RESUMEN
Both anti-glomerular basement membrane (GBM) disease and the anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) are common causes of pulmonary-renal syndrome. Organizing pneumonia (OP), a special pattern of interstitial lung disease, is extremely rare either in AAV or anti-GBM disease. We report an old woman presented with OP on a background of co-presentation with both ANCA and anti-GBM antibodies.
Asunto(s)
Enfermedad por Anticuerpos Antimembrana Basal Glomerular , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos , Glomerulonefritis , Neumonía Organizada , Neumonía , Femenino , Humanos , Anticuerpos Anticitoplasma de Neutrófilos , Autoanticuerpos , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/complicacionesRESUMEN
Renal amyloidosis secondary to anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis is extremely rare. Here, we reported a 77-year-old woman with ANCA-associated vasculitis. Renal biopsy with Masson trichrome staining showed pauci-immune crescentic glomerulonephritis, and electron microscopy showed amyloid deposition in the mesangial area. Immunofluorescence revealed kappa light chain and lambda light chain negative. Bone marrow biopsy revealed no clonal plasma cell. Finally, she was diagnosed as ANCA-associated vasculitis with secondary renal amyloid A amyloidosis.
Asunto(s)
Amiloidosis , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos , Glomerulonefritis , Femenino , Humanos , Anciano , Glomerulonefritis/etiología , Glomerulonefritis/diagnóstico , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/complicaciones , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/patología , Anticuerpos Anticitoplasma de Neutrófilos , Riñón/patología , Amiloidosis/complicacionesRESUMEN
Myeloperoxidase antineutrophil cytoplasmic antibody (MPO-ANCA) associated vasculitis is an autoimmune disease usually with severe multiple dysfunction syndrome, especially prominent acute renal failure. A 65-year-old woman was admitted with progressive dyspnoea for six months and fever, sputum with blood, pain of the lower extremities and intermittent claudication for two days, indicating multiple organ involvement (respiratory system, blood vessels). The renal involvement was relatively mild, presenting with microscopic haematuria. The chest computed tomography demonstrated multiple pulmonary embolisms. Ultrasound and computed tomography angiography for the lower extremity vessels showed venous and arterial thrombosis. Exclusion of other diseases that can cause multiple organ damage and thrombosis, the positive perinuclear ANCA and MPO-ANCA strongly support the diagnosis of MPO-ANAC-associated vasculitis. The patient's physical condition has been greatly improved by treatment with corticosteroids and anticoagulation.
Asunto(s)
Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos , Embolia Pulmonar , Trombosis , Anciano , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/complicaciones , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/diagnóstico , Femenino , Humanos , Extremidad Inferior/diagnóstico por imagen , Peroxidasa , Embolia Pulmonar/diagnóstico por imagenRESUMEN
BACKGROUND: Oxidative stress-induced endothelial dysfunction and pyroptosis play an important role during chronic kidney disease (CKD) progression. Neferine, which is an alkaloid ingredient from the lotus seed embryo, has many biological actions such as anti-inflammatory, anticancer and antioxidant. However, the role of neferine in endothelial cell pyroptosis and the involved mechanism remain obscure. The aim is to probe the protective effects of neferine on cell pyroptosis and the involved underlying mechanism. METHODS: After the HUVECs were primed with neferine treatment for 2 h prior to LPS and ATP exposure for 24 h, the cell proliferation was determined by BrdU; the cell LDH release was detected by LDH kits; the levels of intracellular ROS, MDA and SOD were tested by detection kits; Caspase-1 activity kit was used to determine caspase-1 activity; the contents of NLRP3, ASC, caspase-1, IL-1ß, IL-18 and GSDMD were tested by RT-PCR and western blot. RESULTS: We found that neferine could inhibit LPS-ATP-induced oxidative stress and the activation of NLRP3 inflammasome signaling, and increased the endothelial cell viability and SOD production. siRNA which mediated the knockdown of NLRP3 promoted the neferine-induced inhibition effects of cell pyroptosis. Furthermore, these neferine-induced effects were reversed by the over-expression of NLRP3. CONCLUSIONS: Our findings indicated neferine may reduce ROS by anti-oxidation and inhibit LPS-ATP-induced endothelial cell pyroptosis via blocking ROS/NLRP3/Caspase-1 signaling pathway, which provides the evidence for therapeutic effect in CKD.
Asunto(s)
Bencilisoquinolinas/farmacología , Caspasa 1/metabolismo , Células Endoteliales/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Transducción de Señal , Adenosina Trifosfato/farmacología , Antioxidantes , Supervivencia Celular , Progresión de la Enfermedad , Regulación de la Expresión Génica , Humanos , Lipopolisacáridos/farmacología , Malondialdehído/metabolismo , Estrés Oxidativo , Piroptosis , ARN Interferente Pequeño/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Insuficiencia Renal Crónica/tratamiento farmacológico , Insuficiencia Renal Crónica/metabolismo , Superóxido Dismutasa/metabolismoRESUMEN
Granite is the host rock of the Beishan Underground Research Laboratory (URL) for geological disposal of high-level radioactive waste in China. The mechanical behavior of Beishan granite is the key in determining whether the repository can serve safely for a long time. The surrounding rock of the repository will be exposed to thermal environment induced by radionuclide decay, resulting in significant changes in the physical and mechanical properties of the Beishan granite. This study investigated the pore structure and mechanical properties of Beishan granite after thermal treatment. The T2 spectrum distribution, pore size distribution, porosity, and magnetic resonance imaging (MRI) were obtained through nuclear magnetic resonance (NMR); uniaxial compressive strength (UCS) and acoustic emission (AE) signal characteristic of granite were investigated through uniaxial compression tests. The results showed that high temperature significantly affected the T2 spectrum distribution, pore size distribution, porosity, compressive strength, and elastic modulus of granite, and porosity gradually increases, whereas the strength and elastic modulus gradually decline with increasing temperature. The porosity of granite has a linear relationship with UCS and elastic modulus, indicating that the essential mechanism for the deterioration of macroscopic mechanical properties lies in changes of microstructure. In addition, the thermal damage mechanism of granite was revealed, and a damage variable was defined based on porosity and uniaxial compressive strength.
Asunto(s)
Residuos Radiactivos , Temperatura , Módulo de Elasticidad , Fuerza CompresivaRESUMEN
BACKGROUND: Studies have shown that epinephrine release is impaired in patients with asthma. The pregnancy of female rats (dams) with asthma promotes in their pups the differentiation of adrenal medulla chromaffin cells (AMCCs) into sympathetic neurons, mediated by nerve growth factor, which leads to a reduction in epinephrine secretion. However, the relatedness between the alteration of AMCCs and increased asthma susceptibility in such offspring has not been established. METHODS: In this study, we observed the effects of allergization via ovalbumin on rat pups born of asthmatic dams. RESULTS: Compared to the offspring of untreated controls, bronchial hyperreactivity and airway inflammation were more severe in the pups from sensitized (asthmatic) dams. In pups exposed to nerve growth factor (NGF) in utero these effects were aggravated further, but the effects were blocked in pups whose dams had been treated with anti-NGF. Furthermore, alterations in AMCC phenotype corresponded to the degree of bronchial hyperreactivity and lung lesions of the different treatment groups. Such AMCC alterations included degranulation of chromaffin granules, reduction of epinephrine and phenylethanolamine-n-methyl transferase, and elevation of NGF and peripherin levels. CONCLUSIONS: Our results present evidence that asthma during the pregnancy of rat dams promotes asthma susceptibility in their offspring, and that the transformation of AMCCs to neurons induced by NGF plays an important role in this process.
Asunto(s)
Asma/inmunología , Células Cromafines/inmunología , Células Cromafines/patología , Neuronas/inmunología , Neuronas/patología , Complicaciones del Embarazo/inmunología , Complicaciones del Embarazo/patología , Alérgenos/administración & dosificación , Animales , Asma/patología , Diferenciación Celular/efectos de los fármacos , Células Cromafines/efectos de los fármacos , Susceptibilidad a Enfermedades/inmunología , Susceptibilidad a Enfermedades/patología , Femenino , Humanos , Masculino , Neuronas/efectos de los fármacos , Ovalbúmina/administración & dosificación , Embarazo , Preñez , Ratas Sprague-DawleyRESUMEN
Traditional Chinese medicine suggests that renal deficiency is a causative factor of asthma, and tonifying kidney drugs are believed to be an appropriate and beneficial treatment. The adrenal medullary chromaffin cells (AMCC) transition to the neuronal phenotype is known to occur in asthma, as evidenced by degranulation of chromaffin granules, decline of epinephrine (EPI) and phenylethanolamine-n-methyl transferase (PNMT), and obvious alterations in cellular architecture. In this study, rats were sensitized and challenged with ovalbumin, then treated with Kidney-Tonifying Recipe (KTR) to evaluate the therapeutic effect. Tissues were evaluated for changes in pathology and EPI, PNMT, and peripherin expression. Degranulation of chromaffin granules and appearance of neurite-like process were found in AMCC from asthmatic rats, and these changes were corrected by KTR treatment. EPI and PNMT expressions were decreased in asthmatic rats and increased by KTR treatment. Peripherin expression was increased in asthmatic rats and decreased in the KTR-treated group. Morphological changes and decreases in EPI were observed when cultured AMCC were exposed to sera from asthmatic rats in vitro, and these changes were attenuated with the addition of sera from KRT-treated rats. These results suggest that the Kidney-Tonifying Recipe is capable of repairing asthma-associated alterations in endocrine function and the ultrastructure of AMCC.
RESUMEN
Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) is a recently identified proinflammatory cytokine of the TNF superfamily. Studies have indicated that TWEAK plays an important role in renal, vascular injury and immune disease. The aim of this study was to explore the expression of the TWEAK in peripheral blood mononuclear cells (PBMCs) and analyze the correlation between TWEAK and disease activity and renal damage of SLE. The expression of TWEAK in PBMCs was determined by RT-PCR and western blot. SLE disease activity was evaluated by Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) 2000 score. Next were analyzed the correlations of TWEAK mRNA and protein to serum IL-10, MCP-1 and some laboratory parameters of SLE disease activity. Subjects comprised 48 patients with SLE including 25 patients with renal damage and 23 without, 20 patients with rheumatoid arthrithis (RA) and 15 healthy controls. The results showed that TWEAK expressions in PBMCs from SLE patients were significantly higher than that in RA patients or healthy controls, especially higher in those patients with renal disease. Elevated production of TWEAK is correlated positively and significantly with SLEDAI, proteinuria, serum anti-dsDNA, IL-10 and MCP-1, but inversely associated with serum complements. Our results suggested that TWEAK in PBMCs is positively related to SLE disease activity and might be involved in the pathogenesis of SLE.
Asunto(s)
Leucocitos Mononucleares/metabolismo , Lupus Eritematoso Sistémico/genética , Nefritis Lúpica/genética , Factores de Necrosis Tumoral/genética , Adolescente , Adulto , Artritis Reumatoide/sangre , Artritis Reumatoide/genética , Artritis Reumatoide/metabolismo , Western Blotting , Quimiocina CCL2/sangre , Citocina TWEAK , Ensayo de Inmunoadsorción Enzimática , Femenino , Expresión Génica , Humanos , Interleucina-10/sangre , Enfermedades Renales/sangre , Enfermedades Renales/genética , Enfermedades Renales/metabolismo , Leucocitos Mononucleares/citología , Lupus Eritematoso Sistémico/sangre , Lupus Eritematoso Sistémico/metabolismo , Nefritis Lúpica/sangre , Nefritis Lúpica/metabolismo , Masculino , Persona de Mediana Edad , ARN Mensajero/genética , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de Necrosis Tumoral/metabolismo , Adulto JovenRESUMEN
Upregulation of transforming growth factor-beta (TGF-beta) signaling is interrelated with the development of airway remodeling. In this study, we examined the role of two E3 ubiquitin ligases, Arkadia and Smurf2, which are critically required for TGF-beta signaling in airway remodeling. Rats were immunized with ovalbumin (OVA) and then challenged with an OVA aerosol. In in vitro experiments, normal human bronchial epithelial cells were stimulated with TGF-beta(1) with or without the preincubation of Arkadia/Smurf2 small interfering RNA (siRNA) or lactacystin (an inhibitor of proteasomal degradation). In the lungs of OVA-treated rats, a large number of inflammatory cells were present near the airways. An increased subepithelial collagen deposition was associated with high expression levels of Smad7, SnoN and Ski mRNAs, Arkadia, Smurf2, and TGF-beta type I receptor (TbetaRI), but low expression levels of Smad7, SnoN and Ski proteins. Smad7, SnoN and Ski interacted with both Arkadia and Smurf2 while TbetaRI only interacted with Smurf2 but not with Arkadia. In in vitro experiments, the inhibitory effect of TGF-beta(1) on the expression of Smad7, SnoN and Ski was reversed by Arkadia siRNA and lactacystin, whereas the stimulatory effect of TGF-beta(1) on the expression of TbetaRI protein and Smad7/SnoN/Ski mRNAs was not affected. In contrast, Smurf2 siRNA did not influence the effects of TGF-beta(1) on the expression of the above proteins. Our results suggest that Arkadia may contribute to the pathogenesis of airway remodeling through enhancing TGF-beta signaling by inducing the reduction of Smad7, SnoN and Ski proteins in OVA-sensitized and -challenged rats.
Asunto(s)
Asma/metabolismo , Pulmón/patología , Factor de Crecimiento Transformador beta/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Animales , Asma/etiología , Asma/patología , Células Cultivadas , Células Epiteliales/metabolismo , Humanos , Masculino , Proteínas del Tejido Nervioso/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , ARN Interferente Pequeño/metabolismo , Ratas , Ratas Sprague-Dawley , Receptor Tipo I de Factor de Crecimiento Transformador beta , Receptores de Factores de Crecimiento Transformadores beta/metabolismo , Proteína smad7/metabolismo , Factores de Transcripción/metabolismoRESUMEN
BACKGROUND: Glucocorticoid (GC) is the first-line therapy for asthma, but some asthmatics are insensitive to it. Glucocorticoid-induced transcript 1 gene (GLCCI1) is reported to be associated with GCs efficiency in asthmatics, while its exact mechanism remains unknown. METHODS: A total of 30 asthmatic patients received fluticasone propionate for 12 weeks. Forced expiratory volume in 1 s (FEV1) and GLCCI1 expression were detected. Asthma model was constructed in wild-type and GLCCI1 knockout (GLCCI1-/-) mice. Glucocorticoid receptor (GR) and mitogen-activated protein kinase phosphatase 1 (MKP-1) expression were detected by polymerase chain reaction and Western blotting (WB). The phosphorylation of p38 mitogen-activated protein kinase (MAPK) was also detected by WB. RESULTS: In asthmatic patients, the change of FEV1 was well positively correlated with change of GLCCI1 expression (r = 0.430, P = 0.022). In animal experiment, GR and MKP-1 mRNA levels were significantly decreased in asthmatic mice than in control mice (wild-type: GR: 0.769 vs. 1.000, P = 0.022; MKP-1: 0.493 vs. 1.000, P < 0.001. GLCCI1-/-: GR: 0.629 vs. 1.645, P < 0.001; MKP-1: 0.377 vs. 2.146, P < 0.001). Hydroprednisone treatment significantly increased GR and MKP-1 mRNA expression levels than in asthmatic groups; however, GLCCI1-/- asthmatic mice had less improvement (wild-type: GR: 1.517 vs. 0.769, P = 0.023; MKP-1: 1.036 vs. 0.493, P = 0.003. GLCCI1-/-: GR: 0.846 vs. 0.629, P = 0.116; MKP-1: 0.475 vs. 0.377, P = 0.388). GLCCI1-/- asthmatic mice had more obvious phosphorylation of p38 MAPK than wild-type asthmatic mice (9.060 vs. 3.484, P < 0.001). It was still higher even though after hydroprednisone treatment (6.440 vs. 2.630, P < 0.001). CONCLUSIONS: GLCCI1 deficiency in asthmatic mice inhibits the activation of GR and MKP-1 and leads to more obvious phosphorylation of p38 MAPK, leading to a decremental sensitivity to GCs. TRIAL REGISTRATION: ChiCTR.org.cn, ChiCTR-RCC-13003634; http://www.chictr.org.cn/showproj.aspx?proj=5926.
Asunto(s)
Asma/tratamiento farmacológico , Asma/metabolismo , Glucocorticoides/uso terapéutico , Receptores de Glucocorticoides/deficiencia , Receptores de Glucocorticoides/metabolismo , Animales , Fosfatasa 1 de Especificidad Dual/genética , Fosfatasa 1 de Especificidad Dual/metabolismo , Volumen Espiratorio Forzado/genética , Volumen Espiratorio Forzado/fisiología , Ratones , Ratones Noqueados , Fosforilación/genética , Fosforilación/fisiología , Receptores de Glucocorticoides/genética , Proteínas Quinasas p38 Activadas por Mitógenos/genética , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
BACKGROUND/AIMS: Upregulation of transforming growth factor beta (TGF-beta)/Smad signaling has been implicated in the primary pathogenesis of renal fibrosis. The ubiquitin-proteasome pathway has an important influence on TGF-beta signaling through regulating Smad degradation. As E3 ubiquitin ligases, both Arkadia and Smurf2 are involved in this prosess. In this study, we focused on Arkadia, Smurf2, Smad7, and TGF-beta type I receptor (TbetaRI), principal molecules in the regulation of TGF-beta signaling, to understand the regulatory mechanism of ubiquitin-proteasomal degradation of TGF-beta signaling in the pathogenesis of renal fibrosis. METHODS: A unilateral ureteral obstruction (UUO) model was employed, and sham-operated rats were used as controls. Renal lesions and the expression of Arkadia, Smurf2, Smad7, TbetaRI, TGF-beta1, and type 1 collagen (COL-1) were detected by Western blot, immunoprecipitation, immunohistochemistry, and/or reverse transcription-polymerase chain reaction. RESULTS: The results indicated progressive tubulointerstitial fibrosis, high expression levels of Arkadia, Smurf2, TbetaRI, TGF-beta1 mRNA, type 1 collagen mRNA, and Smad7 mRNA, and low levels of Smad7 protein in the kidneys of rats with unilateral ureteral obstruction, in which Smurf2 interacted with both Smad7 and TbetaRI, and Arkadia only interacted with Samd7 but not with TbetaRI. CONCLUSION: Reduction of Smad7 resulting from ubiquitin-dependent degradation may be mainly attributed to Arkadia, and Arkadia-Smad7-mediated positive regulation of TGF-beta signaling may play a promoting role in the progression of tubulointerstitial fibrosis.
Asunto(s)
Enfermedades Renales/etiología , Proteína smad7/biosíntesis , Factor de Crecimiento Transformador beta/metabolismo , Ubiquitina-Proteína Ligasas/biosíntesis , Receptores de Activinas Tipo I/biosíntesis , Animales , Modelos Animales de Enfermedad , Fibrosis , Enfermedades Renales/patología , Enfermedades Renales/fisiopatología , Masculino , Proteínas Serina-Treonina Quinasas , Ratas , Ratas Sprague-Dawley , Receptor Tipo I de Factor de Crecimiento Transformador beta , Receptores de Factores de Crecimiento Transformadores beta/biosíntesis , Transducción de SeñalRESUMEN
Recently, high levels of neurotrophic factors have been found in bronchial asthma; these factors include nerve growth factor, brain-derived neurotrophic factor, and leukemia inhibitory factor, among others. Neurotrophic factors are first synthesized in bronchial epithelial cells, immune cells, and other cells in the airway; they are then taken up by the synapse and are finally transported to dorsal root ganglia (C7-T5). Increased neurotrophic factors in dorsal root ganglia promote the synthesis and release of substance P. As a result, substance P causes a series of reactions such as contraction of airway smooth muscles, secretion of mucous fluids, seepage of capillary vessels, release of mediators of inflammation, and aggravation of airway hyperreactivity. It is interesting to note that the anatomic locations of dorsal root ganglia (C7-T5) are similar to a series of acupuncture points in traditional Chinese medicine. These points are all situated on 2 sides of the midspinal line, and most of them belong to Back-shu acupuncture points. In traditional Chinese medicine, Back-shu points can be used to treat patients with bronchial asthma through acupuncture and moxibustion. Is it a coincidence, or is there a real connection? These points possess similar neurotonia, physical function, and therapeutic effects; the functional area of Back-shu is composed of these points. When these points are pricked with a needle along the lower border of the spinous process, dorsal root ganglia and spinal nerves are stimulated; this can help to regulate the synthesis and release of neurotransmitters. It is hypothesized that dorsal root ganglia may be the targets of acupuncture in the treatment of asthma; in this process, acupuncture has an inhibitory effect on the uptake of neurotrophic factors, or it inhibits the synthesis and release of substance P in dorsal root ganglia. As a result, airway neurogenic inflammation in asthma is relieved.
Asunto(s)
Terapia por Acupuntura/métodos , Asma/terapia , Ganglios Espinales , Asma/fisiopatología , Humanos , Factores de Crecimiento Nervioso/metabolismoRESUMEN
Renal amyloidosis secondary to anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis is extremely rare. Here, we reported a 77-year-old woman with ANCA-associated vasculitis. Renal biopsy with Masson trichrome staining showed pauci-immune crescentic glomerulonephritis, and electron microscopy showed amyloid deposition in the mesangial area. Immunofluorescence revealed kappa light chain and lambda light chain negative. Bone marrow biopsy revealed no clonal plasma cell. Finally, she was diagnosed as ANCA-associated vasculitis with secondary renal amyloid A amyloidosis.
Asunto(s)
Femenino , Humanos , Anciano , Glomerulonefritis/diagnóstico , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/patología , Anticuerpos Anticitoplasma de Neutrófilos , Riñón/patología , Amiloidosis/complicacionesRESUMEN
BACKGROUND: Decreased epinephrine (EPI) is an important underlying factor of bronchoconstriction in asthma. Exogenous ß(2)-adrenergic receptor agonist is one of the preferred options to treat asthma. We previously showed that this phenomenon involved adrenal medullary chromaffin cell (AMCC) transformation to a neuron phenotype. However, the underlying molecular mechanism is not fully understood. To further explore this, an asthmatic model with unilateral adrenalectomy was established in this study. METHODOLOGY/PRINCIPAL FINDINGS: Thirty-two rats were randomly into four groups (n = 8 each) control rats (controls), unilateral adrenalectomy rats (surgery-control, s-control), asthmatic rats (asthma), unilateral adrenalectomy asthmatic rats (surgery-induced asthma, s-asthma). Asthmatic rats and s-asthmatic rats were sensitized and challenged with ovalbumin (OVA). The pathological changes in adrenal medulla tissues were observed under microscopy. EPI and its rate-limiting enzyme, phenylethanolamine N-methyl transferase (PNMT), were measured. Peripherin, a type III intermediate filament protein, was also detected in each group. The asthmatic rats presented with decreased chromaffin granules and swollen mitochondria in AMCCs, and the s-asthmatic rats presented more serious pathological changes than those in asthmatic rats and s-control rats. The expressions of EPI and PNMT in asthmatic rats were significantly decreased, as compared with levels in controls (P<0.05), and a further decline was observed in s-asthmatic rats (P<0.05). The expression of peripherin was higher in the asthmatic rats than in the controls, and the highest level was found in the s-asthmatic rats (P<0.05). CONCLUSION/SIGNIFICANCE: Compared with asthmatic rats and s-control rats, the transformation tendency of AMCCs to neurons is more obvious in the s-asthmatic rats. Moreover, this phenotype alteration in the asthmatic rats is accompanied by reduced EPI and PNMT, and increased peripherin expression. This result provides further evidence to support the notion that phenotype alteration of AMCCs contributes to asthma pathogenesis.
Asunto(s)
Médula Suprarrenal/citología , Adrenalectomía/métodos , Asma/fisiopatología , Células Cromafines/citología , Médula Suprarrenal/metabolismo , Animales , Asma/terapia , Broncoconstricción , Corticosterona/farmacología , Modelos Animales de Enfermedad , Ensayo de Inmunoadsorción Enzimática/métodos , Epinefrina/farmacología , Histamina/metabolismo , Proteínas de Filamentos Intermediarios/biosíntesis , Masculino , Glicoproteínas de Membrana/biosíntesis , Modelos Biológicos , Proteínas del Tejido Nervioso/biosíntesis , Neuronas/metabolismo , Periferinas , Fenotipo , Feniletanolamina N-Metiltransferasa/biosíntesis , Ratas , Ratas Sprague-DawleyRESUMEN
BACKGROUND: Adrenal neuroendocrine plays an important role in asthma. The activity of the sympathoadrenal system could be altered by early life events. The effects of maternal asthma during pregnancy on the adrenal medulla of offspring remain unknown. METHODOLOGY/PRINCIPAL FINDINGS: This study aims to explore the influence of maternal asthma during pregnancy on the development and function of adrenal medulla in offspring from postnatal day 3 (P3) to postnatal day 60 (P60). Asthmatic pregnant rats (AP), nerve growth factor (NGF)-treated pregnant rats (NP) and NGF antibody-treated pregnant rats (ANP) were sensitized and challenged with ovalbumin (OVA); NP and ANP were treated with NGF and NGF antibody respectively. Offspring rats from the maternal group were divided into four groups: offspring from control pregnant rats (OCP), offspring from AP (OAP), offspring from NP (ONP), and offspring from ANP (OANP). The expressions of phenylethanolamine N-methyltransferase (PNMT) protein in adrenal medulla were analyzed. The concentrations of epinephrine (EPI), corticosterone and NGF in serum were measured. Adrenal medulla chromaffin cells (AMCC) were prone to differentiate into sympathetic nerve cells in OAP and ONP. Both EPI and PNMT were decreased in OAP from P3 to P14, and then reached normal level gradually from P30 to P60, which were lower from birth to adulthood in ONP. Corticosterone concentration increased significantly in OAP and ONP. CONCLUSION/SIGNIFICANCE: Asthma pregnancy may promote AMCC to differentiate into sympathetic neurons in offspring rats and inhibit the synthesis of EPI, resulting in dysfunction of bronchial relaxation.
Asunto(s)
Médula Suprarrenal/citología , Asma , Células Cromafines/citología , Complicaciones del Embarazo , Animales , Animales Recién Nacidos , Líquido del Lavado Bronquioalveolar , Diferenciación Celular , Células Cromafines/metabolismo , Corticosterona/sangre , Epinefrina/sangre , Femenino , Regulación Enzimológica de la Expresión Génica , Histamina/inmunología , Recuento de Leucocitos , Pulmón/inmunología , Masculino , Madres , Factor de Crecimiento Nervioso/sangre , Feniletanolamina N-Metiltransferasa/metabolismo , Embarazo , Ratas , Ratas Sprague-Dawley , Factores de TiempoRESUMEN
Immunoglobulin A nephropathy (IgAN) is an immune-complex-mediated glomerulonephritis characterized by the presence of IgA deposits in mesangial and paramesangial regions. However, the exact mechanism involved in IgA deposition is still unknown. TGF-ß(1) that mediates the progression of IgAN is well established as a critical IgA class (isotype) switching factor, and Smad proteins are critical intracellular mediators in the expression of TGF-ß(1)-targeted genes, which suggest that TGF-ß signaling has been implicated in the primary pathogenesis of IgAN. Arkadia, an E3 ubiquitin ligase, can amplify TGF-ß signaling through regulating Smads degradation. When these findings are considered together, it is of interest to explore how Arkadia and Smad signaling affect TGF-ß(1)-induced IgA expression in IgAN. Therefore, we propose that Arkadia could positively contribute to TGF-ß(1)-induced IgA secretion through up-regulation of Smad signaling in the pathogenesis of IgAN.
Asunto(s)
Glomerulonefritis por IGA/metabolismo , Inmunoglobulina A/metabolismo , Proteínas Nucleares/fisiología , Transducción de Señal , Proteínas Smad/metabolismo , Factor de Crecimiento Transformador beta1/fisiología , Ubiquitina-Proteína Ligasas/fisiología , Regulación hacia Arriba , Animales , Glomerulonefritis por IGA/inmunología , Humanos , Cambio de Clase de InmunoglobulinaRESUMEN
BACKGROUND: Airway symptoms in asthma are related to decrease of epinephrine secretion, which may be ascribed to elevated nerve growth factor (NGF) in the organism. The aim of this study was to monitor the neuroendocrine alteration in the adrenal medulla of asthmatic rats. METHODS: Sixteen rats were randomly divided into two groups (n = 8), control group and asthma group, and the asthmatic rats were sensitized and challenged with ovalbumin (OVA). The levels of NGF, epinephrine and norepinephrine in serum were detected by enzyme linked immunosorbent assay (ELISA), the NGF expression in adrenal medulla was detected by immunohistochemistry, and the changes in the ultrastructure of the adrenal medulla was observed by electron microscopy. RESULTS: The NGF expression was increased in asthmatic rats compared with control rats. Compared with control rats, the results indicated that the epinephrine level was decreased in asthmatic rats, but no significant difference was found in norepinephrine levels. We found more ganglion cells in the adrenal medulla of asthmatic rats than in control rats, with NGF immunostaining mainly located in these ganglion cells. Electron microscopic images showed the density of chromaffin granula decreased and there was shrunken nucleolemma in the adrenal medullary cells of asthmatic rats. CONCLUSION: The innervation of the adrenal medulla is changed in asthmatic rats, and it may contribute to the epinephrine decrease in asthma.
Asunto(s)
Médula Suprarrenal/metabolismo , Asma/sangre , Asma/metabolismo , Médula Suprarrenal/ultraestructura , Animales , Lavado Broncoalveolar , Ensayo de Inmunoadsorción Enzimática , Epinefrina/sangre , Masculino , Microscopía Electrónica de Transmisión , Factor de Crecimiento Nervioso/sangre , Factor de Crecimiento Nervioso/metabolismo , Norepinefrina/sangre , Distribución Aleatoria , Ratas , Ratas Sprague-DawleyRESUMEN
The ubiquitin-proteasome pathway (UPP) can regulate the stability of proteins, which is regarded as an important mechanism in controlling various biological processes. In the pathway, E3 ubiquitin ligases play critical roles in the recognition of target proteins and degradation by 26S proteasomes. Arkadia is one of the E3 ubiquitin ligases, and recent research has shown that Arkadia amplifies TGF-beta signalling through degradation of Smad7. The cellular level of Smad7 plays an important role in the regulation of Smad-mediated TGF-beta signalling during progression of organ fibrosis. Studies indicate that the level of Smad7 protein expression is decreased in progression of tubulointerstitial fibrosis. Moreover, growing evidence suggests renal tubular epithelial to mesenchymal transition (EMT) plays a key role in renal tubulointerstitial fibrosis and transforming growth factor-beta(1) (TGF-beta(1)) is the most potent inducer that is capable of initiating and completing the entire EMT course. Therefore, the activation of Smad signalling induced by TGF-beta(1) plays a key role in the mechanism of renal tubular EMT, and in this process, Arkadia may has an important influence on the mechanism above mentioned through degradation of Smad7.