1 5539 139 ROLE OF CYSTIC FIBROSIS BRONCHIAL EPITHELIUM IN NEUTROPHIL CHEMOTAXIS. A HALLMARK OF CYSTIC FIBROSIS (CF) CHRONIC RESPIRATORY DISEASE IS AN EXTENSIVE NEUTROPHIL INFILTRATE IN THE MUCOSA FILLING THE BRONCHIAL LUMEN, STARTING EARLY IN LIFE FOR CF INFANTS. THE GENETIC DEFECT OF THE CF TRANSMEMBRANE CONDUCTANCE REGULATOR (CFTR) ION CHANNEL PROMOTES DEHYDRATION OF THE AIRWAY SURFACE LIQUID, ALTERS MUCUS PROPERTIES, AND DECREASES MUCOCILIARY CLEARANCE, FAVORING THE ONSET OF RECURRENT AND, ULTIMATELY, CHRONIC BACTERIAL INFECTION. NEUTROPHIL INFILTRATES ARE UNABLE TO CLEAR BACTERIAL INFECTION AND, AS AN ADVERSE EFFECT, CONTRIBUTE TO MUCOSAL TISSUE DAMAGE BY RELEASING PROTEASES AND REACTIVE OXYGEN SPECIES. MOREOVER, THE RAPID CELLULAR TURNOVER OF LUMENAL NEUTROPHILS RELEASES NUCLEIC ACIDS THAT FURTHER ALTER THE MUCUS VISCOSITY. A PROMINENT ROLE IN THE RECRUITMENT OF NEUTROPHIL IN BRONCHIAL MUCOSA IS PLAYED BY CF BRONCHIAL EPITHELIAL CELLS CARRYING THE DEFECTIVE CFTR PROTEIN AND ARE EXPOSED TO WHOLE BACTERIA AND BACTERIAL PRODUCTS, MAKING PHARMACOLOGICAL APPROACHES TO REGULATE THE EXAGGERATED NEUTROPHIL CHEMOTAXIS IN CF A RELEVANT THERAPEUTIC TARGET. HERE WE REVISE: (A) THE MAJOR RECEPTORS, KINASES, AND TRANSCRIPTION FACTORS LEADING TO THE EXPRESSION, AND RELEASE OF NEUTROPHIL CHEMOKINES IN BRONCHIAL EPITHELIAL CELLS; (B) THE ROLE OF INTRACELLULAR CALCIUM HOMEOSTASIS AND, IN PARTICULAR, THE CALCIUM CROSSTALK BETWEEN ENDOPLASMIC RETICULUM AND MITOCHONDRIA; (C) THE EPIGENETIC REGULATION OF THE KEY CHEMOKINES; (D) THE ROLE OF MUTANT CFTR PROTEIN AS A CO-REGULATOR OF CHEMOKINES TOGETHER WITH THE HOST-PATHOGEN INTERACTIONS; AND (E) DIFFERENT PHARMACOLOGICAL STRATEGIES TO REGULATE THE EXPRESSION OF CHEMOKINES IN CF BRONCHIAL EPITHELIAL CELLS THROUGH NOVEL DRUG DISCOVERY AND DRUG REPURPOSING. 2020 2 4027 25 LUNG CANCER IN A CF PATIENT: COMBINATION OF BAD LUCK OR IS THERE MORE TO SAY? PATIENTS WITH CYSTIC FIBROSIS HAVE INCREASED RISK FOR GASTROINTESTINAL CANCER, LYMPHOID LEUKEMIA AND TESTICULAR CARCINOMAS. CHRONIC INFLAMMATION DOES NOT SEEM TO BE THE ONLY CONTRIBUTING FACTOR. MUTATIONS AND EPIGENETIC ALTERATIONS IN THE CFTR GENE MAY ALTER SUSCEPTIBILITY TO DEVELOP CANCER. LUNG CANCER IS UP TO NOW NOT FREQUENTLY OBSERVED IN CF PATIENTS. IN LUNG CANCER PATIENTS WITHOUT CF LOW CFTR EXPRESSION IS SIGNIFICANTLY ASSOCIATED WITH ADVANCED STAGING, LYMPH NODE METASTASIS. AS THE MANAGEMENT AND LIFE EXPECTANCY OF PATIENTS WITH CYSTIC FIBROSIS HAVE IMPROVED SUBSTANTIALLY IN RECENT YEARS, WE EXPECT AN INCREASED NUMBER OF THESE PATIENTS DIAGNOSED WITH LUNG CANCER. IN ADDITION, IT IS POSSIBLE THAT THEY, AS A RESULT OF CFTR-DYSFUNCTION, WILL PRESENT WITH MORE AGGRESSIVE LUNG TUMORS. TREATING CANCER IN CF PATIENTS IS A CHALLENGE BECAUSE OF MULTI-ORGAN INVOLVEMENT AND CHRONIC COLONIZATION BY RESISTANT PATHOGENS. THE EFFECTIVENESS AND SAFETY OF IMMUNOTHERAPY IN THIS POPULATION NEEDS TO BE FURTHER EVALUATED. 2021 3 3514 32 IDIOPATHIC PULMONARY FIBROSIS: PATHOGENESIS AND THERAPEUTIC APPROACHES. IDIOPATHIC PULMONARY FIBROSIS (IPF), ALSO TERMED CRYPTOGENIC FIBROSING ALVEOLITIS, IS A CLINICOPATHOLOGICAL SYNDROME CHARACTERISED BY COUGH, EXERTIONAL DYSPNEOA, BASILAR CRACKLES, A RESTRICTIVE DEFECT ON PULMONARY FUNCTION TESTS, HONEYCOMBING ON HIGH-RESOLUTION, THIN-SECTION COMPUTED TOMOGRAPHIC SCANS AND THE HISTOLOGICAL DIAGNOSIS OF USUAL INTERSTITIAL PNEUMONIA ON LUNG BIOPSY. THE COURSE IS USUALLY INDOLENT BUT INEXORABLE. MOST PATIENTS DIE OF PROGRESSIVE RESPIRATORY FAILURE WITHIN 3-8 YEARS OF THE ONSET OF SYMPTOMS. CURRENT THERAPIES ARE OF UNPROVEN BENEFIT. ALTHOUGH THE PATHOGENESIS OF IPF HAS NOT BEEN ELUCIDATED, EARLY CONCEPTS FOCUSED ON LUNG INJURY LEADING TO A CYCLE OF CHRONIC ALVEOLAR INFLAMMATION EVENTUATING IN FIBROSIS AND DESTRUCTION OF THE LUNG ARCHITECTURE. ANTI-INFLAMMATORY THERAPIES EMPLOYING CORTICOSTEROIDS OR IMMUNOSUPPRESSIVE OR CYTOTOXIC AGENTS HAVE BEEN DISAPPOINTING. MORE RECENT HYPOTHESES ACKNOWLEDGE THAT SEQUENTIAL ALVEOLAR EPITHELIAL CELL INJURY IS LIKELY TO BE A KEY EVENT IN THE PATHOGENESIS OF IPF, BUT THE CARDINAL EVENT IS AN ABERRANT HOST RESPONSE TO WOUND HEALING. IN THIS CONTEXT, ABNORMAL EPITHELIAL-MESENCHYMAL INTERACTIONS, ALTERED FIBROBLAST PHENOTYPES, EXAGGERATED FIBROBLAST PROLIFERATION, AND EXCESSIVE DEPOSITION OF COLLAGEN AND EXTRACELLULAR MATRIX ARE PIVOTAL TO THE FIBROTIC PROCESS. SEVERAL CLINICAL TRIALS ARE CURRENTLY UNDERWAY OR IN THE PLANNING STAGES, AND INCLUDE DRUGS SUCH AS INTERFERON-GAMMA 1B, PIRFENIDONE, ACETYLCYSTEINE, ETANERCEPT (A TUMOR NECROSIS FACTOR-ALPHA ANTAGONIST), BOSENTAN (AN ENDOTHELIN-1 RECEPTOR ANTAGONIST) AND ZILEUTON (A 5-LYPOXYGENASE INHIBITOR). FUTURE THERAPEUTIC STRATEGIES SHOULD BE FOCUSED ON ALVEOLAR EPITHELIAL CELLS AIMED AT ENHANCING RE-EPITHELIALISATION AND ON FIBROBLASTIC/MYOFIBROBLASTIC FOCI, WHICH PLAY AN ESSENTIAL ROLE IN THE DEVELOPMENT OF IPF. STEM CELL PROGENITORS OF THE ALVEOLAR EPITHELIAL CELLS AND GENETIC AND EPIGENETIC THERAPIES ARE ATTRACTIVE FUTURE APPROACHES FOR THIS AND OTHER FIBROTIC LUNG DISORDERS. 2004 4 6782 21 [CHRONIC DISEASES, PRECANCER, AND CANCER OF THE LUNG, WHICH ARE ASSOCIATED WITH PATHOLOGY OF THE CLUB CELLS OF RESPIRATORY AND TERMINAL BRONCHIOLES]. THE REVIEW OF THE LITERATURE DEALS WITH THE PARTICIPATION OF CLARA CELLS NOW CALLED CLUB CELLS (CCS) OF THE EPITHELIUM IN THE RESPIRATORY AND TERMINAL BRONCHIOLES IN THE PATHOGENESIS AND MORPHOGENESIS OF CHRONIC INFLAMMATORY DISEASES, PRECANCER, AND CANCER OF THE LUNG, WHICH DEVELOP IN THE RESPIRATORY SEGMENTS. THE REVIEW SUMMARIZES DATA ON THE HISTOPHYSIOLOGY OF CCS AND THEIR PARTICIPATION IN THE PATHOGENESIS AND MORPHOGENESIS OF CHRONIC INTERSTITIAL LUNG DISEASES, PNEUMOCONIOSIS, CHRONIC OBSTRUCTIVE DISEASES, ADENOMATOSIS, AND ADENOCARCINOMA OF THE LUNG. IN THIS AREA, THERE IS A BRONCHIOLOALVEOLAR JUNCTION AREA (BAJA), ONE OF THE MOST IMPORTANT STEM CELL NICHES. CCS ARE LOCATED IN THE BAJA; THEY ARE PROGENITOR TISSUE STEM CELLS AND PLAY AN IMPORTANT ROLE IN THE REGENERATION OF THE EPITHELIUM OF THE RESPIRATORY BRONCHIOLES AND ALVEOLI. PATHOLOGY OF CCS IN THE BAJA LEADS TO THE MAINTENANCE OF CHRONIC INFLAMMATION, TO THE DESTRUCTION OF THE LUNG ELASTIC FRAME, AND TO IMPAIRED EPITHELIAL REGENERATION, INTERSTITIAL FIBROSIS, AND ADENOMATOSIS. IN THIS CASE, DECOMPENSATED INFLAMMATION, PATHOLOGICAL REGENERATION, AND FIBROSIS DEVELOP, WHICH, ALONG WITH THE ACTION OF CARCINOGENIC AGENTS, CAN CONTRIBUTE TO THE ACCUMULATION OF MUTATIONS AND EPIGENETIC REARRANGEMENTS IN THE CCS, WHICH SUBSEQUENTLY RESULTS IN ATYPICAL ADENOMATOUS HYPERPLASIA AND ADENOCARCINOMA OF THE LUNG. 2018 5 3512 21 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 6 6741 20 WHERE TO STAND WITH STROMAL CELLS AND CHRONIC SYNOVITIS IN RHEUMATOID ARTHRITIS? THE SYNOVIUM EXERCISES ITS MAIN FUNCTION IN JOINT HOMEOSTASIS THROUGH THE SECRETION OF FACTORS (SUCH AS LUBRICIN AND HYALURONIC ACID) THAT ARE CRITICAL FOR THE JOINT LUBRICATION AND FUNCTION. THE MAIN SYNOVIUM CELL COMPONENTS ARE FIBROBLAST-LIKE SYNOVIOCYTES, MESENCHYMAL STROMAL/STEM CELLS AND MACROPHAGE-LIKE SYNOVIAL CELLS. IN THE SYNOVIUM, CELLS OF MESENCHYMAL ORIGIN MODULATE LOCAL INFLAMMATION AND FIBROSIS, AND INTERACT WITH DIFFERENT FIBROBLAST SUBTYPES AND WITH RESIDENT MACROPHAGES. IN PATHOLOGIC CONDITIONS, SUCH AS RHEUMATOID ARTHRITIS, FIBROBLAST-LIKE SYNOVIOCYTES PROLIFERATE ABNORMALLY, RECRUIT MESENCHYMAL STEM CELLS FROM SUBCHONDRAL BONE MARROW, AND INFLUENCE IMMUNE CELL ACTIVITY THROUGH EPIGENETIC AND METABOLIC ADAPTATIONS. THE RESULTING SYNOVIAL HYPERPLASIA LEADS TO SECONDARY CARTILAGE DESTRUCTION, JOINT SWELLING, AND PAIN. IN THE PRESENT REVIEW, WE SUMMARIZE RECENT FINDINGS ON THE MOLECULAR SIGNATURE AND THE ROLES OF STROMAL CELLS DURING SYNOVIAL PANNUS FORMATION AND RHEUMATOID ARTHRITIS PROGRESSION. 2019 7 756 28 CARM1 REGULATES SENESCENCE DURING AIRWAY EPITHELIAL CELL INJURY IN COPD PATHOGENESIS. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS A LIFE-THREATENING LUNG DISEASE. ALTHOUGH CIGARETTE SMOKE WAS CONSIDERED THE MAIN CAUSE OF DEVELOPMENT, THE HETEROGENEOUS NATURE OF THE DISEASE LEAVES IT UNCLEAR WHETHER OTHER FACTORS CONTRIBUTE TO THE PREDISPOSITION OR IMPAIRED REGENERATION RESPONSE OBSERVED. RECENTLY, EPIGENETIC MODIFICATION HAS EMERGED TO BE A KEY PLAYER IN THE PATHOGENESIS OF COPD. THE ADDITION OF METHYL GROUPS TO ARGININE RESIDUES IN BOTH HISTONE AND NONHISTONE PROTEINS BY PROTEIN ARGININE METHYLTRANSFERASES (PRMTS) IS AN IMPORTANT POSTTRANSLATIONAL EPIGENETIC MODIFICATION EVENT REGULATING CELLULAR PROLIFERATION, DIFFERENTIATION, APOPTOSIS, AND SENESCENCE. HERE, WE HYPOTHESIZE THAT COACTIVATOR-ASSOCIATED ARGININE METHYLTRANSFERASE-1 (CARM1) REGULATES AIRWAY EPITHELIAL CELL INJURY IN COPD PATHOGENESIS BY CONTROLLING CELLULAR SENESCENCE. USING THE NAPHTHALENE (NA)-INDUCED MOUSE MODEL OF AIRWAY EPITHELIAL DAMAGE, WE DEMONSTRATE THAT LOSS OF CC10-POSITIVE CLUB CELLS IS ACCOMPANIED BY A REDUCTION IN CARM1-EXPRESSING CELLS OF THE AIRWAY EPITHELIUM. FURTHERMORE, CARM1 HAPLOINSUFFFICENT MICE SHOWED PERTURBED CLUB CELL REGENERATION FOLLOWING NA TREATMENT. IN ADDITION, CARM1 REDUCTION LED TO DECREASED NUMBERS OF ANTISENESCENT SIRTUIN 1-EXPRESSING CELLS ACCOMPANIED BY HIGHER P21, P16, AND BETA-GALACTOSIDASE-POSITIVE SENESCENT CELLS IN THE MOUSE AIRWAY FOLLOWING NA TREATMENT. IMPORTANTLY, CARM1-SILENCED HUMAN BRONCHIAL EPITHELIAL CELLS SHOWED IMPAIRED WOUND HEALING AND HIGHER BETA-GALACTOSIDASE ACTIVITY. THESE RESULTS DEMONSTRATE THAT CARM1 CONTRIBUTES TO AIRWAY REPAIR AND REGENERATION BY REGULATING AIRWAY EPITHELIAL CELL SENESCENCE. 2019 8 6053 21 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 9 4416 29 MOLECULAR AND CELLULAR PATHWAYS CONTRIBUTING TO JOINT DAMAGE IN RHEUMATOID ARTHRITIS. RHEUMATOID ARTHRITIS IS A CHRONIC AUTOIMMUNE SYNDROME ASSOCIATED WITH SEVERAL GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS AFFECTING THE ARTICULAR JOINTS CONTRIBUTING TO CARTILAGE AND BONE DAMAGE. ALTHOUGH ETIOLOGY OF THIS DISEASE IS NOT CLEAR, SEVERAL IMMUNE PATHWAYS, INVOLVING IMMUNE (T CELLS, B CELLS, DENDRITIC CELLS, MACROPHAGES, AND NEUTROPHILS) AND NONIMMUNE (FIBROBLASTS AND CHONDROCYTES) CELLS, PARTICIPATE IN THE SECRETION OF MANY PROINFLAMMATORY CYTOKINES, CHEMOKINES, PROTEASES (MMPS, ADAMTS), AND OTHER MATRIX LYSING ENZYMES THAT COULD DISTURB THE IMMUNE BALANCE LEADING TO CARTILAGE AND BONE DAMAGE. THE PRESENCE OF AUTOANTIBODIES PRECEDING THE CLINICAL ONSET OF ARTHRITIS AND THE INDUCTION OF BONE EROSION EARLY IN THE DISEASE COURSE CLEARLY SUGGEST THAT INITIATION EVENTS DAMAGING THE CARTILAGE AND BONE START VERY EARLY DURING THE AUTOIMMUNE PHASE OF THE ARTHRITIS DEVELOPMENT. DURING THIS PROCESS, SEVERAL SIGNALING MOLECULES (RANKL-RANK, NF-KAPPAB, MAPK, NFATC1, AND SRC KINASE) ARE ACTIVATED IN THE OSTEOCLASTS, CELLS RESPONSIBLE FOR BONE RESORPTION. HENCE, COMPREHENSIVE KNOWLEDGE ON PATHOGENESIS IS A PREREQUISITE FOR PREVENTION AND DEVELOPMENT OF TARGETED CLINICAL TREATMENT FOR RA PATIENTS THAT CAN RESTORE THE IMMUNE BALANCE IMPROVING CLINICAL THERAPY. 2020 10 4952 21 PATHOGENESIS OF CHRONIC CHIKUNGUNYA ARTHRITIS: RESEMBLANCES AND LINKS WITH RHEUMATOID ARTHRITIS. CHIKUNGUNYA VIRUS (CHIKV) INFECTION RESULTS FROM TRANSMISSION BY THE MOSQUITO VECTOR. FOLLOWING AN INCUBATION PERIOD OF 5-7 DAYS, PATIENTS DEVELOP AN ACUTE FEBRILE ILLNESS, CHIKUNGUNYA FEVER (CHIKF), CHARACTERIZED BY HIGH FEVERS, MACULOPAPULAR RASH, HEADACHES, POLYARTHRITIS/ARTHRALGIAS, MYALGIAS, NAUSEA, VOMITING, AND DIARRHEA. JOINT PAIN IS OFTEN SEVERE, AND MOST OFTEN INVOLVES THE HANDS, THE WRISTS, THE ANKLES, AND THE METATARSAL-PHALANGEAL JOINTS OF THE FEET. MANY PATIENTS RECOVER WITHIN SEVERAL WEEKS, BUT UP TO 50% DEVELOP CHRONIC JOINT PAIN AND SWELLING FOR MORE THAN 12 WEEKS, THEN WE REFER TO THESE SYMPTOMS AS CHRONIC CHIKUNGUNYA ARTHRITIS (CCA). THE PATHOGENESIS OF CCA IS NOT WELL UNDERSTOOD. IN THIS ARTICLE, WE SUGGEST THAT MESENCHYMAL STEM CELLS (MSCS) MAY PLAY AN IMPORTANT ROLE IN THIS PATHOGENESIS. THIS HETEROGENEOUS GROUP OF MULTIPOTENT CELLS, MORPHOLOGICALLY SIMILAR TO FIBROBLASTS, MAY UNDERGO EPIGENETIC CHANGES CAPABLE OF GENERATING ABERRANT PROGENIES. HOWEVER, WE BELIEVE THAT THERE IS NO NEED FOR A LATENT INFECTION. IN OUR PATHOGENIC HYPOTHESIS, CHIKV INFECTION OF MSCS WOULD CAUSE EPIGENETIC CHANGES BOTH IN MSCS THEMSELVES AND IN THEIR PROGENIES, WITHOUT THE NEED FOR REACTIVATION OF DORMANT VIRUSES. 2023 11 3245 23 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 12 1646 28 DOES THE HEPATITIS B ANTIGEN HBX PROMOTE THE APPEARANCE OF LIVER CANCER STEM CELLS? HEPATITIS B VIRUS (HBV) IS A MAJOR ETIOLOGIC AGENT OF CHRONIC LIVER DISEASE AND HEPATOCELLULAR CARCINOMA (HCC). HBV-ENCODED X ANTIGEN, HBX, AND PATHWAYS IMPLICATED IN THE SELF-RENEWAL OF STEM CELLS CONTRIBUTE TO HCC, BUT IT IS NOT CLEAR WHETHER HBX EXPRESSION PROMOTES "STEMNESS." THUS, EXPERIMENTS WERE DESIGNED TO TEST THE HYPOTHESIS THAT HBX TRIGGERS MALIGNANT TRANSFORMATION BY PROMOTING PROPERTIES THAT ARE CHARACTERISTIC OF CANCER STEM CELLS (CSC). TO TEST THIS HYPOTHESIS, HEPG2 CELLS WERE STABLY TRANSDUCED WITH HBX AND THEN ASSAYED FOR PHENOTYPIC AND MOLECULAR CHARACTERISTICS OF "STEMNESS." THE RELATIONSHIP BETWEEN HBX AND "STEMNESS"-ASSOCIATED MARKERS WAS ALSO EVALUATED BY IMMUNOHISTOCHEMICAL STAINING OF LIVER AND TUMOR TISSUE SECTIONS FROM HBV-INFECTED PATIENTS. THE RESULTS SHOWED THAT OCT-4, NANOG, KLF-4, BETA-CATENIN, AND EPITHELIAL CELL ADHESION MOLECULE (EPCAM) WERE ACTIVATED BY HBX IN VITRO AND IN VIVO. EPCAM WAS DETECTED IN THE NUCLEI OF HUMAN HCC CELLS FROM INFECTED PATIENTS. HBX PROMOTES "STEMNESS" BY ACTIVATING BETA-CATENIN AND EPIGENETIC UPREGULATION OF MIR-181, BOTH OF WHICH TARGET EPCAM. HBX EXPRESSION WAS ALSO ASSOCIATED WITH DEPRESSED LEVELS OF E-CADHERIN. MOREOVER, HBX STIMULATED CELL MIGRATION, GROWTH IN SOFT AGAR, AND SPHEROID FORMATION. THIS WORK IS THE FIRST TO PROPOSE THAT HBV PROMOTES "STEMNESS" IN THE PATHOGENESIS OF HCC. HBX-ASSOCIATED UPREGULATED EXPRESSION OF MULTIPLE "STEMNESS" MARKERS SUPPORTS THE HYPOTHESIS THAT HBX CONTRIBUTES TO HEPATOCARCINOGENESIS, AT LEAST IN PART, BY PROMOTING CHANGES IN GENE EXPRESSION THAT ARE CHARACTERISTICS OF CSCS. 2011 13 3674 23 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 14 2020 23 EPIGENETIC CHANGES AND FUNCTIONS IN PNEUMOCONIOSIS. PNEUMOCONIOSIS IS ONE OF THE MOST COMMON OCCUPATIONAL DISEASES IN THE WORLD, AND SPECIFIC TREATMENT METHODS OF PNEUMOCONIOSIS ARE LACKING AT PRESENT, SO IT CARRIES GREAT SOCIAL AND ECONOMIC BURDENS. PNEUMOCONIOSIS, CORONAVIRUS DISEASE 2019, AND IDIOPATHIC PULMONARY FIBROSIS ALL HAVE SIMILAR TYPICAL PATHOLOGICAL CHANGES-PULMONARY FIBROSIS. PULMONARY FIBROSIS IS A CHRONIC LUNG DISEASE CHARACTERIZED BY EXCESSIVE DEPOSITION OF THE EXTRACELLULAR MATRIX AND REMODELING OF THE LUNG TISSUE STRUCTURE. CLARIFYING THE PATHOGENESIS OF PNEUMOCONIOSIS PLAYS AN IMPORTANT GUIDING ROLE IN ITS TREATMENT. THE OCCURRENCE AND DEVELOPMENT OF PNEUMOCONIOSIS ARE ACCOMPANIED BY EPIGENETIC FACTORS (E.G., DNA METHYLATION AND NONCODING RNA) CHANGES, WHICH IN TURN CAN PROMOTE OR INHIBIT THE PROCESS OF PNEUMOCONIOSIS. HERE, WE SUMMARIZE EPIGENETIC CHANGES AND FUNCTIONS IN THE SEVERAL KINDS OF EVIDENCE CLASSIFICATION (EPIDEMIOLOGICAL INVESTIGATION, IN VIVO, AND IN VITRO EXPERIMENTS) AND MAIN TYPES OF CELLS (MACROPHAGES, FIBROBLASTS, AND ALVEOLAR EPITHELIAL CELLS) TO PROVIDE SOME CLUES FOR FINDING SPECIFIC THERAPEUTIC TARGETS FOR PNEUMOCONIOSIS AND EVEN FOR PULMONARY FIBROSIS. 2022 15 6009 28 THE ANTI-INFLAMMATORY MEDIATOR, VASOACTIVE INTESTINAL PEPTIDE, MODULATES THE DIFFERENTIATION AND FUNCTION OF TH SUBSETS IN RHEUMATOID ARTHRITIS. GENETIC BACKGROUND, EPIGENETIC MODIFICATIONS, AND ENVIRONMENTAL FACTORS TRIGGER AUTOIMMUNE RESPONSE IN RHEUMATOID ARTHRITIS (RA). SEVERAL PATHOGENIC INFECTIONS HAVE BEEN RELATED TO THE ONSET OF RA AND MAY CAUSE AN INADEQUATE IMMUNOLOGICAL TOLERANCE TOWARDS CRITICAL SELF-ANTIGENS LEADING TO CHRONIC JOINT INFLAMMATION AND AN IMBALANCE BETWEEN DIFFERENT T HELPER (TH) SUBSETS. VASOACTIVE INTESTINAL PEPTIDE (VIP) IS A MEDIATOR THAT MODULATES ALL THE STAGES COMPRISED BETWEEN THE ARRIVAL OF PATHOGENS AND TH CELL DIFFERENTIATION IN RA THROUGH ITS KNOWN ANTI-INFLAMMATORY AND IMMUNOMODULATORY ACTIONS. THIS "NEUROIMMUNOPEPTIDE" MODULATES THE PATHOGENIC ACTIVITY OF DIVERSE CELL SUBPOPULATIONS INVOLVED IN RA AS LYMPHOCYTES, FIBROBLAST-LIKE SYNOVIOCYTES (FLS), OR MACROPHAGES. IN ADDITION, VIP DECREASES THE EXPRESSION OF PATTERN RECOGNITION RECEPTOR (PRR) SUCH AS TOLL-LIKE RECEPTORS (TLRS) IN FLS FROM RA PATIENTS. THESE RECEPTORS ACT AS SENSORS OF PATHOGEN-ASSOCIATED MOLECULAR PATTERN (PAMP) AND DAMAGE-ASSOCIATED MOLECULAR PATTERN (DAMP) CONNECTING THE INNATE AND ADAPTIVE IMMUNE SYSTEM. MOREOVER, VIP MODULATES THE IMBALANCE BETWEEN TH SUBSETS IN RA, DECREASING PATHOGENIC TH1 AND TH17 SUBSETS AND FAVORING TH2 OR TREG PROFILE DURING THE DIFFERENTIATION/POLARIZATION OF NAIVE OR MEMORY TH CELLS. FINALLY, VIP REGULATES THE PLASTICITY BETWEEN THESES SUBSETS. IN THIS REVIEW, WE PROVIDE AN OVERVIEW OF VIP EFFECTS ON THE AFOREMENTIONED FEATURES OF RA PATHOLOGY. 2018 16 4298 27 MICRORNA-146A GOVERNS FIBROBLAST ACTIVATION AND JOINT PATHOLOGY IN ARTHRITIS. SYNOVIAL FIBROBLASTS ARE KEY CELLS ORCHESTRATING THE INFLAMMATORY RESPONSE IN ARTHRITIS. HERE WE DEMONSTRATE THAT LOSS OF MIR-146A, A KEY EPIGENETIC REGULATOR OF THE INNATE IMMUNE RESPONSE, LEADS TO INCREASED JOINT DESTRUCTION IN A TNF-DRIVEN MODEL OF ARTHRITIS BY SPECIFICALLY REGULATING THE BEHAVIOR OF SYNOVIAL FIBROBLASTS. ABSENCE OF MIR-146A IN SYNOVIAL FIBROBLASTS DISPLAY A HIGHLY DEREGULATED GENE EXPRESSION PATTERN AND ENHANCED PROLIFERATION IN VITRO AND IN VIVO. DEFICIENCY OF MIR-146A INDUCES DEREGULATION OF TUMOR NECROSIS FACTOR (TNF) RECEPTOR ASSOCIATED FACTOR 6 (TRAF6) IN SYNOVIAL FIBROBLASTS, LEADING TO INCREASED PROLIFERATION. IN ADDITION, LOSS OF MIR-146A SHIFTS THE METABOLIC STATE OF FIBROBLASTS TOWARDS GLYCOLYSIS AND AUGMENTS THE ABILITY OF SYNOVIAL FIBROBLASTS TO SUPPORT THE GENERATION OF OSTEOCLASTS BY CONTROLLING THE BALANCE OF OSTEOCLASTOGENIC REGULATORY FACTORS RECEPTOR ACTIVATOR OF NF-KAPPAB LIGAND (RANKL) AND OSTEOPROTEGERIN (OPG). BONE MARROW TRANSPLANTATION EXPERIMENTS CONFIRMED THE IMPORTANCE OF MIR-146A IN THE RADIORESISTANT MESENCHYMAL COMPARTMENT FOR THE CONTROL OF ARTHRITIS SEVERITY, IN PARTICULAR FOR INFLAMMATORY JOINT DESTRUCTION. THIS STUDY THEREFORE IDENTIFIES MICRORNA-146A AS AN IMPORTANT LOCAL EPIGENETIC REGULATOR OF THE INFLAMMATORY RESPONSE IN ARTHRITIS. IT IS A CENTRAL ELEMENT OF AN ANTI-INFLAMMATORY FEEDBACK LOOP IN RESIDENT SYNOVIAL FIBROBLASTS, WHO ARE ORCHESTRATING THE INFLAMMATORY RESPONSE IN CHRONIC ARTHRITIS. MIR-146A RESTRICTS THEIR ACTIVATION, THEREBY PREVENTING EXCESSIVE TISSUE DAMAGE DURING ARTHRITIS. 2017 17 3688 35 INFLAMMATION: GEARING THE JOURNEY TO CANCER. CHRONIC INFLAMMATION PLAYS A MULTIFACETED ROLE IN CARCINOGENESIS. MOUNTING EVIDENCE FROM PRECLINICAL AND CLINICAL STUDIES SUGGESTS THAT PERSISTENT INFLAMMATION FUNCTIONS AS A DRIVING FORCE IN THE JOURNEY TO CANCER. THE POSSIBLE MECHANISMS BY WHICH INFLAMMATION CAN CONTRIBUTE TO CARCINOGENESIS INCLUDE INDUCTION OF GENOMIC INSTABILITY, ALTERATIONS IN EPIGENETIC EVENTS AND SUBSEQUENT INAPPROPRIATE GENE EXPRESSION, ENHANCED PROLIFERATION OF INITIATED CELLS, RESISTANCE TO APOPTOSIS, AGGRESSIVE TUMOR NEOVASCULARIZATION, INVASION THROUGH TUMOR-ASSOCIATED BASEMENT MEMBRANE AND METASTASIS, ETC. INFLAMMATION-INDUCED REACTIVE OXYGEN AND NITROGEN SPECIES CAUSE DAMAGE TO IMPORTANT CELLULAR COMPONENTS (E.G., DNA, PROTEINS AND LIPIDS), WHICH CAN DIRECTLY OR INDIRECTLY CONTRIBUTE TO MALIGNANT CELL TRANSFORMATION. OVEREXPRESSION, ELEVATED SECRETION, OR ABNORMAL ACTIVATION OF PROINFLAMMATORY MEDIATORS, SUCH AS CYTOKINES, CHEMOKINES, CYCLOOXYGENASE-2, PROSTAGLANDINS, INDUCIBLE NITRIC OXIDE SYNTHASE, AND NITRIC OXIDE, AND A DISTINCT NETWORK OF INTRACELLULAR SIGNALING MOLECULES INCLUDING UPSTREAM KINASES AND TRANSCRIPTION FACTORS FACILITATE TUMOR PROMOTION AND PROGRESSION. WHILE INFLAMMATION PROMOTES DEVELOPMENT OF CANCER, COMPONENTS OF THE TUMOR MICROENVIRONMENT, SUCH AS TUMOR CELLS, STROMAL CELLS IN SURROUNDING TISSUE AND INFILTRATED INFLAMMATORY/IMMUNE CELLS GENERATE AN INTRATUMORAL INFLAMMATORY STATE BY ABERRANT EXPRESSION OR ACTIVATION OF SOME PROINFLAMMATORY MOLECULES. MANY OF PROINFLAMMATORY MEDIATORS, ESPECIALLY CYTOKINES, CHEMOKINES AND PROSTAGLANDINS, TURN ON THE ANGIOGENIC SWITCHES MAINLY CONTROLLED BY VASCULAR ENDOTHELIAL GROWTH FACTOR, THEREBY INDUCING INFLAMMATORY ANGIOGENESIS AND TUMOR CELL-STROMA COMMUNICATION. THIS WILL END UP WITH TUMOR ANGIOGENESIS, METASTASIS AND INVASION. MOREOVER, CELLULAR MICRORNAS ARE EMERGING AS A POTENTIAL LINK BETWEEN INFLAMMATION AND CANCER. THE PRESENT ARTICLE HIGHLIGHTS THE ROLE OF VARIOUS PROINFLAMMATORY MEDIATORS IN CARCINOGENESIS AND THEIR PROMISE AS POTENTIAL TARGETS FOR CHEMOPREVENTION OF INFLAMMATION-ASSOCIATED CARCINOGENESIS. 2008 18 6147 29 THE EXPRESSION OF NON-CODING RNAS AND THEIR TARGET MOLECULES IN RHEUMATOID ARTHRITIS: A MOLECULAR BASIS FOR RHEUMATOID PATHOGENESIS AND ITS POTENTIAL CLINICAL APPLICATIONS. RHEUMATOID ARTHRITIS (RA) IS A TYPICAL AUTOIMMUNE-MEDIATED RHEUMATIC DISEASE PRESENTING AS A CHRONIC SYNOVITIS IN THE JOINT. THE CHRONIC SYNOVIAL INFLAMMATION IS CHARACTERIZED BY HYPER-VASCULARITY AND EXTRAVASATION OF VARIOUS IMMUNE-RELATED CELLS TO FORM LYMPHOID AGGREGATES WHERE AN INTIMATE CROSS-TALK AMONG INNATE AND ADAPTIVE IMMUNE CELLS TAKES PLACE. THESE INTERACTIONS FACILITATE PRODUCTION OF ABUNDANT PROINFLAMMATORY CYTOKINES, CHEMOKINES AND GROWTH FACTORS FOR THE PROLIFERATION/MATURATION/DIFFERENTIATION OF B LYMPHOCYTES TO BECOME PLASMA CELLS. FINALLY, THE AUTOANTIBODIES AGAINST DENATURED IMMUNOGLOBULIN G (RHEUMATOID FACTORS), EB VIRUS NUCLEAR ANTIGENS (EBNAS) AND CITRULLINATED PROTEIN (ACPAS) ARE PRODUCED TO TRIGGER THE DEVELOPMENT OF RA. FURTHERMORE, IT IS DOCUMENTED THAT GENE MUTATIONS, ABNORMAL EPIGENETIC REGULATION OF PEPTIDYLARGININE DEIMINASE GENES 2 AND 4 (PADI2 AND PADI4), AND THEREBY THE INDUCED AUTOANTIBODIES AGAINST PAD2 AND PAD4 ARE IMPLICATED IN ACPA PRODUCTION IN RA PATIENTS. THE ABERRANT EXPRESSIONS OF NON-CODING RNAS (NCRNAS) INCLUDING MICRORNAS (MIRS) AND LONG NON-CODING RNAS (LNCRNAS) IN THE IMMUNE SYSTEM UNDOUBTEDLY DERANGE THE MRNA EXPRESSIONS OF CYTOKINES/CHEMOKINES/GROWTH FACTORS. IN THE PRESENT REVIEW, WE WILL DISCUSS IN DETAIL THE EXPRESSION OF THESE NCRNAS AND THEIR TARGET MOLECULES PARTICIPATING IN DEVELOPING RA, AND THE POTENTIAL BIOMARKERS FOR THE DISEASE, ITS DIAGNOSIS, CARDIOVASCULAR COMPLICATIONS AND THERAPEUTIC RESPONSE. FINALLY, WE PROPOSE SOME PROSPECTIVE INVESTIGATIONS FOR UNRAVELING THE CONUNDRUMS OF RHEUMATOID PATHOGENESIS. 2021 19 5411 34 REGULATION OF AIRWAY MUCIN GENE EXPRESSION. MUCINS ARE IMPORTANT COMPONENTS THAT EXERT A VARIETY OF FUNCTIONS IN CELL-CELL INTERACTION, EPIDERMAL GROWTH FACTOR RECEPTOR SIGNALING, AND AIRWAYS PROTECTION. IN THE CONDUCTING AIRWAYS OF THE LUNGS, MUCINS ARE THE MAJOR CONTRIBUTOR TO THE VISCOELASTIC PROPERTY OF MUCOUS SECRETION, WHICH IS THE MAJOR BARRIER TO TRAPPING INHALED MICROBIAL ORGANISM, PARTICULATES, AND OXIDATIVE POLLUTANTS. THE HOMEOSTASIS OF MUCIN PRODUCTION IS AN IMPORTANT FEATURE IN CONDUCTING AIRWAYS FOR THE MAINTENANCE OF MUCOCILIARY FUNCTION. ABERRANT MUCIN SECRETION AND ACCUMULATION IN AIRWAY LUMEN ARE CLINICAL HALLMARKS ASSOCIATED WITH VARIOUS LUNG DISEASES, SUCH AS ASTHMA, CHRONIC OBSTRUCTIVE PULMONARY DISEASE, CYSTIC FIBROSIS, EMPHYSEMA, AND LUNG CANCER. AMONG 20 KNOWN MUCIN GENES IDENTIFIED, 11 OF THEM HAVE BEEN VERIFIED AT EITHER THE MRNA AND/OR PROTEIN LEVEL IN AIRWAYS. THE REGULATION OF MUCIN GENES IS COMPLICATED, AS ARE THE MEDIATORS AND SIGNALING PATHWAYS. THIS REVIEW SUMMARIZES THE CURRENT VIEW ON THE MEDIATORS, THE SIGNALING PATHWAYS, AND THE TRANSCRIPTIONAL UNITS THAT ARE INVOLVED IN THE REGULATION OF AIRWAY MUCIN GENE EXPRESSION. IN ADDITION, WE ALSO POINT OUT ESSENTIAL FEATURES OF EPIGENETIC MECHANISMS FOR THE REGULATION OF THESE GENES. 2008 20 4684 27 NEW POTENTIAL THERAPEUTIC APPROACHES TARGETING SYNOVIAL FIBROBLASTS IN RHEUMATOID ARTHRITIS. SYNOVIAL CELLS PLAY A KEY ROLE IN JOINT DESTRUCTION DURING CHRONIC INFLAMMATION. IN PARTICULAR, ACTIVATED SYNOVIAL FIBROBLASTS (SFS) UNDERGO INTRINSIC ALTERATIONS LEADING TO AN AGGRESSIVE PHENOTYPE MEDIATING CARTILAGE DESTRUCTION AND BONE EROSION IN RHEUMATOID ARTHRITIS (RA). RECENT RESEARCH HAS REVEALED A NUMBER OF TARGETS TO CONTROL ARTHRITOGENIC CHANGES IN SFS. THEREFORE, IDENTIFICATION OF SF PHENOTYPES, CONTROL OF EPIGENETIC CHANGES, MODULATION OF CELLULAR FUNCTIONS, OR REGULATION OF THE ACTIVITY OF CATION CHANNELS AND DIFFERENT SIGNALING PATHWAYS HAS BEEN INVESTIGATED. ALTHOUGH MANY OF THESE APPROACHES HAVE SHOWN EFFICACY IN VITRO AND IN ANIMAL MODELS OF RA, FURTHER RESEARCH IS NEEDED TO SELECT THE MOST RELEVANT TARGETS FOR DRUG DEVELOPMENT. THIS REVIEW IS FOCUSED ON THE ROLE OF SFS AS A POTENTIAL STRATEGY TO DISCOVER NOVEL THERAPEUTIC TARGETS IN RA AIMED AT PRESERVING JOINT ARCHITECTURE AND FUNCTION. 2021