1 5632 128 SENESCENT CELLS: SASPECTED DRIVERS OF AGE-RELATED PATHOLOGIES. THE PROGRESSION OF PHYSIOLOGICAL AGEING IS DRIVEN BY INTRACELLULAR ABERRATIONS INCLUDING TELOMERE ATTRITION, GENOMIC INSTABILITY, EPIGENETIC ALTERATIONS AND LOSS OF PROTEOSTASIS. THESE IN TURN DAMAGE CELLS AND COMPROMISE THEIR FUNCTIONALITY. CELLULAR SENESCENCE, A STABLE IRREVERSIBLE CELL-CYCLE ARREST, IS ELICITED IN DAMAGED CELLS AND PREVENTS THEIR PROPAGATION IN THE ORGANISM. UNDER NORMAL CONDITIONS, SENESCENT CELLS RECRUIT THE IMMUNE SYSTEM WHICH FACILITATES THEIR REMOVAL FROM TISSUES. NEVERTHELESS, DURING AGEING, TISSUE-RESIDING SENESCENT CELLS TEND TO ACCUMULATE, AND MIGHT NEGATIVELY IMPACT THEIR MICROENVIRONMENT VIA PROFOUND SECRETORY PHENOTYPE WITH PRO-INFLAMMATORY CHARACTERISTICS, TERMED SENESCENCE-ASSOCIATED SECRETORY PHENOTYPE (SASP). INDEED, SENESCENT CELLS ARE MOSTLY ABUNDANT AT SITES OF AGE-RELATED PATHOLOGIES, INCLUDING DEGENERATIVE DISORDERS AND MALIGNANCIES. INTERESTINGLY, STUDIES ON PROGEROID MICE INDICATE THAT SELECTIVE ELIMINATION OF SENESCENT CELLS CAN DELAY AGE-RELATED DETERIORATION. THIS SUGGESTS THAT CHRONIC INFLAMMATION INDUCED BY SENESCENT CELLS MIGHT BE A MAIN DRIVER OF THESE PATHOLOGIES. IMPORTANTLY, SENESCENT CELLS ACCUMULATE AS A RESULT OF DEFICIENT IMMUNE SURVEILLANCE, AND THEIR REMOVAL IS INCREASED UPON THE USE OF IMMUNE STIMULATORY AGENTS. INSIGHTS INTO MECHANISMS OF SENESCENCE SURVEILLANCE COULD BE COMBINED WITH CURRENT APPROACHES FOR CANCER IMMUNOTHERAPY TO PROPOSE NEW PREVENTIVE AND THERAPEUTIC STRATEGIES FOR AGE-RELATED DISEASES. 2014 2 4974 33 PATHOPHYSIOLOGICAL MECHANISMS LEADING TO MUSCLE LOSS IN CHRONIC KIDNEY DISEASE. LOSS OF MUSCLE PROTEINS IS A DELETERIOUS CONSEQUENCE OF CHRONIC KIDNEY DISEASE (CKD) THAT CAUSES A DECREASE IN MUSCLE STRENGTH AND FUNCTION, AND CAN LEAD TO A REDUCTION IN QUALITY OF LIFE AND INCREASED RISK OF MORBIDITY AND MORTALITY. THE EFFECTIVENESS OF CURRENT TREATMENT STRATEGIES IN PREVENTING OR REVERSING MUSCLE PROTEIN LOSSES IS LIMITED. THE LIMITATIONS LARGELY STEM FROM THE SYSTEMIC NATURE OF DISEASES SUCH AS CKD, WHICH STIMULATE SKELETAL MUSCLE PROTEIN DEGRADATION PATHWAYS WHILE SIMULTANEOUSLY ACTIVATING MECHANISMS THAT IMPAIR MUSCLE PROTEIN SYNTHESIS AND REPAIR. STIMULI THAT INITIATE MUSCLE PROTEIN LOSS INCLUDE METABOLIC ACIDOSIS, INSULIN AND IGF1 RESISTANCE, CHANGES IN HORMONES, CYTOKINES, INFLAMMATORY PROCESSES AND DECREASED APPETITE. A GROWING BODY OF EVIDENCE SUGGESTS THAT SIGNALLING MOLECULES SECRETED FROM MUSCLE CAN ENTER THE CIRCULATION AND SUBSEQUENTLY INTERACT WITH RECIPIENT ORGANS, INCLUDING THE KIDNEYS, WHILE CONVERSELY, PATHOLOGICAL EVENTS IN THE KIDNEY CAN ADVERSELY INFLUENCE PROTEIN METABOLISM IN SKELETAL MUSCLE, DEMONSTRATING THE EXISTENCE OF CROSSTALK BETWEEN KIDNEY AND MUSCLE. TOGETHER, THESE SIGNALS, WHETHER DIRECT OR INDIRECT, INDUCE CHANGES IN THE LEVELS OF REGULATORY AND EFFECTOR PROTEINS VIA ALTERATIONS IN MRNAS, MICRORNAS AND CHROMATIN EPIGENETIC RESPONSES. ADVANCES IN OUR UNDERSTANDING OF THE SIGNALS AND PROCESSES THAT MEDIATE MUSCLE LOSS IN CKD AND OTHER MUSCLE WASTING CONDITIONS WILL SUPPORT THE FUTURE DEVELOPMENT OF THERAPEUTIC STRATEGIES TO REDUCE MUSCLE LOSS. 2022 3 6151 27 THE FIRE WITHIN: CELL-AUTONOMOUS MECHANISMS IN INFLAMMATION-DRIVEN CANCER. INFLAMMATORY CELLS ARE IMPORTANT FOR TUMOR INITIATION AND PROMOTION, PROVIDING CANCER CELLS WITH CYTOKINES THAT ENHANCE CELL PROLIFERATION AND SURVIVAL. ALTHOUGH MALIGNANT EPITHELIAL CELLS WERE TRADITIONALLY CONSIDERED TO BE ON THE RECEIVING END OF THESE MICROENVIRONMENTAL INTERACTIONS, RECENT STUDIES SHOW THAT EPITHELIAL CELLS CAN UNDERGO INFLAMMATORY REPROGRAMMING ON THEIR OWN. SUCH EPIGENETIC SWITCHES ARE OFTEN TRIGGERED BY CHRONIC TISSUE INJURY AND PLAY IMPORTANT ROLES IN TISSUE REPAIR. BY CONVERTING TERMINALLY DIFFERENTIATED CELLS THAT HARBOR EVEN A SINGLE ONCOGENIC MUTATION TO A LESS DIFFERENTIATED STATE WITH A HIGHER PROLIFERATIVE POTENTIAL, CELL-AUTONOMOUS INFLAMMATION IS AN IMPORTANT CONTRIBUTOR TO TUMOR INITIATION. 2019 4 5140 29 POTENTIAL REGULATORS OF THE SENESCENCE-ASSOCIATED SECRETORY PHENOTYPE DURING SENESCENCE AND AGING. SENESCENT CELLS EXPRESS AND SECRETE A VARIETY OF EXTRACELLULAR MODULATORS THAT INCLUDE CYTOKINES, CHEMOKINES, PROTEASES, GROWTH FACTORS, AND SOME ENZYMES ASSOCIATED WITH EXTRACELLULAR MATRIX REMODELING, DEFINED AS THE SENESCENCE-ASSOCIATED SECRETORY PHENOTYPE (SASP). SASP REINFORCES SENESCENT CELL CYCLE ARREST, STIMULATES AND RECRUITS IMMUNE CELLS FOR IMMUNE-MEDIATED CLEARANCE OF POTENTIALLY TUMORIGENIC CELLS, LIMITS OR INDUCES FIBROSIS, AND PROMOTES WOUND HEALING AND TISSUE REGENERATION. ON THE OTHER HAND, SASP MEDIATES CHRONIC INFLAMMATION LEADING TO THE DESTRUCTION OF TISSUE STRUCTURE AND FUNCTION AND STIMULATING THE GROWTH AND SURVIVAL OF TUMOR CELLS. SASP IS HIGHLY HETEROGENEOUS AND THE ROLE OF SASP DEPENDS ON THE CONTEXT. THE REGULATION OF SASP OCCURS AT MULTIPLE LEVELS INCLUDING CHROMATIN REMODELING, TRANSCRIPTION, MRNA TRANSLATION, INTRACELLULAR TRAFFICKING, AND SECRETION. SEVERAL SASP MODULATORS HAVE ALREADY BEEN IDENTIFIED SETTING THE STAGE FOR FUTURE RESEARCH ON THEIR CLINICAL APPLICATIONS. IN THIS REVIEW, WE SUMMARIZE IN DETAIL THE POTENTIAL SIGNALING PATHWAYS THAT TRIGGER AND REGULATE SASP PRODUCTION DURING AGING AND SENESCENCE. 2022 5 6590 34 TUMOR SUPPRESSOR INACTIVATION IN THE PATHOGENESIS OF ADULT T-CELL LEUKEMIA. TUMOR SUPPRESSOR FUNCTIONS ARE ESSENTIAL TO CONTROL CELLULAR PROLIFERATION, TO ACTIVATE THE APOPTOSIS OR SENESCENCE PATHWAY TO ELIMINATE UNWANTED CELLS, TO LINK DNA DAMAGE SIGNALS TO CELL CYCLE ARREST CHECKPOINTS, TO ACTIVATE APPROPRIATE DNA REPAIR PATHWAYS, AND TO PREVENT THE LOSS OF ADHESION TO INHIBIT INITIATION OF METASTASES. THEREFORE, TUMOR SUPPRESSOR GENES ARE INDISPENSABLE TO MAINTAINING GENETIC AND GENOMIC INTEGRITY. CONSEQUENTLY, INACTIVATION OF TUMOR SUPPRESSORS BY SOMATIC MUTATIONS OR EPIGENETIC MECHANISMS IS FREQUENTLY ASSOCIATED WITH TUMOR INITIATION AND DEVELOPMENT. IN CONTRAST, REACTIVATION OF TUMOR SUPPRESSOR FUNCTIONS CAN EFFECTIVELY REVERSE THE TRANSFORMED PHENOTYPE AND LEAD TO CELL CYCLE ARREST OR DEATH OF CANCEROUS CELLS AND BE USED AS A THERAPEUTIC STRATEGY. ADULT T-CELL LEUKEMIA/LYMPHOMA (ATLL) IS AN AGGRESSIVE LYMPHOPROLIFERATIVE DISEASE ASSOCIATED WITH INFECTION OF CD4 T CELLS BY THE HUMAN T-CELL LEUKEMIA VIRUS TYPE 1 (HTLV-I). HTLV-I-ASSOCIATED T-CELL TRANSFORMATION IS THE RESULT OF A MULTISTEP ONCOGENIC PROCESS IN WHICH THE VIRUS INITIALLY INDUCES CHRONIC T-CELL PROLIFERATION AND ALTERS CELLULAR PATHWAYS RESULTING IN THE ACCUMULATION OF GENETIC DEFECTS AND THE DEREGULATED GROWTH OF VIRALLY INFECTED CELLS. THIS REVIEW WILL FOCUS ON THE CURRENT KNOWLEDGE OF THE GENETIC AND EPIGENETIC MECHANISMS REGULATING THE INACTIVATION OF TUMOR SUPPRESSORS IN THE PATHOGENESIS OF HTLV-I. 2015 6 1300 31 DEDIFFERENTIATION AND IN VIVO REPROGRAMMING OF COMMITTED CELLS IN WOUND REPAIR (REVIEW). ACCUMULATING EVIDENCE HAS SHOWN THAT CELL DEDIFFERENTIATION OR REPROGRAMMING IS A PIVOTAL PROCEDURE FOR ANIMALS TO DEAL WITH INJURY AND PROMOTE ENDOGENOUS TISSUE REPAIR. TISSUE DAMAGE IS A CRITICAL FACTOR THAT TRIGGERS CELL DEDIFFERENTIATION OR REPROGRAMMING IN VIVO. BY CONTRAST, MICROENVIRONMENTAL CHANGES, INCLUDING THE LOSS OF STEM CELLS, HYPOXIA, CELL SENESCENCE, INFLAMMATION AND IMMUNITY, CAUSED BY TISSUE DAMAGE CAN RETURN CELLS TO AN UNSTABLE STATE. IF THE WOUND PERSISTS IN THE LONG?TERM DUE TO CHRONIC DAMAGE, THEN DEDIFFERENTIATION OR REPROGRAMMING OF THE SURROUNDING CELLS MAY LEAD TO CARCINOGENESIS. IN RECENT YEARS, EXTENSIVE RESEARCH HAS BEEN PERFORMED INVESTIGATING CELL DEDIFFERENTIATION OR REPROGRAMMING IN VIVO, WHICH CAN HAVE SIGNIFICANT IMPLICATIONS FOR WOUND REPAIR, TREATMENT AND PREVENTION OF CANCER IN THE FUTURE. THE CURRENT REVIEW SUMMARIZES THE MOLECULAR EVENTS THAT ARE KNOWN TO DRIVE CELL DEDIFFERENTIATION DIRECTLY FOLLOWING TISSUE INJURY AND THE EFFECTS OF EPIGENETIC MODIFICATION ON DEDIFFERENTIATION OR REPROGRAMMING IN VIVO. IN ADDITION, THE PRESENT REVIEW EXPLORES THE INTRACELLULAR MECHANISM OF ENDOGENOUS TISSUE REPAIR AND ITS RELATIONSHIP WITH CANCER, WHICH IS ESSENTIAL FOR BALANCING THE RISK BETWEEN TISSUE REPAIR AND MALIGNANT TRANSFORMATION AFTER INJURY. 2022 7 6154 37 THE GENE EXPRESSION PROGRAM OF PROSTATE FIBROBLAST SENESCENCE MODULATES NEOPLASTIC EPITHELIAL CELL PROLIFERATION THROUGH PARACRINE MECHANISMS. THE GREATEST RISK FACTOR FOR DEVELOPING CARCINOMA OF THE PROSTATE IS ADVANCED AGE. POTENTIAL MOLECULAR AND PHYSIOLOGIC CONTRIBUTORS TO THE FREQUENCY OF CANCER OCCURRENCE IN OLDER INDIVIDUALS INCLUDE THE ACCUMULATION OF SOMATIC MUTATIONS THROUGH DEFECTS IN GENOME MAINTENANCE, EPIGENETIC GENE SILENCING, OXIDATIVE STRESS, LOSS OF IMMUNE SURVEILLANCE, TELOMERE DYSFUNCTION, CHRONIC INFLAMMATION, AND ALTERATIONS IN TISSUE MICROENVIRONMENT. IN THIS CONTEXT, THE PROCESS OF PROSTATE CARCINOGENESIS CAN BE INFLUENCED THROUGH INTERACTIONS BETWEEN INTRINSIC CELLULAR ALTERATIONS AND THE EXTRINSIC MICROENVIRONMENT AND MACROENVIRONMENT, BOTH OF WHICH CHANGE SUBSTANTIALLY AS A CONSEQUENCE OF AGING. IN THIS STUDY, WE SOUGHT TO CHARACTERIZE THE MOLECULAR ALTERATIONS THAT OCCUR DURING THE PROCESS OF PROSTATE FIBROBLAST SENESCENCE TO IDENTIFY FACTORS IN THE AGED TISSUE MICROENVIRONMENT CAPABLE OF PROMOTING THE PROLIFERATION AND POTENTIALLY THE NEOPLASTIC PROGRESSION OF PROSTATE EPITHELIUM. WE EVALUATED THREE MECHANISMS LEADING TO CELL SENESCENCE: OXIDATIVE STRESS, DNA DAMAGE, AND REPLICATIVE EXHAUSTION. WE IDENTIFIED A CONSISTENT PROGRAM OF GENE EXPRESSION THAT INCLUDES A SUBSET OF PARACRINE FACTORS CAPABLE OF INFLUENCING ADJACENT PROSTATE EPITHELIAL GROWTH. BOTH DIRECT COCULTURE AND CONDITIONED MEDIUM FROM SENESCENT PROSTATE FIBROBLASTS STIMULATED EPITHELIAL CELL PROLIFERATION, 3-FOLD AND 2-FOLD, RESPECTIVELY. THE PARACRINE-ACTING PROTEINS FIBROBLAST GROWTH FACTOR 7, HEPATOCYTE GROWTH FACTOR, AND AMPHIREGULIN (AREG) WERE ELEVATED IN THE EXTRACELLULAR ENVIRONMENT OF SENESCENT PROSTATE FIBROBLASTS. EXOGENOUS AREG ALONE STIMULATED PROSTATE EPITHELIAL CELL GROWTH, AND NEUTRALIZING ANTIBODIES AND SMALL INTERFERING RNA TARGETING AREG ATTENUATED, BUT DID NOT COMPLETELY ABROGATE THE GROWTH-PROMOTING EFFECTS OF SENESCENT FIBROBLAST CONDITIONED MEDIUM. THESE RESULTS SUPPORT THE CONCEPT THAT AGING-RELATED CHANGES IN THE PROSTATE MICROENVIRONMENT MAY CONTRIBUTE TO THE PROGRESSION OF PROSTATE NEOPLASIA. 2006 8 4882 32 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 9 1150 39 CONNECTION BETWEEN INFLAMMATION AND CARCINOGENESIS IN GASTROINTESTINAL TRACT: FOCUS ON TGF-BETA SIGNALING. INFLAMMATION IS A PRIMARY DEFENSE PROCESS AGAINST VARIOUS EXTRACELLULAR STIMULI, SUCH AS VIRUSES, PATHOGENS, FOODS, AND ENVIRONMENTAL POLLUTANTS. WHEN CELLS RESPOND TO STIMULI FOR SHORT PERIODS OF TIME, IT RESULTS IN ACUTE OR PHYSIOLOGICAL INFLAMMATION. HOWEVER, IF THE STIMULATION IS SUSTAINED FOR LONGER TIME OR A PATHOLOGICAL STATE OCCURS, IT IS KNOWN AS CHRONIC OR PATHOLOGICAL INFLAMMATION. SEVERAL STUDIES HAVE SHOWN THAT TUMORIGENESIS IN THE GASTROINTESTINAL (GI) TRACT IS CLOSELY ASSOCIATED WITH CHRONIC INFLAMMATION, FOR WHICH ABNORMAL CELLULAR ALTERATIONS THAT ACCOMPANY CHRONIC INFLAMMATION SUCH AS OXIDATIVE STRESSES, GENE MUTATIONS, EPIGENETIC CHANGES, AND INFLAMMATORY CYTOKINES, ARE SHARED WITH CARCINOGENIC PROCESSES, WHICH FORMS A CRITICAL CROSS-LINK BETWEEN CHRONIC INFLAMMATION AND CARCINOGENESIS. TRANSFORMING GROWTH FACTOR (TGF)-BETA IS A MULTI-POTENT CYTOKINE THAT PLAYS AN IMPORTANT ROLE IN REGULATION OF CELL GROWTH, APOPTOSIS AND DIFFERENTIATION. MOST IMPORTANTLY, TGF-BETA IS A STRONG ANTI-INFLAMMATORY CYTOKINE THAT REGULATES THE DEVELOPMENT OF EFFECTOR CELLS. TGF-BETA HAS A SUPPRESSIVE EFFECT ON CARCINOGENESIS UNDER NORMAL CONDITIONS BY INHIBITING ABNORMAL CELL GROWTH, BUT ON THE OTHER HAND, MANY GI CANCERS ORIGINATE FROM UNCONTROLLED CELL GROWTH AND DIFFERENTIATION BY GENETIC LOSS OF TGF-BETA SIGNALING MOLECULES OR PERTURBATION OF TGF-BETA ADAPTORS. ONCE A TUMOR HAS DEVELOPED, TGF-BETA EXERTS A PROMOTING EFFECT ON THE TUMOR ITSELF AND STROMAL CELLS TO ENHANCE CELL GROWTH, ALTER THE RESPONSIVENESS OF TUMOR CELLS TO STIMULATE INVASION AND METASTASIS, AND INHIBITED IMMUNE SURVEILLANCE. THEREFORE, NOVEL DEVELOPMENT OF THERAPEUTIC AGENTS TO INHIBIT TGF-BETA-INDUCED PROGRESSION OF TUMOR AND TO RETAIN ITS GROWTH INHIBITORY ACTIVITIES, IN ADDITION TO ANTI-INFLAMMATORY ACTIONS, COULD BE USEFUL IN ONCOLOGY. IN THIS REVIEW, WE DISCUSS THE ROLE OF TGF-BETA IN INFLAMMATION AND CARCINOGENESIS OF THE GI TRACT RELATED TO ABNORMAL TGF-BETA SIGNALING. 2010 10 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 11 4386 28 MITOCHONDRIAL STRESS INDUCED BY CONTINUOUS STIMULATION UNDER HYPOXIA RAPIDLY DRIVES T CELL EXHAUSTION. CANCER AND CHRONIC INFECTIONS INDUCE T CELL EXHAUSTION, A HYPOFUNCTIONAL FATE CARRYING DISTINCT EPIGENETIC, TRANSCRIPTOMIC AND METABOLIC CHARACTERISTICS. HOWEVER, DRIVERS OF EXHAUSTION REMAIN POORLY UNDERSTOOD. AS INTRATUMORAL EXHAUSTED T CELLS EXPERIENCE SEVERE HYPOXIA, WE HYPOTHESIZED THAT METABOLIC STRESS ALTERS THEIR RESPONSES TO OTHER SIGNALS, SPECIFICALLY, PERSISTENT ANTIGENIC STIMULATION. IN VITRO, ALTHOUGH CD8(+) T CELLS EXPERIENCING CONTINUOUS STIMULATION OR HYPOXIA ALONE DIFFERENTIATED INTO FUNCTIONAL EFFECTORS, THE COMBINATION RAPIDLY DROVE T CELL DYSFUNCTION CONSISTENT WITH EXHAUSTION. CONTINUOUS STIMULATION PROMOTED BLIMP-1-MEDIATED REPRESSION OF PGC-1ALPHA-DEPENDENT MITOCHONDRIAL REPROGRAMMING, RENDERING CELLS POORLY RESPONSIVE TO HYPOXIA. LOSS OF MITOCHONDRIAL FUNCTION GENERATED INTOLERABLE LEVELS OF REACTIVE OXYGEN SPECIES (ROS), SUFFICIENT TO PROMOTE EXHAUSTED-LIKE STATES, IN PART THROUGH PHOSPHATASE INHIBITION AND THE CONSEQUENT ACTIVITY OF NUCLEAR FACTOR OF ACTIVATED T CELLS. REDUCING T CELL-INTRINSIC ROS AND LOWERING TUMOR HYPOXIA LIMITED T CELL EXHAUSTION, SYNERGIZING WITH IMMUNOTHERAPY. THUS, IMMUNOLOGIC AND METABOLIC SIGNALING ARE INTRINSICALLY LINKED: THROUGH MITIGATION OF METABOLIC STRESS, T CELL DIFFERENTIATION CAN BE ALTERED TO PROMOTE MORE FUNCTIONAL CELLULAR FATES. 2021 12 2065 26 EPIGENETIC CONTROL OF INTESTINAL BARRIER FUNCTION AND INFLAMMATION IN ZEBRAFISH. THE INTESTINAL EPITHELIUM FORMS A BARRIER PROTECTING THE ORGANISM FROM MICROBES AND OTHER PROINFLAMMATORY STIMULI. THE INTEGRITY OF THIS BARRIER AND THE PROPER RESPONSE TO INFECTION REQUIRES PRECISE REGULATION OF POWERFUL IMMUNE HOMING SIGNALS SUCH AS TUMOR NECROSIS FACTOR (TNF). DYSREGULATION OF TNF LEADS TO INFLAMMATORY BOWEL DISEASES (IBD), BUT THE MECHANISM CONTROLLING THE EXPRESSION OF THIS POTENT CYTOKINE AND THE EVENTS THAT TRIGGER THE ONSET OF CHRONIC INFLAMMATION ARE UNKNOWN. HERE, WE SHOW THAT LOSS OF FUNCTION OF THE EPIGENETIC REGULATOR UBIQUITIN-LIKE PROTEIN CONTAINING PHD AND RING FINGER DOMAINS 1 (UHRF1) IN ZEBRAFISH LEADS TO A REDUCTION IN TNFA PROMOTER METHYLATION AND THE INDUCTION OF TNFA EXPRESSION IN INTESTINAL EPITHELIAL CELLS (IECS). THE INCREASE IN IEC TNFA LEVELS IS MICROBE-DEPENDENT AND RESULTS IN IEC SHEDDING AND APOPTOSIS, IMMUNE CELL RECRUITMENT, AND BARRIER DYSFUNCTION, CONSISTENT WITH CHRONIC INFLAMMATION. IMPORTANTLY, TNFA KNOCKDOWN IN UHRF1 MUTANTS RESTORES IEC MORPHOLOGY, REDUCES CELL SHEDDING, AND IMPROVES BARRIER FUNCTION. WE PROPOSE THAT LOSS OF EPIGENETIC REPRESSION AND TNF INDUCTION IN THE INTESTINAL EPITHELIUM CAN LEAD TO IBD ONSET. 2015 13 737 34 CANCER STEM CELLS. THERE IS AN INCREASING EVIDENCE SUPPORTING THE CANCER STEM CELL HYPOTHESIS. NORMAL STEM CELLS IN THE ADULT ORGANISM ARE RESPONSIBLE FOR TISSUE RENEWAL AND REPAIR OF AGED OR DAMAGED TISSUE. A SUBSTANTIAL CHARACTERISTIC OF STEM CELLS IS THEIR ABILITY FOR SELF-RENEWAL WITHOUT LOSS OF PROLIFERATION CAPACITY WITH EACH CELL DIVISION. THE STEM CELLS ARE IMMORTAL, AND RATHER RESISTANT TO ACTION OF DRUGS. THEY ARE ABLE TO DIFFERENTIATE AND FORM SPECIFIC TYPES OF TISSUE DUE TO THE INFLUENCE OF MICROENVIRONMENTAL AND SOME OTHER FACTORS. STEM CELLS DIVIDE ASYMMETRICALLY PRODUCING TWO DAUGHTER CELLS -- ONE IS A NEW STEM CELL AND THE SECOND IS PROGENITOR CELL, WHICH HAS THE ABILITY FOR DIFFERENTIATION AND PROLIFERATION, BUT NOT THE CAPABILITY FOR SELF-RENEWAL. CANCER STEM CELLS ARE IN MANY ASPECTS SIMILAR TO THE STEM CELLS. IT HAS BEEN PROVEN THAT TUMOR CELLS ARE HETEROGENEOUS COMPRISING RARE TUMOR INITIATING CELLS AND ABUNDANT NON-TUMOR INITIATING CELLS. TUMOR INITIATING CELLS -- CANCER STEM CELLS HAVE THE ABILITY OF SELF-RENEWAL AND PROLIFERATION, ARE RESISTANT TO DRUGS, AND EXPRESS TYPICAL MARKERS OF STEM CELLS. IT IS NOT CLEAR WHETHER CANCER STEM CELLS ORIGINATE FROM NORMAL STEM CELLS IN CONSEQUENCE OF GENETIC AND EPIGENETIC CHANGES AND/OR BY REDIFFERENTIATION FROM SOMATIC TUMOR CELLS TO THE STEM-LIKE CELLS. PROBABLY BOTH MECHANISMS ARE INVOLVED IN THE ORIGIN OF CANCER STEM CELLS. DYSREGULATION OF STEM CELL SELF-RENEWAL IS A LIKELY REQUIREMENT FOR THE DEVELOPMENT OF CANCER. ISOLATION AND IDENTIFICATION OF CANCER STEM CELLS IN HUMAN TUMORS AND IN TUMOR CELL LINES HAS BEEN SUCCESSFUL. TO DATE, THE EXISTENCE OF CANCER STEM CELLS HAS BEEN PROVEN IN ACUTE AND CHRONIC MYELOID LEUKEMIA, IN BREAST CANCER, IN BRAIN TUMORS, IN LUNG CANCER AND GASTROINTESTINAL TUMORS. CANCER STEM CELL MODEL IS ALSO CONSISTENT WITH SOME CLINICAL OBSERVATIONS. ALTHOUGH STANDARD CHEMOTHERAPY KILLS MOST CELLS IN A TUMOR, CANCER STEM CELLS REMAIN VIABLE. DESPITE THE SMALL NUMBER OF SUCH CELLS, THEY MIGHT BE THE CAUSE OF TUMOR RECURRENCE, SOMETIMES MANY YEARS AFTER THE "SUCCESSFUL" TREATMENT OF PRIMARY TUMOR. GROWTH OF METASTASES IN DISTINCT AREAS OF BODY AND THEIR CELLULAR HETEROGENEITY MIGHT BE CONSEQUENCE OF CANCER STEM CELL DIFFERENTIATION AND/OR DEDIFFERENTIATION AND ASYMMETRIC DIVISION OF CANCER STEM CELLS. FURTHER CHARACTERIZATION OF CANCER STEM CELLS IS NEEDED IN ORDER TO FIND WAYS TO DESTROY THEM, WHICH MIGHT CONTRIBUTE SIGNIFICANTLY TO THE THERAPEUTIC MANAGEMENT OF MALIGNANT TUMORS. 2005 14 5816 29 STRESS AND STEM CELLS. THE UNIQUE PROPERTIES AND FUNCTIONS OF STEM CELLS MAKE THEM PARTICULARLY SUSCEPTIBLE TO STRESSES AND ALSO LEAD TO THEIR REGULATION BY STRESS. STEM CELL DIVISION MUST RESPOND TO THE DEMAND TO REPLENISH CELLS DURING NORMAL TISSUE TURNOVER AS WELL AS IN RESPONSE TO DAMAGE. OXIDATIVE STRESS, MECHANICAL STRESS, GROWTH FACTORS, AND CYTOKINES SIGNAL STEM CELL DIVISION AND DIFFERENTIATION. MANY OF THE CONSERVED PATHWAYS REGULATING STEM CELL SELF-RENEWAL AND DIFFERENTIATION ARE ALSO STRESS-RESPONSE PATHWAYS. THE LONG LIFE SPAN AND DIVISION POTENTIAL OF STEM CELLS CREATE A PROPENSITY FOR TRANSFORMATION (CANCER) AND SPECIFIC STRESS RESPONSES SUCH AS APOPTOSIS AND SENESCENCE ACT AS ANTITUMOR MECHANISMS. QUIESCENCE REGULATED BY CDK INHIBITORS AND A HYPOXIC NICHE REGULATED BY FOXO TRANSCRIPTION FACTOR FUNCTION TO REDUCE STRESS FOR SEVERAL TYPES OF STEM CELLS TO FACILITATE LONG-TERM MAINTENANCE. AGING IS A PARTICULARLY RELEVANT STRESS FOR STEM CELLS, BECAUSE REPEATED DEMANDS ON STEM CELL FUNCTION OVER THE LIFE SPAN CAN HAVE CUMULATIVE CELL-AUTONOMOUS EFFECTS INCLUDING EPIGENETIC DYSREGULATION, MUTATIONS, AND TELOMERE EROSION. IN ADDITION, AGING OF THE ORGANISM IMPAIRS FUNCTION OF THE STEM CELL NICHE AND SYSTEMIC SIGNALS, INCLUDING CHRONIC INFLAMMATION AND OXIDATIVE STRESS. 2012 15 1894 36 ENDOTHELIAL CELL SENESCENCE AND INFLAMMAGING: MICRORNAS AS BIOMARKERS AND INNOVATIVE THERAPEUTIC TOOLS. AGING IS ACCOMPANIED BY A PROGRESSIVE DECLINE OF ENDOTHELIAL FUNCTION AND A PROGRESSIVE DRIFT TOWARD A SYSTEMIC PRO-INFLAMMATORY STATUS THAT HAS BEEN DESIGNATED "INFLAMMAGING". BOTH PHENOMENA ARE ACCELERATED AND EXACERBATED IN PATIENTS WITH THE MOST COMMON AGE-RELATED DISEASES (ARDS), INCLUDING CANCER. THE FINDING THAT CHRONIC CELL STRESS ACTIVATES A PRO-INFLAMMATORY PROGRAM LEADING TO ACQUISITION OF THE SENESCENCE-ASSOCIATED SECRETORY PHENOTYPE (SASP) AND TO THE PROPAGATION OF SENESCENCE TO SURROUNDING CELLS THROUGH THE SECRETOME, SUGGESTS THAT CELL SENESCENCE MAY HAVE A ROLE IN BOTH PROCESSES. HERE WE: I) DESCRIBE THE ROLE OF CELL SENESCENCE IN ENDOTHELIAL DYSFUNCTION, II) EMPHASIZE THE CONTRIBUTION OF THE ENDOTHELIAL CELL SASP TO INFLAMMAGING, AND III) SUGGEST THAT SELECTIVE REMOVAL OF SENESCENT ENDOTHELIAL CELLS MAY NOT ONLY HINDER SUCH HARMFUL PROCESSES, BUT ALSO REDUCE THE RISK OF DEVELOPING ARDS AND THEIR COMPLICATIONS. ALTHOUGH IN VIVO DETECTION AND TARGETING OF SENESCENT ENDOTHELIAL CELLS ARE STILL BEING INVESTIGATED, IT IS LIKELY THAT THERAPEUTIC STRATEGIES BASED ON ANTIOXIDANT AND ANTI-INFLAMMATORY COMPOUNDS WOULD INVOLVE GENERALIZED ANTI-AGING EFFECTS ALSO BENEFITING ENDOTHELIAL CELLS. MICRORNA (MIRNAS) - SINGLE-STRANDED, NON-CODING RNAS EXPRESSED BY ALL LIVING CELLS AND INVOLVED IN THE EPIGENETIC MODULATION OF ALL TRANSCRIPTIONAL PROGRAMS - MAY CONSTITUTE AN INNOVATIVE, VALUABLE TOOL TO DETECT AND TARGET SENESCENT ENDOTHELIAL CELLS AND TO DEVISE TREATMENTS THAT CAN SLOW DOWN THE PRO-INFLAMMATORY PROGRAM ACTIVATED IN SENESCENT ENDOTHELIAL CELLS. 2016 16 5432 29 REJUVENATION OF MESENCHYMAL STEM CELLS TO AMELIORATE SKELETAL AGING. ADVANCED AGE IS A SHARED RISK FACTOR FOR MANY CHRONIC AND DEBILITATING SKELETAL DISEASES INCLUDING OSTEOPOROSIS AND PERIODONTITIS. MESENCHYMAL STEM CELLS DEVELOP VARIOUS AGING PHENOTYPES INCLUDING THE ONSET OF SENESCENCE, INTRINSIC LOSS OF REGENERATIVE POTENTIAL AND EXACERBATION OF INFLAMMATORY MICROENVIRONMENT VIA SECRETORY FACTORS. THIS REVIEW ELABORATES ON THE EMERGING CONCEPTS ON THE MOLECULAR AND EPIGENETIC MECHANISMS OF MSC SENESCENCE, SUCH AS THE ACCUMULATION OF OXIDATIVE STRESS, DNA DAMAGE AND MITOCHONDRIAL DYSFUNCTION. SENESCENT MSCS AGGRAVATE LOCAL INFLAMMATION, DISRUPT BONE REMODELING AND BONE-FAT BALANCE, THEREBY CONTRIBUTING TO THE PROGRESSION OF AGE-RELATED BONE DISEASES. VARIOUS REJUVENATION STRATEGIES TO TARGET SENESCENT MSCS COULD PRESENT A PROMISING PARADIGM TO RESTORE SKELETAL AGING. 2023 17 3890 25 KLOTHO, PHOSPHATE AND INFLAMMATION/AGEING IN CHRONIC KIDNEY DISEASE. EVIDENCE IS EMERGING FOR THE INFLAMMATORY NATURE OF MANY AGEING-ASSOCIATED DISEASES, INCLUDING ATHEROSCLEROSIS, VASCULAR CALCIFICATION, DIABETES AND CHRONIC KIDNEY DISEASE (CKD), AMONG OTHERS. AGEING ITSELF RESULTS IN CHRONIC LOW-GRADE INFLAMMATION THAT PROMOTES END-ORGAN DAMAGE. INFLAMMATORY ORGAN DAMAGE, IN TURN, MAY CONTRIBUTE TO INFLAMMATION. RECENT RESEARCH HAS IDENTIFIED THE KIDNEY-SECRETED HORMONE KLOTHO AS A CENTRAL PLAYER AT THE AGEING-INFLAMMATION INTERFACE. THUS, SYSTEMIC OR LOCAL RENAL INFLAMMATION DECREASES KIDNEY KLOTHO EXPRESSION. KLOTHO DOWN-REGULATION MAY BE INDUCED BY SPECIFIC CYTOKINES SUCH AS TUMOUR NECROSIS FACTOR-ALPHA OR TWEAK THROUGH THE CANONICAL ACTIVATION OF THE INFLAMMATORY TRANSCRIPTION FACTOR NUCLEAR FACTOR KAPPA B (NFKAPPAB) AND, SPECIFICALLY RELA. IN ADDITION, INFLAMMATORY CYTOKINES LEAD TO THE EPIGENETIC INACTIVATION OF KLOTHO TRANSCRIPTION. KLOTHO ITSELF HAS ANTIOXIDANT AND ANTI-INFLAMMATORY PROPERTIES AND THE CANONICAL NFKAPPAB COMPONENT RELA IS ONE OF ITS TARGETS. KLOTHO IS A KEY REGULATOR OF PHOSPHATE BALANCE AND A ROLE OF PHOSPHATE IN AGEING HAS BEEN SHOWN. HOWEVER, THE POTENTIAL RELATIONSHIP BETWEEN PHOSPHATE AND INFLAMMATION REQUIRES FURTHER CLARIFICATION. A CORRECT UNDERSTANDING OF THESE INTERACTIONS MAY LEAD TO THE DESIGN OF NOVEL THERAPEUTIC APPROACHES TO CKD AND CKD-RELATED INFLAMMATORY AND AGEING FEATURES AS WELL AS TO INFLAMMATION/AGEING IN GENERAL. 2012 18 3921 34 LINKING INFLAMMATION TO CELL CYCLE PROGRESSION. RISK OF GASTROINTESTINAL CANCERS IS CLOSELY RELATED TO INCREASED LEVELS OF OXIDANTS IN THE BALANCE BETWEEN OXIDANT AND ANTI-OXIDANT AGENTS. A POSSIBLE EXPLANATION OF THIS EPIDEMIOLOGICAL OBSERVATION IS THE LOCAL LOSS OF THE EPITHELIAL BARRIER FUNCTION WITH A FOCAL INFLAMMATORY RESPONSE. ACCORDINGLY, CHRONIC INFLAMMATORY DISEASES REPRESENT WELL-KNOWN RISK FACTORS FOR CANCER AND, ON THE OTHER HAND, IT IS KNOWN THAT ANTI-INFLAMMATORY AGENTS, DEMULCENTS AND ANTIOXIDANTS MARKEDLY INHIBIT THE DEVELOPMENT OF COLON CANCER IN ANIMAL MODELS AS WELL IN HUMANS. AT MOLECULAR LEVEL A KEY ROLE IN THE PROCESS THAT LINK INFLAMMATION TO CELLULAR TRANSFORMATION SEEMS TO BE PLAYED BY ACTIVATION OF CYCLOOXYGENASE-2 (COX-2) TOGETHER WITH PRODUCTION OF REACTIVE OXYGEN INTERMEDIATE (ROI). BOTH THESE EVENTS HAVE BEEN STRICTLY LINKED WITH CELL PROLIFERATION AND TRANSFORMATION, ALTHOUGH THE INTRACELLULAR PATHWAYS INVOLVED IN THESE PROCESSES ARE STILL NOT COMPLETELY UNDERSTOOD. THE UNCONTROLLED PROLIFERATION, WHICH IS A LANDMARK OF CELLULAR TRANSFORMATION, IS ACCOMPANIED BY THE DEREGULATION OF PROTEINS INVOLVED IN THE CONTROL OF CELL CYCLE CHECKPOINTS. ALTERED EXPRESSION AND FUNCTION OF CYCLOOXYGENASE AND NITRIC OXIDE SYNTHASE SEEM TO INFLUENCE, AMONG OTHERS, THE EXPRESSION OF PROTEINS INVOLVED IN THE REGULATION OF CELL CYCLE PROGRESSION. SIMILARLY, ANTI-INFLAMMATORY AND ANTIOXIDANT AGENTS MAY ALSO ACT ON THE EXPRESSION AND FUNCTION OF SEVERAL CELL CYCLE REGULATING PROTEINS. UNDERSTANDING THE MECHANISMS BY WHICH CHRONIC INFLAMMATION CONTRIBUTES TO GENETIC AND EPIGENETIC CHANGES INVOLVED IN THE REGULATION OF CRITICAL CELL CYCLE CHECKPOINTS MAY HELP TO DEVELOP MORE AND MORE SPECIFIC TREATMENT STRATEGIES FOR REDUCING MALIGNANT TRANSFORMATION OF THESE INFLAMMATORY DISEASES. 2004 19 5412 37 REGULATION OF ANTITUMOR IMMUNITY BY INFLAMMATION-INDUCED EPIGENETIC ALTERATIONS. CHRONIC INFLAMMATION PROMOTES TUMOR DEVELOPMENT, PROGRESSION, AND METASTATIC DISSEMINATION AND CAUSES TREATMENT RESISTANCE. THE ACCUMULATION OF GENETIC ALTERATIONS AND LOSS OF NORMAL CELLULAR REGULATORY PROCESSES ARE NOT ONLY ASSOCIATED WITH CANCER GROWTH AND PROGRESSION BUT ALSO RESULT IN THE EXPRESSION OF TUMOR-SPECIFIC AND TUMOR-ASSOCIATED ANTIGENS THAT MAY ACTIVATE ANTITUMOR IMMUNITY. THIS ANTAGONISM BETWEEN INFLAMMATION AND IMMUNITY AND THE ABILITY OF CANCER CELLS TO AVOID IMMUNE DETECTION AFFECT THE COURSE OF CANCER DEVELOPMENT AND TREATMENT OUTCOMES. WHILE INFLAMMATION, PARTICULARLY ACUTE INFLAMMATION, SUPPORTS T-CELL PRIMING, ACTIVATION, AND INFILTRATION INTO INFECTED TISSUES, CHRONIC INFLAMMATION IS MOSTLY IMMUNOSUPPRESSIVE. HOWEVER, THE MAIN MECHANISMS THAT DICTATE THE OUTCOME OF THE INFLAMMATION-IMMUNITY INTERPLAY ARE NOT WELL UNDERSTOOD. RECENT DATA SUGGEST THAT INFLAMMATION TRIGGERS EPIGENETIC ALTERATIONS IN CANCER CELLS AND COMPONENTS OF THE TUMOR MICROENVIRONMENT. THESE ALTERATIONS CAN AFFECT AND MODULATE NUMEROUS ASPECTS OF CANCER DEVELOPMENT, INCLUDING TUMOR GROWTH, THE METABOLIC STATE, METASTATIC SPREAD, IMMUNE ESCAPE, AND IMMUNOSUPPRESSIVE OR IMMUNOSUPPORTIVE LEUKOCYTE GENERATION. IN THIS REVIEW, WE DISCUSS THE ROLE OF INFLAMMATION IN INITIATING EPIGENETIC ALTERATIONS IN IMMUNE CELLS, CANCER-ASSOCIATED FIBROBLASTS, AND CANCER CELLS AND SUGGEST HOW AND WHEN EPIGENETIC INTERVENTIONS CAN BE COMBINED WITH IMMUNOTHERAPIES TO IMPROVE THERAPEUTIC OUTCOMES. 2022 20 6621 35 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