1 2356 123 EPIGENETIC REGULATION OF PULMONARY ARTERIAL HYPERTENSION-INDUCED VASCULAR AND RIGHT VENTRICULAR REMODELING: NEW OPPORTUNITIES? PULMONARY ARTERY HYPERTENSION (PAH) IS A RARE CHRONIC DISEASE WITH HIGH IMPACT ON PATIENTS' QUALITY OF LIFE AND CURRENTLY NO AVAILABLE CURE. PAH IS CHARACTERIZED BY CONSTANT REMODELING OF THE PULMONARY ARTERY BY INCREASED PROLIFERATION AND MIGRATION OF PULMONARY ARTERIAL SMOOTH MUSCLE CELLS (PASMCS), FIBROBLASTS (FBS) AND ENDOTHELIAL CELLS (ECS). THIS REMODELING EVENTUALLY LEADS TO INCREASED PRESSURE IN THE RIGHT VENTRICLE (RV) AND SUBSEQUENT RIGHT VENTRICLE HYPERTROPHY (RVH) WHICH, WHEN LEFT UNTREATED, PROGRESSES INTO RIGHT VENTRICLE FAILURE (RVF). PAH CAN NOT ONLY ORIGINATE FROM HERITABLE MUTATIONS, BUT ALSO DEVELOP AS A CONSEQUENCE OF CONGENITAL HEART DISEASE, EXPOSURE TO DRUGS OR TOXINS, HIV, CONNECTIVE TISSUE DISEASE OR BE IDIOPATHIC. WHILE MUCH ATTENTION WAS DRAWN INTO INVESTIGATING AND DEVELOPING THERAPIES RELATED TO THE MOST WELL UNDERSTOOD SIGNALING PATHWAYS IN PAH, IN THE LAST DECADE, A SHIFT TOWARDS UNDERSTANDING THE EPIGENETIC MECHANISMS DRIVING THE DISEASE OCCURRED. IN THIS REVIEW, WE REFLECT ON THE DIFFERENT EPIGENETIC REGULATORY FACTORS THAT ARE ASSOCIATED WITH THE PATHOLOGY OF RV REMODELING, AND ON THEIR RELEVANCE TOWARDS A BETTER UNDERSTANDING OF THE DISEASE AND SUBSEQUENTLY, THE DEVELOPMENT OF NEW AND MORE EFFICIENT THERAPEUTIC STRATEGIES. 2020 2 4978 33 PATHOPHYSIOLOGY AND NEW ADVANCES IN PULMONARY HYPERTENSION. PULMONARY HYPERTENSION IS A PROGRESSIVE AND OFTEN FATAL CARDIOPULMONARY CONDITION CHARACTERISED BY INCREASED PULMONARY ARTERIAL PRESSURE, STRUCTURAL CHANGES IN THE PULMONARY CIRCULATION, AND THE FORMATION OF VASO-OCCLUSIVE LESIONS. THESE CHANGES LEAD TO INCREASED RIGHT VENTRICULAR AFTERLOAD, WHICH OFTEN PROGRESSES TO MALADAPTIVE RIGHT VENTRICULAR REMODELLING AND EVENTUALLY DEATH. PULMONARY ARTERIAL HYPERTENSION REPRESENTS ONE OF THE MOST SEVERE AND BEST STUDIED TYPES OF PULMONARY HYPERTENSION AND IS CONSISTENTLY TARGETED BY DRUG TREATMENTS. THE UNDERLYING MOLECULAR PATHOGENESIS OF PULMONARY HYPERTENSION IS A COMPLEX AND MULTIFACTORIAL PROCESS, BUT CAN BE CHARACTERISED BY SEVERAL HALLMARKS: INFLAMMATION, IMPAIRED ANGIOGENESIS, METABOLIC ALTERATIONS, GENETIC OR EPIGENETIC ABNORMALITIES, INFLUENCE OF SEX AND SEX HORMONES, AND ABNORMALITIES IN THE RIGHT VENTRICLE. CURRENT TREATMENTS FOR PULMONARY ARTERIAL HYPERTENSION AND SOME OTHER TYPES OF PULMONARY HYPERTENSION TARGET PATHWAYS INVOLVED IN THE CONTROL OF PULMONARY VASCULAR TONE AND PROLIFERATION; HOWEVER, THESE TREATMENTS HAVE LIMITED EFFICACY ON PATIENT OUTCOMES. THIS REVIEW DESCRIBES KEY FEATURES OF PULMONARY HYPERTENSION, DISCUSSES CURRENT AND EMERGING THERAPEUTIC INTERVENTIONS, AND POINTS TO FUTURE DIRECTIONS FOR RESEARCH AND PATIENT CARE. BECAUSE MOST PROGRESS IN THE SPECIALTY HAS BEEN MADE IN PULMONARY ARTERIAL HYPERTENSION, THIS REVIEW FOCUSES ON THIS TYPE OF PULMONARY HYPERTENSION. THE REVIEW HIGHLIGHTS KEY PATHOPHYSIOLOGICAL CONCEPTS AND EMERGING THERAPEUTIC DIRECTIONS, TARGETING INFLAMMATION, CELLULAR METABOLISM, GENETICS AND EPIGENETICS, SEX HORMONE SIGNALLING, BONE MORPHOGENETIC PROTEIN SIGNALLING, AND INHIBITION OF TYROSINE KINASE RECEPTORS. 2023 3 5532 48 RODENT MODELS OF GROUP 1 PULMONARY HYPERTENSION. WORLD HEALTH ORGANIZATION CATEGORY 1 PULMONARY HYPERTENSION (PH) IS A HETEROGENEOUS SYNDROME IN WHICH PH ORIGINATES IN THE SMALL PULMONARY ARTERIES AND IS THEREFORE ALSO REFERRED TO AS PULMONARY ARTERIAL HYPERTENSION (PAH). COMMON PATHOPHYSIOLOGIC FEATURES INCLUDE ENDOTHELIAL DYSFUNCTION, EXCESSIVE PROLIFERATION AND IMPAIRED APOPTOSIS OF VASCULAR CELLS, AND MITOCHONDRIAL FRAGMENTATION. THE PROLIFERATION/APOPTOSIS IMBALANCE RELATES IN PART TO ACTIVATION OF THE TRANSCRIPTION FACTORS HYPOXIA-INDUCIBLE FACTOR-1ALPHA (HIF-1ALPHA) AND NUCLEAR FACTOR OF ACTIVATED T-CELLS (NFAT) AND APOPTOSIS REPRESSORS, SUCH AS SURVIVIN. PERIVASCULAR INFLAMMATION, DISRUPTION OF ADVENTITIAL CONNECTIVE TISSUE, AND A GLYCOLYTIC METABOLIC SHIFT IN VASCULAR CELLS AND RIGHT VENTRICULAR MYOCYTES ALSO OCCUR IN PAH. THERE ARE IMPORTANT GENETIC AND EPIGENETIC PREDISPOSITIONS TO PAH. THIS REVIEW ASSESSES THE FIDELITY OF EXISTING ANIMAL MODELS TO HUMAN PAH. NO SINGLE MODEL CAN PERFECTLY RECAPITULATE THE MANY DIVERSE FORMS OF PH IN CATEGORY 1; HOWEVER, ACCEPTABLE MODELS EXIST. PAH INDUCED BY MONOCROTALINE AND CHRONIC HYPOXIA PLUS SU-5416 (CH+SU) IN RATS DISPLAY ENDOTHELIAL DYSFUNCTION, PROLIFERATION/APOPTOSIS IMBALANCE, AND DEVELOP THE GLYCOLYTIC METABOLIC PROFILE OF HUMAN PAH. HISTOLOGICALLY, CH+SU BEST CONFORMS TO PAH IN THAT IT DEVELOPS COMPLEX VASCULAR LESIONS, INCLUDING PLEXIFORM LESIONS. HOWEVER, THE MONOCROTALINE MODEL CAN BE INDUCED TO MANIFEST COMPLEX VASCULAR LESIONS AND DOES MANIFEST THE TENDENCY OF PAH PATIENTS TO DIE OF RIGHT VENTRICULAR (RV) FAILURE. MURINE MODELS OFFER GREATER MOLECULAR CERTAINTY THAN RAT MODELS BUT RARELY DEVELOP SIGNIFICANT PH, HAVE LESS RIGHT VENTRICULAR HYPERTROPHY (RVH) AND PULMONARY ARTERY (PA) REMODELING, AND ARE HARDER TO IMAGE AND CATHETERIZE. THE USE OF HIGH FIDELITY CATHETERIZATION AND ADVANCED IMAGING (MICROPET-CT, HIGH FREQUENCY ECHOCARDIOGRAPHY, HIGH FIELD STRENGTH MRI) AND FUNCTIONAL TESTING (TREADMILL) PERMIT ACCURATE PHENOTYPING OF EXPERIMENTAL MODELS OF PAH. PRECLINICAL TRIAL DESIGN IS AN IMPORTANT ASPECT OF TESTING EXPERIMENTAL PAH THERAPIES. THE USE OF MULTIPLE COMPLEMENTARY MODELS WITH ADEQUATE SAMPLE SIZE AND TRIAL DURATION AND APPROPRIATE ENDPOINTS ARE REQUIRED FOR PRECLINICAL ASSESSMENT OF EXPERIMENTAL PAH THERAPIES. 2013 4 1505 35 DNA METHYLATION AND HISTONE MODIFICATION IN HYPERTENSION. SYSTEMIC HYPERTENSION, WHICH EVENTUALLY RESULTS IN HEART FAILURE, RENAL FAILURE OR STROKE, IS A COMMON CHRONIC HUMAN DISORDER THAT PARTICULARLY AFFECTS ELDERS. ALTHOUGH MANY SIGNALING PATHWAYS INVOLVED IN THE DEVELOPMENT OF HYPERTENSION HAVE BEEN REPORTED OVER THE PAST DECADES, WHICH HAS LED TO THE IMPLEMENTATION OF A WIDE VARIETY OF ANTI-HYPERTENSIVE THERAPIES, ONE HALF OF ALL HYPERTENSIVE PATIENTS STILL DO NOT HAVE THEIR BLOOD PRESSURE CONTROLLED. THE FRONTIER IN UNDERSTANDING THE MOLECULAR MECHANISMS UNDERLYING HYPERTENSION HAS NOW ADVANCED TO THE LEVEL OF EPIGENOMICS. PARTICULARLY, INCREASING EVIDENCE IS EMERGING THAT DNA METHYLATION AND HISTONE MODIFICATIONS PLAY AN IMPORTANT ROLE IN GENE REGULATION AND ARE INVOLVED IN ALTERATION OF THE PHENOTYPE AND FUNCTION OF VASCULAR CELLS IN RESPONSE TO ENVIRONMENTAL STRESSES. THIS REVIEW SEEKS TO HIGHLIGHT THE RECENT ADVANCES IN OUR KNOWLEDGE OF THE EPIGENETIC REGULATIONS AND MECHANISMS OF HYPERTENSION, FOCUSING ON THE ROLE OF DNA METHYLATION AND HISTONE MODIFICATION IN THE VASCULAR WALL. A BETTER UNDERSTANDING OF THE EPIGENOMIC REGULATION IN THE HYPERTENSIVE VESSEL MAY LEAD TO THE IDENTIFICATION OF NOVEL TARGET MOLECULES THAT, IN TURN, MAY LEAD TO NOVEL DRUG DISCOVERIES FOR THE TREATMENT OF HYPERTENSION. 2018 5 2687 38 EVIDENCE OF EPIGENETIC ALTERATIONS IN THROMBOSIS AND COAGULATION: A SYSTEMATIC REVIEW. THROMBOSIS IN THE CONTEXT OF CARDIOVASCULAR DISEASE (CVD) AFFECTS MAINLY THE BLOOD VESSELS SUPPLYING THE HEART, BRAIN AND PERIPHERIES AND IT IS THE LEADING CAUSE OF DEATH WORLDWIDE. THE PATHOPHYSIOLOGICAL THROMBOTIC MECHANISMS ARE LARGELY UNKNOWN. HERITABILITY CONTRIBUTES TO A 30% OF THE INCIDENCE OF CVD. THE REMAINING VARIATION CAN BE EXPLAINED BY LIFE STYLE FACTORS SUCH AS SMOKING, DIETARY AND EXERCISE HABITS, ENVIRONMENTAL EXPOSURE TO TOXINS, AND DRUG USAGE AND OTHER COMORBIDITIES. EPIGENETIC VARIATION CAN BE ACQUIRED OR INHERITED AND CONSTITUTES AN INTERACTION BETWEEN GENES AND THE ENVIRONMENT. EPIGENETICS HAVE BEEN IMPLICATED IN ATHEROSCLEROSIS, ISCHEMIA/REPERFUSION DAMAGE AND THE CARDIOVASCULAR RESPONSE TO HYPOXIA. EPIGENETIC REGULATORS OF GENE EXPRESSION ARE MAINLY THE METHYLATION OF CPG ISLANDS, HISTONE POST TRANSLATIONAL MODIFICATIONS (PTMS) AND MICRORNAS (MIRNAS). THESE EPIGENETIC REGULATORS CONTROL GENE EXPRESSION EITHER THROUGH ACTIVATION OR SILENCING. EPIGENETIC CONTROL IS MOSTLY DYNAMIC AND CAN POTENTIALLY BE MANIPULATED TO PREVENT OR REVERSE THE UNCONTROLLED EXPRESSION OF GENES, A TRAIT THAT RENDERS THEM PUTATIVE THERAPEUTIC TARGETS. IN THE CURRENT REVIEW, WE SYSTEMATICALLY STUDIED AND PRESENT AVAILABLE DATA ON EPIGENETIC ALTERATIONS IMPLICATED IN THROMBOSIS DERIVED FROM HUMAN STUDIES. EVIDENCE OF EPIGENETIC ALTERATIONS IS OBSERVED IN SEVERAL THROMBOTIC DISEASES SUCH AS CORONARY ARTERY DISEASE AND CEREBROVASCULAR DISEASE, PREECLAMPSIA AND ANTIPHOSPHOLIPID SYNDROME. DIFFERENTIAL CPG METHYLATION AND SPECIFIC HISTONE PTMS THAT CONTROL TRANSCRIPTION OF PROTHROMBOTIC AND PROINFLAMMATORY GENES HAVE ALSO BEEN ASSOCIATED WITH PREDISPOSING FACTORS OF THROMBOSIS AND CVD, SUCH US SMOKING, AIR POLLUTION, HYPERTRIGLYCERIDEMIA, OCCUPATIONAL EXPOSURE TO PARTICULATE MATTER AND COMORBIDITIES INCLUDING CANCER, CHRONIC OBSTRUCTIVE PULMONARY DISEASE AND CHRONIC KIDNEY DISEASE. THESE CLINICAL OBSERVATIONS ARE FURTHER SUPPORTED BY IN VITRO EXPERIMENTS AND INDICATE THAT EPIGENETIC REGULATION AFFECTS THE PATHOPHYSIOLOGY OF THROMBOTIC DISORDERS WITH POTENTIAL DIAGNOSTIC OR THERAPEUTIC UTILITY. 2019 6 6199 33 THE IMPORTANCE OF EPIGENETICS IN THE DEVELOPMENT OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE. IT IS GENERALLY ACCEPTED THAT GENETIC PREDISPOSITION PLAYS A ROLE IN COPD DEVELOPMENT IN SUSCEPTIBLE INDIVIDUALS. THEREFORE, MANY CANDIDATE GENES THAT COULD BE LINKED TO THE DEVELOPMENT OF DISEASE HAVE BEEN EXAMINED IN COPD. HOWEVER, INCONSISTENT RESULTS IN DIFFERENT STUDY POPULATIONS OFTEN LIMIT THIS APPROACH, SUGGESTING THAT NOT ONLY GENETICS, BUT ALSO OTHER FACTORS, MAY BE CONTRIBUTED TO THE SUSCEPTIBILITY TO COPD. EPIGENETIC MECHANISMS CAN AFFECT THE TRANSCRIPTIONAL ACTIVITY OF SPECIFIC GENES, AT DIFFERENT POINTS IN TIME, AND IN DIFFERENT ORGANS. MOREOVER, THESE MECHANISMS CAN HAVE AN EFFECT ON PEOPLE'S HEALTH. RECENTLY, THERE IS EMERGING EVIDENCE SUPPORTING A ROLE OF EPIGENETICS FOR THE REGULATION OF INFLAMMATORY GENES IN DISEASES SUCH AS ASTHMA AND COPD. MOREOVER, RECENT STUDIES SUGGEST THAT THE CURRENTLY USED TREATMENTS INCLUDING CORTICOSTEROIDS MAY WORK THROUGH EPIGENETIC MECHANISMS. EPIGENETIC REGULATION CAN BE REPROGRAMMED, POTENTIALLY AFFECTING THE RISK, AETIOLOGY AND TREATMENT OF VARIOUS DISEASE STATES. THE EPIGENETICALLY INFLUENCED PHENOTYPE COULD BE REVERSED WITH DEMETHYLATING OR DEACETYLATING AGENTS, CONSISTENT WITH EPIGENETIC PLASTICITY. THE POSTNATAL REVERSIBILITY OF THESE METHYLATION OR ACETYLATION EVENTS MAY THEREFORE PROVIDE GOOD OPPORTUNITIES FOR INTERVENTION. THE RECOGNITION OF THE ROLE OF GENETIC AND EPIGENETIC MECHANISMS IN THE DEVELOPMENT OF COPD MAY IDENTIFY NOVEL TARGETS THAT HATCH NEW THERAPIES FOR PATIENTS WITH COPD. 2011 7 2505 39 EPIGENETICS AND MUSCLE DYSFUNCTION IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS A COMMON, PREVENTABLE, AND TREATABLE DISEASE AND A MAJOR LEADING CAUSE OF MORBIDITY AND MORTALITY WORLDWIDE. IN COPD, COMORBIDITIES, ACUTE EXACERBATIONS, AND SYSTEMIC MANIFESTATIONS NEGATIVELY INFLUENCE DISEASE SEVERITY AND PROGRESSION REGARDLESS OF THE RESPIRATORY CONDITION. SKELETAL MUSCLE DYSFUNCTION, WHICH IS ONE OF THE COMMONEST SYSTEMIC MANIFESTATIONS IN PATIENTS WITH COPD, HAS A TREMENDOUS IMPACT ON THEIR EXERCISE CAPACITY AND QUALITY OF LIFE. SEVERAL PATHOPHYSIOLOGICAL AND MOLECULAR UNDERLYING MECHANISMS INCLUDING EPIGENETICS (THE PROCESS WHEREBY GENE EXPRESSION IS REGULATED BY HERITABLE MECHANISMS THAT DO NOT AFFECT DNA SEQUENCE) HAVE BEEN SHOWN TO PARTICIPATE IN THE ETIOLOGY OF COPD MUSCLE DYSFUNCTION. THE EPIGENETIC MODIFICATIONS IDENTIFIED SO FAR IN CELLS INCLUDE DNA METHYLATION, HISTONE ACETYLATION AND METHYLATION, AND NONCODING RNAS SUCH AS MICRORNAS. HEREIN, WE FIRST REVIEW THE ROLE OF EPIGENETIC MECHANISMS IN MUSCLE DEVELOPMENT AND ADAPTATION TO ENVIRONMENTAL FACTORS IN SEVERAL MODELS. MOREOVER, THE EPIGENETIC EVENTS REPORTED SO FAR TO BE POTENTIALLY INVOLVED IN MUSCLE DYSFUNCTION AND MASS LOSS OF PATIENTS WITH COPD ARE ALSO DISCUSSED. FURTHERMORE, THE DIFFERENT EXPRESSION PROFILE OF SEVERAL MUSCLE-ENRICHED MICRORNAS IN THE DIAPHRAGM AND VASTUS LATERALIS MUSCLES OF PATIENTS WITH COPD ARE ALSO REVIEWED FROM RESULTS RECENTLY OBTAINED IN OUR GROUP. THE ROLE OF PROTEIN HYPERACETYLATION IN ENHANCED MUSCLE PROTEIN CATABOLISM OF LIMB MUSCLES IS ALSO DISCUSSED. FUTURE RESEARCH SHOULD FOCUS ON THE FULL ELUCIDATION OF THE TRIGGERS OF EPIGENETIC MECHANISMS AND THEIR SPECIFIC DOWNSTREAM BIOLOGICAL PATHWAYS IN COPD MUSCLE DYSFUNCTION AND WASTING. 2015 8 288 31 AGING AND INDUCED SENESCENCE AS FACTORS IN THE PATHOGENESIS OF LUNG EMPHYSEMA. CLASSICALLY, THE DEVELOPMENT OF EMPHYSEMA IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE IS BELIEVED TO INVOLVE INFLAMMATION INDUCED BY CIGARETTE SMOKE AND LEUKOCYTE ACTIVATION, INCLUDING OXIDANT-ANTIOXIDANT AND PROTEASE-ANTIPROTEASE IMBALANCES. WHILE THERE IS SUBSTANTIAL EVIDENCE FOR THIS, ADDITIONAL ASPECTS HAVE BEEN SUGGESTED BY A NUMBER OF CLINICAL AND EXPERIMENTAL OBSERVATIONS. SMOKERS EXHIBIT SIGNS OF PREMATURE AGING, PARTICULARLY OBVIOUS IN THE SKIN. THE LINK BETWEEN AGING AND CHRONIC DISEASE IS WELL-KNOWN, E.G., FOR THE BRAIN AND MUSCULOSKELETAL OR CARDIOVASCULAR SYSTEM, AS WELL AS THE CLINICAL LINK BETWEEN MALNUTRITION AND EMPHYSEMA, AND THE EXPERIMENTAL LINK TO CALORIC RESTRICTION. INTERESTINGLY, THIS INTERVENTION ALSO INCREASES LIFESPAN, IN PARALLEL WITH ALTERATIONS IN METABOLISM, OXIDANT BURDEN AND ENDOCRINE SIGNALING. OF SPECIAL INTEREST IS THE OBSERVATION THAT, EVEN IN THE ABSENCE OF AN INFLAMMATORY ENVIRONMENT, LUNG FIBROBLASTS FROM PATIENTS WITH EMPHYSEMA SHOW PERSISTENT ALTERATIONS, POSSIBLY BASED ON EPIGENETIC MECHANISMS. THE IMPORTANCE OF THESE MECHANISMS FOR CELLULAR REPROGRAMMING AND RESPONSE PATTERNS, INDIVIDUAL RISK PROFILE AND THERAPEUTIC OPTIONS IS BECOMING INCREASINGLY RECOGNIZED. THE SAME APPLIES TO CELLULAR SENESCENCE. RECENT FINDINGS FROM PATIENTS AND EXPERIMENTAL MODELS OPEN NOVEL VIEWS INTO THE ARENA OF GENE-ENVIRONMENT INTERACTIONS, INCLUDING THE ROLE OF SYSTEMIC ALTERATIONS, CELLULAR STRESS, TELOMERES, CDK INHIBITORS SUCH AS P16, P21, PRB, PI3K, MTOR, FOXO TRANSCRIPTION FACTORS, HISTONE MODIFICATIONS, AND SIRTUINS. THIS ARTICLE AIMS TO OUTLINE THIS EMERGING PICTURE AND TO STIMULATE THE IDENTIFICATION OF CHALLENGING QUESTIONS. SUCH INSIGHTS ALSO BEAR IMPLICATIONS FOR THE LONG-TERM COURSE OF THE DISEASE IN RELATION TO EXISTING OR FUTURE THERAPIES AND THE EXPLORATION OF POTENTIAL LUNG REGENERATION. 2008 9 4410 32 MOLECULAR AND BIOLOGICAL PATHWAYS OF SKELETAL MUSCLE DYSFUNCTION IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) WILL BE A MAJOR LEADING CAUSE OF DEATH WORLDWIDE IN THE NEAR FUTURE. WEAKNESS AND ATROPHY OF THE QUADRICEPS ARE ASSOCIATED WITH A SIGNIFICANTLY POORER PROGNOSIS AND INCREASED MORTALITY IN COPD. DESPITE THAT SKELETAL MUSCLE DYSFUNCTION MAY AFFECT BOTH RESPIRATORY AND LIMB MUSCLE GROUPS IN COPD, THE LATTER ARE FREQUENTLY MORE SEVERELY AFFECTED. THEREFORE, MUSCLE DYSFUNCTION IN COPD IS A COMMON SYSTEMIC MANIFESTATION THAT SHOULD BE EVALUATED ON ROUTINE BASIS IN CLINICAL SETTINGS. IN THE PRESENT REVIEW, SEVERAL ASPECTS OF COPD MUSCLE DYSFUNCTION ARE BEING REVIEWED, WITH SPECIAL EMPHASIS ON THE UNDERLYING BIOLOGICAL MECHANISMS. FIGURES ON THE PREVALENCE OF COPD MUSCLE DYSFUNCTION AND THE MOST RELEVANT ETIOLOGIC CONTRIBUTORS ARE ALSO PROVIDED. DESPITE THAT ONGOING RESEARCH WILL SHED LIGHT INTO THE CONTRIBUTION OF ADDITIONAL MECHANISMS TO COPD MUSCLE DYSFUNCTION, CURRENT KNOWLEDGE POINTS TOWARD THE INVOLVEMENT OF A WIDE SPECTRUM OF CELLULAR AND MOLECULAR EVENTS THAT ARE DIFFERENTIALLY EXPRESSED IN RESPIRATORY AND LIMB MUSCLES. SUCH MECHANISMS ARE THOROUGHLY DESCRIBED IN THE ARTICLE. THE CONTRIBUTION OF EPIGENETIC EVENTS ON COPD MUSCLE DYSFUNCTION IS ALSO REVIEWED. WE CONCLUDE THAT IN VIEW OF THE LATEST DISCOVERIES, FROM NOW, ON NEW AVENUES OF RESEARCH SHOULD BE DESIGNED TO SPECIFICALLY TARGET CELLULAR MECHANISMS AND PATHWAYS THAT IMPAIR MUSCLE MASS AND FUNCTION IN COPD USING PHARMACOLOGICAL STRATEGIES AND/OR EXERCISE TRAINING MODALITIES. 2016 10 2313 39 EPIGENETIC REGULATION OF ENDOTHELIAL CELL FUNCTION BY NUCLEIC ACID METHYLATION IN CARDIAC HOMEOSTASIS AND DISEASE. PATHOLOGICAL REMODELLING OF THE MYOCARDIUM, INCLUDING INFLAMMATION, FIBROSIS AND HYPERTROPHY, IN RESPONSE TO ACUTE OR CHRONIC INJURY IS CENTRAL IN THE DEVELOPMENT AND PROGRESSION OF HEART FAILURE (HF). WHILE BOTH RESIDENT AND INFILTRATING CARDIAC CELLS ARE IMPLICATED IN THESE PATHOPHYSIOLOGICAL PROCESSES, RECENT EVIDENCE HAS SUGGESTED THAT ENDOTHELIAL CELLS (ECS) MAY BE THE PRINCIPAL CELL TYPE RESPONSIBLE FOR ORCHESTRATING PATHOLOGICAL CHANGES IN THE FAILING HEART. EPIGENETIC MODIFICATION OF NUCLEIC ACIDS, INCLUDING DNA, AND MORE RECENTLY RNA, BY METHYLATION IS ESSENTIAL FOR PHYSIOLOGICAL DEVELOPMENT DUE TO THEIR CRITICAL REGULATION OF CELLULAR GENE EXPRESSION. AS ACCUMULATING EVIDENCE HAS HIGHLIGHTED ALTERED PATTERNS OF DNA AND RNA METHYLATION IN HF AT BOTH THE GLOBAL AND INDIVIDUAL GENE LEVELS, MUCH EFFORT HAS BEEN DIRECTED TOWARDS DEFINING THE PRECISE ROLE OF SUCH CELL-SPECIFIC EPIGENETIC CHANGES IN THE CONTEXT OF HF. CONSIDERING THE INCREASINGLY APPARENT CRUCIAL ROLE THAT ECS PLAY IN CARDIAC HOMEOSTASIS AND DISEASE, THIS ARTICLE WILL SPECIFICALLY FOCUS ON NUCLEIC ACID METHYLATION (BOTH DNA AND RNA) IN THE FAILING HEART, EMPHASISING THE KEY INFLUENCE OF THESE EPIGENETIC MECHANISMS IN GOVERNING EC FUNCTION. THIS REVIEW SUMMARISES CURRENT UNDERSTANDING OF DNA AND RNA METHYLATION ALTERATIONS IN HF, ALONG WITH THEIR SPECIFIC ROLE IN REGULATING EC FUNCTION IN RESPONSE TO STRESS (E.G. HYPERGLYCAEMIA, HYPOXIA). IMPROVED APPRECIATION OF THIS IMPORTANT RESEARCH AREA WILL AID IN FURTHER IMPLICATING DYSFUNCTIONAL ECS IN HF PATHOGENESIS, WHILST INFORMING DEVELOPMENT OF EC-TARGETED STRATEGIES AND ADVANCING POTENTIAL TRANSLATION OF EPIGENETIC-BASED THERAPIES FOR SPECIFIC TARGETING OF PATHOLOGICAL CARDIAC REMODELLING IN HF. 2021 11 2062 27 EPIGENETIC CONTROL OF HYPERTENSION BY DNA METHYLATION: A REAL POSSIBILITY. HYPERTENSION IS A COMMON CHRONIC DISEASE THAT PARTICULARLY AFFECTS THE ELDERLY AND CAN TRIGGER SEVERAL CARDIOVASCULAR CONDITIONS. ALTHOUGH THE TREATMENT OF HYPERTENSION HAS EVOLVED IN RECENT DECADES, MANY HYPERTENSIVE PATIENTS STILL DO NOT HAVE PROPERLY CONTROLLED BLOOD PRESSURE. ACCUMULATING EVIDENCE SUPPORTS THE HYPOTHESIS THAT DNA METHYLATION PLAYS AN IMPORTANT ROLE IN REGULATING GENE EXPRESSION, ALTERING THE PHENOTYPE AND FUNCTION OF THE CARDIOVASCULAR SYSTEM. THE PRESENT REVIEW HIGHLIGHTS RECENT ADVANCES IN RESEARCH ON DNA METHYLATION IN THE DEVELOPMENT OF HYPERTENSION. SEVERAL PRECLINICAL AND CLINICAL EVIDENCE SHOW THAT METHYLATION OF DIFFERENT TARGETS APPEARS TO BE INVOLVED IN HYPERTENSION. STUDIES OF THE INVOLVEMENT OF DNA METHYLATION HAVE GREATLY IMPROVED OUR UNDERSTANDING OF HYPERTENSION, BUT ITS USE AS A VALID THERAPEUTIC TARGET IS STILL UNKNOWN. FURTHER STUDIES COULD HELP TO BRING TO LIGHT THE TRUTH ABOUT GENE THERAPY IN HYPERTENSION. 2021 12 5053 42 PHARMACOLOGY OF PULMONARY ARTERIAL HYPERTENSION: AN OVERVIEW OF CURRENT AND EMERGING THERAPIES. PULMONARY ARTERIAL HYPERTENSION IS A RARE AND DEVASTATING DISEASE CHARACTERIZED BY AN ABNORMAL CHRONIC INCREASE IN PULMONARY ARTERIAL PRESSURE ABOVE 20 MMHG AT REST, WITH A POOR PROGNOSIS IF NOT TREATED. CURRENTLY, THERE IS NOT A SINGLE FULLY EFFECTIVE THERAPY, EVEN THOUGH A DOZEN OF DRUGS HAVE BEEN DEVELOPED IN THE LAST DECADES. PULMONARY ARTERIAL HYPERTENSION IS A MULTIFACTORIAL DISEASE, MEANING THAT SEVERAL MOLECULAR MECHANISMS ARE IMPLICATED IN ITS PATHOLOGY. THE MAIN MOLECULAR PATHWAYS REGULATING THE PULMONARY VASOMOTOR TONE-ENDOTHELIN, NITRIC OXIDE, AND PROSTACYCLIN-ARE THE MOST BIOLOGICALLY AND THERAPEUTICALLY EXPLORED TO DATE. HOWEVER, DRUGS TARGETING THESE PATHWAYS HAVE ALREADY FOUND THEIR LIMITATIONS. IN THE LAST YEARS, TRANSLATIONAL RESEARCH AND CLINICAL TRIALS HAVE MADE A STRONG EFFORT IN SUGGESTING AND TESTING NOVEL THERAPEUTIC STRATEGIES FOR THIS DISEASE. THESE APPROACHES INVOLVE TARGETING THE MAIN MOLECULAR PATHWAYS WITH NOVEL DRUGS, DRUG REPURPOSING FOR NOVEL TARGETS, AND ALSO USING COMBINATORIAL THERAPIES. IN THIS REVIEW, WE SUMMARIZE CURRENT STRATEGIES AND DRUGS TARGETING THE ENDOTHELIN, NITRIC OXIDE, AND PROSTACYCLIN PATHWAYS, AS WELL AS, THE EMERGING NEW DRUGS PROPOSED TO COPE WITH VASCULAR REMODELLING, METABOLIC SWITCH, PERIVASCULAR INFLAMMATION, EPIGENETIC MODIFICATIONS, ESTROGEN DEREGULATION, SEROTONIN, AND OTHER NEUROHUMORAL MECHANISMS CHARACTERISTIC OF THIS DISEASE. NOWADAYS, PULMONARY ARTERIAL HYPERTENSION REMAINS AN INCURABLE DISEASE; HOWEVER, THE INCOMING NEW KNOWLEDGE MAKES US BELIEVE THAT NEW PROMISING THERAPIES ARE COMING TO THE CLINICAL ARENA SOON. 2020 13 1188 35 COPD: A MULTIFACTORIAL SYSTEMIC DISEASE. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) HAS TRADITIONALLY BEEN CONSIDERED A DISEASE OF THE LUNGS SECONDARY TO CIGARETTE SMOKING AND CHARACTERIZED BY AIRFLOW OBSTRUCTION DUE TO ABNORMALITIES OF BOTH AIRWAY (BRONCHITIS) AND LUNG PARENCHYMA (EMPHYSEMA). IT IS NOW WELL KNOWN THAT COPD IS ASSOCIATED WITH SIGNIFICANT SYSTEMIC ABNORMALITIES, SUCH AS RENAL AND HORMONAL ABNORMALITIES, MALNUTRITION, MUSCLE WASTING, OSTEOPOROSIS, AND ANEMIA. HOWEVER, IT IS STILL UNCLEAR WHETHER THEY REPRESENT CONSEQUENCES OF THE PULMONARY DISORDER, OR WHETHER COPD SHOULD BE CONSIDERED AS A SYSTEMIC DISEASE. THESE SYSTEMIC ABNORMALITIES HAVE BEEN ATTRIBUTED TO AN INCREASED LEVEL OF SYSTEMIC INFLAMMATION. CHRONIC INFLAMMATION, HOWEVER, MAY NOT BE THE ONLY CAUSE OF THE SYSTEMIC EFFECTS OF COPD. RECENT DATA FROM HUMANS AND ANIMAL MODELS SUPPORT THE VIEW THAT EMPHYSEMA MAY BE A VASCULAR DISEASE. OTHER STUDIES HAVE HIGHLIGHTED THE ROLE OF REPAIR FAILURE, BONE MARROW ABNORMALITY, GENETIC AND EPIGENETIC FACTORS, IMMUNOLOGICAL DISORDERS AND INFECTIONS AS POTENTIAL CAUSES OF COPD SYSTEMIC MANIFESTATIONS. BASED ON THIS NEW EVIDENCE, IT IS REASONABLE TO CONSIDER COPD, AND EMPHYSEMA IN PARTICULAR, AS 'A DISEASE WITH A SIGNIFICANT SYSTEMIC COMPONENT' IF NOT A 'SYSTEMIC DISEASE' PER SE. THE AIM OF THIS REVIEW IS TO GIVE AN OVERVIEW OF THE MOST RELEVANT AND INNOVATIVE HYPOTHESIS ABOUT THE EXTRAPULMONARY MANIFESTATIONS OF COPD. 2011 14 5258 28 PROGRESSION OF TUBULOINTERSTITIAL FIBROSIS AND THE CHRONIC KIDNEY DISEASE PHENOTYPE - ROLE OF RISK FACTORS AND EPIGENETICS. ALTHOUGH THE KIDNEY HAS CAPACITY TO REPAIR AFTER MILD INJURY, ONGOING OR SEVERE DAMAGE RESULTS IN SCARRING (FIBROSIS) AND AN ASSOCIATED PROGRESSIVE LOSS OF KIDNEY FUNCTION. HOWEVER, DESPITE ITS UNIVERSAL SIGNIFICANCE, EVIDENCE HIGHLIGHTS A POPULATION BASED HETEROGENEITY IN THE TRAJECTORY OF CHRONIC KIDNEY DISEASE (CKD) IN THESE PATIENTS. TO EXPLAIN THE HETEROGENEITY OF THE CKD PHENOTYPE REQUIRES AN UNDERSTANDING OF THE RELEVANT RISK FACTORS FOR FIBROSIS. THESE FACTORS INCLUDE BOTH THE EXTRINSIC NATURE OF INJURY, AND INTRINSIC FACTORS SUCH AS AGE, GENDER, GENETICS, AND PERPETUAL ACTIVATION OF FIBROBLASTS THROUGH PRIMING. IN MANY CASES AN ADDITIONAL LEVEL OF REGULATION IS PROVIDED BY EPIGENETIC MECHANISMS WHICH INTEGRATE THE VARIOUS PRO-FIBROTIC AND ANTI-FIBROTIC TRIGGERS IN FIBROGENESIS. IN THIS REVIEW WE THEREFORE EXAMINE THE VARIOUS MOLECULAR AND STRUCTURAL CHANGES OF FIBROSIS, AND HOW THEY ARE INFLUENCED BY EXTRINSIC AND INTRINSIC FACTORS. OUR AIM IS TO PROVIDE A UNIFYING HYPOTHESIS TO HELP EXPLAIN THE TRANSITION FROM ACUTE TO CKD. 2017 15 4882 36 OVERVIEW OF THE CELLULAR AND MOLECULAR BASIS OF KIDNEY FIBROSIS. THE COMMON PATHOGENETIC PATHWAY OF PROGRESSIVE INJURY IN PATIENTS WITH CHRONIC KIDNEY DISEASE (CKD) IS EPITOMIZED AS NORMAL KIDNEY PARENCHYMAL DESTRUCTION DUE TO SCARRING (FIBROSIS). UNDERSTANDING THE FUNDAMENTAL PATHWAYS THAT LEAD TO RENAL FIBROSIS IS ESSENTIAL IN ORDER TO DEVELOP BETTER THERAPEUTIC OPTIONS FOR HUMAN CKD. ALTHOUGH COMPLEX, FOUR CELLULAR RESPONSES ARE PIVOTAL. (1) AN INTERSTITIAL INFLAMMATORY RESPONSE THAT HAS MULTIPLE CONSEQUENCES-SOME HARMFUL AND OTHERS HEALING. (2) THE APPEARANCE OF A UNIQUE INTERSTITIAL CELL POPULATION OF MYOFIBROBLASTS, PRIMARILY DERIVED FROM KIDNEY STROMAL CELLS (FIBROBLASTS AND PERICYTES), THAT ARE THE PRIMARY SOURCE OF THE VARIOUS EXTRACELLULAR MATRIX PROTEINS THAT FORM INTERSTITIAL SCARS. (3) TUBULAR EPITHELIAL CELLS THAT HAVE VARIABLE AND TIME-DEPENDENT ROLES AS EARLY RESPONDERS TO INJURY AND LATER AS VICTIMS OF FIBROSIS DUE TO THE LOSS OF THEIR REGENERATIVE ABILITIES. (4) LOSS OF INTERSTITIAL CAPILLARY INTEGRITY THAT COMPROMISES OXYGEN DELIVERY AND LEADS TO A VICIOUS CASCADE OF HYPOXIA-OXIDANT STRESS THAT ACCENTUATES INJURY AND FIBROSIS. IN THE ABSENCE OF ADEQUATE ANGIOGENIC RESPONSES, A HEALTHY INTERSTITIAL CAPILLARY NETWORK IS NOT MAINTAINED. THE FIBROTIC 'SCAR' THAT TYPIFIES CKD IS AN INTERESTING CONSORTIUM OF MULTIFUNCTIONAL MACROMOLECULES THAT NOT ONLY CHANGE IN COMPOSITION AND STRUCTURE OVER TIME, BUT CAN BE DEGRADED VIA EXTRACELLULAR AND INTRACELLULAR PROTEASES. ALTHOUGH TRANSFORMING GROWTH FACTOR BETA APPEARS TO BE THE PRIMARY DRIVER OF KIDNEY FIBROSIS, A VAST ARRAY OF ADDITIONAL MOLECULES MAY HAVE MODULATING ROLES. THE IMPORTANCE OF GENETIC AND EPIGENETIC FACTORS IS INCREASINGLY APPRECIATED. AN INTRIGUING BUT INCOMPLETELY UNDERSTOOD CARDIORENAL SYNDROME UNDERLIES THE HIGH MORBIDITY AND MORTALITY RATES THAT DEVELOP IN ASSOCIATION WITH PROGRESSIVE KIDNEY FIBROSIS. 2014 16 2348 36 EPIGENETIC REGULATION OF MUSCLE PHENOTYPE AND ADAPTATION: A POTENTIAL ROLE IN COPD MUSCLE DYSFUNCTION. QUADRICEPS MUSCLE DYSFUNCTION OCCURS IN ONE-THIRD OF PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IN VERY EARLY STAGES OF THEIR CONDITION, EVEN PRIOR TO THE DEVELOPMENT OF AIRWAY OBSTRUCTION. AMONG SEVERAL FACTORS, DECONDITIONING AND MUSCLE MASS LOSS ARE THE MOST RELEVANT CONTRIBUTING FACTORS LEADING TO THIS DYSFUNCTION. MOREOVER, EPIGENETICS, DEFINED AS THE PROCESS WHEREBY GENE EXPRESSION IS REGULATED BY HERITABLE MECHANISMS THAT DO NOT AFFECT DNA SEQUENCE, COULD BE INVOLVED IN THE SUSCEPTIBILITY TO MUSCLE DYSFUNCTION, PATHOGENESIS, AND PROGRESSION. HEREIN, WE REVIEW THE ROLE OF EPIGENETIC MECHANISMS IN MUSCLE DEVELOPMENT AND ADAPTATION TO ENVIRONMENTAL FACTORS SUCH AS IMMOBILIZATION AND EXERCISE, AND THEIR IMPLICATIONS IN THE PATHOPHYSIOLOGY AND SUSCEPTIBILITY TO MUSCLE DYSFUNCTION IN COPD. THE EPIGENETIC MODIFICATIONS IDENTIFIED SO FAR INCLUDE DNA METHYLATION, HISTONE ACETYLATION AND METHYLATION, AND NON-CODING RNAS SUCH AS MICRORNAS (MIRNAS). IN THE PRESENT REVIEW, WE DESCRIBE THE SPECIFIC CONTRIBUTION OF EPIGENETIC MECHANISMS TO THE REGULATION OF EMBRYONIC MYOGENESIS, MUSCLE STRUCTURE AND METABOLISM, IMMOBILIZATION, AND EXERCISE, AND IN MUSCLES OF COPD PATIENTS. EVENTS RELATED TO MUSCLE DEVELOPMENT AND REGENERATION AND THE RESPONSE TO EXERCISE AND IMMOBILIZATION ARE TIGHTLY REGULATED BY EPIGENETIC MECHANISMS. THESE ENVIRONMENTAL FACTORS PLAY A KEY ROLE IN THE OUTCOME OF MUSCLE MASS AND FUNCTION AS WELL AS IN THE SUSCEPTIBILITY TO MUSCLE DYSFUNCTION IN COPD. FUTURE RESEARCH REMAINS TO BE DONE TO SHED LIGHT ON THE SPECIFIC TARGET PATHWAYS OF MIRNA FUNCTION AND OTHER EPIGENETIC MECHANISMS IN THE SUSCEPTIBILITY, PATHOGENESIS, AND PROGRESSION OF COPD MUSCLE DYSFUNCTION. 2013 17 6834 28 [IMMUNOPATHOLOGY OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE]. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS A COMMON, PREVENTABLE AND TREATABLE CONDITION THAT HAS A COMPLEX PATHOPHYSIOLOGY AND AN EVEN MORE COMPLEX IMMUNOPATHOLOGICAL PROCESS. THE PURPOSE OF THIS REVIEW WAS TO ANALYZE COPD IMMUNOPATHOLOGICAL ASPECTS, WHICH WAS ADDRESSED BY UNDERTAKING A LITERATURE SEARCH FOR THE MOST RELEVANT DOCUMENTS INDEXED IN THE PUBMED DATABASE OVER THE LAST 10 YEARS. DIFFERENT CONCLUSIONS COULD BE DRAWN: IN COPD IMMUNOPATHOLOGY THERE ARE IMMUNE AND NON-IMMUNE INFLAMMATORY CHANGES WITH OXIDATIVE STRESS IMBALANCE, THERE ARE ALTERATIONS IN THE PROTEASE/ANTI-PROTEASE RATIO CAUSED BY DIRECT AND INDIRECT GENETIC AND EPIGENETIC-ENVIRONMENTAL DEFECTS; COPD PRODUCES IRREVERSIBLE TISSUE DAMAGE AND CHRONIC INFLAMMATION WITH TISSUE REPAIR ALTERATION, WHICH INDUCES CHRONIC OBSTRUCTION OF THE AIRWAY, BRONCHITIS AND SYSTEMIC DAMAGE. MOST COMMON RESULTING COMORBIDITIES INCLUDE CARDIOVASCULAR DISEASE, METABOLIC SYNDROME, OSTEOPOROSIS, DEPRESSION, MUSCULOSKELETAL DYSFUNCTION, INCREASED BIOLOGICAL AGE, LUNG CANCER AND OTHER TYPES OF MALIGNANCIES. IN THE CONCEPTION OF COPD, RECOGNIZING THAT IT IS A NON-TRANSMITTABLE AND PREVENTABLE DISEASE IS INDISPENSABLE. 2017 18 2154 35 EPIGENETIC MECHANISMS AND KIDNEY DISEASES. IN RECENT YEARS, MOLECULAR RESEARCH HAS BROUGHT TO LIGHT A SERIES OF MECHANISMS INVOLVED IN THE REGULATION OF GENE FUNCTION WITHOUT ALTERING THE DNA SEQUENCE. THESE MECHANISMS ARE DESCRIBED WITH THE TERM "EPIGENETICS" AND INCLUDE MODIFICATIONS IN THE STRUCTURE OF THE HUMAN GENOME, LEADING TO HERITABLE AND POTENTIALLY REVERSIBLE CHANGES IN GENE EXPRESSION. THERE IS NOW INCREASING EVIDENCE SUGGESTING THAT SEVERAL CHARACTERISTIC FEATURES OF CHRONIC KIDNEY DISEASE SUCH AS HYPERHOMOCYSTEINEMIA, SUBCLINICAL INFLAMMATION, INCREASED OXIDATIVE STRESS AND OTHERS MAY AFFECT THE HUMAN EPIGENOME. IN ADDITION, ANIMAL STUDIES HAVE SUGGESTED A POSSIBLE LINK BETWEEN NUTRITION AND ENVIRONMENTAL EXPOSURE DURING THE PERICONCEPTIONAL PERIOD AND EPIGENETIC CHANGES IN THE EXPRESSION OF MAJOR GENES IMPLICATED IN KIDNEY ORGANOGENESIS; THESE CHANGES RESULT IN A DIMINISHED NUMBER OF NEPHRONS IN THE DEVELOPING KIDNEY, WHICH PREDISPOSES TO AN INCREASED RISK FOR HYPERTENSION AND CHRONIC KIDNEY DISEASE IN FUTURE LIFE. THE UNDERSTANDING OF THE ROLE OF EPIGENETIC PHENOMENA IN THE PATHOGENESIS OF CHRONIC KIDNEY DISEASE OPENS NEW AVENUES FOR FUTURE THERAPEUTIC STRATEGIES, THROUGH THE DEVELOPMENT OF PHARMACEUTICAL AGENTS THAT TARGET DIRECTLY WITH THE CHANGES IN THE HUMAN EPIGENOME. SUCH EPIGENETIC DRUGS ARE ALREADY IN CLINICAL USE FOR THE TREATMENT OF CANCER AS WELL AS UNDER INVESTIGATION FOR THE USE IN OTHER DISEASES. THIS REVIEW WILL SUMMARIZE THE EXISTING DATA ON THE LINK BETWEEN EPIGENETIC MECHANISMS AND CHRONIC UREMIC MILIEU, AS WELL AS THE PROMISING RESULTS OF ONGOING RESEARCH IN THE FIELD OF EPIGENETIC DRUGS THAT COULD REPRESENT ADDITIONAL OPTIONS IN OUR THERAPEUTIC ARMAMENTARIUM FOR PATIENTS WITH CHRONIC KIDNEY DISEASE. 2011 19 4029 31 LUNGS, BONE MARROW, AND ADIPOSE TISSUE. A NETWORK APPROACH TO THE PATHOBIOLOGY OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE. PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) OFTEN SUFFER OTHER CONCOMITANT DISORDERS, SUCH AS CARDIOVASCULAR DISEASES AND METABOLIC DISORDERS, THAT INFLUENCE SIGNIFICANTLY (AND INDEPENDENTLY OF LUNG FUNCTION) THEIR HEALTH STATUS AND PROGNOSIS. THUS, COPD IS NOT A SINGLE ORGAN CONDITION, AND DISTURBANCES OF A COMPLEX NETWORK OF INTERORGAN CONNECTED RESPONSES OCCUR AND MODULATE THE NATURAL HISTORY OF THE DISEASE. HERE, WE PROPOSE A NOVEL HYPOTHESIS THAT CONSIDERS A VASCULARLY CONNECTED NETWORK WITH (1) THE LUNGS AS THE MAIN EXTERNAL SENSOR OF THE SYSTEM AND A MAJOR SOURCE OF "DANGER SIGNALS"; (2) THE ENDOTHELIUM AS AN INTERNAL SENSOR OF THE SYSTEM (ALSO A POTENTIAL TARGET TISSUE); AND (3) TWO KEY RESPONDING ELEMENTS, BONE MARROW AND ADIPOSE TISSUE, WHICH PRODUCE BOTH INFLAMMATORY AND REPAIR SIGNALS. ACCORDING TO THE MODEL, THE DEVELOPMENT OF COPD, AND ASSOCIATED MULTIMORBIDITIES (HERE WE FOCUS ON CARDIOVASCULAR DISEASE AS AN IMPORTANT EXAMPLE), DEPEND ON THE MANNER IN WHICH THE VASCULAR CONNECTED NETWORK RESPONDS, ADAPTS, OR FAILS TO ADAPT (DICTATED BY THE GENETIC AND EPIGENETIC BACKGROUND OF THE INDIVIDUAL) TO THE INHALATION OF PARTICLES AND GASES, MAINLY IN CIGARETTE SMOKE. THE CAVEATS AND LIMITATIONS OF THE HYPOTHESIS, AS WELL AS THE EXPERIMENTAL AND CLINICAL RESEARCH NEEDED TO TEST AND EXPLORE THE PROPOSED MODEL, ARE ALSO BRIEFLY DISCUSSED. 2013 20 5471 31 RESPIRATORY MUSCLE SENESCENCE IN AGEING AND CHRONIC LUNG DISEASES. AGEING IS A PROGRESSIVE CONDITION THAT USUALLY LEADS TO THE LOSS OF PHYSIOLOGICAL PROPERTIES. THIS PROCESS IS ALSO PRESENT IN RESPIRATORY MUSCLES, WHICH ARE AFFECTED BY BOTH SENESCENT CHANGES OCCURRING IN THE WHOLE ORGANISM AND THOSE THAT ARE MORE SPECIFIC FOR MUSCLES. THE MECHANISMS OF THE LATTER CHANGES INCLUDE OXIDATIVE STRESS, DECREASE IN NEUROTROPHIC FACTORS AND DNA ABNORMALITIES. AGEING NORMALLY COEXISTS WITH COMORBIDITIES, INCLUDING RESPIRATORY DISEASES, WHICH FURTHER DETERIORATE THE STRUCTURE AND FUNCTION OF RESPIRATORY MUSCLES. IN THIS CONTEXT, CHANGES INTRINSIC TO AGEING BECOME ENHANCED BY MORE SPECIFIC FACTORS SUCH AS THE IMPAIRMENT IN LUNG MECHANICS AND GAS EXCHANGE, EXACERBATIONS AND HYPOXIA. HYPOXIA IN PARTICULAR HAS A DIRECT EFFECT ON MUSCLES, MAINLY THROUGH THE EXPRESSION OF INDUCIBLE FACTORS (HYPOXIC-INDUCIBLE FACTOR), AND CAN RESULT IN OXIDATIVE STRESS AND CHANGES IN DNA, DECREASE IN MITOCHONDRIAL BIOGENESIS AND DEFECTS IN THE TISSUE REPAIR MECHANISMS. INTENSE EXERCISE CAN ALSO CAUSE DAMAGE IN RESPIRATORY MUSCLES OF ELDERLY RESPIRATORY PATIENTS, BUT THIS CAN BE FOLLOWED BY TISSUE REPAIR AND REMODELLING. HOWEVER, AGEING INTERFERES WITH MUSCLE REPAIR BY TAMPERING WITH THE FUNCTION OF SATELLITE CELLS, MAINLY DUE TO OXIDATIVE STRESS, DNA DAMAGE AND EPIGENETIC MECHANISMS. IN ADDITION TO THE NORMAL PROCESS OF AGEING, STRESS-INDUCED PREMATURE SENESCENCE CAN ALSO OCCUR, INVOLVING CHANGES IN THE EXPRESSION OF MULTIPLE GENES BUT WITHOUT MODIFICATIONS IN TELOMERE LENGTH. 2020