RESUMEN
In a Japanese chemical factory, lung diseases such as pneumoconiosis have been reported among workers handling cross-linked water-soluble acrylic acid polymers (CWAAP). Our previous study reported that a single intratracheal administration of CWAAP induces acute inflammation and fibrosis. In this study, we investigated the effects of multiple intratracheal administrations of CWAAP on inflammatory responses and pulmonary fibrosis along with inducible bronchus-associated lymphoid tissues (iBALT) formation, which is involved in allergic inflammation. Male F344 rats (190-200 g) received single or multiple intratracheal administrations of phosphate-buffered saline (PBS) or CWAAP. To assess inflammatory responses and pulmonary fibrosis, immunohistochemical and histological staining was performed. CD68, CD163, CD169, TGF-ß, and collagen I positive cells/areas in the lungs of the CWAAP-group rats were significantly increased than those in the PBS group. Furthermore, the number of iBALT structures, CD4 + T cells, along with CD19, PAX5, IL-4, GATA-3, T-bet, and IgE-positive cells in the terminal bronchioles and blood vessels of the lungs were significantly increased in the CWAAP group. Moreover, pulmonary fibrosis, iBALT formation, and levels of specific IgG were significantly increased in rats who received multiple intratracheal administrations of CWAAP compared to those with single intratracheal administration. Multiple intratracheal administrations of CWAAP potentiated the classical fibrotic pathway (M2 macrophage-TGF-ß-collagen I) more potently than single intratracheal administration. Furthermore, it was possible that iBALT was formed around terminal bronchioles and blood vessels and the number of immune cells was increased, resulting in enhanced allergic inflammation and pulmonary fibrosis.
Asunto(s)
Acrilatos , Fibrosis Pulmonar , Masculino , Ratas , Animales , Fibrosis Pulmonar/patología , Polímeros , Ratas Endogámicas F344 , Tejido Linfoide , Bronquios/patología , Pulmón/patología , Inflamación/patología , Factor de Crecimiento Transformador beta , ColágenoRESUMEN
AIM: Hepatocellular adenoma (HCA) has a lower prevalence in Japan than in Western countries and HCA subtypes have been reported for only a few Japanese patients. We analyzed HCA subtype data 38 patients from 23 hospitals in Japan in order to examine character and difference between Western countries. METHODS: To confirm HCA and to analyze subtypes, we performed immunohistochemical examinations. RESULTS: Thirty-eight cases were found to have HCA without cirrhosis. The male/female ratio was 18/20. Ages ranged from 15 to 79 (average, 43.2) years. Male and elder patients are not rare, furthermore, most of elder patients are male. Glycogen storage disease, past history of medicament use, hepatitis B virus surface antigen-positivity, antihepatitis C virus -positivity, diabetes mellitus, obesity, lipid metabolism disorder and alcoholism were present in of 6, 8, 1, 1, 6, 6, 4, and 6 cases, respectively. As to HCA subtypes, HNF1alpha-inactivated HCA, beta-catenin activated HCA (b-HCA), inflammatory HCA (IHCA) and unclassified HCA (U-HCA) accounted for nine (23.7%), four (10.5%), 17 (44.7%) and eight (21.1%) cases, respectively. Two cases showed coexistence of HCA and hepatocellular carcinoma (HCC) at surgery, and another had HCC which had been detected 23 years after HCA diagnosis. The HCA subtype of one of the former cases was U-HCA, while the remaining two had b-HCA and U-HCA. CONCLUSIONS: In Japanese HCA cases, the proportions of U-HCA, male and elder cases were slightly higher than in Western countries, and most of elder patients were male. IHCA was however common regardless of race, and was assumed to be the predominant subtype of HCA.
RESUMEN
In a Japanese chemical factory, a lung disease like pneumoconiosis appeared at a high rate among workers handling cross-linked water-soluble acrylic acid polymer (CWAAP). To our knowledge, no such case was known in the world until very recently. The present study was designed to elucidate the effect of single intratracheal CWAAP instillation on the lung of rats. The CWAAP group had a significant increase in relative lung weight accompanied by a significant elevation in the number of total cells, total protein concentrations, and myeloperoxidase concentrations in bronchoalveolar lavage fluid when compared to the control group. The histopathological study revealed acute lung inflammation with the destruction of alveoli. The factors promoting fibrosis, macrophages, TGF-ß1, collagen and fibronectin vs. the factors suppressing fibrosis, matrix metalloproteinases were more powerfully driven in the CWAAP group, resultantly leading to fibrotic formation. In turn, we examined if acute lung inflammation and the subsequent fibrotic formation seen in the CWAAP group appeared in the other water-soluble polymer groups. Their histopathological findings were observed only in the polyacrylic acid sodium (PAAS), a monomer of CWAAP, group. The degree of inflammation and fibrogenesis was stronger in the CWAAP group than in the PAAS group. In conclusion, the present study demonstrated the induction of acute lung inflammation and the subsequent fibrotic formation by single intratracheal CWAAP instillation. The structural features of CWAAP that contains many carboxyl groups and cross-linked chains may be responsible for enhanced inflammation and fibrogenesis in the lung.
Asunto(s)
Acrilatos/toxicidad , Reactivos de Enlaces Cruzados/toxicidad , Polímeros/toxicidad , Alveolos Pulmonares/metabolismo , Fibrosis Pulmonar/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Acrilatos/administración & dosificación , Animales , Reactivos de Enlaces Cruzados/administración & dosificación , Inflamación/inducido químicamente , Inflamación/metabolismo , Inflamación/patología , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Pulmón/patología , Masculino , Polímeros/administración & dosificación , Alveolos Pulmonares/efectos de los fármacos , Alveolos Pulmonares/patología , Fibrosis Pulmonar/inducido químicamente , Fibrosis Pulmonar/patología , Ratas , Ratas Endogámicas F344 , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Tráquea/efectos de los fármacos , Tráquea/metabolismo , Tráquea/patologíaRESUMEN
Transforming growth factor-ß (TGF-ß) is a key driver for liver fibrogenesis. TGF-ß must be activated in order to function. Plasma kallikrein (PLK) is a TGF-ß activator that cleaves the latency-associated protein (LAP) between arginine58 and lysine59 residues and releases active TGF-ß from the latent TGF-ß-LAP complex. Thus, the generation of two LAP degradation products, ending at arginine58 (R58/LAP-DPs) and beginning from lysine59 (L59/LAP-DPs), reflects PLK-dependent TGF-ß activation. However, the significance and details of TGF-ß activation in patients with chronic liver disease (CLD) remain uncertain. We herein examined the PLK-dependent TGF-ß activation in patients by detecting R58 and L59/LAP-DPs. A total of 234 patients with CLD were included in this study. Liver biopsy specimens were used for immunostaining to detect R58/LAP-DPs, while plasma samples were subjected to an enzyme-linked immunosorbent assay to measure the L59/LAP-DP concentration. R58/LAP-DP was robustly expressed in and around the sinusoidal cells before the development of the fibrous regions. The R58/LAP-DP expression at fibrosis stage 1 was higher than at any other stages, and the relationship between the plasma L59/LAP-DP level and the stage of fibrosis also showed a similar trend. The abundance of plasma L59/LAP-DP showed no correlation with the levels of direct serum biomarkers of liver fibrosis; however, its changes during interferon-based therapy for chronic hepatitis C were significantly associated with virological responses. Our results suggest that PLK-dependent TGF-ß activation occurs in the early stages of fibrosis and that its unique surrogate markers, R58 and L59/LAP-DPs, are useful for monitoring the clinical course of CLD.
RESUMEN
A 32-year-old Japanese woman was admitted to our hospital for the diagnosis and treatment of multiple liver tumors. She had been receiving 125 mg testosterone enanthate every 2 weeks following female-to-male gender identity disorder (GID) diagnosis at 20 years of age. Ultrasonography, computed tomography, and magnetic resonance imaging showed 11 hepatic nodular tumors with a maximum diameter of 28 mm. Liver tumors with hepatocellular adenoma (HCA) were diagnosed with needle biopsy. Segmentectomy of the left lateral lobe including two lesions, subsegmentectomy of S6 including two lesions, enucleation of each tumor in S5 and S7, and open surgical radiofrequency ablation for each tumor in S4 and S7 were performed. Immunohistochemical specimens showed that the tumor cells were diffusely and strongly positive for glutamine synthetase and that the nuclei were ectopically positive for ß-catenin. Thus, the tumors were diagnosed as ß-catenin-activated HCA (b-HCA). Transcatheter arterial chemoembolization plus subsequent radiofrequency ablation was performed for the 3 residual lesions in S4 and S8. Although testosterone enanthate was being continued for GID, no recurrence was observed until at least 22 months after the intensive treatments. HCA development in such patients receiving testosterone should be closely monitored using image inspection.
Asunto(s)
Andrógenos/efectos adversos , Carcinoma Hepatocelular/inducido químicamente , Identidad de Género , Neoplasias Hepáticas/inducido químicamente , Neoplasias Primarias Múltiples/inducido químicamente , Testosterona/análogos & derivados , Adulto , Carcinoma Hepatocelular/clasificación , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/cirugía , Femenino , Humanos , Neoplasias Hepáticas/clasificación , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/cirugía , Neoplasias Primarias Múltiples/clasificación , Neoplasias Primarias Múltiples/diagnóstico , Neoplasias Primarias Múltiples/cirugía , Testosterona/efectos adversosRESUMEN
AIM: Serum Mac-2 binding protein (M2BP) and Wisteria floribunda agglutinin-positive Mac-2 binding protein (WFA+ -M2BP) are used to estimate the liver fibrosis stage in chronic liver diseases. However, few head-to-head studies have been carried out to compare the two biomarkers in non-alcoholic fatty liver disease (NAFLD). METHODS: Serum M2BP and WFA+ -M2BP levels were compared against clinical characteristics and liver histological manifestations in the same samples collected from 213 biopsy-proven NAFLD patients. RESULTS: Median levels (range) of M2BP and WFA+ -M2BP were 1.58 (0.70-7.75) pg/mL and 0.85 (0.22-11.32) cut-off index (COI), respectively. Fibrosis stages 1, 2, 3, and 4 were determined in 136, 37, 17, and 23 patients, respectively. Median levels of both biomarkers increased stepwise with fibrosis progression. The M2BP and WFA+ -M2BP levels showed a significant positive correlation (r = 0.643, P = 2.91 × 10-26 ), but a marked discrepancy between both biomarkers was noted in five stage 4 and three stage 1 patients, who had high WFA+ -M2BP but relatively low M2BP levels. Most of these outliers had findings suggestive of more advanced fibrosis. For diagnosing any fibrosis severity, WFA+ -M2BP had greater area under the receiver operating characteristic curve (AUC) and predictive accuracy than M2BP. Among eight fibrosis markers/indices, WFA+ -M2BP yielded the second highest AUC (0.832) and the highest predictive accuracy (82.2%) to diagnose cirrhosis. In addition, WFA+ -M2BP showed the second highest predictive accuracy to diagnose severe fibrosis (78.4%) and significant fibrosis (76.1%). CONCLUSION: This head-to-head comparison suggests that WFA+ -M2BP is superior to M2BP for distinguishing liver fibrosis stages in NAFLD patients. A marked discrepancy between the two biomarkers may be indicative of advanced NAFLD (UMIN000023286).
RESUMEN
The contamination of ground water by fluoride has been reported worldwide. Most fluoride (approximately 70%) is filtered by the kidneys; humans or experimental animals with renal damage therefore may be more affected by fluoride exposure than those with normal kidney function. Tubulointerstitial fibrosis, which involves macrophage-promoted extracellular matrix production and myofibroblast migration, can be induced in rats by unilateral ureteral obstruction (UUO). We examined the effects of fluoride exposure on tubulointerstitial fibrosis in the obstructed kidney of UUO rats. The left ureters of 6-week-old male rats were ligated using silk sutures. Fluoride was then administered for 2 weeks at doses of 0, 75, and 150ppm in the drinking water. Real-time polymerase chain reaction was performed to analyze transforming growth factor beta 1 (TGF-ß1) transcription; histological and immunohistochemical staining were used to identify positive areas within the renal cortex and staining-positive cells by image analysis. Significant increases were observed in the obstructed kidneys of UUO rats exposed to 150ppm fluoride (compared to 0ppm) for areas or number of cells that stained with Masson trichrome or with antibodies against collagen type I, alpha-smooth muscle actin (α-SMA, a myofibroblast marker), ED1, ED2, and ED3 (macrophage markers), and TGF-ß1. Taken together, these observations suggested that fluoride exacerbates tuburointerstitial nephropathy resulting from UUO, and that this effect occurs via activation of the M2 macrophage-TGF-ß1-fibroblast/myofibroblast-collagen synthesis pathway.
Asunto(s)
Fluoruros/toxicidad , Enfermedades Renales/patología , Obstrucción Ureteral/patología , Actinas/genética , Actinas/metabolismo , Animales , Relación Dosis-Respuesta a Droga , Fluoruros/sangre , Riñón/efectos de los fármacos , Riñón/fisiopatología , Macrófagos/citología , Macrófagos/efectos de los fármacos , Masculino , Miofibroblastos/citología , Miofibroblastos/efectos de los fármacos , Tamaño de los Órganos/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Factor de Crecimiento Transformador beta1/genética , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
BACKGROUND: Thrombin is a serine protease known to be the final product of the coagulation cascade. However, thrombin plays other physiological roles in processes such as gastric contractions and vessel wound healing, and a state of coagulability is increased in patients with dilated cardiomyopathy (DCM). In this study, we investigate the role of thrombin in the pathogenesis of DCM. The purpose of this study is to clarify the role of thrombin in the pathogenesis of DCM and investigate the possibility of treatment against DCM by thrombin inhibition. METHODS: We investigated the expression of thrombin in the left ventricles of five patients with DCM who underwent the Batista operation and four patients without heart disease. Furthermore, we investigated the involvement of thrombin in the development of DCM using knock-in mice with a deletion mutation of cardiac troponin T that causes human DCM (∆K210 knock-in mouse) (B6;129-Tnnt2tm2Mmto) and assessed the effects of a direct thrombin inhibitor, dabigatran on ∆K210 knock-in mice using echocardiographic examinations, the Kaplan-Meier method and Western blotting. RESULTS: The immunohistochemical analysis showed a strong thrombin expression in the DCM patients compared to the patients without heart disease. In immunohistochemical analysis, a strong thrombin expression was observed in the heart tissues analysis in the ∆K210 knock-in mice. Dabigatran administration significantly improved fractional shortening according to the echocardiographic examination and the survival outcomes in ∆K210 knock-in mice. CONCLUSION: Tissue thrombin is involved in the pathogenesis of DCM and thrombin inhibition can be beneficial for the treatment of DCM.
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Cardiomiopatía Dilatada/etiología , Cardiomiopatía Dilatada/metabolismo , Trombina/metabolismo , Animales , Antitrombinas/uso terapéutico , Cardiomiopatía Dilatada/patología , Estudios de Casos y Controles , Dabigatrán/uso terapéutico , Modelos Animales de Enfermedad , Humanos , RatonesRESUMEN
AIM: To reassess the role of bridging fibrosis in the lobular distortion of the liver from an angioarchitectural aspect. METHODS: Two tissue samples obtained from surgically resected livers with chronic hepatitis and one obtained from an autopsy case with chronic hepatitis were used for the three-dimensional observation of angioarchitecture by histological reconstruction. RESULTS: Samples showed bridging fibrosis with various degrees of severity, without cirrhotic changes. Two different types of portal-portal bridging fibrosis were found. In our samples, the type that developed in the bifurcation region of the portal tracts was more common than the type observed between the distal portions originating from different parent portal tracts. The angioarchitecture tended to be generally maintained in these lesions. Concerning portal-central bridging fibrosis, two types were observed. One type developed in the lesion with partial paucity of the third-step portal branches in the portal tract at a relatively early stage of chronic hepatitis. The other type developed in an advanced lesion with a complete loss of the normal angioarchitecture of the parenchymal portion of the portal veins. The former was likely developed after large-scale necrosis, such as bridging necrosis, while the latter was presumed to be attributable to portal vein damage associated with long standing chronic inflammation. CONCLUSION: As has been previously noted regarding lobular angioarchitecture, portal-central bridging fibrosis clearly affects the lobular structure of the liver more than portal-portal bridging fibrosis. Therefore, portal vein damage may be a critical event in the eventual distortion of the lobular structure.
RESUMEN
BACKGROUND: The receptor for advanced glycation end products (RAGE) is recognized to be responsible for cancer progression in several human cancers. In this study, we investigated the clinical impact of RAGE expression in patients with hepatocellular carcinoma (HCC) after hepatectomy. MATERIALS AND METHODS: Sixty-five consecutive patients who underwent initial hepatectomy for HCC were investigated. The relationships between immunohistochemical expression of RAGE and clinicopathologic features, clinical outcome (overall survival [OS], and disease-free survival [DFS]) were evaluated. RESULTS: The cytoplasmic expression of RAGE in HCC cells was observed in 46 patients (70.8%) and correlated with histologic grade (poorly differentiated versus moderately differentiated HCC, P = 0.021). Five-year OS in RAGE-positive and RAGE-negative groups were 72% and 94%, respectively, whereas 5-y DFS were 29% and 55%, respectively. There were significant differences between OS and DFS (P = 0.018 and 0.031, respectively). Multivariate analysis indicated that RAGE was an independent predictor for both OS and DFS (P = 0.048 and 0.032, respectively). CONCLUSIONS: Our data suggest for the first time a positive correlation between RAGE expression and poor therapeutic outcome. Furthermore, RAGE downregulation may provide a novel therapeutic target for HCC.
Asunto(s)
Carcinoma Hepatocelular , Hepatectomía/mortalidad , Neoplasias Hepáticas , Receptores Inmunológicos/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/metabolismo , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/mortalidad , Carcinoma Hepatocelular/cirugía , Regulación hacia Abajo , Femenino , Humanos , Estimación de Kaplan-Meier , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/cirugía , Masculino , Persona de Mediana Edad , Análisis Multivariante , Valor Predictivo de las Pruebas , Pronóstico , Receptor para Productos Finales de Glicación AvanzadaRESUMEN
BACKGROUND & AIMS: Precisely what type of cells mainly contributes to portal fibrosis, especially in chronic viral hepatitis, such as hepatic stellate cells (HSCs) in the parenchyma or myofibroblasts in the portal area, still remains unclear. It is necessary to clarify the characteristics of cells that contribute to portal fibrosis in order to determine the mechanism of portal fibrogenesis and to develop a therapeutic target for portal fibrosis. This study was undertaken to examine whether LRAT+/CRBP-1+ HSCs contribute to portal fibrosis on viral hepatitis. METHODS: Antibodies to lecithin:retinol acyltransferase (LRAT), cellular retinol-binding protein-1 (CRBP-1) and widely ascertained antibodies to HSCs (alpha-smooth muscle actin, neurotrophin-3) and endothelial cells (CD31) were used for immunohistochemical studies to assess the distribution of cells that contribute to the development of portal fibrosis with the aid of fluorescence microscopy. A quantitative analysis of LRAT+/CRBP-1+ HSCs was performed. RESULTS: The number of LRAT+/CRBP-1+ HSCs was increased in fibrotic liver in comparison with normal liver in the portal area and fibrous septa. The number of double positive cells was less than 20% of all cells/field in maximum. CONCLUSION: This study provides evidence that functional HSCs coexpressing both LRAT and CRBP-1 that continue to maintain the ability to store vitamin A contribute in part to the development of portal fibrogenesis in addition to parenchymal fibrogenesis in patients with viral hepatitis.
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Aciltransferasas/metabolismo , Fibrosis/patología , Células Estrelladas Hepáticas/metabolismo , Hepatitis/fisiopatología , Vena Porta/patología , Proteínas Celulares de Unión al Retinol/metabolismo , Aciltransferasas/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Fibrosis/etiología , Fibrosis/metabolismo , Hepatitis/complicaciones , Hepatitis/metabolismo , Humanos , Inmunohistoquímica , Masculino , Microscopía Fluorescente , Persona de Mediana Edad , Proteínas Celulares de Unión al Retinol/inmunología , Vitamina A/metabolismoRESUMEN
The morphogenesis of lobular restructuring to liver cirrhosis in nonalcoholic steatohepatitis (NASH) is yet to be clearly understood. Therefore, we observed tissue samples from three biopsies and one autopsy with NASH in the non-cirrhotic stage three-dimensionally to elucidate the evolution of fibrosis and the changes of angioarchitecture. Histologic reconstructions revealed that pericellular fibrosis developed around the central vein in the early stage and gradually progressed to arch-shaped band-like fibrosis connecting the central veins in the neighboring lobules. In contrast, the basic angioarchitecture of the portal vein in the portal tracts tended to be preserved in the non-cirrhotic stage, although the portal vein architecture was slightly altered as the portal tract underwent gradual fibrous expansion. In addition, a striking development of arteries originating from the portal tract was found in the fibrotic area around the central and sublobular veins. In summary, while central-central bridging fibrosis and ectopic arterial development were conspicuous, the lobular architecture was maintained relatively well in the non-cirrhotic stage of NASH because of only mildly damaged angioarchitecture of the portal veins. The process of lobular restructuring in NASH is considered to be different from that in chronic viral hepatitis in the non-cirrhotic stage.
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Hígado Graso/patología , Hígado/patología , Vena Porta/patología , Adulto , Femenino , Humanos , Interpretación de Imagen Asistida por Computador , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Marked accumulation of alveolar macrophages (AM) conferred by apoptosis resistance has been implicated in pathogenesis of chronic obstructive pulmonary disease (COPD). Apoptosis inhibitor of macrophage (AIM), has been shown to be produced by mature tissue macrophages and AIM demonstrates anti-apoptotic property against multiple apoptosis-inducing stimuli. Accordingly, we attempt to determine if AIM is expressed in AM and whether AIM is involved in the regulation of apoptosis in the setting of cigarette smoke extract (CSE) exposure. METHODS: Immunohistochemical evaluations of AIM were performed. Immunostaining was assessed by counting total and positively staining AM numbers in each case (n = 5 in control, n = 5 in non-COPD smoker, n = 5 in COPD). AM were isolated from bronchoalveolar lavage fluid (BALF). The changes of AIM expression levels in response to CSE exposure in AM were evaluated. Knock-down of anti-apoptotic Bcl-xL was mediated by siRNA transfection. U937 monocyte-macrophage cell line was used to explore the anti-apoptotic properties of AIM. RESULTS: The numbers of AM and AIM-positive AM were significantly increased in COPD lungs. AIM expression was demonstrated at both mRNA and protein levels in isolated AM, which was enhanced in response to CSE exposure. AIM significantly increased Bcl-xL expression levels in AM and Bcl-xL was involved in a part of anti-apoptotic mechanisms of AIM in U937 cells in the setting of CSE exposure. CONCLUSIONS: These results suggest that AIM expression in association with cigarette smoking may be involved in accumulation of AM in COPD.
Asunto(s)
Proteínas Reguladoras de la Apoptosis/biosíntesis , Regulación de la Expresión Génica , Macrófagos Alveolares/metabolismo , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Anciano , Antígenos CD/biosíntesis , Antígenos CD/genética , Antígenos de Diferenciación de Linfocitos T/biosíntesis , Antígenos de Diferenciación de Linfocitos T/genética , Proteínas Reguladoras de la Apoptosis/genética , Líquido del Lavado Bronquioalveolar , Células Cultivadas , Femenino , Células HEK293 , Humanos , Lectinas Tipo C/biosíntesis , Lectinas Tipo C/genética , Macrófagos Alveolares/patología , Masculino , Persona de Mediana Edad , Enfermedad Pulmonar Obstructiva Crónica/genética , Enfermedad Pulmonar Obstructiva Crónica/patología , Células U937RESUMEN
When 100 mg/kg/day of di(n-butyl) phthalate (DBP) was intragastrically administered to pregnant Sprague-Dawley rats throughout gestation days 12 to 21, the male pups had similar body weights with no apparent physical differences (e.g., litter size, sex ratio) compared to that of the vehicle group. However, prominent age-related morphological alterations in the smooth endoplasmic reticulum (sER) of testicular Leydig cells (LCs) were observed once these animals reached puberty. At weeks 5 to 7, the abundant sER with non-dilated cisternae was distributed in LCs. Subsequently, although the number of LCs significantly increased, the amount of sER was significantly decreased at 9 to 14 weeks of age and had disappeared at 17 weeks. In contrast, the number of LCs and the amount of sER in LCs of the lower dose groups (10, 30, and 50 mg/kg/day) were similar to those of the vehicle group. Further, serum testosterone levels in the 100 mg/kg dose group were significantly lower during 5 to 17 weeks of age. While their luteinizing hormone (LH) level was significantly lower at 5 to 7 weeks of age, it became significantly higher during 9 to 17 weeks. The amount of sER in LCs decreased with age with the increase in LCs proliferation and serum LH levels in rat exposed in utero to DBP in a dose-dependent manner.
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Dibutil Ftalato/toxicidad , Retículo Endoplásmico Liso/efectos de los fármacos , Células Intersticiales del Testículo/efectos de los fármacos , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Testosterona/metabolismo , Factores de Edad , Animales , Peso Corporal/efectos de los fármacos , Dibutil Ftalato/administración & dosificación , Relación Dosis-Respuesta a Droga , Retículo Endoplásmico Liso/metabolismo , Retículo Endoplásmico Liso/patología , Femenino , Células Intersticiales del Testículo/metabolismo , Células Intersticiales del Testículo/patología , Hormona Luteinizante/metabolismo , Masculino , Exposición Materna , Embarazo , Efectos Tardíos de la Exposición Prenatal/metabolismo , Efectos Tardíos de la Exposición Prenatal/patología , Ratas , Ratas Sprague-Dawley , Testículo/efectos de los fármacos , Testículo/metabolismoRESUMEN
The present study describes atypical Leydig cell (LC) hyperplasia in 20-week-old Sprague-Dawley rats with low testosterone and high luteinizing hormone levels after prenatal administration of 100 mg/kg/day di(n-butyl) phthalate on days 12 to 21 postconception. Light microscopy revealed LC hyperplasia surrounded by severely degenerated seminiferous tubules. Aggregated LCs had large ovoid nuclei with nucleoli and abundant eosinophilic cytoplasm. Immunohistochemical analysis showed expression of proliferating cell nuclear antigen and vimentin in many hyperplastic LCs. Electron microscopy revealed atypical nuclei, abundant free ribosomes, stripped rough endoplasmic reticulum, intermediate-size filaments, elongated cytoplasmic filopodia, atypical tight junctions, and cilia formations, but smooth endoplasmic reticulum was scarcely observed.
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Dibutil Ftalato/toxicidad , Células Intersticiales del Testículo/efectos de los fármacos , Células Intersticiales del Testículo/patología , Hormona Luteinizante/sangre , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Efectos Tardíos de la Exposición Prenatal/patología , Testosterona/metabolismo , Animales , Femenino , Histocitoquímica , Hiperplasia/inducido químicamente , Hiperplasia/patología , Masculino , Embarazo , Ratas , Ratas Sprague-Dawley , Testículo/química , Testículo/efectos de los fármacos , Testículo/patologíaRESUMEN
Autophagy, a process that helps maintain homeostatic balance between the synthesis, degradation, and recycling of organelles and proteins to meet metabolic demands, plays an important regulatory role in cellular senescence and differentiation. Here we examine the regulatory role of autophagy in idiopathic pulmonary fibrosis (IPF) pathogenesis. We test the hypothesis that epithelial cell senescence and myofibroblast differentiation are consequences of insufficient autophagy. Using biochemical evaluation of in vitro models, we find that autophagy inhibition is sufficient to induce acceleration of epithelial cell senescence and myofibroblast differentiation in lung fibroblasts. Immunohistochemical evaluation of human IPF biospecimens reveals that epithelial cells show increased cellular senescence, and both overlaying epithelial cells and fibroblasts in fibroblastic foci (FF) express both ubiquitinated proteins and p62. These findings suggest that insufficient autophagy is an underlying mechanism of both accelerated cellular senescence and myofibroblast differentiation in a cell-type-specific manner and is a promising clue for understanding the pathogenesis of IPF.
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Autofagia , Fibrosis Pulmonar Idiopática/fisiopatología , Proteínas Adaptadoras Transductoras de Señales/biosíntesis , Diferenciación Celular/fisiología , Senescencia Celular/fisiología , Estrés del Retículo Endoplásmico/fisiología , Células Epiteliales/patología , Células Epiteliales/fisiología , Humanos , Miofibroblastos/citología , Proteína Sequestosoma-1 , Tunicamicina/farmacología , Ubiquitina/biosíntesisRESUMEN
We present a case of organizing pneumonia complicated by pneumothorax in association with cyst formation that developed during corticosteroid treatment. Although it has been reported that the check-valve mechanism is a plausible cause of cyst and pneumothorax formation in patients with organizing pneumonia, the details of the corresponding pathological changes that occur in air-trapping have not been elucidated. A pathological examination of lung specimens obtained with video-assisted thoracoscopic surgery suggested that granulation tissues plugging the bronchiole lumens might be a potential cause of the check-valve mechanism in this case. In this report, we also reviewed eight other cases of organizing pneumonia with pneumothorax or cyst formation.
Asunto(s)
Quistes/etiología , Enfermedades Pulmonares/etiología , Neumonía/complicaciones , Neumotórax/etiología , Corticoesteroides/efectos adversos , Adulto , Quistes/diagnóstico , Humanos , Enfermedades Pulmonares/diagnóstico , Masculino , Neumonía/diagnóstico , Neumonía/tratamiento farmacológico , Neumotórax/diagnóstico , Neumotórax/cirugía , Cirugía Torácica Asistida por Video , Tomografía Computarizada por Rayos XRESUMEN
Autoimmune pancreatitis (AIP) can be difficult to distinguish from pancreatic cancer. We report a case of histopathologically proven AIP mimicking neuroendocrine tumor (NET) or pancreatic cancer in a 53-year-old man. He was referred to our hospital for further evaluation of a pancreatic mass detected on ultrasonography at a medical check-up. Abdominal ultrasonography showed a 15-mm hypoechoic mass located in the pancreatic body. Computed tomography revealed a tumor without any contrast enhancement, and magnetic resonance imaging demonstrated the mass to be hyperintense on diffusion-weighted image. Endoscopic retrograde cholangiopancreatography revealed slight dilatation of a branch of the pancreatic duct without stricture of the main pancreatic duct. The common bile duct seemed intact. Under suspicion of a non-functioning NET or malignant neoplasm, laparotomy was performed. At laparotomy, an elastic firm and well-circumscribed mass was found suggestive of a non-functioning NET, thus enucleation was performed. Histopathologically, the lesion corresponded to AIP.
RESUMEN
Cigarette smoke induces damage to proteins and organelles by oxidative stress, resulting in accelerated epithelial cell senescence in the lung, which is implicated in chronic obstructive pulmonary disease (COPD) pathogenesis. Although the detailed molecular mechanisms are not fully understood, cellular energy status is one of the most crucial determinants for cell senescence. Creatine kinase (CK) is a constitutive enzyme, playing regulatory roles in energy homeostasis of cells. Among two isozymes, brain-type CK (CKB) is the predominant CK in lung tissue. In this study, we investigated the role of CKB in cigarette smoke extract (CSE)-induced cellular senescence in human bronchial epithelial cells (HBECs). Primary HBECs and Beas2B cells were used. Protein carbonylation was evaluated as a marker of oxidative protein damage. Cellular senescence was evaluated by senescence-associated ß-galactosidase staining. CKB inhibition was examined by small interfering RNA and cyclocreatine. Secretion of IL-8, a hallmark of senescence-associated secretary phenotype, was measured by ELISA. CKB expression levels were reduced in HBECs from patients with COPD compared with that of HBECs from nonsmokers. CSE induced carbonylation of CKB and subsequently decreased CKB protein levels, which was reversed by a proteasome inhibitor. CKB inhibition alone induced cell senescence, and further enhanced CSE-induced cell senescence and IL-8 secretion. CSE-induced oxidation of CKB is a trigger for proteasomal degradation. Concomitant loss of enzymatic activity regulating energy homeostasis may lead to the acceleration of bronchial epithelial cell senescence, which is implicated in the pathogenesis of COPD.
Asunto(s)
Bronquios/efectos de los fármacos , Senescencia Celular/efectos de los fármacos , Forma BB de la Creatina-Quinasa/metabolismo , Células Epiteliales/efectos de los fármacos , Humo/efectos adversos , Fumar/efectos adversos , Bronquios/enzimología , Bronquios/inmunología , Bronquios/patología , Células Cultivadas , Forma BB de la Creatina-Quinasa/antagonistas & inhibidores , Forma BB de la Creatina-Quinasa/genética , Ciclina B1/metabolismo , Regulación hacia Abajo , Ensayo de Inmunoadsorción Enzimática , Células Epiteliales/enzimología , Células Epiteliales/inmunología , Células Epiteliales/patología , Humanos , Inmunohistoquímica , Interleucina-8/metabolismo , Estrés Oxidativo/efectos de los fármacos , Inhibidores de Proteasas/farmacología , Complejo de la Endopetidasa Proteasomal/metabolismo , Inhibidores de Proteasoma , Carbonilación Proteica/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Interferencia de ARN , Transducción de Señal/efectos de los fármacos , Ubiquitinación , beta-Galactosidasa/metabolismoRESUMEN
Sertoli cells play a critical role in spermatogenesis, and in adults, they are terminally differentiated with loss of proliferative activity. This study revealed Sertoli cell proliferation in 17-week-old Sprague-Dawley rats whose dams had been intragastrically administered 250 ng of 3,3',4,4',5-pentachlorobiphenyl/kg on days 13-19 postconception. Immunohistochemical evidence of proliferating cell nuclear antigen (PCNA) expression and electron microscope observation of mitotic figures confirmed the proliferation. Because the serum follicle stimulating hormone (FSH), luteinizing hormone (LH) and testosterone concentrations were similar to those of vehicle-treated rats, a direct endocrine cause for the observed effects was unlikely.