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1.
BMC Infect Dis ; 21(1): 176, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33588779

RESUMO

BACKGROUND: Epidemiological and clinical features of patients with corona virus disease 2019 (COVID-19) were well delineated. However, no researches described the patients complicated with pleural effusion (PE). In the present study, we aimed to clinically characterize the COVID-19 patients complicated with PE and to create a predictive model on the basis of PE and other clinical features to identify COVID-19 patients who may progress to critical condition. METHODS: This retrospective study examined 476 COVID-19 inpatients, involving 153 patients with PE and 323 without PE. The data on patients' past history, clinical features, physical checkup findings, laboratory results and chest computed tomography (CT) findings were collected and analyzed. LASSO regression analysis was employed to identify risk factors associated with the severity of COVID-19. RESULTS: Laboratory findings showed that patients with PE had higher levels of white blood cells, neutrophils, lactic dehydrogenase, C-reactive protein and D-dimer, and lower levels of lymphocytes, platelets, hemoglobin, partial pressure of oxygen and oxygen saturation. Meanwhile, patients with PE had higher incidence of severe or critical illness and mortality rate, and longer hospital stay time compared to their counterparts without pleural effusion. Moreover, LASSO regression analysis exhibited that pleural effusion, lactic dehydrogenase (LDH), D-dimer and total bilirubin (TBIL) might be risk factors for critical COVID-19. CONCLUSIONS: Pleural effusion could serve as an indicator for severe inflammation and poor clinical outcomes, and might be a complementary risk factor for critical type of COVID-19.


Assuntos
COVID-19/patologia , Derrame Pleural/patologia , Adulto , Proteína C-Reativa/análise , COVID-19/diagnóstico por imagem , COVID-19/fisiopatologia , China , Exsudatos e Transudatos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Derrame Pleural/fisiopatologia , Estudos Retrospectivos , Fatores de Risco , SARS-CoV-2/fisiologia , Índice de Gravidade de Doença , Tomografia Computadorizada por Raios X
2.
Oxid Med Cell Longev ; 2020: 8822361, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33101593

RESUMO

Acute lung injury (ALI) and the subsequent acute respiratory distress syndrome remain devastating diseases with high mortality rates and poor prognoses among patients in intensive care units. The present study is aimed at investigating the role and underlying mechanisms of microRNA-31-5p (miR-31-5p) on lipopolysaccharide- (LPS-) induced ALI. Mice were pretreated with miR-31-5p agomir, antagomir, and their negative controls at indicated doses for 3 consecutive days, and then they received a single intratracheal injection of LPS (5 mg/kg) for 12 h to induce ALI. MH-S murine alveolar macrophage cell lines were cultured to further verify the role of miR-31-5p in vitro. For AMP-activated protein kinase α (AMPKα) and calcium-binding protein 39 (Cab39) inhibition, compound C or lentiviral vectors were used in vivo and in vitro. We observed an upregulation of miR-31-5p in lung tissue upon LPS injection. miR-31-5p antagomir alleviated, while miR-31-5p agomir exacerbated LPS-induced inflammation, oxidative damage, and pulmonary dysfunction in vivo and in vitro. Mechanistically, miR-31-5p antagomir activated AMPKα to exert the protective effects that were abrogated by AMPKα inhibition. Further studies revealed that Cab39 was required for AMPKα activation and pulmonary protection by miR-31-5p antagomir. We provide the evidence that endogenous miR-31-5p is a key pathogenic factor for inflammation and oxidative damage during LPS-induced ALI, which is related to Cab39-dependent inhibition of AMPKα.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Lesão Pulmonar Aguda/patologia , Proteínas de Ligação ao Cálcio/metabolismo , MicroRNAs/metabolismo , Proteínas Quinases Ativadas por AMP/genética , Lesão Pulmonar Aguda/tratamento farmacológico , Animais , Antagomirs/metabolismo , Antagomirs/uso terapêutico , Gasometria , Proteínas de Ligação ao Cálcio/antagonistas & inibidores , Proteínas de Ligação ao Cálcio/genética , Modelos Animais de Doenças , Interleucina-6/genética , Interleucina-6/metabolismo , Lipopolissacarídeos/toxicidade , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Estresse Oxidativo/efeitos dos fármacos , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Transdução de Sinais/efeitos dos fármacos , Superóxido Dismutase/metabolismo , Regulação para Cima/efeitos dos fármacos
4.
Sci Rep ; 10(1): 10263, 2020 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-32581324

RESUMO

COVID-19 is "public enemy number one" and has placed an enormous burden on health authorities across the world. Given the wide clinical spectrum of COVID-19, understanding the factors that can predict disease severity will be essential since this will help frontline clinical staff to stratify patients with increased confidence. To investigate the diagnostic value of the temporal radiographic changes, and the relationship to disease severity and viral clearance in COVID-19 patients. In this retrospective cohort study, we included 99 patients admitted to the Renmin Hospital of Wuhan University, with laboratory confirmed moderate or severe COVID-19. Temporal radiographic changes and viral clearance were explored using appropriate statistical methods. Radiographic features from HRCT scans included ground-glass opacity, consolidation, air bronchogram, nodular opacities and pleural effusion. The HRCT scores (peak) during disease course in COVID-19 patients with severe pneumonia (median: 24.5) were higher compared to those with pneumonia (median: 10) (p = 3.56 × 10 -12), with more frequency of consolidation (p = 0.025) and air bronchogram (p = 7.50 × 10-6). The median values of days when the peak HRCT scores were reached in pneumonia or severe pneumonia patients were 12 vs. 14, respectively (p = 0.048). Log-rank test and Spearman's Rank-Order correlation suggested temporal radiographic changes as a valuable predictor for viral clearance. In addition, follow up CT scans from 11 pneumonia patients showed full recovery. Given the values of HRCT scores for both disease severity and viral clearance, a standardised HRCT score system for COVID-19 is highly demanded.


Assuntos
Infecções por Coronavirus/diagnóstico por imagem , Infecções por Coronavirus/patologia , Pneumonia Viral/diagnóstico por imagem , Pneumonia Viral/patologia , Tomografia Computadorizada por Raios X/métodos , Adulto , Idoso , Betacoronavirus , COVID-19 , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias , Interpretação de Imagem Radiográfica Assistida por Computador , Estudos Retrospectivos , SARS-CoV-2
5.
Cell Metab ; 31(6): 1068-1077.e3, 2020 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-32369736

RESUMO

Type 2 diabetes (T2D) is a major comorbidity of COVID-19. However, the impact of blood glucose (BG) control on the degree of required medical interventions and on mortality in patients with COVID-19 and T2D remains uncertain. Thus, we performed a retrospective, multi-centered study of 7,337 cases of COVID-19 in Hubei Province, China, among which 952 had pre-existing T2D. We found that subjects with T2D required more medical interventions and had a significantly higher mortality (7.8% versus 2.7%; adjusted hazard ratio [HR], 1.49) and multiple organ injury than the non-diabetic individuals. Further, we found that well-controlled BG (glycemic variability within 3.9 to 10.0 mmol/L) was associated with markedly lower mortality compared to individuals with poorly controlled BG (upper limit of glycemic variability exceeding 10.0 mmol/L) (adjusted HR, 0.14) during hospitalization. These findings provide clinical evidence correlating improved glycemic control with better outcomes in patients with COVID-19 and pre-existing T2D.


Assuntos
Glicemia/análise , Infecções por Coronavirus/mortalidade , Diabetes Mellitus Tipo 2/sangue , Índice Glicêmico/fisiologia , Hiperglicemia/sangue , Pneumonia Viral/mortalidade , Idoso , Betacoronavirus/patogenicidade , COVID-19 , Infecções por Coronavirus/complicações , Infecções por Coronavirus/patologia , Diabetes Mellitus Tipo 2/complicações , Suscetibilidade a Doenças/patologia , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Hiperglicemia/complicações , Hipoglicemiantes/uso terapêutico , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Insuficiência de Múltiplos Órgãos/complicações , Insuficiência de Múltiplos Órgãos/mortalidade , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/patologia , Estudos Retrospectivos , SARS-CoV-2
7.
Biochim Biophys Acta Biomembr ; 1862(5): 183205, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32001212

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a chronic disease characterized by an abnormal healing response to injury of the alveolar epithelium. Tight junctions provide a physical barrier at the apical intercellular space between epithelial cells and regulate paracellular flux. While tight junction alterations are known to contribute to barrier dysfunction in a number of disease states, the role of tight junction proteins in IPF is poorly defined. To determine a potential role for tight junction protein alterations in IPF, we performed immunohistochemical staining for tight junction proteins ZO-1, occludin, claudin-2, claudin-3, claudin-4, claudin-5, and claudin-18. Staining intensity and localization were compared between IPF and control lung tissues. IPF was associated with type II pneumocyte hyperplasia and altered tight junction protein expression. While there was no difference in the expression of ZO-1, claudin-3, or claudin-5, between IPF and normal control, there was an overall increase in claudin-2 expression in bronchiolar and alveolar epithelium and a decrease in claudin-4 expression in type II pneumocytes. There was also increased occludin and decreased claudin-18 expression in pneumocytes overlying fibroblastic foci. These findings suggest that epithelial barrier alterations may be important to the pathogenesis of IPF.


Assuntos
Fibrose Pulmonar Idiopática/metabolismo , Junções Íntimas/metabolismo , Idoso , Células Epiteliais Alveolares/metabolismo , Claudina-4/genética , Claudina-4/metabolismo , Claudinas/genética , Claudinas/metabolismo , Feminino , Humanos , Fibrose Pulmonar Idiopática/fisiopatologia , Pulmão/metabolismo , Masculino , Pessoa de Meia-Idade , Ocludina/metabolismo , Mucosa Respiratória/metabolismo , Mucosa Respiratória/patologia , Proteínas de Junções Íntimas/análise , Proteínas de Junções Íntimas/metabolismo , Junções Íntimas/fisiologia , Proteína da Zônula de Oclusão-1/metabolismo
8.
Curr Med Sci ; 39(5): 748-753, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31612392

RESUMO

Although several studies confirmed that berberine may attenuate airway inflammation in mice with chronic obstructive pulmonary disease (COPD), its underlying mechanisms were not clear until now. We aimed to establish an experiment mouse model for COPD and to investigate the effects of berberine on airway inflammation and its possible mechanism in COPD model mice induced by cigarette smoke extract (CSE). Twenty SPF C57BL/6 mice were randomly divided into PBS control group, COPD model group, low-dose berberine group and high-dose berberine group, 5 mice in each group. The neutrophils and macrophages were examined by Wright's staining. The levels of inflammatory cytokines TNF-α and IL-6 in bronchoalveolar lavage fluid (BALF) were determined by enzyme-linked immunosorbent assay. The expression levels of TGF-ß1, Smad2 and Smad3 mRNA and proteins in lung tissues were respectively detected by quantitative real-time polymerase chain reaction and Western blotting. It was found that CSE increased the number of inflammation cells in BALF, elevated lung inflammation scores, and enhanced the TGF-ß1/Smads signaling activity in mice. High-dose berberine restrained the alterations in the COPD mice induced by CSE. It was concluded that high-dose berberine ameliorated CSE-induced airway inflammation in COPD mice. TGF-ß1/Smads signaling pathway might be involved in the mechanism. These findings suggested a therapeutic potential of high-dose berberine on the CSE-induced airway inflammation.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Berberina/farmacologia , Pulmão/efeitos dos fármacos , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Proteína Smad2/genética , Proteína Smad3/genética , Fator de Crescimento Transformador beta1/genética , Animais , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/imunologia , Fumar Cigarros/efeitos adversos , Misturas Complexas/antagonistas & inibidores , Misturas Complexas/farmacologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Esquema de Medicação , Regulação da Expressão Gênica , Inflamação , Interleucina-6/genética , Interleucina-6/imunologia , Pulmão/imunologia , Pulmão/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Neutrófilos/patologia , Doença Pulmonar Obstrutiva Crônica/genética , Doença Pulmonar Obstrutiva Crônica/imunologia , Doença Pulmonar Obstrutiva Crônica/patologia , Transdução de Sinais , Proteína Smad2/imunologia , Proteína Smad3/imunologia , Fator de Crescimento Transformador beta1/antagonistas & inibidores , Fator de Crescimento Transformador beta1/imunologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
9.
FASEB J ; 33(2): 2132-2143, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30252535

RESUMO

Epithelial barrier maintenance and regulation requires an intact perijunctional actomyosin ring underneath the cell-cell junctions. By searching for known factors affecting the actin cytoskeleton, we identified Krev interaction trapped protein 1 (KRIT1) as a major regulator for epithelial barrier function through multiple mechanisms. KRIT1 is expressed in both small intestinal and colonic epithelium, and KRIT1 knockdown in differentiated Caco-2 intestinal epithelium decreases epithelial barrier function and increases cation selectivity. KRIT1 knockdown abolished Rho-associated protein kinase-induced and myosin II motor inhibitor-induced barrier loss by limiting both small and large molecule permeability but did not affect myosin light chain kinase-induced increases in epithelial barrier function. These data suggest that KRIT1 participates in Rho-associated protein kinase- and myosin II motor-dependent (but not myosin light chain kinase-dependent) epithelial barrier regulation. KRIT1 knockdown exacerbated low-dose TNF-induced barrier loss, along with increased cleaved caspase-3 production. Both events are blocked by pan-caspase inhibition, indicating that KRIT1 regulates TNF-induced barrier loss through limiting epithelial apoptosis. These data indicate that KRIT1 controls epithelial barrier maintenance and regulation through multiple pathways, suggesting that KRIT1 mutation in cerebral cavernous malformation disease may alter epithelial function and affect human health.-Wang, Y., Li, Y., Zou, J., Polster, S. P., Lightle, R., Moore, T., Dimaano, M., He, T.-C., Weber, C. R., Awad, I. A., Shen, L. The cerebral cavernous malformation disease causing gene KRIT1 participates in intestinal epithelial barrier maintenance and regulation.


Assuntos
Apoptose , Permeabilidade da Membrana Celular , Hemangioma Cavernoso do Sistema Nervoso Central/patologia , Mucosa Intestinal/patologia , Proteína KRIT1/metabolismo , Miosina Tipo II/metabolismo , Quinases Associadas a rho/metabolismo , Citoesqueleto de Actina/metabolismo , Células CACO-2 , Hemangioma Cavernoso do Sistema Nervoso Central/metabolismo , Humanos , Mucosa Intestinal/metabolismo , Proteína KRIT1/genética , Miosina Tipo II/genética , Fosforilação , Transdução de Sinais , Quinases Associadas a rho/genética
10.
Mol Med Rep ; 18(6): 5009-5015, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30320393

RESUMO

Reactive oxygen species (ROS) impair neovascularization and perfusion recovery following limb ischemia in patients with peripheral arterial disease (PAD). Hydrogen molecules (H2) comprise an antioxidant gas that has been reported to neutralize cytotoxic ROS. The present study investigated whether H2 may serve as a novel therapeutic strategy for PAD. H2­saturated water or dehydrogenized water was supplied to mice with experimental PAD. Laser Doppler perfusion imaging demonstrated that H2­saturated water improved perfusion recovery, decreased the rate of necrosis, increased the capillary density in the gastrocnemius muscle and increased the artery density in the abductor muscle in the ischemic limbs, at 14 and 21 days post­hindlimb ischemia. Ischemic muscle tissue was harvested 7 days after experimental PAD for biochemical testing and H2 was observed to reduce the levels of malondialdehyde and increase the levels of cyclic guanine monophosphate (cGMP). In cultured endothelial cells, H2­saturated culture medium resulted in reduced ROS levels, increased tube formation and increased cGMP levels. In macrophages, H2 decreased cellular ROS levels and promoted M2 polarization. H2­saturated water increases angiogenesis and arteriogenesis and subsequently improves perfusion recovery in a mouse PAD model via reduction of ROS levels.


Assuntos
Antioxidantes/metabolismo , Hidrogênio/metabolismo , Doença Arterial Periférica/metabolismo , Fluxo Sanguíneo Regional , Animais , Antioxidantes/farmacologia , Biomarcadores , GMP Cíclico/metabolismo , Células Endoteliais , Macrófagos/metabolismo , Masculino , Camundongos , Neovascularização Fisiológica , Doença Arterial Periférica/etiologia , Espécies Reativas de Oxigênio/metabolismo
11.
J Gen Physiol ; 150(7): 949-968, 2018 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-29915162

RESUMO

Tight junctions are macromolecular structures that traverse the space between adjacent cells in epithelia and endothelia. Members of the claudin family are known to determine tight junction permeability in a charge- and size-selective manner. Here, we use molecular dynamics simulations to build and refine an atomic model of claudin-15 channels and study its transport properties. Our simulations indicate that claudin-15 forms well-defined channels for ions and molecules and otherwise "seals" the paracellular space through hydrophobic interactions. Ionic currents, calculated from simulation trajectories of wild-type as well as mutant channels, reflect in vitro measurements. The simulations suggest that the selectivity filter is formed by a cage of four aspartic acid residues (D55), contributed by four claudin-15 molecules, which creates a negative electrostatic potential to favor cation flux over anion flux. Charge reversal or charge ablation mutations of D55 significantly reduce cation permeability in silico and in vitro, whereas mutations of other negatively charged pore amino acid residues have a significantly smaller impact on channel permeability and selectivity. The simulations also indicate that water and small ions can pass through the channel, but larger cations, such as tetramethylammonium, do not traverse the pore. Thus, our model provides an atomic view of claudin channels, their transport function, and a potential three-dimensional organization of its selectivity filter.


Assuntos
Claudinas/química , Simulação de Dinâmica Molecular , Animais , Sítios de Ligação , Claudinas/metabolismo , Transporte de Íons , Camundongos
12.
Int J Infect Dis ; 17(3): e206-8, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23218674

RESUMO

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease in six epidemic provinces of China and was identified to be caused by a novel bunyavirus in 2009. It is progressive in nature and potentially fatal. SFTS usually occurs as sporadic cases and is considered a tick-transmitted disease. Here we present a group of three patients with proven SFTS and one with probable SFTS, for whom the epidemiological data show person-to-person transmission characteristics. The index patient and two secondary patients died. None reported a tick bite.


Assuntos
Infecções por Bunyaviridae/transmissão , Transmissão de Doença Infecciosa , Febre/virologia , Trombocitopenia/virologia , Idoso , Infecções por Bunyaviridae/epidemiologia , Infecções por Bunyaviridae/virologia , China/epidemiologia , Evolução Fatal , Feminino , Febre/complicações , Febre/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Orthobunyavirus , Síndrome , Trombocitopenia/complicações , Trombocitopenia/epidemiologia
13.
J Huazhong Univ Sci Technolog Med Sci ; 32(3): 303-310, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22684549

RESUMO

Store-operated Ca(2+) channels (SOCs) are plasma membrane Ca(2+) permeable channels activated by depletion of intracellular Ca(2+) store. Ca(2+) entry through SOCs is known as store-operated Ca(2+) entry (SOCE), which plays an important role in the functional regulation of airway smooth muscle cells (ASMCs). Protein kinase C (PKC) has been shown to have an activating or inhibiting effect on SOCE, depending on cell types and PKC isoforms that are involved. In ASMCs, the effect of PKC on SOCE has not been elucidated so far. In this study, the role of PKC in the activation of SOCE in rat ASMCs was examined by using Ca(2+) fluorescence imaging technique. The results showed that acute application of PKC activators PMA and PDBu did not affect SOCE induced by the sarcoplasmic reticulum Ca(2+)-ATPase (SERCA) inhibitor thapsigargin. The non-selective PKC inhibitor chelerythrine significantly inhibited thapsigargin- and bradykinin-induced SOCE. RT-PCR assay identified PKCα, δ and ɛ isoforms in rat ASMCs. PKCα-selective inhibitor Gö6976 and PKCɛ-inhibiting peptide Epsilon-V1-2 had no effect on SOCE; by contrast, PKCδ-selective inhibitor rottlerin attenuated SOCE dramatically, suggesting that PKCδ was the major PKC isoform involved in the activation of SOCE in ASMCs. Moreover, PKC down-regulation by extended exposure to high doses of PMA or PDBu also reduced SOCE, confirming the essential role of PKC in the activation of SOCE in ASMCs. In addition, PKC down-regulation did not influence the expression of stromal interaction molecule 1 (STIM1) and Orai1, two elementary molecules in the regulation and activation of SOCs. These results identified PKCδ as an essential PKC isoform involved in the activation of SOCE, and confirmed that PKC regulates the function of ASMCs in a SOCE-dependent manner.


Assuntos
Brônquios/metabolismo , Sinalização do Cálcio/fisiologia , Cálcio/metabolismo , Glicoproteínas de Membrana/metabolismo , Miócitos de Músculo Liso/metabolismo , Proteína Quinase C-delta/metabolismo , Animais , Canais de Cálcio , Células Cultivadas , Masculino , Proteína ORAI1 , Ratos , Ratos Sprague-Dawley , Molécula 1 de Interação Estromal
14.
Int Immunopharmacol ; 12(2): 358-67, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22212353

RESUMO

Store-operated calcium entry (SOCE) is the main Ca(2+) influx pathway of dendritic cells (DCs). DCs primed with histamine facilitate Th2 immune response via different types of histamine receptors. Histamine induces DCs to release Ca(2+) from internal store. Therefore, we wonder that whether histamine could activate SOCE in DCs through its receptors, and what's the functional relevance of the Ca(2+) influx through SOCE induced by histamine in Th(2) response. We certificate that histamine induced a transient Ca(2+) release followed by pronounced Ca(2+) influx after re-addition of external Ca(2+) which could be inhibited by SOCE blockers SKF-96365 and BTP-2. Moreover, the percentages of DCs that showed an obvious Ca(2+) release response to histamine were decreased in the presence of histamine 1 (H1) receptor antagonist pyridylethylamine (Pyr) or histamine 4 (H4) receptor antagonist JNJ7777120 (JNJ). Histamine up-regulated the mRNA expression of STIM1 in DCs, one of the two major proteins of SOCE channel. SOCE blocker BTP-2 and histamine receptor antagonists JNJ and Pyr inhibited the increase of CD86 induced by histamine on DCs. Histamine increased the level of IL-10 and decreased the level of IL-12p70 secreted by DCs. SOC blockers SKF and BTP-2 inhibited the level of both IL-10 and IL-12p70 secreted by DCs. Pretreatment of SOC blockers and H1, H4 receptor antagonists with DCs inhibited the Th2 polarization of T helper cells induced by histamine in mixed lymphocyte responses (MLR). We demonstrated that SOCE was involved in histamine-induced maturation and Th(2) response of DCs which was through histamine 1 and 4 receptor.


Assuntos
Cálcio/metabolismo , Células Dendríticas/metabolismo , Histamina/farmacologia , Monócitos/metabolismo , Células Th2/metabolismo , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/metabolismo , Canais de Cálcio/genética , Canais de Cálcio/metabolismo , Sinalização do Cálcio/efeitos dos fármacos , Células do Cúmulo , Células Dendríticas/efeitos dos fármacos , Histamina/metabolismo , Antagonistas dos Receptores Histamínicos H1/farmacologia , Humanos , Interleucina-10/metabolismo , Interleucina-12/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Monócitos/efeitos dos fármacos , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Proteína ORAI1 , Receptores Histamínicos/metabolismo , Receptores Histamínicos H1/metabolismo , Molécula 1 de Interação Estromal , Células Th2/efeitos dos fármacos
15.
J Appl Physiol (1985) ; 110(5): 1256-63, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21330611

RESUMO

Hyperplasia of airway smooth muscle cells (ASMCs) is a characteristic change of chronic asthma patients. However, the underlying mechanisms that trigger this process are not yet completely understood. Store-operated Ca(2+) (SOC) entry (SOCE) occurs in response to the intracellular sarcoplasma reticulum (SR)/endoplasmic reticulum (ER) Ca(2+) store depletion. SOCE plays an important role in regulating Ca(2+) signaling and cellular responses of ASMCs. Stromal interaction molecule (STIM)1 has been proposed as an ER/SR Ca(2+) sensor and translocates to the ER underneath the plasma membrane upon depletion of the ER Ca(2+) store, where it interacts with Orai1, the molecular component of SOC channels, and brings about SOCE. STIM1 and Orai1 have been proved to mediate SOCE of ASMCs. In this study, we investigated whether STIM1/Orai1-mediated SOCE is involved in rat ASMC proliferation. We found that SOCE was upregulated during ASMC proliferation accompanied by a mild increase of STIM1 and a significant increase of Orai1 mRNA expression, whereas the proliferation of ASMCs was partially inhibited by the SOC channel blockers SKF-96365, NiCl(2), and BTP-2. Suppressing the mRNA expression of STIM1 or Orai1 with specific short hairpin RNA resulted in the attenuation of SOCE and ASMC proliferation. Moreover, after knockdown of STIM1 or Orai1, the SOC channel blocker SKF-96365 had no inhibitory effect on the proliferation of ASMCs anymore. These results suggested that STIM1/Orai1-mediated SOCE is involved in ASMC proliferation.


Assuntos
Canais de Cálcio/metabolismo , Sinalização do Cálcio/fisiologia , Cálcio/fisiologia , Pulmão/fisiologia , Glicoproteínas de Membrana/metabolismo , Miócitos de Músculo Liso/fisiologia , Animais , Proliferação de Células , Células Cultivadas , Pulmão/citologia , Masculino , Proteína ORAI1 , Ratos , Ratos Sprague-Dawley , Molécula 1 de Interação Estromal
16.
Pulm Pharmacol Ther ; 23(3): 182-9, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20045483

RESUMO

Th2 cytokine interleukin (IL)-13 plays a central role in the pathogenesis of allergic asthma. IL-13 exhibits a direct effect on airway smooth muscle cells (ASMCs) to cause airway hyperresponsiveness. IL-13 has been demonstrated to regulate Ca(2+) signaling in ASMCs, but the underlying mechanisms are not fully understood. Store-operated Ca(2+) entry (SOCE) plays an important role in regulating Ca(2+) signaling and cellular responses of ASMCs, whether IL-13 affects SOCE in ASMCs has not been reported. In this study, by using confocal Ca(2+) fluorescence imaging, we found that IL-13 (10 ng/ml) treatment increased basal intracellular Ca(2+) ([Ca(2+)](i)) level, Ca(2+) release and SOCE induced by SERCA inhibitor thapsigargin in rat bronchial smooth muscle cells. The glucocorticoid dexamethasone and the short-acting beta2 adrenergic agonist (beta2 agonist) salbutamol suppressed IL-13-augumented basal [Ca(2+)](i), Ca(2+) release and SOCE, whereas the long-acting beta2 agonist salmeterol had no effect on altered Ca(2+) signaling in IL-13-treated ASMCs. Membrane-permeable cAMP analog dibutyryl-cAMP (db-cAMP) similarly decreased Ca(2+) release and SOCE induced by thapsigargin in IL-13-treated ASMCs, confirmed a role of cAMP/PKA signaling pathway in the regulation of SOCE. IL-13 promoted the proliferation of ASMCs stimulated by serum; this effect was inhibited by nonspecific Ca(2+) channel blockers SKF-96365 and NiCl(2), by salmeterol, but not by salbutamol and dexamethasone. IL-13 treatment did not change the expression of SOC channel-associated molecules STIM1, Orai1 and TRPC1 at mRNA level. Our findings identified a promoting effect of IL-13 on Ca(2+) release and SOCE in ASMCs, which partially contributes to its effect on the proliferation of ASMCs; the differences of glucocorticoids and beta2 agonists in inhibiting Ca(2+) signal and proliferation potentiated by IL-13 suggest that these therapies of asthma may have distinct effect on the relief of airway contraction and remodeling in bronchial asthma.


Assuntos
Brônquios/efeitos dos fármacos , Cálcio/metabolismo , Interleucina-13/farmacologia , Miócitos de Músculo Liso/efeitos dos fármacos , Albuterol/farmacologia , Animais , Brônquios/citologia , Brônquios/metabolismo , Broncodilatadores/farmacologia , Bucladesina/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio/fisiologia , Sinalização do Cálcio/efeitos dos fármacos , Dexametasona/farmacologia , Técnicas In Vitro , Interleucina-13/fisiologia , Masculino , Miócitos de Músculo Liso/metabolismo , Ratos , Tapsigargina/farmacologia
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