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The case was an 80-year-old Japanese man. He was diagnosed with right renal cell carcinoma when he was 74. After laparoscopic radical nephrectomy, the patient received interferon, sorafenib, axitinib, and nivolumab therapy. The patient developed rapid progressive insulin-dependent diabetes mellitus (DM) after 46 courses of nivolumab monotherapy (772 days from the first nivolumab treatment). Glutamic acid decarboxylase antibody, islet cell cytoplasmic antibody, islet cell antigen-2 antibody, insulin antibody, and zinc transporter 8 antibody were all negative. Human leukocyte antigen (HLA) typing showed DRB1*09:01, DRB1 *13:02, DQB1*03:03, and DQB1 *06:04. Multiple daily insulin injections were started. However, controlling his blood glucose by standard multiple daily insulin injection treatments was difficult. The patient survived more than two years after the onset of immune checkpoint inhibitor-associated DM (ICI-DM). This is a valuable report of late-onset ICI-DM with a detailed patient background and clinical course over two years after the first dose of nivolumab.
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BACKGROUND: Coagulopathy is a major cause of morbidity and mortality in COVID-19 patients. Hypercoagulability in COVID-19 results in deep vein thrombosis, thromboembolic complications, and diffuse intravascular coagulation. Microbiome dysbiosis influences the clinical course of COVID-19. However, the role of dysbiosis in COVID-19-associated coagulopathy is not fully understood. OBJECTIVES: The present study tested the hypothesis that the microbiota-derived proapoptotic corisin is involved in the coagulation system activation during SARS-CoV-2 infection. METHODS: This cross-sectional study included 47 consecutive patients who consulted for symptoms of COVID-19. A mouse acute lung injury model was used to recapitulate the clinical findings. A549 alveolar epithelial, THP-1, and human umbilical vein endothelial cells were used to evaluate procoagulant and anticoagulant activity of corisin. RESULTS: COVID-19 patients showed significantly high circulating levels of corisin, thrombin-antithrombin complex, D-dimer, tumor necrosis factor-α, and monocyte-chemoattractant protein-1 with reduced levels of free protein S compared with healthy subjects. The levels of thrombin-antithrombin complex, D-dimer, and corisin were significantly correlated. A monoclonal anticorisin-neutralizing antibody significantly inhibited the inflammatory response and coagulation system activation in a SARS-CoV-2 spike protein-associated acute lung injury mouse model, and the levels of corisin and thrombin-antithrombin complex were significantly correlated. In an in vitro experiment, corisin increased the tissue factor activity and decreased the anticoagulant activity of thrombomodulin in epithelial, endothelial, and monocytic cells. CONCLUSION: The microbiota-derived corisin is significantly increased and correlated with activation of the coagulation system during SARS-CoV-2 infection, and corisin may directly increase the procoagulant activity in epithelial, endothelial, and monocytic cells.
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Coagulación Sanguínea , COVID-19 , Células Endoteliales de la Vena Umbilical Humana , SARS-CoV-2 , Humanos , COVID-19/sangre , COVID-19/complicaciones , COVID-19/inmunología , Animales , Masculino , Femenino , Persona de Mediana Edad , Estudios Transversales , Ratones , Células A549 , Lesión Pulmonar Aguda/microbiología , Lesión Pulmonar Aguda/sangre , Células THP-1 , Anciano , Modelos Animales de Enfermedad , Microbiota , Disbiosis , Adulto , Antitrombina III , Ratones Endogámicos C57BL , Péptido HidrolasasRESUMEN
A 42-year-old Japanese woman with end-stage renal failure due to hypertension presented with a systolic blood pressure of 160-200 mmHg despite treatment with 4 different antihypertensive agents. The plasma aldosterone concentration (PAC) and plasma renin activity (PRA) were elevated. Adrenal vein sampling suggested bilateral excessive aldosterone secretion, whereas adrenocortical scintigraphy showed right-dominant accumulation. Open bilateral nephrectomy and right adrenalectomy improved the systolic blood pressure, PAC, and PRA. A pathological examination revealed zona glomerulosa hyperplasia but not microaldosteronoma. This report shows that bilateral nephrectomy, not unilateral adrenalectomy, is a potentially effective treatment option for resistant hypertension with an elevated renin-angiotensin-aldosterone system in hemodialysis patients.
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Idiopathic pulmonary fibrosis is a progressive and fatal disease with a poor prognosis. Matrix metalloproteinase-2 is involved in the pathogenesis of organ fibrosis. The role of matrix metalloproteinase-2 in lung fibrosis is unclear. This study evaluated whether overexpression of matrix metalloproteinase-2 affects the development of pulmonary fibrosis. Lung fibrosis was induced by bleomycin in wild-type mice and transgenic mice overexpressing human matrix metalloproteinase-2. Mice expressing human matrix metalloproteinase-2 showed significantly decreased infiltration of inflammatory cells and inflammatory and fibrotic cytokines in the lungs compared to wild-type mice after induction of lung injury and fibrosis with bleomycin. The computed tomography score, Ashcroft score of fibrosis, and lung collagen deposition were significantly reduced in human matrix metalloproteinase transgenic mice compared to wild-type mice. The expression of anti-apoptotic genes was significantly increased, while caspase-3 activity was significantly reduced in the lungs of matrix metalloproteinase-2 transgenic mice compared to wild-type mice. Active matrix metalloproteinase-2 significantly decreased bleomycin-induced apoptosis in alveolar epithelial cells. Matrix metalloproteinase-2 appears to protect against pulmonary fibrosis by inhibiting apoptosis of lung epithelial cells.
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Fibrosis Pulmonar Idiopática , Metaloproteinasa 2 de la Matriz , Ratones , Humanos , Animales , Metaloproteinasa 2 de la Matriz/genética , Metaloproteinasa 2 de la Matriz/metabolismo , Pulmón/patología , Fibrosis Pulmonar Idiopática/metabolismo , Bleomicina/efectos adversos , Ratones Transgénicos , Fibrosis , Ratones Endogámicos C57BLRESUMEN
Acute lung injury (ALI) is a clinical syndrome characterized by a diffuse lung inflammation that commonly evolves into acute respiratory distress syndrome and respiratory failure. The lung microbiota is involved in the pathogenesis of ALI. Corisin, a proapoptotic peptide derived from the lung microbiota, plays a role in ALI and acute exacerbation of pulmonary fibrosis. Preventive therapeutic intervention with a monoclonal anticorisin antibody inhibits ALI in mice. However, whether inhibition of corisin with the antibody ameliorates established ALI is unknown. Here, the therapeutic effectiveness of the anticorisin antibody in already established ALI in mice was assessed. Lipopolysaccharide was used to induce ALI in mice. After causing ALI, the mice were treated with a neutralizing anticorisin antibody. Mice treated with the antibody showed significant improvement in lung radiological and histopathologic findings, decreased lung infiltration of inflammatory cells, reduced markers of lung tissue damage, and inflammatory cytokines in bronchoalveolar lavage fluid compared with untreated mice. In addition, the mice treated with anticorisin antibody showed significantly increased expression of antiapoptotic proteins with decreased caspase-3 activation in the lungs compared with control mice treated with an irrelevant antibody. In conclusion, these observations suggest that the inhibition of corisin is a novel and promising approach for treating established ALI.
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Lesión Pulmonar Aguda , Neumonía , Ratones , Animales , Pulmón/patología , Lesión Pulmonar Aguda/patología , Líquido del Lavado Bronquioalveolar , Neumonía/metabolismo , Péptidos/farmacología , Inflamación/patología , Lipopolisacáridos/farmacología , Ratones Endogámicos C57BLRESUMEN
Diabetes mellitus is a global health problem. Diabetic nephropathy is a common complication of diabetes mellitus and the leading cause of end-stage renal disease. The clinical course, response to therapy, and prognosis of nephropathy are worse in diabetic than in non-diabetic patients. The role of transforming growth factorß1 in kidney fibrosis is undebatable. This study assessed whether the overexpression of transforming growth factorß1 is associated with insulin resistance and the rapid progression of transforming growth factorß1-mediated nephropathy under diabetic conditions. Diabetes mellitus was induced with streptozotocin in wild-type mice and transgenic mice with the kidney-specific overexpression of human transforming growth factorß1. Mice treated with saline were the controls. Glucose tolerance and kidney fibrosis were evaluated. The blood glucose levels, the values of the homeostasis model assessment for insulin resistance, and the area of kidney fibrosis were significantly increased, and the renal function was significantly impaired in the diabetic transforming growth factorß1 transgenic mice compared to the non-diabetic transgenic mice, diabetic wild-type mice, and non-diabetic mice. Transforming growth factorß1 impaired the regulatory effect of insulin on glucose in the hepatocyte and skeletal muscle cell lines. This study shows that transforming growth factorß1 overexpression is associated with insulin resistance and rapidly progressive kidney fibrosis under diabetic conditions in mice.
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Diabetes Mellitus , Nefropatías Diabéticas , Resistencia a la Insulina , Humanos , Ratones , Animales , Nefropatías Diabéticas/genética , Nefropatías Diabéticas/tratamiento farmacológico , Fibrosis , Riñón/metabolismo , Ratones Transgénicos , Glucosa/metabolismo , Diabetes Mellitus/patologíaRESUMEN
BACKGROUND: Ectopic adrenocorticotropic hormone (ACTH)-secreting neuroendocrine tumors are rare diseases. Patients with ACTH-secreting pancreatic neuroendocrine carcinomas have a poor prognosis. Infections and coagulopathies have been reported as the cause of death. However, detailed clinical descriptions of the morbid complications of ACTH-secreting neuroendocrine carcinomas have not been reported. CASE SUMMARY: A 78-year-old Japanese woman consulted a medical center due to systemic edema and epigastric discomfort. Laboratory analysis revealed hypercortisolemia with increased ACTH secretion without diurnal variation in serum cortisol level. An enhanced computed tomography (CT) scan revealed a 3-cm tumor in the pancreatic head. The cytological material from endoscopic ultrasound-guided fine-needle aspiration was compatible with ACTH-secreting pancreatic neuroendocrine carcinoma. The Ki-67 index was 40%. She was transferred to Mie University Hospital for surgical treatment. The patient was diagnosed with urinary tract infection, cytomegalovirus hepatitis, esophageal candidiasis, pulmonary infiltrates suspicious for Pneumocystis carinii pneumonia, peripheral deep vein thrombosis, pulmonary embolism, and disseminated intravascular coagulation. The multiple organ infections and thromboses responded well to antimicrobial and anticoagulant therapy. Radioisotope studies disclosed a pancreatic tumor and a metastatic lesion in the liver, whereas somatostatin receptor scintigraphy showed negative findings, suggesting the primary and metastatic tumors were poorly differentiated. A CT scan before admission showed no metastatic liver lesion, suggesting that the pancreatic tumor was rapidly progressing. Instead of surgery, antitumor chemotherapy was indicated. The patient was transferred to another hospital to initiate chemotherapy. However, she died four months later due to the rapidly progressive tumor. CONCLUSION: ACTH-secreting pancreatic neuroendocrine neoplasm is a rare disease with a very poor prognosis. The clinical course and acute complications of the tumor remain unreported. Here we report the clinical course of a rapidly progressive case of ACTH-secreting pancreatic neuroendocrine tumor that developed infectious complications due to many types of pathogens in multiple organs, widespread thromboses, pulmonary embolism, and disseminated intravascular coagulation.
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Idiopathic pulmonary fibrosis is an incurable disease of unknown etiology. Acute exacerbation of idiopathic pulmonary fibrosis is associated with high mortality. Excessive apoptosis of lung epithelial cells occurs in pulmonary fibrosis acute exacerbation. We recently identified corisin, a proapoptotic peptide that triggers acute exacerbation of pulmonary fibrosis. Here, we provide insights into the mechanism underlying the processing and release of corisin. Furthermore, we demonstrate that an anticorisin monoclonal antibody ameliorates lung fibrosis by significantly inhibiting acute exacerbation in the human transforming growth factorß1 model and acute lung injury in the bleomycin model. By investigating the impact of the anticorisin monoclonal antibody in a general model of acute lung injury, we further unravel the potential of corisin to impact such diseases. These results underscore the role of corisin in the pathogenesis of acute exacerbation of pulmonary fibrosis and acute lung injury and provide a novel approach to treating this incurable disease.
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Lesión Pulmonar Aguda , Fibrosis Pulmonar Idiopática , Microbiota , Lesión Pulmonar Aguda/patología , Anticuerpos Monoclonales , Bleomicina , Humanos , Fibrosis Pulmonar Idiopática/etiología , Pulmón/patología , Péptidos/farmacologíaRESUMEN
The leading cause of death worldwide is cancer. Many reports have proved the beneficial effect of mushrooms in cancer. However, the precise mechanism is not completely clear. In the present study, we focused on the medicinal properties of biomolecules released by fairy ring-forming mushrooms. Fairy chemicals generally stimulate or inhibit the growth of surrounding vegetation. In the present study, we evaluated whether fairy chemicals (2-azahypoxanthine, 2-aza-8-oxohypoxanthine, and imidazole-4-carboxamide) exert anticancer activity by decreasing the expression of Axl and immune checkpoint molecules in melanoma cells. We used B16F10 melanoma cell lines and a melanoma xenograft model in the experiments. Treatment of melanoma xenograft with cisplatin combined with imidazole-4-carboxamide significantly decreased the tumor volume compared to untreated mice or mice treated cisplatin alone. In addition, mice treated with cisplatin and imidazole-4-carboxamide showed increased peritumoral infiltration of T cells compared to mice treated with cisplatin alone. In vitro studies showed that all fairy chemicals, including imidazole-4-carboxamide, inhibit the expression of immune checkpoint molecules and Axl compared to controls. Imidazole-4-carboxamide also significantly blocks the cisplatin-induced upregulation of PD-L1. These observations point to the fairy chemical imidazole-4-carboxamide as a promising coadjuvant therapy with cisplatin in patients with cancer.
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Cisplatino , Melanoma , Aminoimidazol Carboxamida/análogos & derivados , Animales , Antígeno B7-H1 , Cisplatino/farmacología , Cisplatino/uso terapéutico , Humanos , Proteínas de Punto de Control Inmunitario , Melanoma/tratamiento farmacológico , RatonesRESUMEN
Apoptosis is a programmed cell death involved in embryogenesis and tissue homeostasis under physiological conditions. However, abnormalities in the process of apoptosis are implicated in the pathogenesis of various diseases. The human microbiota may release products that induce apoptosis of host cells. We recently identified a novel microbiome-derived peptide called corisin that worsens lung fibrosis by inducing apoptosis of lung epithelial cells. We hypothesized that corisin and a corisin-like peptide might also induce apoptosis of cells from different tissues. We cultured podocytes, renal tubular epithelial cells, keratinocytes, retinal and intestinal cells treated with corisin and evaluated apoptosis by flow cytometry and Western blotting. Although at different grades, flow cytometry analysis and Western blotting showed that corisin and a corisin-like peptide induced apoptosis of podocytes, keratinocytes, tubular epithelial cells, retinal, and intestinal cells. In addition, we found that corisin synergistically enhances the proapoptotic activity of transforming growth factor-ß1 on podocytes. In conclusion, these results suggest that corisin and corisin-like peptides may play a role in the pathogenesis of disease in different organs by promoting apoptosis of parenchymal cells.
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Apoptosis , Microbiota , Especificidad de Órganos , Péptidos/farmacología , Apoptosis/efectos de los fármacos , Caspasa 3/metabolismo , Línea Celular Tumoral , Células Epiteliales/efectos de los fármacos , Células Epiteliales/patología , Células HaCaT , Humanos , Queratinocitos/efectos de los fármacos , Queratinocitos/patología , Microbiota/efectos de los fármacos , Membranas Mitocondriales/efectos de los fármacos , Membranas Mitocondriales/metabolismo , Especificidad de Órganos/efectos de los fármacos , Podocitos/efectos de los fármacos , Podocitos/patología , Especies Reactivas de Oxígeno/metabolismo , Retina/patología , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
Diabetes mellitus is a global threat to human health. The ultimate cause of diabetes mellitus is insufficient insulin production and secretion associated with reduced pancreatic ß-cell mass. Apoptosis is an important and well-recognized mechanism of the progressive loss of functional ß-cells. However, there are currently no available antiapoptotic drugs for diabetes mellitus. This study evaluated whether recombinant human thrombomodulin can inhibit ß-cell apoptosis and improve glucose intolerance in a diabetes mouse model. A streptozotocin-induced diabetes mouse model was prepared and treated with thrombomodulin or saline three times per week for eight weeks. The glucose tolerance and apoptosis of ß-cells were evaluated. Diabetic mice treated with recombinant human thrombomodulin showed significantly improved glucose tolerance, increased insulin secretion, decreased pancreatic islet areas of apoptotic ß-cells, and enhanced proportion of regulatory T cells and tolerogenic dendritic cells in the spleen compared to counterpart diseased mice treated with saline. Non-diabetic mice showed no changes. This study shows that recombinant human thrombomodulin, a drug currently used to treat patients with coagulopathy in Japan, ameliorates glucose intolerance by protecting pancreatic islet ß-cells from apoptosis and modulating the immune response in diabetic mice. This observation points to recombinant human thrombomodulin as a promising antiapoptotic drug for diabetes mellitus.
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Apoptosis/efectos de los fármacos , Glucemia/efectos de los fármacos , Diabetes Mellitus Experimental/prevención & control , Hipoglucemiantes/administración & dosificación , Islotes Pancreáticos/efectos de los fármacos , Trombomodulina/administración & dosificación , Animales , Biomarcadores/sangre , Glucemia/metabolismo , Línea Celular Tumoral , Células Dendríticas/efectos de los fármacos , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Diabetes Mellitus Experimental/sangre , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Experimental/patología , Inyecciones Intraperitoneales , Islotes Pancreáticos/metabolismo , Islotes Pancreáticos/patología , Masculino , Ratones Endogámicos C57BL , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Recombinantes/administración & dosificación , Bazo/efectos de los fármacos , Bazo/inmunología , Bazo/metabolismo , Estreptozocina , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismoRESUMEN
INTRODUCTION: Diabetes mellitus is a serious threat to public health worldwide. It causes a substantial economic burden, mental and physical disabilities, poor quality of life, and high mortality. Limonite is formed when iron-rich materials from the underground emerge and oxidized on the ground surface. It is currently used to purify contaminated water, absorption of irritant gases, and improve livestock breeding. Limonite can change the composition of environmental microbial communities. In the present study, we evaluated whether limonite can ameliorate glucose metabolism abnormalities by remodeling the gut microbiome. METHODS: The investigation was performed using mouse models of streptozotocin-induced diabetes mellitus and high-calorie diet-induced metabolic syndrome. RESULTS: Oral limonite supplement was associated with significant body weight recovery, reduced glycemia with improved insulin secretion, increased number of regulatory T cells, and abundant beneficial gut microbial populations in mice with diabetes mellitus compared to control. Similarly, mice with obesity fed with limonite supplements had significantly reduced body weight, insulin resistance, steatohepatitis, and systemic inflammatory response with significant gut microbiome remodeling. CONCLUSION: This study demonstrates that limonite supplement ameliorates abnormal glucose metabolism in diabetes mellitus and obesity. Gut microbiome remodeling, inhibition of inflammatory cytokines, and the host immune response regulation may explain the limonite's beneficial activity under pathological conditions in vivo.
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Kidney fibrosis is the common consequence of chronic kidney diseases that inexorably progresses to end-stage kidney disease with organ failure treatable only with replacement therapy. Since transforming growth factor-ß1 is the main player in the pathogenesis of kidney fibrosis, we posed the hypothesis that recombinant thrombomodulin can ameliorate transforming growth factor-ß1-mediated progressive kidney fibrosis and failure. To interrogate our hypothesis, we generated a novel glomerulus-specific human transforming growth factor-ß1 transgenic mouse to evaluate the therapeutic effect of recombinant thrombomodulin. This transgenic mouse developed progressive glomerular sclerosis and tubulointerstitial fibrosis with kidney failure. Therapy with recombinant thrombomodulin for four weeks significantly inhibited kidney fibrosis and improved organ function compared to untreated transgenic mice. Treatment with recombinant thrombomodulin significantly inhibited apoptosis and mesenchymal differentiation of podocytes by interacting with the G-protein coupled receptor 15 to activate the Akt signaling pathway and to upregulate the expression of anti-apoptotic proteins including survivin. Thus, our study strongly suggests the potential therapeutic efficacy of recombinant thrombomodulin for the treatment of chronic kidney disease and subsequent organ failure.
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Insuficiencia Renal Crónica , Factor de Crecimiento Transformador beta1 , Fibrosis , Proteínas de Unión al GTP , Humanos , Riñón/patología , Proteínas Proto-Oncogénicas c-akt , Insuficiencia Renal Crónica/tratamiento farmacológico , Insuficiencia Renal Crónica/patología , Transducción de Señal , Trombomodulina/genética , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
Background: Lung cancer is the leading cause of mortality for cancer worldwide. A point mutation in exon 21 of the epidermal growth factor receptor resulting in the substitution of arginine for leucine at position 858 (L858R) is a frequent cause of lung adenocarcinoma. Tyrosine kinase inhibitors are effective for treating patients with lung cancer associated with mutant epidermal growth factor receptors but most tumors become resistant shortly after treatment. The substitution of methionine for threonine at position 790 (T790M) on exon 20 is the most frequently acquired mutation leading to resistance to tyrosine kinase inhibitors. Whether the T790M mutation occurred after tyrosine kinase inhibitor therapy or it already existed before therapy is unclear. Methods: Here, we developed mice with tetracycline-inducible lung-specific expression of the full-length genomic DNA of the human epidermal growth factor receptor containing an L858R mutation or both L858R and T790M mutations and evaluated de novo T790M mutation in untreated transgenic mice carrying a single L858R EGFR mutation. Results: The L858R mutation-associated lung adenocarcinoma acquired de novo T790 mutation without previous therapy. Conclusions: The results of this study suggest that lung tumors may spontaneously acquire T790M mutations without any drug-related selective pressure.
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Idiopathic pulmonary fibrosis (IPF) is a chronic and fatal disease of unknown etiology; however, apoptosis of lung alveolar epithelial cells plays a role in disease progression. This intractable disease is associated with increased abundance of Staphylococcus and Streptococcus in the lungs, yet their roles in disease pathogenesis remain elusive. Here, we report that Staphylococcus nepalensis releases corisin, a peptide conserved in diverse staphylococci, to induce apoptosis of lung epithelial cells. The disease in mice exhibits acute exacerbation after intrapulmonary instillation of corisin or after lung infection with corisin-harboring S. nepalensis compared to untreated mice or mice infected with bacteria lacking corisin. Correspondingly, the lung corisin levels are significantly increased in human IPF patients with acute exacerbation compared to patients without disease exacerbation. Our results suggest that bacteria shedding corisin are involved in acute exacerbation of IPF, yielding insights to the molecular basis for the elevation of staphylococci in pulmonary fibrosis.
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Proteínas Reguladoras de la Apoptosis/inmunología , Proteínas Bacterianas/inmunología , Fibrosis Pulmonar Idiopática/inmunología , Péptidos/inmunología , Staphylococcus/inmunología , Anciano , Animales , Apoptosis/inmunología , Proteínas Reguladoras de la Apoptosis/análisis , Proteínas Reguladoras de la Apoptosis/metabolismo , Proteínas Bacterianas/análisis , Proteínas Bacterianas/metabolismo , Líquido del Lavado Bronquioalveolar/química , Líquido del Lavado Bronquioalveolar/inmunología , Modelos Animales de Enfermedad , Células Epiteliales/inmunología , Células Epiteliales/patología , Femenino , Voluntarios Sanos , Humanos , Fibrosis Pulmonar Idiopática/genética , Fibrosis Pulmonar Idiopática/microbiología , Fibrosis Pulmonar Idiopática/patología , Pulmón/inmunología , Pulmón/microbiología , Pulmón/patología , Macrófagos/inmunología , Masculino , Ratones , Ratones Transgénicos , Péptidos/análisis , Péptidos/metabolismo , Staphylococcus/metabolismo , Staphylococcus/patogenicidad , Brote de los Síntomas , Linfocitos T Reguladores/inmunología , Factor de Crecimiento Transformador beta1/genética , Factor de Crecimiento Transformador beta1/inmunologíaRESUMEN
BACKGROUND: Bronchial asthma is a chronic disease characterized by inflammation, obstruction, and hyperresponsiveness of the airways. There is currently no curative therapy for asthma. Type 2 helper T cell response plays a critical role in the pathogenesis of the disease. Protein S is a glycoprotein endowed with anticoagulant, anti-inflammatory, and anti-apoptotic properties. Whether protein S can suppress bronchial asthma and be useful for its therapy is unknown. METHODS: To address this question here we compared the development of allergen-associated bronchial asthma between wild type and protein S-overexpressing transgenic mice. Mice were sensitized and challenged with ovalbumin. We also evaluated the circulating levels of total and active protein S in patients with bronchial asthma and healthy controls. RESULTS: The circulating level of total protein S and of its active form was significantly decreased in patients with bronchial asthma compared to controls. Allergic protein S transgenic mice showed a significant reduction of airway hyperresponsiveness, lung tissue inflammatory cell infiltration, lung levels of Th2 cytokines and IgE compared to their wild-type counterparts. Administration of exogenous human protein S also decreased airway hyperresponsiveness and Th2-mediated lung inflammation in allergic wild-type mice compared with their untreated mouse counterparts. Human protein S significantly shifted the Th1/Th2 balance to Th1 and promoted the secretion of Th1 cytokines (IL-12, tumor necrosis factor-α) from dendritic cells. CONCLUSIONS: These observations suggest the strong protective activity of protein S against the development of allergic bronchial asthma implicating its potential usefulness for the disease treatment.
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Asma , Hiperreactividad Bronquial , Animales , Asma/prevención & control , Citocinas , Modelos Animales de Enfermedad , Humanos , Inmunoglobulina E , Pulmón , Ratones , Ratones Endogámicos BALB C , Ovalbúmina , Proteína S , Células Th2RESUMEN
Idiopathic pulmonary fibrosis is a chronic, progressive, and lethal lung disease of unknown etiology. Antifibrotic drugs, including pirfenidone, are currently used for the treatment of the disease. The oral administration of pirfenidone is an effective therapy, as demonstrated by several clinical trials, although it causes severe adverse events in some patients. We hypothesized that low-dose intrapulmonary delivery of pirfenidone is effective in human transforming growth factorß1-driven pulmonary fibrosis. To demonstrate our hypothesis, we compared the therapeutic efficacy of varying doses of pirfenidone administered by oral and intranasal routes in a human transforming growth factor-ß1 transgenic mouse with established pulmonary fibrosis. We found similar amelioration of lung cell infiltration, inflammatory and fibrotic cytokines, lung fibrosis score, and hydroxyproline content in mice with human transforming growth factor-ß1-mediated pulmonary fibrosis treated with low-dose intranasal pirfenidone and high-dose oral pirfenidone. This study showed that pirfenidone is a potent inhibitor of human transforming growth factor-ß1-driven lung fibrosis and that intrapulmonary delivery of low-dose pirfenidone produces therapeutic responses equivalent to high-dose of oral pirfenidone.
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Inflammation, reversible obstruction, and hyperresponsiveness of the airways are characteristic findings of bronchial asthma. Several evidence has demonstrated the involvement of matrix metalloproteinase-2 in allergic airway inflammation. Matrix metalloproteinase-2 may promote aberrant tissue remodeling in late stages of allergic airway inflammation. However, whether matrix metalloproteinase-2 is detrimental or protective in early stages of allergic airway inflammation remains unclear. To evaluate this here we compared the severity of allergic bronchial asthma between mice overexpressing human matrix metalloproteinase-2 and wild type mice. After sensitization and challenge with an allergen, mice overexpressing the human matrix metalloproteinase-2 showed a significant reduction in airway hyperresponsiveness and in the expression of Th2 cytokines and IgE compared to their wild type counterparts. An inhibitor of matrix metalloproteinases abolished this beneficial effect of human matrix metalloproteinase-2 overexpression. Allergen-sensitized and challenged human matrix metalloproteinase-2 transgenic mice had enhanced percentage of M1 macrophages with increased expression of inducible nitric oxide synthase and STAT1 activation in the lungs compared to their wild type counterparts. There was no difference in the percentage of regulatory T cells between mouse groups. The results of this study showed that matrix metalloproteinase-2 is protective in allergic bronchial asthma by promoting polarization of macrophages to M1 phenotype.
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Asma/metabolismo , Metaloproteinasa 2 de la Matriz/metabolismo , Hipersensibilidad Respiratoria/metabolismo , Alérgenos/inmunología , Animales , Asma/inmunología , Citocinas/inmunología , Citocinas/metabolismo , Modelos Animales de Enfermedad , Femenino , Humanos , Inmunoglobulina E/inmunología , Inmunoglobulina E/metabolismo , Inflamación/inmunología , Inflamación/metabolismo , Pulmón/inmunología , Pulmón/metabolismo , Macrófagos/inmunología , Macrófagos/metabolismo , Masculino , Metaloproteinasa 2 de la Matriz/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Persona de Mediana Edad , Ovalbúmina/inmunología , Hipersensibilidad Respiratoria/inmunología , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Células Th2/inmunología , Células Th2/metabolismoRESUMEN
Acute lung injury is a fatal disease characterized by inflammatory cell infiltration, alveolar-capillary barrier disruption, protein-rich edema, and impairment of gas exchange. Protein S is a vitamin K-dependent glycoprotein that exerts anticoagulant, immunomodulatory, anti-inflammatory, anti-apoptotic, and neuroprotective effects. The aim of this study was to evaluate whether human protein S inhibits cell apoptosis in acute lung injury. Acute lung injury in human protein S transgenic and wild-type mice was induced by intratracheal instillation of lipopolysaccharide. The effect of human protein S on apoptosis of lung tissue cells was evaluated by Western blotting. Inflammatory cell infiltration, alveolar wall thickening, myeloperoxidase activity, and the expression of inflammatory cytokines were reduced in human protein S transgenic mice compared to the wild-type mice after lipopolysaccharide instillation. Apoptotic cells and caspase-3 activity were reduced while phosphorylation of extracellular signal-regulated kinase was enhanced in the lung tissue from human protein S transgenic mice compared to wild-type mice after lipopolysaccharide instillation. The results of this study suggest that human protein S is protective in lipopolysaccharide-induced acute lung injury by inhibiting apoptosis of lung cells.