCED PHYSICAL ACTIVITY FOR LIMB MUSCLES. NONETHELESS, CIGARETTE SMOKE, SYSTEMIC INFLAMMATION, NUTRITIONAL ABNORMALITIES, EXERCISE, EXACERBATIONS, ANABOLIC INSUFFICIENCY, DRUGS AND COMORBIDITIES ALSO SEEM TO PLAY A RELEVANT ROLE. ALL THESE FACTORS MODIFY THE PHENOTYPE OF THE MUSCLES, THROUGH THE INDUCTION OF SEVERAL BIOLOGICAL PHENOMENA IN PATIENTS WITH COPD. WHILE RESPIRATORY MUSCLES IMPROVE THEIR AEROBIC PHENOTYPE (PERCENTAGE OF OXIDATIVE FIBERS, CAPILLARIZATION, MITOCHONDRIAL DENSITY, ENZYME ACTIVITY IN THE AEROBIC PATHWAYS, ETC.), LIMB MUSCLES EXHIBIT THE OPPOSITE PHENOTYPE. IN ADDITION, BOTH MUSCLE GROUPS SHOW OXIDATIVE STRESS, SIGNS OF DAMAGE AND EPIGENETIC CHANGES. HOWEVER, FIBER ATROPHY, INCREASED NUMBER OF INFLAMMATORY CELLS, ALTERED REGENERATIVE CAPACITY; SIGNS OF APOPTOSIS AND AUTOPHAGY, AND AN IMBALANCE BETWEEN PROTEIN SYNTHESIS AND BREAKDOWN ARE RATHER CHARACTERISTIC FEATURES OF THE LIMB MUSCLES, MOSTLY IN PATIENTS WITH REDUCED BODY WEIGHT. DESPITE THAT SIGNIFICANT PROGRESS HAS BEEN ACHIEVED IN THE LAST DECADES, FULL ELUCIDATION OF THE SPECIFIC ROLES OF THE TARGET BIOLOGICAL MECHANISMS INVOLVED IN COPD MUSCLE DYSFUNCTION IS STILL REQUIRED. SUCH AN ACHIEVEMENT WILL BE CRUCIAL TO ADEQUATELY TACKLE WITH THIS RELEVANT CLINICAL PROBLEM OF COPD PATIENTS IN THE NEAR-FUTURE. 2015 6 298 43 AIR POLLUTION AND AIRWAY DISEASE. EPIDEMIOLOGICAL AND TOXICOLOGICAL RESEARCH CONTINUES TO SUPPORT A LINK BETWEEN URBAN AIR POLLUTION AND AN INCREASED INCIDENCE AND/OR SEVERITY OF AIRWAY DISEASE. DETRIMENTAL EFFECTS OF OZONE (O(3)), NITROGEN DIOXIDE (NO(2)) AND PARTICULATE MATTER (PM), AS WELL AS TRAFFIC-RELATED POLLUTION AS A WHOLE, ON RESPIRATORY SYMPTOMS AND FUNCTION ARE WELL DOCUMENTED. NOT ONLY DO WE HAVE STRONG EPIDEMIOLOGICAL EVIDENCE OF A RELATIONSHIP BETWEEN AIR POLLUTION AND EXACERBATION OF ASTHMA AND RESPIRATORY MORBIDITY AND MORTALITY IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD), BUT RECENT STUDIES, PARTICULARLY IN URBAN AREAS, HAVE SUGGESTED A ROLE FOR POLLUTANTS IN THE DEVELOPMENT OF BOTH ASTHMA AND COPD. SIMILARLY, WHILE PREVALENCE AND SEVERITY OF ATOPIC CONDITIONS APPEAR TO BE MORE COMMON IN URBAN COMPARED WITH RURAL COMMUNITIES, EVIDENCE IS EMERGING THAT TRAFFIC-RELATED POLLUTANTS MAY CONTRIBUTE TO THE DEVELOPMENT OF ALLERGY. FURTHERMORE, NUMEROUS EPIDEMIOLOGICAL AND EXPERIMENTAL STUDIES SUGGEST AN ASSOCIATION BETWEEN EXPOSURE TO NO(2) , O(3) , PM AND COMBUSTION PRODUCTS OF BIOMASS FUELS AND AN INCREASED SUSCEPTIBILITY TO AND MORBIDITY FROM RESPIRATORY INFECTION. GIVEN THE CONSIDERABLE CONTRIBUTION THAT TRAFFIC EMISSIONS MAKE TO URBAN AIR POLLUTION RESEARCHERS HAVE SOUGHT TO CHARACTERIZE THE RELATIVE TOXICITY OF TRAFFIC-RELATED PM POLLUTANTS. RECENT ADVANCES IN MECHANISMS IMPLICATED IN THE ASSOCIATION OF AIR POLLUTANTS AND AIRWAY DISEASE INCLUDE EPIGENETIC ALTERATION OF GENES BY COMBUSTION-RELATED POLLUTANTS AND HOW POLYMORPHISMS IN GENES INVOLVED IN ANTIOXIDANT PATHWAYS AND AIRWAY INFLAMMATION CAN MODIFY RESPONSES TO AIR POLLUTION EXPOSURES. OTHER INTERESTING EPIDEMIOLOGICAL OBSERVATIONS RELATED TO INCREASED HOST SUSCEPTIBILITY INCLUDE A POSSIBLE LINK BETWEEN CHRONIC PM EXPOSURE DURING CHILDHOOD AND VULNERABILITY TO COPD IN ADULTHOOD, AND THAT INFANTS SUBJECTED TO HIGHER PRENATAL LEVELS OF AIR POLLUTION MAY BE AT GREATER RISK OF DEVELOPING RESPIRATORY CONDITIONS. WHILE THE CHARACTERIZATION OF POLLUTANT COMPONENTS AND SOURCES PROMISE TO GUIDE POLLUTION CONTROL STRATEGIES, THE IDENTIFICATION OF SUSCEPTIBLE SUBPOPULATIONS WILL BE NECESSARY IF TARGETED THERAPY/PREVENTION OF POLLUTION-INDUCED RESPIRATORY DISEASES IS TO BE DEVELOPED. 2011 7 6440 27 THERAPEUTIC APPROACHES FOR CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) EXACERBATIONS. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS A PROGRESSIVE PULMONARY DISORDER UNDERPINNED BY POORLY REVERSIBLE AIRFLOW RESULTING FROM CHRONIC BRONCHITIS OR EMPHYSEMA. THE PREVALENCE AND MORTALITY OF COPD CONTINUE TO INCREASE. PHARMACOTHERAPY FOR PATIENTS WITH COPD HAS INCLUDED ANTIBIOTICS, BRONCHODILATORS, AND ANTI-INFLAMMATORY CORTICOSTEROIDS (BUT WITH LITTLE SUCCESS). ORAL DISEASES HAVE LONG BEEN ESTABLISHED AS CLINICAL RISK FACTORS FOR DEVELOPING RESPIRATORY DISEASES. THE ESTABLISHMENT OF A VERY SIMILAR MICROBIOME IN THE MOUTH AND THE LUNG CONFIRMS THE ORAL-LUNG CONNECTION. THE ASPIRATION OF PATHOGENIC MICROBES FROM THE ORAL CAVITY HAS BEEN IMPLICATED IN SEVERAL RESPIRATORY DISEASES, INCLUDING PNEUMONIA AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). THIS REVIEW FOCUSES ON CURRENT AND FUTURE PHARMACOTHERAPEUTIC APPROACHES FOR COPD EXACERBATION INCLUDING ANTIMICROBIALS, MUCOREGULATORS, THE USE OF BRONCHODILATORS AND ANTI-INFLAMMATORY DRUGS, MODIFYING EPIGENETIC MARKS, AND MODULATING DYSBIOSIS OF THE MICROBIOME. 2022 8 5314 31 PSYCHOLOGICAL STRESS IN ASTHMA: REPERCUSSIONS ON EPIGENETICS-GENETICS, IMMUNE RESPONSES, AND PULMONARY FUNCTION IN THE PEDIATRIC POPULATION. IN THE ASSESSMENT OF CHILDHOOD ASTHMA, IDENTIFYING THE RISK FACTORS ASSOCIATED WITH EXACERBATIONS AND BROADENING THIS VIEW TO UNDERSTAND PSYCHOLOGICAL STRESS AND ITS REPERCUSSIONS ON THE INFLAMMATORY PROCESS OF ASTHMA ALLOW A DIFFERENT PERSPECTIVE ON THIS BIOPSYCHOSOCIAL DISEASE. PSYCHOLOGICAL STRESS, AS A RISK FACTOR FOR THE ONSET AND NONCONTROL OF ASTHMA, HAS BEEN INCREASINGLY EVALUATED FROM THE PERSPECTIVE OF THE REPERCUSSIONS ON THE BODY OF THE STIMULUS GENERATED IN THE HYPOTHALAMIC-PITUITARY AXIS AND ADRENAL GLANDS, WITH CORTISOL RELEASE AND IMMUNE SYSTEM ACTION. THESE PROCESSES TRIGGER CHANGES IN T HELPER 2 CELLS, WHICH POLARIZE ALLERGIC PROCESSES, AND DYSFUNCTIONS IN IMMUNE TOLERANCE MECHANISMS, WITH A DECREASE IN REGULATORY T CELLS. GENETIC AND EPIGENETIC CHANGES IN BETA(2)-ADRENERGIC AND GLUCOCORTICOID RECEPTORS, WITH DECREASED RESPONSE TO THESE DRUGS, WERE ALSO IDENTIFIED IN STUDIES, IN ADDITION TO CHANGES IN RESPIRATORY FUNCTION PATTERNS, WITH WORSENING OF OBSTRUCTION AND INFLAMMATION IDENTIFIED VIA DECREASED FORCED EXPIRATORY VOLUME IN ONE SECOND AND INCREASED EXHALED INFLAMMATORY GASES IN ALLERGIC ASTHMA. THEREFORE, THE PRESENT REVIEW SOUGHT TO IDENTIFY STUDIES ON THE EFFECT OF PERSONAL AND PARENTAL ACUTE OR CHRONIC PSYCHOLOGICAL STRESS, EMPHASIZING THE REPERCUSSIONS ON GENETICS, EPIGENETICS, AND IMMUNE AND PULMONARY FUNCTIONAL AND INFLAMMATORY RESPONSES IN THE PEDIATRIC POPULATION. 2022 9 6450 31 THERAPEUTIC TARGETS FOR INFLAMMATION-MEDIATED AIRWAY REMODELING IN CHRONIC LUNG DISEASE. ACUTE EXACERBATIONS OF CHRONIC LUNG DISEASE ACCOUNT FOR SUBSTANTIAL MORBIDITY AND HEALTH COSTS. REPEATED INFLAMMATORY EPISODES AND ATTENDANT BRONCHOCONSTRICTION CAUSE STRUCTURAL REMODELING OF THE AIRWAY. REMODELING IS A MULTICELLULAR RESPONSE TO MUCOSAL INJURY THAT RESULTS IN EPITHELIAL CELL-STATE CHANGES, ENHANCED EXTRACELLULAR DEPOSITION, AND EXPANSION OF PRO-FIBROTIC MYOFIBROBLAST POPULATIONS. AREAS COVERED: THIS MANUSCRIPT OVERVIEWS MECHANISTIC STUDIES IDENTIFYING KEY SENTINEL CELL POPULATIONS IN THE AIRWAY AND HOW PATTERN RECOGNITION SIGNALING INDUCES MALADAPTIVE MUCOSAL CHANGES AND AIRWAY REMODELING. STUDIES ELUCIDATING HOW NFKAPPAB COUPLES WITH AN ATYPICAL HISTONE ACETYLTRANSFERASE, BROMODOMAIN-CONTAINING PROTEIN 4 (BRD4) THAT REPROGRAMS MUCOSAL FIBROGENIC RESPONSES, ARE DESCRIBED. THE APPROACHES TO DEVELOPMENT AND CHARACTERIZATION OF SELECTIVE INHIBITORS OF EPIGENETIC REPROGRAMMING ON INNATE INFLAMMATION AND STRUCTURAL REMODELING IN PRECLINICAL MODELS ARE DETAILED. EXPERT COMMENTARY: BRONCHIOLAR CELLS DERIVED FROM SCGB1A1-EXPRESSING PROGENITORS FUNCTION AS MAJOR SENTINEL CELLS OF THE AIRWAY, RESPONSIBLE FOR INITIATING ANTIVIRAL AND AEROALLERGEN RESPONSES. IN THESE SENTINEL CELLS, ACTIVATION OF INNATE INFLAMMATION IS COUPLED TO NEUTROPHILIC RECRUITMENT, MESENCHYMAL TRANSITION AND MYOFIBROBLAST EXPANSION. THERAPEUTICS TARGETING THE NFKB-BRD4 MAY BE EFFICACIOUS IN REDUCING PATHOLOGICAL EFFECTS OF ACUTE EXACERBATIONS IN CHRONIC LUNG DISEASE. 2018 10 4116 35 MECHANISMS OF AIRWAY EPITHELIAL INJURY AND ABNORMAL REPAIR IN ASTHMA AND COPD. THE AIRWAY EPITHELIUM COMPRISES OF DIFFERENT CELL TYPES AND ACTS AS A PHYSICAL BARRIER PREVENTING PATHOGENS, INCLUDING INHALED PARTICLES AND MICROBES, FROM ENTERING THE LUNGS. GOBLET CELLS AND SUBMUCOSAL GLANDS PRODUCE MUCUS THAT TRAPS PATHOGENS, WHICH ARE EXPELLED FROM THE RESPIRATORY TRACT BY CILIATED CELLS. BASAL CELLS ACT AS PROGENITOR CELLS, DIFFERENTIATING INTO DIFFERENT EPITHELIAL CELL TYPES, TO MAINTAIN HOMEOSTASIS FOLLOWING INJURY. ADHERENS AND TIGHT JUNCTIONS BETWEEN CELLS MAINTAIN THE EPITHELIAL BARRIER FUNCTION AND REGULATE THE MOVEMENT OF MOLECULES ACROSS IT. IN THIS REVIEW WE DISCUSS HOW ABNORMAL EPITHELIAL STRUCTURE AND FUNCTION, CAUSED BY CHRONIC INJURY AND ABNORMAL REPAIR, DRIVES AIRWAY DISEASE AND SPECIFICALLY ASTHMA AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). IN BOTH DISEASES, INHALED ALLERGENS, POLLUTANTS AND MICROBES DISRUPT JUNCTIONAL COMPLEXES AND PROMOTE CELL DEATH, IMPAIRING THE BARRIER FUNCTION AND LEADING TO INCREASED PENETRATION OF PATHOGENS AND A CONSTANT AIRWAY IMMUNE RESPONSE. IN ASTHMA, THE INFLAMMATORY RESPONSE PRECIPITATES THE EPITHELIAL INJURY AND DRIVES ABNORMAL BASAL CELL DIFFERENTIATION. THIS LEADS TO REDUCED CILIATED CELLS, GOBLET CELL HYPERPLASIA AND INCREASED EPITHELIAL MESENCHYMAL TRANSITION, WHICH CONTRIBUTE TO IMPAIRED MUCOCILIARY CLEARANCE AND AIRWAY REMODELLING. IN COPD, CHRONIC OXIDATIVE STRESS AND INFLAMMATION TRIGGER PREMATURE EPITHELIAL CELL SENESCENCE, WHICH CONTRIBUTES TO LOSS OF EPITHELIAL INTEGRITY AND AIRWAY INFLAMMATION AND REMODELLING. INCREASED NUMBERS OF BASAL CELLS SHOWING DEREGULATED DIFFERENTIATION, CONTRIBUTES TO CILIARY DYSFUNCTION AND MUCOUS HYPERPRODUCTION IN COPD AIRWAYS. DEFECTIVE ANTIOXIDANT, ANTIVIRAL AND DAMAGE REPAIR MECHANISMS, POSSIBLY DUE TO GENETIC OR EPIGENETIC FACTORS, MAY CONFER SUSCEPTIBILITY TO AIRWAY EPITHELIAL DYSFUNCTION IN THESE DISEASES. THE CURRENT EVIDENCE SUGGESTS THAT A CONSTANT CYCLE OF INJURY AND ABNORMAL REPAIR OF THE EPITHELIUM DRIVES CHRONIC AIRWAY INFLAMMATION AND REMODELLING IN ASTHMA AND COPD. MECHANISTIC UNDERSTANDING OF INJURY SUSCEPTIBILITY AND DAMAGE RESPONSE MAY LEAD TO IMPROVED THERAPIES FOR THESE DISEASES. 2023 11 4380 27 MITOCHONDRIAL DYSFUNCTION AND OXIDATIVE STRESS IN RHEUMATOID ARTHRITIS. CONTROL OF EXCESSIVE MITOCHONDRIAL OXIDATIVE STRESS COULD PROVIDE NEW TARGETS FOR BOTH PREVENTIVE AND THERAPEUTIC INTERVENTIONS IN THE TREATMENT OF CHRONIC INFLAMMATION OR ANY PATHOLOGY THAT DEVELOPS UNDER AN INFLAMMATORY SCENARIO, SUCH AS RHEUMATOID ARTHRITIS (RA). INCREASING EVIDENCE HAS DEMONSTRATED THE ROLE OF MITOCHONDRIAL ALTERATIONS IN AUTOIMMUNE DISEASES MAINLY DUE TO THE INTERPLAY BETWEEN METABOLISM AND INNATE IMMUNITY, BUT ALSO IN THE MODULATION OF INFLAMMATORY RESPONSE OF RESIDENT CELLS, SUCH AS SYNOVIOCYTES. THUS, MITOCHONDRIAL DYSFUNCTION DERIVED FROM SEVERAL DANGER SIGNALS COULD ACTIVATE TRICARBOXYLIC ACID (TCA) DISRUPTION, THEREBY FAVORING A VICIOUS CYCLE OF OXIDATIVE/MITOCHONDRIAL STRESS. MITOCHONDRIAL DYSFUNCTION CAN ACT THROUGH MODULATING INNATE IMMUNITY VIA REDOX-SENSITIVE INFLAMMATORY PATHWAYS OR DIRECT ACTIVATION OF THE INFLAMMASOME. BESIDES, MITOCHONDRIA ALSO HAVE A CENTRAL ROLE IN REGULATING CELL DEATH, WHICH IS DEEPLY ALTERED IN RA. ADDITIONALLY, MULTIPLE EVIDENCE SUGGESTS THAT PATHOLOGICAL PROCESSES IN RA CAN BE SHAPED BY EPIGENETIC MECHANISMS AND THAT IN TURN, MITOCHONDRIA ARE INVOLVED IN EPIGENETIC REGULATION. FINALLY, WE WILL DISCUSS ABOUT THE INVOLVEMENT OF SOME DIETARY COMPONENTS IN THE ONSET AND PROGRESSION OF RA. 2022 12 302 32 AIR POLLUTION EXPOSURE AND AUTO-INFLAMMATORY AND AUTOIMMUNE DISEASES OF THE MUSCULOSKELETAL SYSTEM: A REVIEW OF EPIDEMIOLOGIC AND MECHANISTIC EVIDENCE. AUTO-INFLAMMATORY AND AUTOIMMUNE DISEASES OF THE MUSCULOSKELETAL SYSTEM CAN BE PERCEIVED AS A SPECTRUM OF RHEUMATIC DISEASES, WITH THE JOINTS AND CONNECTIVE TISSUES ARE ERODED SEVERELY THAT PROGRESSIVELY DEVELOP CHRONIC INFLAMMATION AND LESION. A WIDE RANGE OF RISK FACTORS REPRESENTED BY GENETIC AND ENVIRONMENTAL FACTORS HAVE BEEN UNCOVERED BY POPULATION-BASED SURVEYS AND EXPERIMENTAL STUDIES. LATELY, THE EXPOSURE TO AIR POLLUTION HAS BEEN FOUND TO BE POTENTIALLY INVOLVED IN THE MECHANISMS OF OCCURRENCE OR DEVELOPMENT OF SUCH DISEASES, PRINCIPALLY MANIFEST IN OXIDATIVE STRESS, LOCAL AND SYSTEMIC INFLAMMATION, AND EPIGENETIC MODIFICATIONS, AS WELL AS THE MITOCHONDRIAL DYSFUNCTION, WHICH HAS BEEN REPORTED TO PARTICIPATE IN THE INTERMEDIATE LINKS. THE LUNGS MIGHT SERVE AS A STARTING AREA OF AIR POLLUTANTS, WHICH WOULD CAUSE OXIDATIVE STRESS-INDUCED BRONCHIAL-ASSOCIATED LYMPHOID TISSUE (IBALT) TO FURTHER TO INFLUENCE T, B CELLS, AND THE SECRETION OF PRO-INFLAMMATORY CYTOKINES. THE BINDING OF AROMATIC HYDROCARBON RECEPTOR (AHR) TO THE CORRESPONDING CONTAMINANT LIGANDS TENDS TO REGULATE THE REACTION OF TH17 AND TREGS. FURTHERMORE, AIR POLLUTION COMPONENTS MIGHT SPUR ON IMMUNE AND INFLAMMATORY RESPONSES BY DAMAGING MITOCHONDRIA THAT COULD INTERACT WITH AND EXACERBATE OXIDATIVE STRESS AND PRO-INFLAMMATORY CYTOKINES. IN THIS REVIEW, WE FOCUSED ON THE ASSOCIATION BETWEEN AIR POLLUTION AND TYPICAL AUTO-INFLAMMATORY AND AUTOIMMUNE DISEASES OF THE MUSCULOSKELETAL SYSTEM, MAINLY INCLUDING OSTEOARTHRITIS (OA), RHEUMATOID ARTHRITIS (RA), SPONDYLOARTHRITIS (SPA) AND JUVENILE IDIOPATHIC ARTHRITIS (JIA), AND AIM TO COLLATE THE MECHANISMS INVOLVED AND THE POTENTIAL CHANNELS. A COMPLETE SUMMARY AND IN-DEPTH UNDERSTANDING OF THE AUTOIMMUNE AND INFLAMMATORY EFFECTS OF AIR POLLUTION EXPOSURE SHOULD HOPEFULLY CONTRIBUTE NEW PERSPECTIVES ON HOW TO FORMULATE BETTER PUBLIC HEALTH POLICIES TO ALLEVIATE THE ADVERSE HEALTH EFFECTS OF AIR POLLUTANTS. 2023 13 5315 33 PSYCHOLOGICAL STRESS IN CHILDHOOD AND SUSCEPTIBILITY TO THE CHRONIC DISEASES OF AGING: MOVING TOWARD A MODEL OF BEHAVIORAL AND BIOLOGICAL MECHANISMS. AMONG PEOPLE EXPOSED TO MAJOR PSYCHOLOGICAL STRESSORS IN EARLY LIFE, THERE ARE ELEVATED RATES OF MORBIDITY AND MORTALITY FROM CHRONIC DISEASES OF AGING. THE MOST COMPELLING DATA COME FROM STUDIES OF CHILDREN RAISED IN POVERTY OR MALTREATED BY THEIR PARENTS, WHO SHOW HEIGHTENED VULNERABILITY TO VASCULAR DISEASE, AUTOIMMUNE DISORDERS, AND PREMATURE MORTALITY. THESE FINDINGS RAISE CHALLENGING THEORETICAL QUESTIONS. HOW DOES CHILDHOOD STRESS GET UNDER THE SKIN, AT THE MOLECULAR LEVEL, TO AFFECT RISK FOR LATER DISEASES? AND HOW DOES IT INCUBATE THERE, GIVING RISE TO DISEASES SEVERAL DECADES LATER? HERE WE PRESENT A BIOLOGICAL EMBEDDING MODEL, WHICH ATTEMPTS TO ADDRESS THESE QUESTIONS BY SYNTHESIZING KNOWLEDGE ACROSS SEVERAL BEHAVIORAL AND BIOMEDICAL LITERATURES. THIS MODEL MAINTAINS THAT CHILDHOOD STRESS GETS "PROGRAMMED" INTO MACROPHAGES THROUGH EPIGENETIC MARKINGS, POSTTRANSLATIONAL MODIFICATIONS, AND TISSUE REMODELING. AS A CONSEQUENCE THESE CELLS ARE ENDOWED WITH PROINFLAMMATORY TENDENCIES, MANIFEST IN EXAGGERATED CYTOKINE RESPONSES TO CHALLENGE AND DECREASED SENSITIVITY TO INHIBITORY HORMONAL SIGNALS. THE MODEL GOES ON TO PROPOSE THAT OVER THE LIFE COURSE, THESE PROINFLAMMATORY TENDENCIES ARE EXACERBATED BY BEHAVIORAL PROCLIVITIES AND HORMONAL DYSREGULATION, THEMSELVES THE PRODUCTS OF EXPOSURE TO EARLY STRESS. BEHAVIORALLY, THE MODEL POSITS THAT CHILDHOOD STRESS GIVES RISE TO EXCESSIVE THREAT VIGILANCE, MISTRUST OF OTHERS, POOR SOCIAL RELATIONSHIPS, IMPAIRED SELF-REGULATION, AND UNHEALTHY LIFESTYLE CHOICES. HORMONALLY, EARLY STRESS CONFERS ALTERED PATTERNS OF ENDOCRINE AND AUTONOMIC DISCHARGE. THIS MILIEU AMPLIFIES THE PROINFLAMMATORY ENVIRONMENT ALREADY INSTANTIATED BY MACROPHAGES. ACTING IN CONCERT WITH OTHER EXPOSURES AND GENETIC LIABILITIES, THE RESULTING INFLAMMATION DRIVES FORWARD PATHOGENIC MECHANISMS THAT ULTIMATELY FOSTER CHRONIC DISEASE. 2011 14 1244 33 CURRENT CONCEPTS ON OXIDATIVE/CARBONYL STRESS, INFLAMMATION AND EPIGENETICS IN PATHOGENESIS OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS A GLOBAL HEALTH PROBLEM. THE CURRENT THERAPIES FOR COPD ARE POORLY EFFECTIVE AND THE MAINSTAYS OF PHARMACOTHERAPY ARE BRONCHODILATORS. A BETTER UNDERSTANDING OF THE PATHOBIOLOGY OF COPD IS CRITICAL FOR THE DEVELOPMENT OF NOVEL THERAPIES. IN THE PRESENT REVIEW, WE HAVE DISCUSSED THE ROLES OF OXIDATIVE/ALDEHYDE STRESS, INFLAMMATION/IMMUNITY, AND CHROMATIN REMODELING IN THE PATHOGENESIS OF COPD. AN IMBALANCE OF OXIDANTS/ANTIOXIDANTS CAUSED BY CIGARETTE SMOKE AND OTHER POLLUTANTS/BIOMASS FUELS PLAYS AN IMPORTANT ROLE IN THE PATHOGENESIS OF COPD BY REGULATING REDOX-SENSITIVE TRANSCRIPTION FACTORS (E.G., NF-KAPPAB), AUTOPHAGY AND UNFOLDED PROTEIN RESPONSE LEADING TO CHRONIC LUNG INFLAMMATORY RESPONSE. CIGARETTE SMOKE ALSO ACTIVATES CANONICAL/ALTERNATIVE NF-KAPPAB PATHWAYS AND THEIR UPSTREAM KINASES LEADING TO SUSTAINED INFLAMMATORY RESPONSE IN LUNGS. RECENTLY, EPIGENETIC REGULATION HAS BEEN SHOWN TO BE CRITICAL FOR THE DEVELOPMENT OF COPD BECAUSE THE EXPRESSION/ACTIVITY OF ENZYMES THAT REGULATE THESE EPIGENETIC MODIFICATIONS HAVE BEEN REPORTED TO BE ABNORMAL IN AIRWAYS OF COPD PATIENTS. HENCE, THE SIGNIFICANT ADVANCES MADE IN UNDERSTANDING THE PATHOPHYSIOLOGY OF COPD AS DESCRIBED HEREIN WILL IDENTIFY NOVEL THERAPEUTIC TARGETS FOR INTERVENTION IN COPD. 2011 15 3736 31 INNATE IMMUNE TOLERANCE IN MICROGLIA DOES NOT IMPACT ON CENTRAL NERVOUS SYSTEM PRION DISEASE. PRION DISEASES SUCH AS CREUTZFELDT-JAKOB DISEASE IN HUMANS, BOVINE SPONGIFORM ENCEPHALOPATHY IN CATTLE, AND SCRAPIE IN SHEEP, ARE INFECTIOUS AND CHRONIC NEURODEGENERATIVE DISEASES TO WHICH THERE ARE NO CURES. INFECTION WITH PRIONS IN THE CENTRAL NERVOUS SYSTEM (CNS) ULTIMATELY CAUSES EXTENSIVE NEURODEGENERATION, AND THIS IS ACCOMPANIED BY PROMINENT MICROGLIAL AND ASTROCYTIC ACTIVATION IN AFFECTED REGIONS. THE MICROGLIA ARE THE CNS MACROPHAGES AND HELP MAINTAIN NEURONAL HOMEOSTASIS, CLEAR DEAD OR DYING CELLS AND PROVIDE DEFENSE AGAINST PATHOGENS. THE MICROGLIA ALSO PROVIDE NEUROPROTECTION DURING CNS PRION DISEASE, BUT THEIR PRO-INFLAMMATORY ACTIVATION MAY EXACERBATE THE DEVELOPMENT OF THE NEUROPATHOLOGY. INNATE IMMUNE TOLERANCE INDUCED BY CONSECUTIVE SYSTEMIC BACTERIAL LIPOPOLYSACCHARIDE (LPS) TREATMENT CAN INDUCE LONG-TERM EPIGENETIC CHANGES IN THE MICROGLIA IN THE BRAIN THAT SEVERAL MONTHS LATER CAN DAMPEN THEIR RESPONSIVENESS TO SUBSEQUENT LPS TREATMENT AND IMPEDE THE DEVELOPMENT OF NEURITIC DAMAGE IN A TRANSGENIC MOUSE MODEL OF ALZHEIMER'S DISEASE-LIKE PATHOLOGY. WE THEREFORE REASONED THAT INNATE IMMUNE TOLERANCE IN MICROGLIA MIGHT SIMILARLY IMPEDE THE SUBSEQUENT DEVELOPMENT OF CNS PRION DISEASE. TO TEST THIS HYPOTHESIS GROUPS OF MICE WERE FIRST INFECTED WITH PRIONS BY INTRACEREBRAL INJECTION, AND 35 DAYS LATER GIVEN FOUR CONSECUTIVE SYSTEMIC INJECTIONS WITH LPS TO INDUCE INNATE IMMUNE TOLERANCE. OUR DATA SHOW THAT CONSECUTIVE SYSTEMIC LPS TREATMENT DID NOT AFFECT THE SUBSEQUENT DEVELOPMENT OF CNS PRION DISEASE. OUR DATA SUGGESTS INNATE IMMUNE TOLERANCE IN MICROGLIA DOES NOT INFLUENCE THE SUBSEQUENT ONSET OF PRION DISEASE-INDUCED NEUROPATHOLOGY IN MICE, DESPITE PREVIOUSLY PUBLISHED EVIDENCE OF THIS EFFECT IN AN ALZHEIMER'S DISEASE MOUSE MODEL. 2022 16 3711 37 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 17 4278 31 MICROGLIAL INNATE MEMORY AND EPIGENETIC REPROGRAMMING IN NEUROLOGICAL DISORDERS. MICROGLIA ARE MYELOID-DERIVED CELLS RECOGNIZED AS BRAIN-RESIDENT MACROPHAGES. THEY ACT AS THE FIRST AND MAIN LINE OF IMMUNE DEFENSE IN THE CENTRAL NERVOUS SYSTEM (CNS). MICROGLIA HAVE HIGH PHENOTYPIC PLASTICITY AND ARE ESSENTIAL FOR REGULATING HEALTHY BRAIN HOMEOSTASIS, AND THEIR DYSREGULATION UNDERLIES THE ONSET AND PROGRESSION OF SEVERAL CNS PATHOLOGIES THROUGH IMPAIRED INFLAMMATORY RESPONSES. ABERRANT MICROGLIAL ACTIVATION, FOLLOWING AN INFLAMMATORY INSULT, IS ASSOCIATED WITH EPIGENETIC DYSREGULATION IN VARIOUS CNS PATHOLOGIES. EMERGING DATA SUGGEST THAT CERTAIN STIMULI TO MYELOID CELLS DETERMINE ENHANCED OR ATTENUATED RESPONSES TO SUBSEQUENT STIMULI. THESE PHENOMENA, GENERALLY TERMED INNATE IMMUNE MEMORY (IIM), ARE HIGHLY DEPENDENT ON EPIGENETIC REPROGRAMMING. MICROGLIAL PRIMING HAS BEEN REPORTED IN SEVERAL NEUROLOGICAL DISEASES AND CORRESPONDS TO A STATE OF INCREASED PERMISSIVENESS OR EXACERBATED RESPONSE, PROMOTED BY CONTINUOUS EXPOSURE TO A CHRONIC PRO-INFLAMMATORY ENVIRONMENT. IN THIS ARTICLE, WE PROVIDE EXTENSIVE EVIDENCE OF THESE EPIGENETIC-MEDIATED PHENOMENA UNDER NEUROLOGICAL CONDITIONS AND DISCUSS THEIR CONTRIBUTION TO PATHOGENESIS AND THEIR CLINICAL IMPLICATIONS, INCLUDING THOSE CONCERNING POTENTIAL NOVEL THERAPEUTIC APPROACHES. 2021 18 874 34 CHRONIC ALLERGY SIGNALING: IS IT ALL STRESSED-OUT MITOCHONDRIA? ALLERGIC DISEASES IN GENERAL, AND CHRONIC ALLERGIC INFLAMMATION IN PARTICULAR, ARE ON THE RISE IN THE UNITED STATES AND OTHER DEVELOPED COUNTRIES. THE IDEA OF CHRONIC ALLERGIC DISEASE AS A CHRONIC TYPE 2 IMMUNE RESPONSE HAS BEEN AROUND FOR SEVERAL DECADES. HOWEVER, DATA SUGGEST THAT OTHER MECHANISMS MAY BE IMPORTANT IN CHRONIC DISEASE. THEREFORE, WE BELIEVE IT IS TIME FOR A PARADIGM SHIFT IN UNDERSTANDING THE MECHANISTIC CAUSES OF DISEASE SYMPTOMS IN THESE DISEASES. IN THIS REVIEW, WE HAVE AVOIDED THE CLASSIC CANONICAL PATHWAYS AND FOCUSED ON THE EMERGING IDEA THAT OXIDATIVE STRESS, CHANGES IN IMMUNO-METABOLISM, MITOCHONDRIAL DYSFUNCTION, AND EPIGENETIC CHANGES (PARTICULARLY MICRORNA PROFILE) MAY BE WORKING CONCURRENTLY OR SYNERGISTICALLY TO POTENTIATE ALLERGIC DISEASE SYMPTOMS. FURTHERMORE, WE HAVE ADDRESSED HOW THE EPIDEMIC OF OBESITY EXACERBATES ALLERGIC DISEASE VIA THE DYSREGULATION OF THE AFOREMENTIONED FACTORS. 2022 19 4896 30 OXIDATIVE STRESS IN AIRWAY DISEASES. AIRWAY OXIDATIVE STRESS IS BROADLY DEFINED AS AN IMBALANCE BETWEEN PROOXIDATIVE AND ANTIOXIDATIVE PROCESSES IN THE AIRWAY. GIVEN ITS DIRECT EXPOSURE TO THE ENVIRONMENT, THE LUNG HAS SEVERAL MECHANISMS TO PREVENT AN EXCESSIVE DEGREE OF OXIDATIVE STRESS. BOTH ENZYMATIC AND NONENZYMATIC SYSTEMS CAN BUFFER A WIDE RANGE OF REACTIVE OXIDATIVE SPECIES AND OTHER COMPOUNDS WITH OXIDATIVE POTENTIAL. IN DISEASES LIKE ASTHMA AND CHRONIC OBSTRUCTIVE LUNG DISEASE, AIRWAY OXIDATIVE STRESS CAN OCCUR FROM A NUMBER OF SOURCES, INCLUDING GREATER EXPOSURE TO ENVIRONMENTAL PROOXIDANTS, AIRWAY INFILTRATION OF INFLAMMATORY CELLS, METABOLIC DEREGULATION, AND REDUCED LEVELS OF ANTIOXIDANTS. AIRWAY OXIDATIVE STRESS HAS BEEN ASSOCIATED WITH WORSE DISEASE SEVERITY, REDUCED LUNG FUNCTION, AND EPIGENETIC CHANGES THAT CAN DIMINISH RESPONSE TO STEROIDS. ALTHOUGH OXIDATIVE STRESS HAS BEEN LINKED TO A WIDE RANGE OF ADVERSE BIOLOGICAL EFFECTS, IT HAS ALSO BEEN ASSOCIATED WITH ADAPTIVE RESPONSES AND WITH RESOLUTION OF INFLAMMATION. THEREFORE, MORE THAN BEING AN IMBALANCE WITH A PREDICTABLE THRESHOLD AFTER WHICH DISEASE OR INJURY ENSUES, OXIDATIVE STRESS IS A DYNAMIC AND CONTINUOUS PROCESS. THIS MIGHT EXPLAIN WHY SUPPLEMENTING ANTIOXIDANTS HAS LARGELY FAILED TO IMPROVE DISEASES SUCH AS ASTHMA AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE. HOWEVER, THE THERAPEUTIC POTENTIAL OF ANTIOXIDANTS COULD BE GREATLY IMPROVED BY TAKING AN APPROACH THAT CONSIDERS INDIVIDUAL AND ENVIRONMENTAL RISK FACTORS, INSTEAD OF TREATING OXIDATIVE AIRWAY STRESS BROADLY. 2013 20 6783 27 [CHRONIC OBSTRUCTIVE PULMONARY DISEASE IN WOMEN]. FOR THE PAST SEVERAL YEARS THE NUMBER OF WOMEN SUFFERING FROM CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) HAS BEEN STEADILY INCREASING. THIS FACT PROMPTS THE DEBATE WHICH FACTORS, IN ADDITION TO CONSIDERABLY INCREASING PREVALENCE OF CIGARETTE SMOKING AMONG YOUNG WOMEN, ARE RESPONSIBLE FOR THESE EPIDEMIOLOGIC CHANGES. DIFFERENCES IN THE NATURAL HISTORY AND PROGNOSIS OF COPD IN FEMALES AND MALES ARE PRESENTED IN THE PAPER, AS WELL AS THE NUMBER OF POTENTIAL ETHIOPATHOGENETIC AND PATHOPHYSIOLOGIC FACTORS INFLUENCING THESE VARIATIONS. AMONG THEM, DIFFERENCES IN THE COPD RISK FACTORS SPECTRUM IN BOTH GENDERS AND IN AIRWAYS ANATOMY ARE POINTED OUT, AND THE MECHANISMS RESPONSIBLE FOR GREATER WOMEN'S SUSCEPTIBILITY TO COMPONENTS OF CIGARETTE SMOKE, WHICH REFLECT GENETIC (ENZYME POLYMORPHISMS), EPIGENETIC (DIMINISHED DNA METHYLATION) AND HORMONAL (ESTROGENS) INFLUENCES ON XENOBIOTICS METABOLISM. FURTHER, SEX-RELATED DIFFERENCES REGARDING COPD PHENOTYPES (CHRONIC BRONCHITIS VS. EMPHYSEMA), IMMUNOLOGICAL MARKERS AND CLINICAL MANIFESTATION OF DISEASE ARE UNDERLINED IN THE PAPER. MORE FREQUENT COEXISTENCE OF ANXIETY AND DEPRESSION, COPD EXACERBATIONS AND WORSE QUALITY OF LIFE IN WOMEN ARE ALSO EMPHASIZED. OTHER DIFFERENCES, POINTED OUT BY AUTHORS INCLUDE AUTOIMMUNOLOGICAL CONCEPTION OF PATHOGENESIS OF COPD (GREATER FEMALE SUSCEPTIBILITY TO PRODUCE AUTOANTIBODIES), RISK FACTORS OF DISEASE EXACERBATION AND, AT LAST, RESPONSE TO CERTAIN FORMS OF COPD TREATMENT (NICOTINE REPLACEMENT THERAPY, LONG-TERM OXYGEN THERAPY). 2012