1 1177 141 CONTROL OF BREATHING AND THE CIRCULATION IN HIGH-ALTITUDE MAMMALS AND BIRDS. HYPOXIA IS AN UNREMITTING STRESSOR AT HIGH ALTITUDES THAT PLACES A PREMIUM ON OXYGEN TRANSPORT BY THE RESPIRATORY AND CARDIOVASCULAR SYSTEMS. PHENOTYPIC PLASTICITY AND GENOTYPIC ADAPTATION AT VARIOUS STEPS IN THE O2 CASCADE COULD HELP OFFSET THE EFFECTS OF HYPOXIA ON CELLULAR O2 SUPPLY IN HIGH-ALTITUDE NATIVES. IN THIS REVIEW, WE WILL DISCUSS THE UNIQUE MECHANISMS BY WHICH VENTILATION, CARDIAC OUTPUT, AND BLOOD FLOW ARE CONTROLLED IN HIGH-ALTITUDE MAMMALS AND BIRDS. ACCLIMATIZATION TO HIGH ALTITUDES LEADS TO SOME CHANGES IN RESPIRATORY AND CARDIOVASCULAR CONTROL THAT INCREASE O2 TRANSPORT IN HYPOXIA (E.G., VENTILATORY ACCLIMATIZATION TO HYPOXIA). HOWEVER, ACCLIMATIZATION OR DEVELOPMENT IN HYPOXIA CAN ALSO MODIFY CARDIORESPIRATORY CONTROL IN WAYS THAT ARE MALADAPTIVE FOR O2 TRANSPORT. HYPOXIA RESPONSES THAT AROSE AS SHORT-TERM SOLUTIONS TO O2 DEPRIVATION (E.G., PERIPHERAL VASOCONSTRICTION) OR REGIONAL VARIATION IN O2 LEVELS IN THE LUNGS (I.E., HYPOXIC PULMONARY VASOCONSTRICTION) ARE DETRIMENTAL AT IN CHRONIC HIGH-ALTITUDE HYPOXIA. EVOLVED CHANGES IN CARDIORESPIRATORY CONTROL HAVE ARISEN IN MANY HIGH-ALTITUDE TAXA, INCLUDING INCREASES IN EFFECTIVE VENTILATION, ATTENUATION OF HYPOXIC PULMONARY VASOCONSTRICTION, AND CHANGES IN CATECHOLAMINE SENSITIVITY OF THE HEART AND SYSTEMIC VASCULATURE. PARALLEL EVOLUTION OF SOME OF THESE CHANGES IN INDEPENDENT HIGHLAND LINEAGES SUPPORTS THEIR ADAPTIVE SIGNIFICANCE. MUCH LESS IS KNOWN ABOUT THE GENOMIC BASES AND POTENTIAL INTERACTIVE EFFECTS OF ADAPTATION, ACCLIMATIZATION, DEVELOPMENTAL PLASTICITY, AND TRANS-GENERATIONAL EPIGENETIC TRANSFER ON CARDIORESPIRATORY CONTROL. FUTURE WORK TO UNDERSTAND THESE VARIOUS INFLUENCES ON BREATHING AND CIRCULATION IN HIGH-ALTITUDE NATIVES WILL HELP ELUCIDATE HOW COMPLEX PHYSIOLOGICAL SYSTEMS CAN BE PUSHED TO THEIR LIMITS TO MAINTAIN CELLULAR FUNCTION IN HYPOXIA. 2015 2 231 34 ADAPTIVE CARDIORESPIRATORY CHANGES TO CHRONIC CONTINUOUS AND INTERMITTENT HYPOXIA. THIS CHAPTER REVIEWS CARDIORESPIRATORY ADAPTATIONS TO CHRONIC HYPOXIA (CH) EXPERIENCED AT HIGH ALTITUDE AND CARDIORESPIRATORY PATHOLOGIES ELICITED BY CHRONIC INTERMITTENT HYPOXIA (CIH) OCCURRING WITH OBSTRUCTIVE SLEEP APNEA (OSA). SHORT-TERM CH INCREASES BREATHING (VENTILATORY ACCLIMATIZATION TO HYPOXIA) AND BLOOD PRESSURE (BP) THROUGH CAROTID BODY (CB) CHEMO REFLEX. HYPERPLASIA OF GLOMUS CELLS, ALTERATIONS IN ION CHANNELS, AND RECRUITMENT OF ADDITIONAL EXCITATORY MOLECULES ARE IMPLICATED IN THE HEIGHTENED CB CHEMO REFLEX BY CH. TRANSCRIPTIONAL ACTIVATION OF HYPOXIA-INDUCIBLE FACTORS (HIF-1 AND 2) IS A MAJOR MOLECULAR MECHANISM UNDERLYING RESPIRATORY ADAPTATIONS TO SHORT-TERM CH. HIGH-ALTITUDE NATIVES EXPERIENCING LONG-TERM CH EXHIBIT BLUNTED HYPOXIC VENTILATORY RESPONSE (HVR) AND REDUCED BP DUE TO DESENSITIZATION OF CB RESPONSE TO HYPOXIA AND IMPAIRED PROCESSING OF CB SENSORY INFORMATION AT THE CENTRAL NERVOUS SYSTEM. VENTILATORY CHANGES EVOKED BY LONG-TERM CH ARE NOT READILY REVERSED AFTER RETURN TO SEA LEVEL. OSA PATIENTS AND RODENTS SUBJECTED TO CIH EXHIBIT HEIGHTENED CB CHEMO REFLEX, INCREASED HYPOXIC VENTILATORY RESPONSE, AND HYPERTENSION. INCREASED GENERATION OF REACTIVE OXYGEN SPECIES (ROS) IS A MAJOR CELLULAR MECHANISM UNDERLYING CIH-INDUCED ENHANCED CB CHEMO REFLEX AND THE ENSUING CARDIORESPIRATORY PATHOLOGIES. ROS GENERATION BY CIH IS MEDIATED BY NONTRANSCRIPTIONAL, DISRUPTED HIF-1 AND HIF-2-DEPENDENT TRANSCRIPTIONS AS WELL AS EPIGENETIC MECHANISMS. 2022 3 680 19 BRAIN INJURY IN CHRONICALLY VENTILATED PRETERM NEONATES: COLLATERAL DAMAGE RELATED TO VENTILATION STRATEGY. BRAIN INJURY IS A FREQUENT COMORBIDITY IN CHRONICALLY VENTILATED PRETERM INFANTS. HOWEVER, THE MOLECULAR BASIS OF THE BRAIN INJURY REMAINS INCOMPLETELY UNDERSTOOD. THIS ARTICLE DISCUSSES THE SUBTLE (DIFFUSE) FORM OF BRAIN INJURY THAT HAS WHITE MATTER AND GRAY MATTER LESIONS WITHOUT GERMINAL MATRIX HEMORRHAGE-INTRAVENTRICULAR HEMORRHAGE, POSTHEMORRHAGIC HYDROCEPHALUS, OR CYSTIC PERIVENTRICULAR LEUKOMALACIA. THIS ARTICLE SYNTHESIZES DATA THAT SUGGEST THAT DIFFUSE LESIONS TO WHITE MATTER AND GRAY MATTER ARE COLLATERAL DAMAGE RELATED TO VENTILATOR STRATEGY. EVIDENCE IS INTRODUCED FROM THE 2 LARGE-ANIMAL, PHYSIOLOGIC MODELS OF EVOLVING NEONATAL CHRONIC LUNG DISEASE THAT SUGGEST THAT AN EPIGENETIC MECHANISM MAY UNDERLIE THE COLLATERAL DAMAGE. 2012 4 5128 31 POSTNATAL INTERMITTENT HYPOXIA ENHANCES PHRENIC AND REDUCES VAGAL UPPER AIRWAY MOTOR ACTIVITIES IN RATS BY EPIGENETIC MECHANISMS. NEW FINDINGS: WHAT IS THE CENTRAL QUESTION OF THIS STUDY? WHAT ARE THE ALTERATIONS IN RESPIRATORY MOTOR ACTIVITY THAT MAY UNDERLIE VENTILATORY DYSFUNCTIONS IN JUVENILE AND ADULT ANIMALS EXPOSED TO POSTNATAL CHRONIC INTERMITTENT HYPOXIA? WHAT IS THE MAIN FINDING AND ITS IMPORTANCE? POSTNATAL CHRONIC INTERMITTENT HYPOXIA MODIFIES THE MOTOR ACTIVITY TO PUMPING AND UPPER AIRWAY RESPIRATORY MUSCLES IN RATS, MEDIATED BY EPIGENETIC DNA HYPERMETHYLATION, ENHANCING RESTING PULMONARY VENTILATION AND PREDISPOSING TO COLLAPSE OF THE UPPER AIRWAYS IN JUVENILE AND ADULT LIFE. ABSTRACT: PERIODS OF APNOEA, COMMONLY OBSERVED IN PREMATURES AND NEWBORNS, ARE AN IMPORTANT RISK FACTOR FOR THE DEVELOPMENT OF CARDIORESPIRATORY DISEASES IN ADULTHOOD. IN THE PRESENT STUDY, WE EVALUATED CHANGES IN PULMONARY VENTILATION AND RESPIRATORY MOTOR PATTERN IN JUVENILE AND ADULT RATS EXPOSED TO POSTNATAL CHRONIC INTERMITTENT HYPOXIA (PCIH). NEWBORN MALE HOLTZMAN RATS (P1) WERE SUBMITTED TO PCIH (6% O(2) FOR 30 S, EVERY 9 MIN, 8 H A DAY (09.30-17.30 H)) DURING THEIR FIRST 10 DAYS OF LIFE, WHILE CONTROL ANIMALS WERE MAINTAINED UNDER NORMOXIC CONDITIONS (20.8% O(2) ). THEREAFTER, ANIMALS OF BOTH GROUPS WERE MAINTAINED UNDER NORMOXIA UNTIL THE EXPERIMENTS. UNANAESTHETIZED JUVENILE PCIH RATS (N = 27) EXHIBITED ELEVATED TIDAL VOLUME AND RESPIRATORY IRREGULARITIES (P < 0.05) COMPARED TO CONTROL RATS (N = 7). DECEREBRATE, ARTERIALLY PERFUSED IN SITU PREPARATIONS OF JUVENILE PCIH RATS (N = 11) DISPLAYED AUGMENTED PHRENIC NERVE (PN) BURST AMPLITUDE AND REDUCED CENTRAL VAGUS NERVE ACTIVITY IN COMPARISON TO CONTROLS (N = 10). AT ADULTHOOD, PCIH RATS (N = 5) SHOWED ENHANCED TIDAL VOLUME (P < 0.05) AND INCREASED RESPIRATORY VARIABILITY COMPARED TO THE CONTROL GROUP (N = 5). THE PCIH-INDUCED CHANGES IN VENTILATION AND RESPIRATORY MOTOR OUTPUTS WERE PREVENTED BY TREATMENT WITH THE DNA METHYLTRANSFERASE INHIBITOR DECITABINE (1 MG KG(-1) , I.P.) DURING THE EXPOSURE TO PCIH. OUR DATA DEMONSTRATE THAT PCIH IN RATS IMPACTS, IN A PERSISTENT WAY, CONTROL OF THE RESPIRATORY PATTERN, INCREASING PN ACTIVITY TO THE DIAPHRAGM AND REDUCING THE VAGAL-RELATED ACTIVITY TO LARYNGEAL MUSCLES, WHICH, RESPECTIVELY, MAY CONTRIBUTE TO IMPROVE RESTING PULMONARY VENTILATION AND PREDISPOSE TO COLLAPSE OF THE UPPER AIRWAYS DURING QUIET BREATHING. 2020 5 5255 26 PROGRESS IN UNDERSTANDING THE PATHOGENESIS OF BPD USING THE BABOON AND SHEEP MODELS. BRONCHOPULMONARY DYSPLASIA (BPD) IS AMONG THE MOST COMMON CHRONIC LUNG DISEASES IN INFANTS IN THE US. IMPROVED SURVIVAL OF PRETERM INFANTS WHO DEVELOPED BPD IS BECOMING INCREASINGLY IMPORTANT BECAUSE OF THE HIGH RISK FOR PERSISTENT PULMONARY MORBIDITIES SUCH AS POOR RESPIRATORY GAS EXCHANGE, PULMONARY HYPERTENSION, AND EXCESS AIRWAY EXPIRATORY RESISTANCE LATER IN LIFE. THIS REVIEW FOCUSES ON UNIQUE INSIGHTS PROVIDED BY THE TWO LARGE-ANIMAL, PHYSIOLOGICAL MODELS OF NEONATAL CHRONIC LUNG DISEASE: PRETERM BABOONS AND PRETERM LAMBS. THE MODELS' ARE VALUABLE BECAUSE THEY CONTRIBUTE TO BETTER UNDERSTANDING OF THE UNDERLYING MOLECULAR PATHOGENIC MECHANISMS. AN EPIGENETIC HYPOTHESIS IS PROPOSED AS A PATHOGENIC MECHANISM FOR BPD AND ITS PERSISTENT PULMONARY MORBIDITIES. 2013 6 1392 34 DIAGNOSTIC APPROACH TO PULMONARY HYPERTENSION IN PREMATURE NEONATES. BRONCHOPULMONARY DYSPLASIA (BPD) IS A FORM OF CHRONIC LUNG DISEASE IN PREMATURE INFANTS FOLLOWING RESPIRATORY DISTRESS AT BIRTH. WITH INCREASING SURVIVAL OF EXTREMELY LOW BIRTH WEIGHT INFANTS, ALVEOLAR SIMPLIFICATION IS THE DEFINING LUNG CHARACTERISTIC OF INFANTS WITH BPD, AND ALONG WITH PULMONARY HYPERTENSION, INCREASINGLY CONTRIBUTES TO BOTH RESPIRATORY MORBIDITY AND MORTALITY IN THESE INFANTS. GROWTH RESTRICTED INFANTS, INFANTS BORN TO MOTHERS WITH OLIGOHYDRAMNIOS OR FOLLOWING PROLONGED PRETERM RUPTURE OF MEMBRANES ARE AT PARTICULAR RISK FOR EARLY ONSET PULMONARY HYPERTENSION. ALTERED VASCULAR AND ALVEOLAR GROWTH PARTICULARLY IN CANALICULAR AND EARLY SACCULAR STAGES OF LUNG DEVELOPMENT FOLLOWING MECHANICAL VENTILATION AND OXYGEN THERAPY, RESULTS IN DEVELOPMENTAL LUNG ARREST LEADING TO BPD WITH PULMONARY HYPERTENSION (PH). EARLY RECOGNITION OF PH IN INFANTS WITH RISK FACTORS IS IMPORTANT FOR OPTIMAL MANAGEMENT OF THESE INFANTS. SCREENING TOOLS FOR EARLY DIAGNOSIS OF PH ARE EVOLVING; HOWEVER, ECHOCARDIOGRAPHY IS THE MAINSTAY FOR NON-INVASIVE DIAGNOSIS OF PH IN INFANTS. CARDIAC COMPUTED TOMOGRAPHY (CT) AND MAGNETIC RESONANCE ARE BEING USED AS IMAGING MODALITIES, HOWEVER THEIR ROLE IN IMPROVING OUTCOMES IN THESE PATIENTS IS UNCERTAIN. FOLLOW-UP OF INFANTS AT RISK FOR PH WILL HELP NOT ONLY IN EARLY DIAGNOSIS, BUT ALSO IN APPROPRIATE MANAGEMENT OF THESE INFANTS. AGGRESSIVE MANAGEMENT OF LUNG DISEASE, AVOIDANCE OF HYPOXEMIC EPISODES, AND OPTIMAL NUTRITION DETERMINE THE PROGRESSION OF PH, AS EPIGENETIC FACTORS MAY HAVE SIGNIFICANT EFFECTS, PARTICULARLY IN GROWTH-RESTRICTED INFANTS. INFANTS WITH DIAGNOSIS OF PH ARE MANAGED WITH PULMONARY VASODILATORS AND THOSE RESISTANT TO THERAPY NEED TO BE WORKED UP FOR THE PRESENCE OF CARDIO-VASCULAR ANOMALIES. THE MANAGEMENT OF INFANTS AND TODDLERS WITH PH, ESPECIALLY FOLLOWING PREMATURE BIRTH IS AN EMERGING FIELD. NONETHELESS, COMBINATION THERAPIES IN A MULTI-DISCIPLINARY SETTING IMPROVES OUTCOMES FOR THESE INFANTS. 2017 7 292 40 AGING AND SUSCEPTIBILITY TO PULMONARY DISEASE. THE LUNGS ARE CONTINUALLY SUBJECTED TO NOXIOUS AND INERT SUBSTANCES, ARE IMMUNOLOGICALLY ACTIVE, AND ARE IN A CONSTANT STATE OF DAMAGE AND REPAIR. THIS MAKES THE PULMONARY SYSTEM PARTICULARLY VULNERABLE TO DISEASES OF AGING. AGING CAN BE UNDERSTOOD AS RANDOM MOLECULAR DAMAGE THAT IS UNREPAIRED AND ACCUMULATES OVER TIME, RESULTING IN CELLULAR DEFECTS AND TISSUE DYSFUNCTION. THE BREAKDOWN OF CELLULAR MECHANISMS, INCLUDING STEM CELL EXHAUSTION, GENOMIC INSTABILITY, TELOMERE ATTRITION, EPIGENETIC ALTERATION, LOSS OF PROTEOSTASIS, DEREGULATED NUTRIENT SENSING, MITOCHONDRIAL DYSFUNCTION, CELLULAR SENESCENCE, ALTERED INTERCELLULAR COMMUNICATION, AND CHANGES IN THE EXTRACELLULAR MATRIX IS THOUGHT TO ADVANCE THE AGING PROCESS ITSELF. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD), IDIOPATHIC PULMONARY FIBROSIS (IPF), AND CANCERS ILLUSTRATE A PATHOLOGIC BREAKDOWN IN THESE MECHANISMS BEYOND NORMAL AGING. THE IMMUNE SYSTEM BECOMES LESS EFFECTIVE WITH ADVANCING AGE. THERE IS A LOW-LEVEL STATE OF CHRONIC INFLAMMATION TERMED INFLAMMAGING WHICH IS THOUGHT TO BE DRIVEN BY IMMUNOSENESCENCE, THE CHANGES IN THE INNATE AND ADAPTIVE IMMUNE SYSTEMS WITH ADVANCING AGE THAT LEAD TO DYSREGULATION AND DECREASED EFFECTIVENESS OF THE IMMUNE SYSTEM. THESE PROCESSES OF AGING LEAD TO EXPECTED CHANGES IN THE FORM AND FUNCTION OF THE RESPIRATORY SYSTEM, MOST NOTABLY A LOSS OF LUNG ELASTICITY, DECREASE IN RESPIRATORY MUSCLE STRENGTH, INCREASE IN VENTILATION-PERFUSION MISMATCHING, AND STIFFENING OF THE VASCULATURE. THE ASTUTE CLINICIAN IS AWARE OF THESE EXPECTED FINDINGS AND DOES NOT OFTEN ATTRIBUTE DYSPNEA TO AGING ALONE. MAINTAINING A LOW THRESHOLD TO INVESTIGATE FOR COMORBID DISEASE AND UNDERSTANDING HOW PULMONARY DISEASE PRESENTS DIFFERENTLY IN THE ELDERLY THAN IN YOUNGER ADULTS CAN IMPROVE CLINICAL OUTCOMES. (C) 2022 AMERICAN PHYSIOLOGICAL SOCIETY. COMPR PHYSIOL 12:3509-3522, 2022. 2022 8 3814 30 INTRAUTERINE HYPOXIA AND EPIGENETIC PROGRAMMING IN LUNG DEVELOPMENT AND DISEASE. CLINICALLY, INTRAUTERINE HYPOXIA IS THE FOREMOST CAUSE OF PERINATAL MORBIDITY AND DEVELOPMENTAL PLASTICITY IN THE FETUS AND NEWBORN INFANT. UNDER HYPOXIA, DEVIATIONS OCCUR IN THE LUNG CELL EPIGENOME. EPIGENETIC MECHANISMS (E.G., DNA METHYLATION, HISTONE MODIFICATION, AND MIRNA EXPRESSION) CONTROL PHENOTYPIC PROGRAMMING AND ARE ASSOCIATED WITH PHYSIOLOGICAL RESPONSES AND THE RISK OF DEVELOPMENTAL DISORDERS, SUCH AS BRONCHOPULMONARY DYSPLASIA. THIS DEVELOPMENTAL DISORDER IS THE MOST FREQUENT CHRONIC PULMONARY COMPLICATION IN PRETERM LABOR. THE PATHOGENESIS OF THIS DISEASE INVOLVES MANY FACTORS, INCLUDING ABERRANT OXYGEN CONDITIONS AND MECHANICAL VENTILATION-MEDIATED LUNG INJURY, INFECTION/INFLAMMATION, AND EPIGENETIC/GENETIC RISK FACTORS. THIS REVIEW IS FOCUSED ON VARIOUS ASPECTS RELATED TO INTRAUTERINE HYPOXIA AND EPIGENETIC PROGRAMMING IN LUNG DEVELOPMENT AND DISEASE, SUMMARIZES OUR CURRENT KNOWLEDGE OF HYPOXIA-INDUCED EPIGENETIC PROGRAMMING AND DISCUSSES POTENTIAL THERAPEUTIC INTERVENTIONS FOR LUNG DISEASE. 2021 9 6440 23 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 10 4661 17 NEW ASPECTS OF THE EPIGENETIC REGULATION OF EMT RELATED TO PULMONARY FIBROSIS. PULMONARY FIBROSIS IS A CHRONIC AND PROGRESSIVE FIBROTIC DISEASE THAT RESULTS IN IMPAIRED GAS EXCHANGE, VENTILATION, AND EVENTUAL DEATH. THE PRO-FIBROTIC ENVIRONMENT IS INSTIGATED BY VARIOUS FACTORS, LEADING TO THE TRANSFORMATION OF EPITHELIAL CELLS INTO MYOFIBROBLASTS AND/OR FIBROBLASTS THAT TRIGGER FIBROSIS. EPITHELIAL MESENCHYMAL TRANSITION (EMT) IS A BIOLOGICAL PROCESS THAT PLAYS A CRITICAL ROLE IN THE PATHOGENESIS OF PULMONARY FIBROSIS. EPIGENETIC REGULATION OF TISSUE-STROMAL CROSSTALK INVOLVING DNA METHYLATION, HISTONE MODIFICATIONS, NON-CODING RNA, AND CHROMATIN REMODELING PLAYS A KEY ROLE IN THE CONTROL OF EMT. THE REVIEW INVESTIGATES THE EPIGENETIC REGULATION OF EMT AND ITS SIGNIFICANCE IN PULMONARY FIBROSIS. 2023 11 1948 36 EPIGENETIC ACQUISITION OF INDUCIBILITY OF TYPE III CYTOTOXICITY IN P. AERUGINOSA. BACKGROUND: PSEUDOMONAS AERUGINOSA, AN OPPORTUNISTIC PATHOGEN, IS OFTEN ENCOUNTERED IN CHRONIC LUNG DISEASES SUCH AS CYSTIC FIBROSIS OR CHRONIC OBSTRUCTIVE PNEUMONIA, AS WELL AS ACUTE SETTINGS LIKE MECHANICAL VENTILATION ACQUIRED PNEUMONIA OR NEUTROPENIC PATIENTS. IT IS A MAJOR CAUSE OF MORTALITY AND MORBIDITY IN THESE DISEASES. IN LUNGS, P. AERUGINOSA SETTLES IN A BIOFILM MODE OF GROWTH WITH THE SECRETION OF EXOPOLYSACCHARIDES IN WHICH IT IS ENCAPSULATED, ENHANCING ITS ANTIBIOTIC RESISTANCE AND CONTRIBUTING TO THE RESPIRATORY DEFICIENCY OF PATIENTS. HOWEVER, BACTERIA MUST FIRST MULTIPLY TO A HIGH DENSITY AND DISPLAY A CYTOTOXIC PHENOTYPE TO AVOID THE HOST'S DEFENCES. A VIRULENCE DETERMINANT IMPLICATED IN THIS STEP OF INFECTION IS THE TYPE III SECRETION SYSTEM (TTSS), ALLOWING TOXIN INJECTION DIRECTLY INTO HOST CELLS. AT THE BEGINNING OF THE INFECTION, MOST STRAINS ISOLATED FROM PATIENTS' LUNGS POSSESS AN INDUCIBLE TTSS ALLOWING TOXINS INJECTION OR SECRETION UPON IN VIVO OR IN VITRO ACTIVATION SIGNALS. AS THE INFECTION PERSISTS MOST OF THE BACTERIA PERMANENTLY LOOSE THIS CAPACITY, ALTHOUGH NO MUTATIONS HAVE BEEN EVIDENCED. WE NAME "NON INDUCIBLE" THIS PHENOTYPE. AS SUGGESTED BY THE PRESENCE OF A POSITIVE FEEDBACK CIRCUIT IN THE REGULATORY NETWORK CONTROLLING TTSS EXPRESSION, IT MAY BE DUE TO AN EPIGENETIC SWITCH ALLOWING HERITABLE PHENOTYPIC MODIFICATIONS WITHOUT GENOTYPE'S MUTATIONS. RESULTS: USING THE GENERALISED LOGICAL METHOD, WE DESIGNED A MINIMAL MODEL OF THE TTSS REGULATORY NETWORK THAT COULD SUPPORT THE EPIGENETIC HYPOTHESIS, AND STUDIED ITS DYNAMICS WHICH HELPED TO DEFINE A DISCRIMINATING EXPERIMENTAL SCENARIO SUFFICIENT TO VALIDATE THE EPIGENETIC HYPOTHESIS. A MATHEMATICAL FRAMEWORK BASED ON FORMAL METHODS FROM COMPUTER SCIENCE ALLOWED A RIGOROUS VALIDATION AND CERTIFICATION OF PARAMETERS OF THIS MODEL LEADING TO EPIGENETIC BEHAVIOUR. THEN, WE DEMONSTRATED THAT A NON INDUCIBLE STRAIN OF P. AERUGINOSA CAN STABLY ACQUIRE THE CAPACITY TO BE INDUCED BY CALCIUM DEPLETION FOR THE TTSS AFTER A SHORT PULSE OF A REGULATORY PROTEIN. FINALLY, THE INCREASED CYTOTOXICITY OF A STRAIN AFTER THIS EPIGENETIC SWITCH WAS DEMONSTRATED IN VIVO IN AN ACUTE PULMONARY INFECTION MODEL. CONCLUSION: THESE RESULTS MAY OFFER NEW PERSPECTIVES FOR THERAPEUTIC STRATEGIES TO PREVENT LETHAL INFECTIONS BY P. AERUGINOSA BY REVERTING THE EPIGENETIC INDUCIBILITY OF TYPE III CYTOTOXICITY. 2006 12 3514 31 IDIOPATHIC PULMONARY FIBROSIS: PATHOGENESIS AND THERAPEUTIC APPROACHES. IDIOPATHIC PULMONARY FIBROSIS (IPF), ALSO TERMED CRYPTOGENIC FIBROSING ALVEOLITIS, IS A CLINICOPATHOLOGICAL SYNDROME CHARACTERISED BY COUGH, EXERTIONAL DYSPNEOA, BASILAR CRACKLES, A RESTRICTIVE DEFECT ON PULMONARY FUNCTION TESTS, HONEYCOMBING ON HIGH-RESOLUTION, THIN-SECTION COMPUTED TOMOGRAPHIC SCANS AND THE HISTOLOGICAL DIAGNOSIS OF USUAL INTERSTITIAL PNEUMONIA ON LUNG BIOPSY. THE COURSE IS USUALLY INDOLENT BUT INEXORABLE. MOST PATIENTS DIE OF PROGRESSIVE RESPIRATORY FAILURE WITHIN 3-8 YEARS OF THE ONSET OF SYMPTOMS. CURRENT THERAPIES ARE OF UNPROVEN BENEFIT. ALTHOUGH THE PATHOGENESIS OF IPF HAS NOT BEEN ELUCIDATED, EARLY CONCEPTS FOCUSED ON LUNG INJURY LEADING TO A CYCLE OF CHRONIC ALVEOLAR INFLAMMATION EVENTUATING IN FIBROSIS AND DESTRUCTION OF THE LUNG ARCHITECTURE. ANTI-INFLAMMATORY THERAPIES EMPLOYING CORTICOSTEROIDS OR IMMUNOSUPPRESSIVE OR CYTOTOXIC AGENTS HAVE BEEN DISAPPOINTING. MORE RECENT HYPOTHESES ACKNOWLEDGE THAT SEQUENTIAL ALVEOLAR EPITHELIAL CELL INJURY IS LIKELY TO BE A KEY EVENT IN THE PATHOGENESIS OF IPF, BUT THE CARDINAL EVENT IS AN ABERRANT HOST RESPONSE TO WOUND HEALING. IN THIS CONTEXT, ABNORMAL EPITHELIAL-MESENCHYMAL INTERACTIONS, ALTERED FIBROBLAST PHENOTYPES, EXAGGERATED FIBROBLAST PROLIFERATION, AND EXCESSIVE DEPOSITION OF COLLAGEN AND EXTRACELLULAR MATRIX ARE PIVOTAL TO THE FIBROTIC PROCESS. SEVERAL CLINICAL TRIALS ARE CURRENTLY UNDERWAY OR IN THE PLANNING STAGES, AND INCLUDE DRUGS SUCH AS INTERFERON-GAMMA 1B, PIRFENIDONE, ACETYLCYSTEINE, ETANERCEPT (A TUMOR NECROSIS FACTOR-ALPHA ANTAGONIST), BOSENTAN (AN ENDOTHELIN-1 RECEPTOR ANTAGONIST) AND ZILEUTON (A 5-LYPOXYGENASE INHIBITOR). FUTURE THERAPEUTIC STRATEGIES SHOULD BE FOCUSED ON ALVEOLAR EPITHELIAL CELLS AIMED AT ENHANCING RE-EPITHELIALISATION AND ON FIBROBLASTIC/MYOFIBROBLASTIC FOCI, WHICH PLAY AN ESSENTIAL ROLE IN THE DEVELOPMENT OF IPF. STEM CELL PROGENITORS OF THE ALVEOLAR EPITHELIAL CELLS AND GENETIC AND EPIGENETIC THERAPIES ARE ATTRACTIVE FUTURE APPROACHES FOR THIS AND OTHER FIBROTIC LUNG DISORDERS. 2004 13 4954 23 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 14 4109 38 MECHANISMS AND DRUG THERAPY OF PULMONARY HYPERTENSION AT HIGH ALTITUDE. PULMONARY VASOCONSTRICTION REPRESENTS A PHYSIOLOGICAL ADAPTIVE MECHANISM TO HIGH ALTITUDE. IF EXAGGERATED, HOWEVER, IT IS ASSOCIATED WITH IMPORTANT MORBIDITY AND MORTALITY. RECENT MECHANISTIC STUDIES USING SHORT-TERM ACUTE HIGH ALTITUDE EXPOSURE HAVE PROVIDED INSIGHT INTO THE IMPORTANCE OF DEFECTIVE VASCULAR ENDOTHELIAL AND RESPIRATORY EPITHELIAL NITRIC OXIDE (NO) SYNTHESIS, INCREASED ENDOTHELIN-1 BIOAVAILABILITY, AND OVERACTIVATION OF THE SYMPATHETIC NERVOUS SYSTEM IN CAUSING EXAGGERATED HYPOXIC PULMONARY HYPERTENSION IN HUMANS. BASED ON THESE STUDIES, DRUGS THAT INCREASE NO BIOAVAILABILITY, ATTENUATE ENDOTHELIN-1 INDUCED PULMONARY VASOCONSTRICTION, OR PREVENT EXAGGERATED SYMPATHETIC ACTIVATION HAVE BEEN SHOWN TO BE USEFUL FOR THE TREATMENT/PREVENTION OF EXAGGERATED PULMONARY HYPERTENSION DURING ACUTE SHORT-TERM HIGH ALTITUDE EXPOSURE. THE MECHANISMS UNDERPINNING CHRONIC PULMONARY HYPERTENSION IN HIGH ALTITUDE DWELLERS ARE LESS WELL UNDERSTOOD, BUT RECENT EVIDENCE SUGGESTS THAT THEY DIFFER IN SOME ASPECTS FROM THOSE INVOLVED IN SHORT-TERM ADAPTATION TO HIGH ALTITUDE. THESE DIFFERENCES HAVE CONSEQUENCES FOR THE CHOICE OF THE TREATMENT FOR CHRONIC PULMONARY HYPERTENSION AT HIGH ALTITUDE. FINALLY, RECENT DATA INDICATE THAT FETAL PROGRAMMING OF PULMONARY VASCULAR DYSFUNCTION IN OFFSPRING OF PREECLAMPSIA AND CHILDREN GENERATED BY ASSISTED REPRODUCTIVE TECHNOLOGIES REPRESENTS A NOVEL AND FREQUENT CAUSE OF PULMONARY HYPERTENSION AT HIGH ALTITUDE. IN ANIMAL MODELS OF FETAL PROGRAMMING OF HYPOXIC PULMONARY HYPERTENSION, EPIGENETIC MECHANISMS PLAY A ROLE, AND TARGETING OF THESE MECHANISMS WITH DRUGS LOWERS PULMONARY ARTERY PRESSURE. IF EPIGENETIC MECHANISMS ALSO ARE OPERATIONAL IN THE FETAL PROGRAMMING OF PULMONARY VASCULAR DYSFUNCTION IN HUMANS, SUCH DRUGS MAY BECOME NOVEL TOOLS FOR THE TREATMENT OF HYPOXIC PULMONARY HYPERTENSION. 2013 15 1528 32 DNA METHYLATION CHANGES IN REGIONAL LUNG MACROPHAGES ARE ASSOCIATED WITH METABOLIC DIFFERENCES. A NUMBER OF PULMONARY DISEASES OCCUR WITH UPPER LOBE PREDOMINANCE, INCLUDING CYSTIC FIBROSIS AND SMOKING-RELATED CHRONIC OBSTRUCTIVE PULMONARY DISEASE. IN THE HEALTHY LUNG, SEVERAL PHYSIOLOGIC AND METABOLIC FACTORS EXHIBIT DISPARITY WHEN COMPARING THE UPPER LOBE OF THE LUNG TO LOWER LOBE, INCLUDING DIFFERENCES IN OXYGENATION, VENTILATION, LYMPHATIC FLOW, PH, AND BLOOD FLOW. IN THIS STUDY, WE ASKED WHETHER THESE REGIONAL DIFFERENCES IN THE LUNG ARE ASSOCIATED WITH DNA METHYLATION CHANGES IN LUNG MACROPHAGES THAT COULD POTENTIALLY LEAD TO ALTERED CELL RESPONSIVENESS UPON SUBSEQUENT ENVIRONMENTAL CHALLENGE. ALL ANALYSES WERE PERFORMED USING PRIMARY LUNG MACROPHAGES COLLECTED VIA BRONCHOALVEOLAR LAVAGE FROM HEALTHY HUMAN SUBJECTS WITH NORMAL PULMONARY FUNCTION. EPIGENOME-WIDE DNA METHYLATION WAS EXAMINED VIA INFINIUM METHYLATIONEPIC (850K) ARRAY AND VALIDATED BY TARGETED NEXT-GENERATION BISULFITE SEQUENCING. WE OBSERVED 95 CPG LOCI WITH SIGNIFICANT DIFFERENTIAL METHYLATION IN LUNG MACROPHAGES, COMPARING UPPER LOBE TO LOWER LOBE (ALL FALSE DISCOVERY RATE < 0.05). SEVERAL OF THESE GENES, INCLUDING CLIP4, HSH2D, NR4A1, SNX10, AND TYK2, HAVE BEEN IMPLICATED AS PARTICIPANTS IN INFLAMMATORY/IMMUNE-RELATED BIOLOGICAL PROCESSES. FUNCTIONALLY, WE IDENTIFIED PHENOTYPIC DIFFERENCES IN OXYGEN USE, COMPARING UPPER VERSUS LOWER LUNG MACROPHAGES. OUR RESULTS SUPPORT A HYPOTHESIS THAT EPIGENETIC CHANGES, SPECIFICALLY DNA METHYLATION, AT A MULTITUDE OF GENE LOCI IN LUNG MACROPHAGES ARE ASSOCIATED WITH METABOLIC DIFFERENCES REGIONALLY IN LUNG. 2019 16 6915 21 [VULNERABILITY OF WOMEN TO TOBACCO: THE BRONCHO-PULMONARY CONSEQUENCES (ASTHMA, COPD)]. SMOKING REMAINS COMMON, WITH AN EXPOSURE THAT BEGINS EARLY DURING PREGNANCY. IT INDUCES EPIGENETIC CHANGES, WITH A TRANS-GENERATIONAL TRANSMISSION. SMOKING INCREASES THE RISK OF UNCONTROLLED ASTHMA DURING CHILDHOOD AND ADULT LIFE. ASTHMA IS ALSO ASSOCIATED WITH INCREASED RISK OF A DECLINE OF LUNG FUNCTION AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). WOMEN ARE MORE AT RISK OF DEVELOPING EARLY AND SEVERE COPD. THE MECHANISMS ARE CURRENTLY POORLY KNOWN. 2019 17 2169 25 EPIGENETIC MECHANISMS IN PARENCHYMAL LUNG DISEASES: BYSTANDERS OR THERAPEUTIC TARGETS? EPIGENETIC RESPONSES DUE TO ENVIRONMENTAL CHANGES ALTER CHROMATIN STRUCTURE, WHICH IN TURN MODIFIES THE PHENOTYPE, GENE EXPRESSION PROFILE, AND ACTIVITY OF EACH CELL TYPE THAT HAS A ROLE IN THE PATHOPHYSIOLOGY OF A DISEASE. PULMONARY DISEASES ARE ONE OF THE MAJOR CAUSES OF DEATH IN THE WORLD, INCLUDING LUNG CANCER, IDIOPATHIC PULMONARY FIBROSIS (IPF), CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD), PULMONARY HYPERTENSION (PH), LUNG TUBERCULOSIS, PULMONARY EMBOLISM, AND ASTHMA. SEVERAL LINES OF EVIDENCE INDICATE THAT EPIGENETIC MODIFICATIONS MAY BE ONE OF THE MAIN FACTORS TO EXPLAIN THE INCREASING INCIDENCE AND PREVALENCE OF LUNG DISEASES INCLUDING IPF AND COPD. INTERESTINGLY, ISOLATED FIBROBLASTS AND SMOOTH MUSCLE CELLS FROM PATIENTS WITH PULMONARY DISEASES SUCH AS IPF AND PH THAT WERE CULTURED EX VIVO MAINTAINED THE DISEASE PHENOTYPE. THE CELLS OFTEN SHOW A HYPER-PROLIFERATIVE, APOPTOSIS-RESISTANT PHENOTYPE WITH INCREASED EXPRESSION OF EXTRACELLULAR MATRIX (ECM) AND ACTIVATED FOCAL ADHESIONS SUGGESTING THE PRESENCE OF AN EPIGENETICALLY IMPRINTED PHENOTYPE. MOREOVER, MANY ABNORMALITIES OBSERVED IN MOLECULAR PROCESSES IN IPF PATIENTS ARE SHOWN TO BE EPIGENETICALLY REGULATED, SUCH AS INNATE IMMUNITY, CELLULAR SENESCENCE, AND APOPTOTIC CELL DEATH. DNA METHYLATION, HISTONE MODIFICATION, AND MICRORNA REGULATION CONSTITUTE THE MOST COMMON EPIGENETIC MODIFICATION MECHANISMS. 2022 18 2610 35 EPIGENETICS: A POTENTIAL MECHANISM INVOLVED IN THE PATHOGENESIS OF VARIOUS ADVERSE CONSEQUENCES OF OBSTRUCTIVE SLEEP APNEA. EPIGENETICS IS DEFINED AS THE HERITABLE PHENOTYPIC CHANGES WHICH DO NOT INVOLVE ALTERATIONS IN THE DNA SEQUENCE, INCLUDING HISTONE MODIFICATIONS, NON-CODING RNAS, AND DNA METHYLATION. RECENTLY, MUCH ATTENTION HAS BEEN PAID TO THE ROLE OF HYPOXIA-MEDIATED EPIGENETIC REGULATION IN CANCER, PULMONARY HYPERTENSION, ADAPTATION TO HIGH ALTITUDE, AND CARDIORENAL DISEASE. IN CONTRAST TO SUSTAINED HYPOXIA, CHRONIC INTERMITTENT HYPOXIA WITH RE-OXYGENATION (IHR) PLAYS A MAJOR ROLE IN THE PATHOGENESIS OF VARIOUS ADVERSE CONSEQUENCES OF OBSTRUCTIVE SLEEP APNEA (OSA), RESEMBLING ISCHEMIA RE-PERFUSION INJURY. NEVERTHELESS, THE ROLE OF EPIGENETICS IN THE PATHOGENESIS OF OSA IS CURRENTLY UNDEREXPLORED. THIS REVIEW PROPOSES THAT EPIGENETIC PROCESSES ARE INVOLVED IN THE DEVELOPMENT OF VARIOUS ADVERSE CONSEQUENCES OF OSA BY INFLUENCING ADAPTIVE POTENTIAL AND PHENOTYPIC VARIABILITY UNDER CONDITIONS OF CHRONIC IHR. IMPROVED UNDERSTANDING OF THE INTERACTION BETWEEN GENETIC AND ENVIRONMENTAL FACTORS THROUGH EPIGENETIC REGULATIONS HOLDS GREAT VALUE TO GIVE DEEPER INSIGHT INTO THE MECHANISMS UNDERLYING IHR-RELATED LOW-GRADE INFLAMMATION, OXIDATIVE STRESS, AND SYMPATHETIC HYPERACTIVITY, AND CLARIFY THEIR IMPLICATIONS FOR BIOMEDICAL RESEARCH. 2019 19 5484 32 REVEALING THE PATHOGENIC AND AGING-RELATED MECHANISMS OF THE ENIGMATIC IDIOPATHIC PULMONARY FIBROSIS. AN INTEGRAL MODEL. A GROWING BODY OF EVIDENCE INDICATES THAT ABERRANT ACTIVATION OF ALVEOLAR EPITHELIAL CELLS AND FIBROBLASTS IN AN AGING LUNG PLAYS A CRITICAL ROLE IN THE PATHOGENESIS OF IDIOPATHIC PULMONARY FIBROSIS (IPF). HOWEVER, THE BIOPATHOLOGICAL PROCESSES LINKING AGING WITH IPF AND THE MECHANISMS RESPONSIBLE FOR THE ABNORMAL ACTIVATION OF EPITHELIAL CELLS AND FIBROBLASTS HAVE NOT BEEN ELUCIDATED. MANY OF THE HALLMARKS OF AGING (E.G., GENOMIC INSTABILITY, TELOMERE ATTRITION, EPIGENETIC ALTERATIONS, MITOCHONDRIAL DYSFUNCTION, AND CELLULAR SENESCENCE) HAVE BEEN PROPOSED AS ESSENTIAL MECHANISMS FOR THE DEVELOPMENT OF IPF; HOWEVER, THESE DISTURBANCES ARE NOT RESTRICTED TO IPF AND ALSO OCCUR IN OTHER AGING-RELATED LUNG DISORDERS, PRIMARILY CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). THEREFORE, AN UNANSWERED QUESTION IS WHY A CURRENT/FORMER SMOKER OF ABOUT 60 YEARS OF AGE WITH SHORTER TELOMERES, ALVEOLAR EPITHELIAL SENESCENCE, EXCESSIVE OXIDATIVE STRESS, AND MITOCHONDRIAL DYSFUNCTION DEVELOPS IPF AND NOT COPD; IN OTHER WORDS, WHAT MAKES OLD LUNGS SPECIFICALLY SUSCEPTIBLE TO DEVELOP IPF? IN THIS PERSPECTIVE, WE PROPOSE AN INTEGRAL MODEL IN WHICH THE COMBINATION OF SOME GENE VARIANTS AND/OR GENE EXPRESSION IN THE AGING LUNG RESULTS IN THE LOSS OF EPITHELIAL INTEGRITY AND CONSEQUENTLY IN THE FAILURE OF THE ALVEOLI TO CORRECTLY RESPOND TO INJURY AND TO FACE THE STRESS ASSOCIATED WITH MECHANICAL STRETCH. AFTERWARD, A DISTINCTIVE EPIGENETIC "REPROGRAMMING" THAT AFFECTS BOTH EPITHELIAL CELLS AND FIBROBLASTS PROVOKES, AMONG OTHERS, THE RECAPITULATION OF DEVELOPMENTAL PATHWAYS AND THE ABERRANT ACTIVATION AND MISCOMMUNICATION BETWEEN BOTH CELL TYPES, RESULTING IN THE EXAGGERATED PRODUCTION AND ACCUMULATION OF EXTRACELLULAR MATRIX AND THE SUBSEQUENT DESTRUCTION OF THE LUNG ARCHITECTURE. 2014 20 2738 41 EXPOSOMES TO EXOSOMES: EXOSOMES AS TOOLS TO STUDY EPIGENETIC ADAPTIVE MECHANISMS IN HIGH-ALTITUDE HUMANS. HUMANS ON EARTH INHABIT A WIDE RANGE OF ENVIRONMENTAL CONDITIONS AND SOME ENVIRONMENTS ARE MORE CHALLENGING FOR HUMAN SURVIVAL THAN OTHERS. HOWEVER, MANY LIVING BEINGS, INCLUDING HUMANS, HAVE DEVELOPED ADAPTIVE MECHANISMS TO LIVE IN SUCH INHOSPITABLE, HARSH ENVIRONMENTS. AMONG DIFFERENT DIFFICULT ENVIRONMENTS, HIGH-ALTITUDE LIVING IS ESPECIALLY DEMANDING BECAUSE OF DIMINISHED PARTIAL PRESSURE OF OXYGEN AND RESULTING CHRONIC HYPOBARIC HYPOXIA. THIS RESULTS IN POOR BLOOD OXYGENATION AND REDUCES AEROBIC OXIDATIVE RESPIRATION IN THE MITOCHONDRIA, LEADING TO INCREASED REACTIVE OXYGEN SPECIES GENERATION AND ACTIVATION OF HYPOXIA-INDUCIBLE GENE EXPRESSION. GENETIC MECHANISMS IN THE ADAPTATION TO HIGH ALTITUDE IS WELL-STUDIED, BUT THERE ARE ONLY LIMITED STUDIES REGARDING THE ROLE OF EPIGENETIC MECHANISMS. THE PURPOSE OF THIS REVIEW IS TO UNDERSTAND THE EPIGENETIC MECHANISMS BEHIND HIGH-ALTITUDE ADAPTIVE AND MALADAPTIVE PHENOTYPES. HYPOBARIC HYPOXIA IS A FORM OF CELLULAR HYPOXIA, WHICH IS SIMILAR TO THE ONE SUFFERED BY CRITICALLY-ILL HYPOXEMIA PATIENTS. THUS, UNDERSTANDING THE ADAPTIVE EPIGENETIC SIGNALS OPERATING IN IN HIGH-ALTITUDE ADJUSTED INDIGENOUS POPULATIONS MAY HELP IN THERAPEUTICALLY MODULATING SIGNALING PATHWAYS IN HYPOXEMIA PATIENTS BY COPYING THE MOST SUCCESSFUL EPIGENOTYPE. IN ADDITION, WE HAVE SUMMARIZED THE CURRENT INFORMATION ABOUT EXOSOMES IN HYPOXIA RESEARCH AND PROSPECTS TO USE THEM AS DIAGNOSTIC TOOLS TO STUDY THE EPIGENOME OF HIGH-ALTITUDE ADAPTED HEALTHY OR MALADAPTED INDIVIDUALS. 2021