1 3674 107 INFLAMMATION AND DYSREGULATED FIBROBLAST PROLIFERATION--NEW MECHANISMS? IDIOPATHIC PULMONARY FIBROSIS (IPF) IS A DEVASTATING, AGE-RELATED LUNG DISEASE OF UNKNOWN CAUSE THAT HAS FEW TREATMENT OPTIONS. ONCE THOUGHT TO BE A CHRONIC INFLAMMATORY PROCESS, CURRENT EVIDENCE INDICATES THAT THE FIBROTIC RESPONSE MAY PRIMARILY BE DRIVEN BY ABNORMALLY ACTIVATED ALVEOLAR EPITHELIAL CELLS AND THE UNDERLYING MESENCHYME. THE MEDIATORS PRODUCED AND PRESENT IN THIS MICROENVIRONMENT INDUCE THE FORMATION OF FIBROBLAST FOCI THROUGH THE PROLIFERATION OF RESIDENT MESENCHYMAL CELLS, ATTRACTION OF CIRCULATING FIBROCYTES, AND STIMULATION OF EPITHELIAL TO MESENCHYMAL TRANSITION. THE FIBROBLAST AND MYOFIBROBLAST FOCI SECRETE EXCESSIVE AMOUNTS OF EXTRACELLULAR MATRIX, MAINLY COLLAGENS, RESULTING IN SCARRING AND DESTRUCTION OF THE LUNG ARCHITECTURE. THE DETAILED MECHANISMS THAT LINK IPF WITH AGEING AND ABERRANT EPITHELIAL ACTIVATION ARE UNKNOWN, BUT SOME EVIDENCE SUGGESTS THAT THE ABNORMAL RECAPITULATION OF DEVELOPMENTAL PATHWAYS AND EPIGENETIC CHANGES MAY PLAY A ROLE. THIS REVIEW PROVIDES A BRIEF SYNOPSIS OF HIGHLIGHTS IN THE CURRENT UNDERSTANDING OF THE PATHOPHYSIOLOGY OF IPF, AS WELL AS NOVEL THERAPEUTICS BEING EXPLORED IN CLINICAL TRIALS FOR THE TREATMENT OF THIS DEVASTATING DISEASE. 2013 2 3512 84 IDIOPATHIC PULMONARY FIBROSIS. IDIOPATHIC PULMONARY FIBROSIS IS A DEVASTATING, AGE-RELATED LUNG DISEASE OF UNKNOWN CAUSE THAT HAS FEW TREATMENT OPTIONS. THIS DISEASE WAS ONCE THOUGHT TO BE A CHRONIC INFLAMMATORY PROCESS, BUT CURRENT EVIDENCE INDICATES THAT THE FIBROTIC RESPONSE IS DRIVEN BY ABNORMALLY ACTIVATED ALVEOLAR EPITHELIAL CELLS (AECS). THESE CELLS PRODUCE MEDIATORS THAT INDUCE THE FORMATION OF FIBROBLAST AND MYOFIBROBLAST FOCI THROUGH THE PROLIFERATION OF RESIDENT MESENCHYMAL CELLS, ATTRACTION OF CIRCULATING FIBROCYTES, AND STIMULATION OF THE EPITHELIAL TO MESENCHYMAL TRANSITION. THE FIBROBLAST AND MYOFIBROBLAST FOCI SECRETE EXCESSIVE AMOUNTS OF EXTRACELLULAR MATRIX, MAINLY COLLAGENS, RESULTING IN SCARRING AND DESTRUCTION OF THE LUNG ARCHITECTURE. THE MECHANISMS THAT LINK IDIOPATHIC PULMONARY FIBROSIS WITH AGEING AND ABERRANT EPITHELIAL ACTIVATION ARE UNKNOWN; EVIDENCE SUGGESTS THAT THE ABNORMAL RECAPITULATION OF DEVELOPMENTAL PATHWAYS AND EPIGENETIC CHANGES HAVE A ROLE. IN THIS SEMINAR, WE REVIEW RECENT DATA ON THE CLINICAL COURSE, THERAPEUTIC OPTIONS, AND UNDERLYING MECHANISMS THOUGHT TO BE INVOLVED IN THE PATHOGENESIS OF IDIOPATHIC PULMONARY FIBROSIS. 2011 3 5769 33 SPECIFIC EPIGENETIC REGULATORS SERVE AS POTENTIAL THERAPEUTIC TARGETS IN IDIOPATHIC PULMONARY FIBROSIS. IDIOPATHIC PULMONARY FIBROSIS (IPF), A DISORDER OBSERVED MOSTLY IN OLDER HUMAN BEINGS, IS CHARACTERISED BY CHRONIC AND PROGRESSIVE LUNG SCARRING LEADING TO AN IRREVERSIBLE DECLINE IN LUNG FUNCTION. THIS HEALTH CONDITION HAS A DISMAL PROGNOSIS AND THE CURRENTLY AVAILABLE DRUGS ONLY DELAY BUT FAIL TO REVERSE THE PROGRESSION OF LUNG DAMAGE. CONSEQUENTLY, IT BECOMES IMPERATIVE TO DISCOVER IMPROVED THERAPEUTIC COMPOUNDS AND THEIR CELLULAR TARGETS TO CURE IPF. IN THIS REGARD, A NUMBER OF RECENT STUDIES HAVE TARGETED THE EPIGENETIC REGULATION BY HISTONE DEACETYLASES (HDACS) TO DEVELOP AND CATEGORISE ANTIFIBROTIC DRUGS FOR LUNGS. THEREFORE, THIS REVIEW FOCUSES ON HOW ABERRANT EXPRESSION OR ACTIVITY OF CLASSES I, II AND III HDACS ALTER TGF-BETA SIGNALLING TO PROMOTE EVENTS SUCH AS EPITHELIAL-MESENCHYMAL TRANSITION, DIFFERENTIATION OF ACTIVATED FIBROBLASTS INTO MYOFIBROBLASTS, AND EXCESS DEPOSITION OF THE EXTRACELLULAR MATRIX TO PROPEL LUNG FIBROSIS. FURTHER, THIS STUDY DESCRIBES HOW CERTAIN CHEMICAL COMPOUNDS OR DIETARY CHANGES MODULATE DYSREGULATED HDACS TO ATTENUATE FIVE FAULTY TGF-BETA-DEPENDENT PROFIBROTIC PROCESSES, BOTH IN ANIMAL MODELS AND CELL LINES REPLICATING IPF, THEREBY IDENTIFYING PROMISING MEANS TO TREAT THIS LUNG DISORDER. 2022 4 5950 35 TARGETING THE PROGRESSION OF CHRONIC KIDNEY DISEASE. CHRONIC KIDNEY DISEASE (CKD) IS A DEVASTATING CONDITION THAT IS REACHING EPIDEMIC LEVELS OWING TO THE INCREASING PREVALENCE OF DIABETES MELLITUS, HYPERTENSION AND OBESITY, AS WELL AS AGEING OF THE POPULATION. REGARDLESS OF THE UNDERLYING AETIOLOGY, CKD IS SLOWLY PROGRESSIVE AND LEADS TO IRREVERSIBLE NEPHRON LOSS, END-STAGE RENAL DISEASE AND/OR PREMATURE DEATH. FACTORS THAT CONTRIBUTE TO CKD PROGRESSION INCLUDE PARENCHYMAL CELL LOSS, CHRONIC INFLAMMATION, FIBROSIS AND REDUCED REGENERATIVE CAPACITY OF THE KIDNEY. CURRENT THERAPIES HAVE LIMITED EFFECTIVENESS AND ONLY DELAY DISEASE PROGRESSION, UNDERSCORING THE NEED TO DEVELOP NOVEL THERAPEUTIC APPROACHES TO EITHER STOP OR REVERSE PROGRESSION. PRECLINICAL STUDIES HAVE IDENTIFIED SEVERAL APPROACHES THAT REDUCE FIBROSIS IN EXPERIMENTAL MODELS, INCLUDING TARGETING CYTOKINES, TRANSCRIPTION FACTORS, DEVELOPMENTAL AND SIGNALLING PATHWAYS AND EPIGENETIC MODULATORS, PARTICULARLY MICRORNAS. SOME OF THESE NEPHROPROTECTIVE STRATEGIES ARE NOW BEING TESTED IN CLINICAL TRIALS. LESSONS LEARNED FROM THE FAILURE OF CLINICAL STUDIES OF TRANSFORMING GROWTH FACTOR BETA1 (TGFBETA1) BLOCKADE UNDERSCORE THE NEED FOR ALTERNATIVE APPROACHES TO CKD THERAPY, AS STRATEGIES THAT TARGET A SINGLE PATHOGENIC PROCESS MAY RESULT IN UNEXPECTED NEGATIVE EFFECTS ON SIMULTANEOUSLY OCCURRING PROCESSES. ADDITIONAL PROMISING AVENUES INCLUDE PREVENTING TUBULAR CELL INJURY AND ANTI-FIBROTIC THERAPIES THAT TARGET ACTIVATED MYOFIBROBLASTS, THE MAIN COLLAGEN-PRODUCING CELLS. 2020 5 6223 52 THE LEADING ROLE OF EPITHELIAL CELLS IN THE PATHOGENESIS OF IDIOPATHIC PULMONARY FIBROSIS. IDIOPATHIC PULMONARY FIBROSIS (IPF) IS A RELENTLESSLY PROGRESSIVE AND DEVASTATING INTERSTITIAL LUNG DISEASE OF UNKNOWN ETIOLOGY, WHERE THE NORMAL LUNG ARCHITECTURE IS LOST AND REPLACED BY FIBROTIC TISSUE LEADING TO AN IRREVERSIBLE AND PROGRESSIVE RESPIRATORY INSUFFICIENCY. HISTORICALLY, IPF WAS CONSIDERED A CHRONIC INFLAMMATORY DISORDER, WHICH GRADUALLY PROGRESSED TO ESTABLISHED FIBROSIS. HOWEVER, STRONG CLINICAL AND EXPERIMENTAL EVIDENCE INDICATES THAT THE DISEASE REPRESENTS AN EPITHELIAL-DRIVEN DISORDER WHICH RESULTS FROM A COMPLEX INTERPLAY OF GENETIC AND ENVIRONMENTAL RISK FACTORS, AGING-ASSOCIATED PROCESSES AND A PROFIBROTIC EPIGENETIC REPROGRAMMING. THE CONVERGENCE OF THESE FACTORS RESULTS IN THE ABERRANT ACTIVATION OF EPITHELIAL CELLS THAT INITIATE THE DEVELOPMENT OF THE DISEASE, PRODUCING VIRTUALLY ALL THE MEDIATORS THAT PARTICIPATE IN THE MIGRATION, PROLIFERATION AND ACTIVATION OF FIBROBLASTS, THEIR DIFFERENTIATION TO MYOFIBROBLASTS AND THE EXCESSIVE AND CHAOTIC SECRETION OF EXTRACELLULAR MATRIX PROTEINS. ALTHOUGH PROGRESS HAS BEEN MADE IN UNDERSTANDING THE CAUSES AND CONSEQUENCES OF THIS ABNORMAL BEHAVIOR OF DISTAL AIRWAYS AND ALVEOLAR EPITHELIUM, THE MECHANISMS THAT INITIATE AND PERPETUATE THE VICIOUS CIRCLE OF MULTIDIRECTIONAL ABNORMAL COMMUNICATIONS BETWEEN THE EPITHELIUM AND FIBROBLASTS AND OTHER RESIDENT CELLS HAVE NOT BEEN ELUCIDATED. IN THIS REVIEW, WE DISCUSS THE ROLE OF EPITHELIAL CELLS AND THE MECHANISMS UNDERLYING THE FIBROTIC RESPONSE IN IPF, AND HIGHLIGHT SOME PROMISING THERAPEUTIC TARGETS FOR THESE CELLS. 2020 6 6621 33 UNDERSTANDING FIBROSIS IN SYSTEMIC SCLEROSIS: SHIFTING PARADIGMS, EMERGING OPPORTUNITIES. FIBROSIS IN MULTIPLE ORGANS IS A PROMINENT PATHOLOGICAL FINDING AND DISTINGUISHING HALLMARK OF SYSTEMIC SCLEROSIS (SSC). FINDINGS DURING THE PAST 5 YEARS HAVE CONTRIBUTED TO A MORE COMPLETE UNDERSTANDING OF THE COMPLEX CELLULAR AND MOLECULAR UNDERPINNING OF FIBROSIS IN SSC. FIBROBLASTS, THE PRINCIPAL EFFECTOR CELLS, ARE ACTIVATED IN THE PROFIBROTIC CELLULAR MILIEU BY CYTOKINES AND GROWTH FACTORS, DEVELOPMENTAL PATHWAYS, ENDOTHELIN 1 AND THROMBIN. INNATE IMMUNE SIGNALING VIA TOLL-LIKE RECEPTORS, MATRIX-GENERATED BIOMECHANICAL STRESS SIGNALING VIA INTEGRINS, HYPOXIA AND OXIDATIVE STRESS SEEM TO BE IMPLICATED IN PERPETUATING THE PROCESS. BEYOND CHRONIC FIBROBLAST ACTIVATION, FIBROSIS REPRESENTS A FAILURE TO TERMINATE TISSUE REPAIR, COUPLED WITH AN EXPANDED POPULATION OF MESENCHYMAL CELLS ORIGINATING FROM BONE MARROW AND TRANSDIFFERENTIATION OF EPITHELIAL CELLS, ENDOTHELIAL CELLS AND PERICYTES. IN ADDITION, STUDIES HAVE IDENTIFIED INTRINSIC ALTERATIONS IN SSC FIBROBLASTS RESULTING FROM EPIGENETIC CHANGES, AS WELL AS ALTERED MICRORNA EXPRESSION THAT MIGHT UNDERLIE THE CELL-AUTONOMOUS, PERSISTENT ACTIVATION PHENOTYPE OF THESE CELLS. PRECISE CHARACTERIZATION OF THE DEREGULATED EXTRACELLULAR AND INTRACELLULAR SIGNALING PATHWAYS, MEDIATORS AND CELLULAR DIFFERENTIATION PROGRAMS THAT CONTRIBUTE TO FIBROSIS IN SSC WILL FACILITATE THE DEVELOPMENT OF SELECTIVE, TARGETED THERAPEUTIC STRATEGIES. EFFECTIVE ANTIFIBROTIC THERAPY WILL ULTIMATELY INVOLVE NOVEL COMPOUNDS AND REPURPOSING OF DRUGS THAT ARE ALREADY APPROVED FOR OTHER INDICATIONS. 2011 7 4675 31 NEW INSIGHTS INTO UNDERSTANDING THE MECHANISMS, PATHOGENESIS, AND MANAGEMENT OF MALIGNANT MESOTHELIOMAS. MALIGNANT MESOTHELIOMA (MM) IS A RELATIVELY RARE BUT DEVASTATING TUMOR THAT IS INCREASING WORLDWIDE. YET, BECAUSE OF DIFFICULTIES IN EARLY DIAGNOSIS AND RESISTANCE TO CONVENTIONAL THERAPIES, MM REMAINS A CHALLENGE FOR PATHOLOGISTS AND CLINICIANS TO TREAT. IN RECENT YEARS, MUCH HAS BEEN REVEALED REGARDING THE MECHANISMS OF INTERACTIONS OF PATHOGENIC FIBERS WITH MESOTHELIAL CELLS, CRUCIAL SIGNALING PATHWAYS, AND GENETIC AND EPIGENETIC EVENTS THAT MAY OCCUR DURING THE PATHOGENESIS OF THESE UNUSUAL, PLEIOMORPHIC TUMORS. THESE OBSERVATIONS SUPPORT A SCENARIO WHEREBY MESOTHELIAL CELLS UNDERGO A SERIES OF CHRONIC INJURY, INFLAMMATION, AND PROLIFERATION IN THE LONG LATENCY PERIOD OF MM DEVELOPMENT THAT MAY BE PERPETUATED BY DURABLE FIBERS, THE TUMOR MICROENVIRONMENT, AND INFLAMMATORY STIMULI. ONE CULPRIT IN SUSTAINED INFLAMMATION IS THE ACTIVATED INFLAMMASOME, A COMPONENT OF MACROPHAGES OR MESOTHELIAL CELLS THAT LEADS TO PRODUCTION OF CHEMOTACTIC, GROWTH-PROMOTING, AND ANGIOGENIC CYTOKINES. THIS INFORMATION HAS BEEN VITAL TO DESIGNING NOVEL THERAPEUTIC APPROACHES FOR PATIENTS WITH MM THAT FOCUS ON IMMUNOTHERAPY, TARGETING GROWTH FACTOR RECEPTORS AND PATHWAYS, OVERCOMING RESISTANCE TO APOPTOSIS, AND MODIFYING EPIGENETIC CHANGES. 2013 8 5026 40 PERSONALIZED MEDICINE IN IDIOPATHIC PULMONARY FIBROSIS: FACTS AND PROMISES. PURPOSE OF REVIEW: IN THIS ARTICLE, WE SUMMARIZE AND DISCUSS THE MOST RECENT LITERATURE ON PERSONALIZED MEDICINE IN IDIOPATHIC PULMONARY FIBROSIS (IPF), A CHRONIC PROGRESSIVE AND ALMOST INVARIABLY LETHAL DISEASE OF UNKNOWN CAUSE. THIS REVIEW IS TIMELY AS MAJOR ADVANCES IN OUR UNDERSTANDING OF DISEASE PATHOBIOLOGY AND IMPROVEMENTS IN MOLECULAR TECHNIQUES HAVE RECENTLY LED TO THE IDENTIFICATION OF POTENTIAL SURROGATES OF DIAGNOSIS, PROGNOSIS AND RESPONSE TO TREATMENT. RECENT FINDINGS: THE MOST PROMISING AND ADVANCED CANDIDATE BIOMARKERS ARE PRESENTED BASED ON THEIR PROPOSED MECHANISTIC PATHWAYS (E.G. ALVEOLAR EPITHELIAL CELL DYSFUNCTION, IMMUNE DYSREGULATION, MICROBIOME, EXTRACELLULAR MATRIX REMODELING AND FIBROPROLIFERATION, EPIGENETIC MARKERS AND METABOLOMICS). RECENT DATA SUGGEST THAT COMPONENTS OF THE IMMUNE SYSTEM MAY CONTRIBUTE TO THE DEVELOPMENT OF IPF. A POTENTIAL ROLE FOR INFECTIONS AS A COFACTOR IN DISEASE DEVELOPMENT AND PROGRESSION OR AS A TRIGGER IN DISEASE EXACERBATION HAS ALSO RECENTLY BEEN PROPOSED. SUMMARY: CLINICAL MANAGEMENT OF IPF IS UNSATISFACTORY BECAUSE OF LIMITED AVAILABILITY OF TRULY EFFECTIVE THERAPIES, LACK OF ACCURATE PREDICTORS OF DISEASE BEHAVIOR AND ABSENCE OF SIMPLE SHORT-TERM MEASURES OF THERAPEUTIC RESPONSE. A NUMBER OF PUTATIVE BIOMARKERS HAVE BEEN IDENTIFIED IN PATIENTS WITH IPF, ALTHOUGH NONE HAS BEEN VALIDATED TO THE STANDARD NECESSARY FOR THEIR USE IN EITHER THERAPEUTIC TRIALS OR CLINICAL PRACTICE. CURRENTLY, ONGOING PROSPECTIVE LONGITUDINAL STUDIES WILL HOPEFULLY PERMIT SUCH VALIDATION. 2015 9 3245 25 HEPATIC STELLATE CELLS AS KEY TARGET IN LIVER FIBROSIS. PROGRESSIVE LIVER FIBROSIS, INDUCED BY CHRONIC VIRAL AND METABOLIC DISORDERS, LEADS TO MORE THAN ONE MILLION DEATHS ANNUALLY VIA DEVELOPMENT OF CIRRHOSIS, ALTHOUGH NO ANTIFIBROTIC THERAPY HAS BEEN APPROVED TO DATE. TRANSDIFFERENTIATION (OR "ACTIVATION") OF HEPATIC STELLATE CELLS IS THE MAJOR CELLULAR SOURCE OF MATRIX PROTEIN-SECRETING MYOFIBROBLASTS, THE MAJOR DRIVER OF LIVER FIBROGENESIS. PARACRINE SIGNALS FROM INJURED EPITHELIAL CELLS, FIBROTIC TISSUE MICROENVIRONMENT, IMMUNE AND SYSTEMIC METABOLIC DYSREGULATION, ENTERIC DYSBIOSIS, AND HEPATITIS VIRAL PRODUCTS CAN DIRECTLY OR INDIRECTLY INDUCE STELLATE CELL ACTIVATION. DYSREGULATED INTRACELLULAR SIGNALING, EPIGENETIC CHANGES, AND CELLULAR STRESS RESPONSE REPRESENT CANDIDATE TARGETS TO DEACTIVATE STELLATE CELLS BY INDUCING REVERSION TO INACTIVATED STATE, CELLULAR SENESCENCE, APOPTOSIS, AND/OR CLEARANCE BY IMMUNE CELLS. CELL TYPE- AND TARGET-SPECIFIC PHARMACOLOGICAL INTERVENTION TO THERAPEUTICALLY INDUCE THE DEACTIVATION WILL ENABLE MORE EFFECTIVE AND LESS TOXIC PRECISION ANTIFIBROTIC THERAPIES. 2017 10 6053 33 THE CRUCIAL ROLE OF NLRP3 INFLAMMASOME IN VIRAL INFECTION-ASSOCIATED FIBROSING INTERSTITIAL LUNG DISEASES. IDIOPATHIC PULMONARY FIBROSIS (IPF), ONE OF THE MOST COMMON FIBROSING INTERSTITIAL LUNG DISEASES (ILD), IS A CHRONIC-AGE-RELATED RESPIRATORY DISEASE THAT RISES FROM REPEATED MICRO-INJURY OF THE ALVEOLAR EPITHELIUM. ENVIRONMENTAL INFLUENCES, INTRINSIC FACTORS, GENETIC AND EPIGENETIC RISK FACTORS THAT LEAD TO CHRONIC INFLAMMATION MIGHT BE IMPLICATED IN THE DEVELOPMENT OF IPF. THE EXACT TRIGGERS THAT INITIATE THE FIBROTIC RESPONSE IN IPF REMAIN ENIGMATIC, BUT THERE IS NOW INCREASING EVIDENCE SUPPORTING THE ROLE OF CHRONIC EXPOSURE OF VIRAL INFECTION. DURING VIRAL INFECTION, ACTIVATION OF THE NLRP3 INFLAMMASOME BY INTEGRATING MULTIPLE CELLULAR AND MOLECULAR SIGNALING IMPLICATES ROBUST INFLAMMATION, FIBROBLAST PROLIFERATION, ACTIVATION OF MYOFIBROBLAST, MATRIX DEPOSITION, AND ABERRANT EPITHELIAL-MESENCHYMAL FUNCTION. OVERALL, THE CROSSTALK OF THE NLRP3 INFLAMMASOME AND VIRUSES CAN ACTIVATE IMMUNE RESPONSES AND INFLAMMASOME-ASSOCIATED MOLECULES IN THE DEVELOPMENT, PROGRESSION, AND EXACERBATION OF IPF. 2021 11 3885 36 KIDNEY FIBROSIS: FROM MECHANISMS TO THERAPEUTIC MEDICINES. CHRONIC KIDNEY DISEASE (CKD) IS ESTIMATED TO AFFECT 10-14% OF GLOBAL POPULATION. KIDNEY FIBROSIS, CHARACTERIZED BY EXCESSIVE EXTRACELLULAR MATRIX DEPOSITION LEADING TO SCARRING, IS A HALLMARK MANIFESTATION IN DIFFERENT PROGRESSIVE CKD; HOWEVER, AT PRESENT NO ANTIFIBROTIC THERAPIES AGAINST CKD EXIST. KIDNEY FIBROSIS IS IDENTIFIED BY TUBULE ATROPHY, INTERSTITIAL CHRONIC INFLAMMATION AND FIBROGENESIS, GLOMERULOSCLEROSIS, AND VASCULAR RAREFACTION. FIBROTIC NICHE, WHERE ORGAN FIBROSIS INITIATES, IS A COMPLEX INTERPLAY BETWEEN INJURED PARENCHYMA (LIKE TUBULAR CELLS) AND MULTIPLE NON-PARENCHYMAL CELL LINEAGES (IMMUNE AND MESENCHYMAL CELLS) LOCATED SPATIALLY WITHIN SCARRING AREAS. ALTHOUGH THE MECHANISMS OF KIDNEY FIBROSIS ARE COMPLICATED DUE TO THE KINDS OF CELLS INVOLVED, WITH THE HELP OF SINGLE-CELL TECHNOLOGY, MANY KEY QUESTIONS HAVE BEEN EXPLORED, SUCH AS WHAT KIND OF RENAL TUBULES ARE PROFIBROTIC, WHERE MYOFIBROBLASTS ORIGINATE, WHICH IMMUNE CELLS ARE INVOLVED, AND HOW CELLS COMMUNICATE WITH EACH OTHER. IN ADDITION, GENETICS AND EPIGENETICS ARE DEEPER MECHANISMS THAT REGULATE KIDNEY FIBROSIS. AND THE REVERSIBLE NATURE OF EPIGENETIC CHANGES INCLUDING DNA METHYLATION, RNA INTERFERENCE, AND CHROMATIN REMODELING, GIVES AN OPPORTUNITY TO STOP OR REVERSE KIDNEY FIBROSIS BY THERAPEUTIC STRATEGIES. MORE MARKETED (E.G., RAS BLOCKAGE, SGLT2 INHIBITORS) HAVE BEEN DEVELOPED TO DELAY CKD PROGRESSION IN RECENT YEARS. FURTHERMORE, A BETTER UNDERSTANDING OF RENAL FIBROSIS IS ALSO FAVORED TO DISCOVER BIOMARKERS OF FIBROTIC INJURY. IN THE REVIEW, WE UPDATE RECENT ADVANCES IN THE MECHANISM OF RENAL FIBROSIS AND SUMMARIZE NOVEL BIOMARKERS AND ANTIFIBROTIC TREATMENT FOR CKD. 2023 12 2455 30 EPIGENETIC TARGETS FOR NOVEL THERAPIES OF LUNG DISEASES. IN SPITE OF SUBSTANTIAL ADVANCES IN DEFINING THE IMMUNOBIOLOGY AND FUNCTION OF STRUCTURAL CELLS IN LUNG DISEASES THERE IS STILL INSUFFICIENT KNOWLEDGE TO DEVELOP FUNDAMENTALLY NEW CLASSES OF DRUGS TO TREAT MANY LUNG DISEASES. FOR EXAMPLE, THERE IS A COMPELLING NEED FOR NEW THERAPEUTIC APPROACHES TO ADDRESS SEVERE PERSISTENT ASTHMA THAT IS INSENSITIVE TO INHALED CORTICOSTEROIDS. ALTHOUGH THE PREVALENCE OF STEROID-RESISTANT ASTHMA IS 5-10%, SEVERE ASTHMATICS REQUIRE A DISPROPORTIONATE LEVEL OF HEALTH CARE SPENDING AND CONSTITUTE A MAJORITY OF FATAL ASTHMA EPISODES. NONE OF THE ESTABLISHED DRUG THERAPIES INCLUDING LONG-ACTING BETA AGONISTS OR INHALED CORTICOSTEROIDS REVERSE ESTABLISHED AIRWAY REMODELING. OBSTRUCTIVE AIRWAYS REMODELING IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD), RESTRICTIVE REMODELING IN IDIOPATHIC PULMONARY FIBROSIS (IPF) AND OCCLUSIVE VASCULAR REMODELING IN PULMONARY HYPERTENSION ARE SIMILARLY UNRESPONSIVE TO CURRENT DRUG THERAPY. THEREFORE, DRUGS ARE NEEDED TO ACHIEVE LONG-ACTING SUPPRESSION AND REVERSAL OF PATHOLOGICAL AIRWAY AND VASCULAR REMODELING. NOVEL DRUG CLASSES ARE EMERGING FROM ADVANCES IN EPIGENETICS. NOVEL MECHANISMS ARE EMERGING BY WHICH CELLS ADAPT TO ENVIRONMENTAL CUES, WHICH INCLUDE CHANGES IN DNA METHYLATION, HISTONE MODIFICATIONS AND REGULATION OF TRANSCRIPTION AND TRANSLATION BY NONCODING RNAS. IN THIS REVIEW WE WILL SUMMARIZE CURRENT EPIGENETIC APPROACHES BEING APPLIED TO PRECLINICAL DRUG DEVELOPMENT ADDRESSING IMPORTANT THERAPEUTIC CHALLENGES IN LUNG DISEASES. THESE CHALLENGES ARE BEING ADDRESSED BY ADVANCES IN LUNG DELIVERY OF OLIGONUCLEOTIDES AND SMALL MOLECULES THAT MODIFY THE HISTONE CODE, DNA METHYLATION PATTERNS AND MIRNA FUNCTION. 2015 13 5575 42 ROLE OF MICRORNAS IN SIGNALING PATHWAYS ASSOCIATED WITH THE PATHOGENESIS OF IDIOPATHIC PULMONARY FIBROSIS: A FOCUS ON EPITHELIAL-MESENCHYMAL TRANSITION. IDIOPATHIC PULMONARY FIBROSIS (IPF) IS A CHRONIC AND PROGRESSIVE DISEASE WITH HIGH MORTALITY AND UNCLEAR ETIOLOGY. PREVIOUS EVIDENCE SUPPORTS THAT THE ORIGIN OF THIS DISEASE IS ASSOCIATED WITH EPIGENETIC ALTERATIONS, AGE, AND ENVIRONMENTAL FACTORS. IPF INITIATES WITH CHRONIC EPITHELIAL LUNG INJURIES, FOLLOWED BY BASAL MEMBRANE DESTRUCTION, WHICH PROMOTES THE ACTIVATION OF MYOFIBROBLASTS AND EXCESSIVE SYNTHESIS OF EXTRACELLULAR MATRIX (ECM) PROTEINS, AS WELL AS EPITHELIAL-MESENCHYMAL TRANSITION (EMT). DUE TO MIRNAS' ROLE AS REGULATORS OF APOPTOSIS, PROLIFERATION, DIFFERENTIATION, AND CELL-CELL INTERACTION PROCESSES, SOME STUDIES HAVE INVOLVED MIRNAS IN THE BIOGENESIS AND PROGRESSION OF IPF. IN THIS CONTEXT, THE ANALYSIS AND DISCUSSION OF THE PROBABLE ASSOCIATION OF MIRNAS WITH THE SIGNALING PATHWAYS INVOLVED IN THE DEVELOPMENT OF IPF WOULD IMPROVE OUR KNOWLEDGE OF THE ASSOCIATED MOLECULAR MECHANISMS, THEREBY FACILITATING ITS EVALUATION AS A THERAPEUTIC TARGET FOR THIS SEVERE LUNG DISEASE. IN THIS WORK, THE MOST RECENT PUBLICATIONS EVALUATING THE ROLE OF MIRNAS AS REGULATORS OR ACTIVATORS OF SIGNAL PATHWAYS ASSOCIATED WITH THE PATHOGENESIS OF IPF WERE ANALYZED. THE SEARCH IN PUBMED WAS MADE USING THE FOLLOWING TERMS: "MIRNAS AND IDIOPATHIC PULMONARY FIBROSIS (IPF)"; "MIRNAS AND IPF AND SIGNALING PATHWAYS (SP)"; AND "MIRNAS AND IPF AND SP AND IPF PATHOGENESIS". ADDITIONALLY, WE FOCUS MAINLY ON THOSE WORKS WHERE THE SIGNALING PATHWAYS INVOLVED WITH EMT, FIBROBLAST DIFFERENTIATION, AND SYNTHESIS OF ECM COMPONENTS WERE ASSESSED. FINALLY, THE IMPORTANCE AND SIGNIFICANCE OF MIRNAS AS POTENTIAL THERAPEUTIC OR DIAGNOSTIC TOOLS FOR THE TREATMENT OF IPF ARE DISCUSSED. 2022 14 4575 35 MYOFIBROBLASTS. PURPOSE OF REVIEW: INTEREST IN THE MYOFIBROBLAST AS A KEY PLAYER IN PROPAGATION OF CHRONIC PROGRESSIVE FIBROSIS CONTINUES TO ELICIT MANY PUBLICATIONS, WITH FOCUS ON ITS CELLULAR ORIGINS AND THE MECHANISMS UNDERPINNING THEIR DIFFERENTIATION AND/OR TRANSITION. THE OBJECTIVE OF THE REVIEW IS TO HIGHLIGHT THIS RECENT PROGRESS. RECENT FINDINGS: THE EPITHELIAL ORIGIN OF THE MYOFIBROBLAST IN FIBROSIS HAS BEEN CHALLENGED BY RECENT STUDIES, WITH THE PERICYTE SUGGESTED AS A POSSIBLE PRECURSOR INSTEAD. ADDITIONAL SIGNALING PATHWAYS, INCLUDING NOTCH, WNT, AND HEDGEHOG, ARE IMPLICATED IN MYOFIBROBLAST DIFFERENTIATION. THE IMPORTANCE OF NADPH OXIDASE 4 WAS HIGHLIGHTED RECENTLY TO SUGGEST A POTENTIAL LINK BETWEEN CELLULAR/OXIDATIVE STRESS AND THE GENESIS OF THE MYOFIBROBLAST. RECENT OBSERVATIONS ON THE IMPORTANCE OF LYSOPHOSPHATIDIC ACID IN FIBROSIS SUGGEST THAT THIS MAY BE DUE, IN PART, TO ITS ABILITY TO REGULATE MYOFIBROBLAST DIFFERENTIATION. FINALLY, THERE IS INCREASING EVIDENCE FOR THE ROLE OF EPIGENETIC MECHANISMS IN REGULATING MYOFIBROBLAST DIFFERENTIATION, INCLUDING DNA METHYLATION AND MIRNA REGULATION OF GENE EXPRESSION. SUMMARY: THESE RECENT DISCOVERIES OPEN UP A WHOLE NEW ARRAY OF POTENTIAL TARGETS FOR NOVEL ANTIFIBROTIC THERAPIES. THIS IS OF SPECIAL IMPORTANCE GIVEN THE CURRENT BLEAK OUTLOOK FOR CHRONIC PROGRESSIVE FIBROTIC DISEASES, SUCH AS SCLERODERMA, DUE TO LACK OF EFFECTIVE THERAPIES. 2013 15 1113 38 COMMON PATHWAYS IN IDIOPATHIC PULMONARY FIBROSIS AND CANCER. IDIOPATHIC PULMONARY FIBROSIS (IPF) IS MARKED BY A VERY DISAPPOINTING SURVIVAL RATE AND STILL REPRESENTS A CLINICAL DILEMMA. ACCORDING TO THE CURRENT PATHOGENIC HYPOTHESIS, CHRONIC DAMAGE OF THE ALVEOLAR EPITHELIUM IS FOLLOWED BY ABNORMAL TISSUE REPAIR AND IMPAIRMENT OF THE ALVEOLAR STRUCTURE. THIS PROCESS IS DRIVEN BY PATHOGENIC EVENTS VERY SIMILAR TO CANCER, INCLUDING EPIGENETIC AND GENETIC CHANGES, ALTERED RESPONSE TO REGULATORY SIGNALS, ABNORMAL EXPRESSION OF MICRORNAS AND ACTIVATION OF SPECIFIC SIGNALLING PATHWAYS. IPF ALSO RESEMBLES CANCER WITH REGARD TO ITS POOR RESPONSE TO MEDICAL TREATMENT AND PROGNOSIS, WHICH IS VERY OFTEN WORSE THAN MANY CANCERS. WE HAVE HYPOTHESISED THAT IPF MIGHT BE ASSIMILATED TO A NEOPROLIFERATIVE DISORDER OF THE LUNG. VIEWING IPF AS A CANCER-LIKE DISEASE MAY SATISFY THE NEED FOR A BETTER UNDERSTANDING OF THE PATHOGENESIS OF IPF BY EXPLOITING THE LARGE AMOUNT OF KNOWLEDGE THAT CANCER BIOLOGY EVOKES. THE RECOGNITION OF COMMON PATHOGENIC PATHWAYS BETWEEN THE TWO DISEASES MAY STIMULATE NEW CLINICAL TRIALS WITH CANCER DRUGS, DIFFERENT DRUG COMBINATIONS AND DIFFERENT LINES OF DRUGS, AS ALREADY EXPERIMENTED IN ONCOLOGY. MOREOVER, THE CONCEPT OF IPF AS A CANCER-LIKE DISORDER MAY IMPROVE THE ATTENTION GIVEN TO THIS DREADFUL DISEASE ON A PUBLIC, POLITICAL AND HEALTHCARE LEVEL. 2013 16 5939 37 TARGETING MECHANOTRANSDUCTION AT THE TRANSCRIPTIONAL LEVEL: YAP AND BRD4 ARE NOVEL THERAPEUTIC TARGETS FOR THE REVERSAL OF LIVER FIBROSIS. LIVER FIBROSIS IS THE RESULT OF A DEREGULATED WOUND HEALING PROCESS CHARACTERIZED BY THE EXCESSIVE DEPOSITION OF EXTRACELLULAR MATRIX. HEPATIC STELLATE CELLS (HSCS), WHICH ARE ACTIVATED IN RESPONSE TO LIVER INJURY, ARE THE MAJOR SOURCE OF EXTRACELLULAR MATRIX AND DRIVE THE WOUND HEALING PROCESS. HOWEVER, CHRONIC LIVER DAMAGE LEADS TO PERPETUAL HSC ACTIVATION, PROGRESSIVE FORMATION OF PATHOLOGICAL SCAR TISSUE AND ULTIMATELY, CIRRHOSIS AND ORGAN FAILURE. HSC ACTIVATION IS TRIGGERED LARGELY IN RESPONSE TO MECHANOSIGNALING FROM THE MICROENVIRONMENT, WHICH INDUCES A PROFIBROTIC NUCLEAR TRANSCRIPTION PROGRAM THAT PROMOTES HSC PROLIFERATION AND EXTRACELLULAR MATRIX SECRETION THEREBY SETTING UP A POSITIVE FEEDBACK LOOP LEADING TO MATRIX STIFFENING AND SELF-SUSTAINED, PATHOLOGICAL, HSC ACTIVATION. DESPITE THE SIGNIFICANT PROGRESS IN OUR UNDERSTANDING OF LIVER FIBROSIS, THE MOLECULAR MECHANISMS THROUGH WHICH THE EXTRACELLULAR MATRIX PROMOTES HSC ACTIVATION ARE NOT WELL UNDERSTOOD AND NO EFFECTIVE THERAPIES HAVE BEEN APPROVED TO DATE THAT CAN TARGET THIS EARLY, REVERSIBLE, STAGE IN LIVER FIBROSIS. SEVERAL NEW LINES OF INVESTIGATION NOW PROVIDE IMPORTANT INSIGHT INTO THIS AREA OF STUDY AND IDENTIFY TWO NUCLEAR TARGETS WHOSE INHIBITION HAS THE POTENTIAL OF REVERSING LIVER FIBROSIS BY INTERFERING WITH HSC ACTIVATION: YES-ASSOCIATED PROTEIN (YAP), A TRANSCRIPTIONAL CO-ACTIVATOR AND EFFECTOR OF THE MECHANOSENSITIVE HIPPO PATHWAY, AND BROMODOMAIN-CONTAINING PROTEIN 4 (BRD4), AN EPIGENETIC REGULATOR OF GENE EXPRESSION. YAP AND BRD4 ACTIVITY IS INDUCED IN RESPONSE TO MECHANICAL STIMULATION OF HSCS AND EACH PROTEIN INDEPENDENTLY CONTROLS WAVES OF EARLY GENE EXPRESSION NECESSARY FOR HSC ACTIVATION. SIGNIFICANTLY, INHIBITION OF EITHER PROTEIN CAN REVERT THE CHRONIC ACTIVATION OF HSCS AND IMPEDE PATHOLOGICAL PROGRESSION OF LIVER FIBROSIS IN CLINICALLY RELEVANT MODEL SYSTEMS. IN THIS REVIEW WE WILL DISCUSS THE ROLES OF THESE NUCLEAR CO-ACTIVATORS IN HSC ACTIVATION, THEIR MECHANISM OF ACTION IN THE FIBROTIC PROCESS IN THE LIVER AND OTHER ORGANS, AND THE POTENTIAL OF TARGETING THEIR ACTIVITY WITH SMALL MOLECULE DRUGS FOR FIBROSIS REVERSAL. 2016 17 5778 29 SPINAL CORD INJURY INDUCED NEUROPATHIC PAIN: MOLECULAR TARGETS AND THERAPEUTIC APPROACHES. NEUROPATHIC PAIN, ESPECIALLY THAT RESULTING FROM SPINAL CORD INJURY, IS A TREMENDOUS CLINICAL CHALLENGE. A MYRIAD OF BIOLOGICAL CHANGES HAVE BEEN IMPLICATED IN PRODUCING THESE PAIN STATES INCLUDING CELLULAR INTERACTIONS, EXTRACELLULAR PROTEINS, ION CHANNEL EXPRESSION, AND EPIGENETIC INFLUENCES. PHYSIOLOGICAL CONSEQUENCES OF THESE CHANGES ARE VARIED AND INCLUDE FUNCTIONAL DEFICITS AND PAIN RESPONSES. DEVELOPING THERAPIES THAT EFFECTIVELY ADDRESS THE CAUSE OF THESE SYMPTOMS REQUIRE A DEEPER KNOWLEDGE OF ALTERATIONS IN THE MOLECULAR PATHWAYS. MATRIX METALLOPROTEINASES AND TISSUE INHIBITORS OF METALLOPROTEINASES ARE TWO PROMISING THERAPEUTIC TARGETS. MATRIX METALLOPROTEINASES INTERACT WITH AND INFLUENCE MANY OF THE STUDIED PAIN PATHWAYS. GENE EXPRESSION OF ION CHANNELS AND INFLAMMATORY MEDIATORS CLEARLY CONTRIBUTES TO NEUROPATHIC PAIN. LOCALIZED AND TIME DEPENDENT TARGETING OF THESE PROTEINS COULD ALLEVIATE AND EVEN PREVENT NEUROPATHIC PAIN FROM DEVELOPING. CURRENT THERAPEUTIC OPTIONS FOR NEUROPATHIC PAIN ARE LIMITED PRIMARILY TO ANALGESICS TARGETING THE OPIOID PATHWAY. THERAPIES DIRECTED AT MOLECULAR TARGETS ARE HIGHLY DESIRABLE AND IN EARLY STAGES OF DEVELOPMENT. THESE INCLUDE TRANSPLANTATION OF EXOGENOUSLY ENGINEERED CELL POPULATIONS AND TARGETED GENE MANIPULATION. THIS REVIEW DESCRIBES SPECIFIC MOLECULAR TARGETS AMENABLE TO THERAPEUTIC INTERVENTION USING CURRENTLY AVAILABLE DELIVERY SYSTEMS. 2015 18 6687 26 VALIDATION OF THE EPIGENETIC READER BROMODOMAIN-CONTAINING PROTEIN 4 (BRD4) AS A THERAPEUTIC TARGET FOR TREATMENT OF AIRWAY REMODELING. STRUCTURAL REMODELING IS CENTRAL TO THE INITIATION AND PROGRESSION OF MANY CHRONIC LUNG DISEASES, REPRESENTING AN IMPORTANT UNMET NEED. WE EXAMINE THE EVIDENCE SUPPORTING BROMODOMAIN-CONTAINING PROTEIN 4 (BRD4) AS A VALIDATED BIOLOGICAL TARGET FOR TREATMENT OF AIRWAY REMODELING. IN EPITHELIAL CELLS AND FIBROBLASTS, BRD4 SERVES AS A SCAFFOLD FOR CHROMATIN REMODELING COMPLEXES IN ACTIVE SUPER-ENHANCERS. IN RESPONSE TO INFLAMMATORY STIMULI, BRD4 IS REPOSITIONED TO INNATE AND MESENCHYMAL GENES ACTIVATING THEIR PRODUCTION. PROOF-OF-CONCEPT STUDIES SHOW PROMISING BENEFIT OF SELECTIVE BRD4 INHIBITORS IN DISRUPTING EPITHELIAL MESENCHYMAL TRANSITION AND MYOFIBROBLAST TRANSITION IN DIVERSE MODELS OF LUNG INJURY. RECENT IDENTIFICATION OF BIOMARKERS OF BRD4 PROVIDES A BASIS FOR FURTHER DRUG DEVELOPMENT FOR APPLICATION IN VIRAL-INDUCED AIRWAY INFLAMMATION, COPD AND INTERSTITIAL LUNG DISEASES. 2020 19 2817 26 FIBROSIS IN THE LIVER: ACUTE PROTECTION AND CHRONIC DISEASE. THE UNDERSTANDING OF THE CELLULAR AND MOLECULAR MECHANISMS OF THE FIBROTIC WOUND-HEALING RESPONSE OF THE LIVER HAS MADE DRAMATIC PROGRESS IN THE PAST 20 YEARS. HEPATIC STELLATE CELLS (HSCS), WHICH AFTER LIVER INJURY PROLIFERATE AND TRANSDIFFERENTIATE TO MYOFIBROBLASTS, HAVE EMERGED AS THE PRIMARY SOURCE OF THE FIBROTIC RESPONSE, EVEN THOUGH OTHER FIBROGENIC CELLS MAY ALSO CONTRIBUTE TO THE PRODUCTION OF EXTRACELLULAR MATRIX (ECM). ADVANCES IN THE UNDERSTANDING OF HSC REGULATION INCLUDE APOPTOTIC SIGNALING, ANGIOGENIC SIGNALING, AND RESPONSES TO OXIDATIVE STRESS. THE ECM HAS EMERGED NOT ONLY AS A STRUCTURAL SCAFFOLD, BUT ALSO AS A DYNAMIC AND INTERACTIVE MATRIX REGULATING STELLATE CELL ACTIVATION. ADDITIONALLY, THE INNATE IMMUNE SYSTEM AND IMMUNE SIGNALING, AS WELL AS A BROADENING UNDERSTANDING OF THE TRANSCRIPTIONAL REGULATION INCLUDING MICRORNAS AND EPIGENETIC EVENTS OFFER POTENTIAL THERAPEUTIC TARGETS. UNRAVELING GENETIC DETERMINANTS RELATED TO MECHANISMS OF HEPATIC FIBROGENESIS PROMISE INDIVIDUALIZED THERAPY OR PREVENTION. HEPATIC FIBROSIS AND CIRRHOSIS HAVE EMERGED AS TREATABLE AND POTENTIALLY REVERSIBLE CONSEQUENCE OF CHRONIC LIVER DISEASE. 2010 20 1255 34 CURRENT STATUS OF NOVEL ANTIFIBROTIC THERAPIES IN PATIENTS WITH CHRONIC LIVER DISEASE. FIBROSIS ACCUMULATION IS A DYNAMIC PROCESS RESULTING FROM A WOUND-HEALING RESPONSE TO ACUTE OR CHRONIC LIVER INJURY OF ALL CAUSES. THE CASCADE STARTS WITH HEPATOCYTE NECROSIS AND APOPTOSIS, WHICH INSTIGATE INFLAMMATORY SIGNALING BY CHEMOKINES AND CYTOKINES, RECRUITMENT OF IMMUNE CELL POPULATIONS, AND ACTIVATION OF FIBROGENIC CELLS, CULMINATING IN THE DEPOSITION OF EXTRACELLULAR MATRIX. THESE KEY ELEMENTS, ALONG WITH PATHWAYS OF TRANSCRIPTIONAL AND EPIGENETIC REGULATION, REPRESENT FERTILE THERAPEUTIC TARGETS. NEW THERAPIES INCLUDE DRUGS SPECIFICALLY DESIGNED AS ANTIFIBROTICS, AS WELL AS DRUGS ALREADY AVAILABLE WITH WELL-ESTABLISHED SAFETY PROFILES, WHOSE MECHANISM OF ACTION MAY ALSO BE ANTIFIBROTIC. AT THE SAME TIME, THE DEVELOPMENT OF NONINVASIVE FIBROGENIC MARKERS, AND TECHNIQUES (E.G. FIBROSCAN), AS WELL AS COMBINED SCORING SYSTEMS INCORPORATING SERUM AND CLINICAL FEATURES WILL ALLOW IMPROVED ASSESSMENT OF THERAPY RESPONSE. IN AGGREGATE, THE ADVANCES IN THE ELUCIDATION OF THE BIOLOGY OF FIBROSIS, COMBINED WITH IMPROVED TECHNOLOGIES FOR ASSESSMENT WILL PROVIDE A COMPREHENSIVE FRAMEWORK FOR DESIGN OF ANTIFIBROTICS AND THEIR ANALYSIS IN WELL-DESIGNED CLINICAL TRIALS. THESE EFFORTS MAY ULTIMATELY YIELD SUCCESS IN HALTING THE PROGRESSION OF, OR REVERSING, LIVER FIBROSIS. 2011