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1.
Crit Care Med ; 47(7): e587-e596, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31205087

RESUMO

OBJECTIVES: The R-spondin family attenuates tissue damage via tightening endothelium and preventing vascular leakage. This study aims to investigate whether R-spondins protect against mechanical stretch-induced endothelial dysfunction and lung injury and to reveal the underlying mechanisms. DESIGN: Randomized controlled study. SETTING: University research laboratory. SUBJECTS: Patients scheduled to undergo surgery with mechanical ventilation support. Adult male Institute of Cancer Research mice. Primary cultured mouse lung vascular endothelial cells. INTERVENTIONS: Patients underwent a surgical procedure with mechanical ventilation support of 3 hours or more. Mice were subjected to mechanical ventilation (6 or 30 mL/kg) for 0.5-4 hours. Another group of mice were intraperitoneally injected with 1 mg/kg lipopolysaccharide, and 12 hours later subjected to mechanical ventilation (10 mL/kg) for 4 hours. Mouse lung vascular endothelial cells were subjected to cyclic stretch for 4 hours. MEASUREMENTS AND MAIN RESULTS: R-spondin1 were downregulated in both surgical patients and experimental animals exposed to mechanical ventilation. Intratracheal instillation of R-spondin1 attenuated, whereas knockdown of pulmonary R-spondin1 exacerbated ventilator-induced lung injury and mechanical stretch-induced lung vascular endothelial cell apoptosis. The antiapoptotic effect of R-spondin1 was mediated through the leucine-rich repeat containing G-protein coupled receptor 5 in cyclic stretched mouse lung vascular endothelial cells. We identified apoptosis-stimulating protein of p53 2 as the intracellular signaling protein interacted with leucine-rich repeat containing G-protein coupled receptor 5. R-spondin1 treatment decreased the interaction of apoptosis-stimulating protein of p53 2 with p53 while increased the binding of apoptosis-stimulating protein of p53 2 to leucine-rich repeat containing G-protein coupled receptor 5, therefore resulting in inactivation of p53-mediated proapoptotic pathway in cyclic stretched mouse lung vascular endothelial cells. CONCLUSIONS: Mechanical ventilation leads to down-regulation of R-spondin1. R-spondin1 may enhance the interaction of leucine-rich repeat containing G-protein coupled receptor 5 and apoptosis-stimulating protein of p53 2, thus inactivating p53-mediated proapoptotic pathway in cyclic stretched mouse lung vascular endothelial cells. R-spondin1 may have clinical benefit in alleviating mechanical ventilator-induced lung injury.

2.
Front Pharmacol ; 9: 959, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30197594

RESUMO

Interleukin (IL) -35 is an anti-inflammatory cytokine which exerts various beneficial effects on autoimmune diseases. However, whether IL-35 plays a role in endotoxin induced hepatitis demands clarification. This study aims to reveal the effect and mechanism of IL-35 on endotoxin induced liver injury. Acute hepatic injury was induced by D-galactosamine (D-GalN, 400 mg/kg) and lipopolysaccharide (LPS, 5 µg/kg) administration in mice. IL-35 treatment ameliorated D-GalN/LPS induced liver injury in a dose dependent manner as shown by histological examination, ALT determination and Caspase-3 activity assay. It also reduced production of pro-inflammatory cytokines, tumor necrosis factor (TNF)-α, IL-1ß, and IL-6, and increased production of anti-inflammatory cytokines, IL-4, IL-10, and transforming growth factor (TGF)-ß. This hepato-protective effect was proved mainly mediated by Kupffer cells (KC) via gadolinium chloride depletion and cell adoptive transfer experiment. In addition, IL-35 emolliated the cytotoxicity of LPS-triggered KCs to hepatocytes, suppressed nitric oxide (NO) and TNF-α production, and elevated IL-10 production in LPS stimulated KCs. Furthermore, IL-35 could not exert hepato-protective effect in IL-10-deficient mice in vivo and it could not suppress LPS induced NO and TNF-α production in IL-10-deficient KCs in vitro. In conclusion, IL-35 protects endotoxin-induced acute liver injury, which mainly acts thought increasing IL-10 production in KCs. This finding demonstrates a role of IL-35 in anti-infectious immunity and provides a potential therapeutic target in treating fulminant hepatitis.

3.
Crit Care Med ; 46(1): e49-e58, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29088003

RESUMO

OBJECTIVES: Mechanical ventilation can induce lung fibrosis. This study aimed to investigate whether ventilator-induced lung fibrosis was associated with endothelial-mesenchymal transition and to uncover the underlying mechanisms. DESIGN: Randomized, controlled animal study and cell culture study. SETTING: University research laboratory. SUBJECTS: Adult male Institute of Cancer Research, NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) knockout and wild-type mice. Primary cultured mouse lung vascular endothelial cells. INTERVENTIONS: Institute of Cancer Research, NLRP3 knockout and wild-type mice were subjected to mechanical ventilation (20 mL/kg) for 2 hours. Mouse lung vascular endothelial cells were subjected to cyclic stretch for 24 hours. MEASUREMENTS AND MAIN RESULTS: Mice subjected to mechanical ventilation exhibited increases in collagen deposition, hydroxyproline and type I collagen contents, and transforming growth factor-ß1 in lung tissues. Ventilation-induced lung fibrosis was associated with increased expression of mesenchymal markers (α smooth muscle actin and vimentin), as well as decreased expression of endothelial markers (vascular endothelial-cadherin and CD31). Double immunofluorescence staining showed the colocalization of CD31/α smooth muscle actin, CD31/vimentin, and CD31/fibroblast-specific protein-1 in lung tissues, indicating endothelial-mesenchymal transition formation. Mechanical ventilation also induced NLRP3 inflammasome activation in lung tissues. In vitro direct mechanical stretch of primary mouse lung vascular endothelial cells resulted in similar NLRP3 activation and endothelial-mesenchymal transition formation, which were prevented by NLRP3 knockdown. Furthermore, mechanical stretch-induced endothelial-mesenchymal transition and pulmonary fibrosis were ameliorated in NLRP3-deficient mice as compared to wild-type littermates. CONCLUSIONS: Mechanical stretch may promote endothelial-mesenchymal transition and pulmonary fibrosis through a NLRP3-dependent pathway. The inhibition of endothelial-mesenchymal transition by NLRP3 inactivation may be a viable therapeutic strategy against pulmonary fibrosis associated with mechanical ventilation.


Assuntos
Modelos Animais de Doenças , Endotélio Vascular/fisiopatologia , Inflamassomos/fisiologia , Pulmão/irrigação sanguínea , Mecanotransdução Celular/fisiologia , Mesoderma/fisiopatologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/fisiologia , Fibrose Pulmonar/fisiopatologia , Animais , Células Cultivadas , Células Endoteliais/fisiologia , Camundongos , Camundongos Endogâmicos ICR , Camundongos Knockout
4.
Cell Physiol Biochem ; 42(1): 34-43, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28490015

RESUMO

BACKGROUND: Salidroside (SDS) is the main effective ingredient of Rhodiola rosea L with a variety of pharmacologic properties. We aim to investigate the effects of SDS on ventilation induced lung injury (VILI) and explore the possible underlying molecular mechanism. METHODS: Lung injury was induced in male ICR mice via mechanical ventilation (30 ml/kg) for 4h. The mice were divided in four groups:(1) Control group; (2) Ventilation group; (3) SDS group; (4) Ventilation with SDS group. SDS (50 mg/kg) was injected intraperitoneally 1h before operation. Mouse lung vascular endothelial cells (MLVECs) were subjected to cyclic stretch for 4h. RESULTS: It was found that SDS attenuated VILI as shown in HE staining, cell count and protein content levels in BAL fluid, W/D and Evans blue dye leakage into the lung tissue. SDS treatment inhibited the activation of NLRP3 inflammasome and subsequent caspase-1 cleavage as well as interleukin (IL)-1ß secretion both in vivo and in vitro. Moreover, SDS administration up-regulated SIRT1 expression. Importantly, knockdown of SIRT1 reversed the inhibitory effect of SDS on NLRP3 inflammasome activation. CONCLUSIONS: Taken together, these findings indicate that SDS may confer protection against ventilation induced lung injury via SIRT1-de-pendent inhibition of NLRP3 inflammasome activation.


Assuntos
Glucosídeos/farmacologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Fenóis/farmacologia , Sirtuína 1/metabolismo , Regulação para Cima/efeitos dos fármacos , Animais , Líquido da Lavagem Broncoalveolar/química , Caspase 1/metabolismo , Células Cultivadas , Células Endoteliais/citologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Ensaio de Imunoadsorção Enzimática , Glucosídeos/uso terapêutico , Inflamassomos/metabolismo , Interleucina-1beta/análise , Interleucina-1beta/metabolismo , Pulmão/metabolismo , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Fenóis/uso terapêutico , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Sirtuína 1/antagonistas & inibidores , Sirtuína 1/genética , Estresse Mecânico , Lesão Pulmonar Induzida por Ventilação Mecânica/metabolismo , Lesão Pulmonar Induzida por Ventilação Mecânica/patologia , Lesão Pulmonar Induzida por Ventilação Mecânica/prevenção & controle
5.
Med Sci Monit ; 23: 2357-2364, 2017 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-28522797

RESUMO

BACKGROUND Fibrotic change is one of the important reasons for the poor prognosis of patients with acute respiratory distress syndrome (ARDS). The present study investigated the effects of hydrogen-rich saline, a selective hydroxyl radical scavenger, on lipopolysaccharide (LPS)-induced pulmonary fibrosis. MATERIAL AND METHODS Male ICR mice were divided randomly into 5 groups: Control, LPS-treated plus vehicle treatment, and LPS-treated plus hydrogen-rich saline (2.5, 5, or 10 ml/kg) treatment. Twenty-eight days later, fibrosis was assessed by determination of collagen deposition, hydroxyproline, and type I collagen levels. Development of epithelial-to-mesenchymal transition (EMT) was identified by examining protein expressions of E-cadherin and α-smooth muscle actin (α-SMA). Transforming growth factor (TGF)-ß1 content, total antioxidant capacity (T-AOC), malondialdehyde (MDA) content, catalase (CAT), and superoxide dismutase (SOD) activity were determined. RESULTS Mice exhibited increases in collagen deposition, hydroxyproline, type I collagen contents, and TGF-ß1 production in lung tissues after LPS treatment. LPS-induced lung fibrosis was associated with increased expression of α-SMA, as well as decreased expression of E-cadherin. In addition, LPS treatment increased MDA levels but decreased T-AOC, CAT, and SOD activities in lung tissues, indicating that LPS induced pulmonary oxidative stress. Hydrogen-rich saline treatment at doses of 2.5, 5, or 10 ml/kg significantly attenuated LPS-induced pulmonary fibrosis. LPS-induced loss of E-cadherin in lung tissues was largely reversed, whereas the acquisition of α-SMA was dramatically decreased by hydrogen-rich saline treatment. In addition, hydrogen-rich saline treatment significantly attenuated LPS-induced oxidative stress. CONCLUSIONS Hydrogen-rich saline may protect against LPS-induced EMT and pulmonary fibrosis through suppressing oxidative stress.


Assuntos
Hidrogênio/uso terapêutico , Fibrose Pulmonar/terapia , Cloreto de Sódio/uso terapêutico , Animais , Caderinas/metabolismo , Colágeno/metabolismo , Colágeno Tipo I/metabolismo , Células Epiteliais/metabolismo , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Fibrose , Hidroxiprolina/metabolismo , Lipopolissacarídeos , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Estresse Oxidativo/efeitos dos fármacos , Fibrose Pulmonar/prevenção & controle , Síndrome do Desconforto Respiratório do Adulto/terapia , Fator de Crescimento Transformador beta1/metabolismo
6.
Free Radic Biol Med ; 88(Pt B): 404-416, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25979658

RESUMO

High-mobility group box 1 (HMGB1) contributes to lung vascular hyperpermeability during ventilator-induced lung injury. We aimed to determine whether the natural antioxidant resveratrol protected against HMGB1-induced endothelial hyperpermeability both in vitro and in vivo. We found that HMGB1 decreased vascular endothelial (VE)-cadherin expression and increased endothelial permeability, leading to mitochondrial oxidative damage in primary cultured mouse lung vascular endothelial cells (MLVECs). Both the mitochondrial superoxide dismutase 2 mimetic MnTBAP and resveratrol blocked HMGB1-induced mitochondrial oxidative damage, VE-cadherin downregulation, and endothelial hyperpermeability. In in vivo studies, anesthetized male ICR mice were ventilated for 4h using low tidal volume (6 ml/kg) or high tidal volume (HVT; 30 ml/kg) ventilation. The mice were injected intraperitoneally with resveratrol immediately before the onset of ventilation. We found that resveratrol attenuated HVT-associated lung vascular hyperpermeability and HMGB1 production. HVT caused a significant increase in nuclear factor-erythroid 2-related factor 2 (Nrf2) nuclear translocation and Nrf2 target gene expression in lung tissues, which was further enhanced by resveratrol treatment. HMGB1 had no effect on Nrf2 activation, whereas resveratrol treatment activated the Nrf2 signaling pathway in HMGB1-treated MLVECs. Moreover, Nrf2 knockdown reversed the inhibitory effects of resveratrol on HMGB1-induced mitochondrial oxidative damage and endothelial hyperpermeability. The inhibitory effect of resveratrol on cyclic stretch-induced HMGB1 mRNA expression in primary cultured MLVECs was also abolished by Nrf2 knockdown. In summary, this study demonstrates that resveratrol protects against lung endothelial barrier dysfunction initiated by HVT. Lung endothelial barrier protection by resveratrol involves inhibition of mechanical stretch-induced HMGB1 release and HMGB1-induced mitochondrial oxidative damage. These protective effects of resveratrol might be mediated through an Nrf2-dependent mechanism.


Assuntos
Antioxidantes/farmacologia , Proteína HMGB1/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Estilbenos/farmacologia , Lesão Pulmonar Induzida por Ventilação Mecânica/metabolismo , Animais , Western Blotting , Modelos Animais de Doenças , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Imunofluorescência , Técnicas de Silenciamento de Genes , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , RNA Interferente Pequeno , Reação em Cadeia da Polimerase em Tempo Real , Resveratrol , Estresse Mecânico , Transfecção , Lesão Pulmonar Induzida por Ventilação Mecânica/fisiopatologia
7.
Clin Nutr ; 34(4): 752-60, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25234611

RESUMO

BACKGROUND & AIMS: Fibrotic changes seem to be responsible for the high mortality rate observed in patients with acute respiratory distress syndrome (ARDS). The present study aimed to determine whether resveratrol, a natural antioxidant polyphenol, had anti-fibrotic effects in the murine model of lipopolysaccharide (LPS)-induced pulmonary fibrosis. METHODS: Fibrosis was assessed by determination of collagen deposition, hydroxyproline and type I collagen levels in lung tissues. Development of epithelial-mesenchymal transition (EMT) was identified by the loss of E-cadherin accompanying by the acquisition of α-smooth muscle actin (α-SMA). Transforming growth factor (TGF)-ß1 content, levels of phosphorylated Smad2/Smad3 and Smad4, malondialdehyde (MDA) content, total antioxidant capacity (T-AOC), superoxide dismutase (SOD) activity, and catalase (CAT) activity in lung tissues were determined. RESULTS: LPS increased collagen deposition, hydroxyproline and type I collagen contents, and meanwhile induced EMT process, stimulated TGF-ß1 production and Smad activation in lung tissues on day 21 to day 28 after LPS administration. In addition, LPS treatment resulted in a rapid induction of oxidative stress as evidenced by increase of MDA and decreases of T-AOC, CAT and SOD activities as early as 7 days after LPS treatment, which was persistent for at least 4 weeks. In contrast, resveratrol treatment attenuated LPS-induced EMT and pulmonary fibrosis, meanwhile it suppressed LPS-induced oxidative stress, TGF-ß1 production and activation of Smad signaling pathway. CONCLUSIONS: Resveratrol may ameliorate LPS-induced EMT and pulmonary fibrosis through suppression of oxidative stress and TGF-ß1/Smad signaling pathway. Application of antioxidants may represent a useful adjuvant pharmacologic approach to reduce ARDS-associated pulmonary fibrosis.


Assuntos
Transição Epitelial-Mesenquimal/efeitos dos fármacos , Lipopolissacarídeos/efeitos adversos , Estresse Oxidativo/efeitos dos fármacos , Fibrose Pulmonar/tratamento farmacológico , Estilbenos/farmacologia , Fator de Crescimento Transformador beta1/genética , Animais , Catalase/metabolismo , Colágeno Tipo I/metabolismo , Modelos Animais de Doenças , Masculino , Malondialdeído/metabolismo , Camundongos , Camundongos Endogâmicos ICR , Fibrose Pulmonar/induzido quimicamente , Resveratrol , Transdução de Sinais , Superóxido Dismutase/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
8.
Cell Biochem Biophys ; 67(3): 1421-31, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23760612

RESUMO

Mechanical ventilation with large tidal volumes can increase lung alveolar permeability and initiate inflammatory responses, termed ventilator-induced lung injury (VILI). VILI is characterized by an influx of inflammatory cells, increased pulmonary permeability, and endothelial and epithelial cell death. But the underlying molecular mechanisms that regulate VILI remain unclear. The purpose of this study was to investigate the mechanisms that regulate pulmonary endothelial barrier in an animal model of VILI. These data suggest that SC5b-9, as the production of the complement activation, causes increase in rat pulmonary microvascular permeability by inducing activation of RhoA and subsequent phosphorylation of myosin light chain and contraction of endothelial cells, resulting in gap formation. In general, the complement-mediated increase in pulmonary microvascular permeability may participate in VILI.


Assuntos
Complexo de Ataque à Membrana do Sistema Complemento/farmacologia , Células Endoteliais/efeitos dos fármacos , Lesão Pulmonar Induzida por Ventilação Mecânica/etiologia , Animais , Permeabilidade da Membrana Celular/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Células Endoteliais/citologia , Células Endoteliais/metabolismo , Masculino , Cadeias Leves de Miosina/metabolismo , Fosforilação/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Lesão Pulmonar Induzida por Ventilação Mecânica/metabolismo , Proteína rhoA de Ligação ao GTP/metabolismo
9.
Nitric Oxide ; 27(3): 137-42, 2012 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-22743255

RESUMO

Stress-related hormone norepinephrine (NE) displayed diverse effects on immune system including macrophages, which influenced many kinds of inflammatory diseases. Nitric oxide (NO) from activated macrophages played an important role in inflammatory diseases. In this study, we investigated under chronic restraint stress how NE influenced the joint swell of Complete Freund's Adjuvant (CFA)-induced arthritis of rats and whether NE regulated macrophage's production of NO through influencing phosphorylation of protein kinases C (PKC). The results showed chronic restraint stress exacerbated paw swell of rats with arthritis. Inhibitor of inducible nitric oxide synthase, S-methylisothiourea (SMT), and 6-hydroxydopamine (6-OHDA) could counteract the effect of restraint stress on arthritis. NE, NO and endotoxin in plasma of rats underwent restraint were improved significantly. In vitro experiments, NE could promote macrophage to produce more NO and iNOS when macrophage was activated by lipopolysaccharide (LPS). This effect could be inhibited by α adrenergic antagonist phentolamine. Nevertheless, through α receptor NE could promote the phosphorylation of PKC and PKC inhibitor staurosporine could counteract NE's enhancive effect on production of NO and iNOS of macrophages. This study revealed that NE could exacerbate arthritic joint swell through promoting NO production, which was in α receptor dependent way through enhancing phosphorylation of PKC for NE to enhance the iNOS expression of activated macrophage.


Assuntos
Artrite Experimental/metabolismo , Artrite Experimental/patologia , Óxido Nítrico/biossíntese , Norepinefrina/metabolismo , Restrição Física/efeitos adversos , Antagonistas Adrenérgicos alfa/farmacologia , Análise de Variância , Animais , Artrite Experimental/sangue , Artrite Experimental/enzimologia , Endotoxemia/metabolismo , Endotoxemia/patologia , Adjuvante de Freund , Macrófagos/enzimologia , Macrófagos/metabolismo , Masculino , Óxido Nítrico Sintase Tipo II/metabolismo , Norepinefrina/sangue , Fentolamina/farmacologia , Fosforilação , Proteína Quinase C/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores Adrenérgicos alfa/metabolismo , Sistema Nervoso Simpático/metabolismo
10.
Shock ; 35(3): 308-14, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20926985

RESUMO

Various anti-inflammatory agents have been used to treat acute or chronic lung injury-induced pulmonary fibrosis (PF). However, the efficacy of the available treatments is disappointing, and new therapies are urgently needed. In the current study, we investigated the effect of a novel α-melanocyte-stimulating hormone analog, STY39, on bleomycin (BLM)-induced pulmonary inflammation and fibrosis in mice. C57BL/6 mice received an intratracheal injection of BLM before being treated with STY39 (0.625, 1.25, or 2.5 mg/kg, i.p.) once a day for 14 consecutive days. Various parameters, reflecting the inflammatory reaction, metabolism of extracellular matrix, myofibroblast proliferation, and degree of fibrosis in the lung, were evaluated. We found that STY39 significantly improved the survival of mice with lethal BLM-induced lung injury, limited body weight loss and the increase in the lung index, reduced the mRNA expression of types I and III procollagen and the production of hydroxyproline in the lung, diminished myofibroblast proliferation, and ultimately reduced BLM-induced lung damage. Further investigation revealed that, in a dose-dependent manner, STY39 treatment inhibited leukocyte migration into the lung; reduced the production of TNF-α, IL-6, macrophage inflammatory protein 2, and transforming growth factor ß1 in the lung; and altered the ratio of matrix metalloproteinase 1 to tissue inhibitors of metalloproteinase 1. These findings suggest that STY39 attenuates BLM-induced experimental PF by limiting the inflammatory reaction through the inhibition of proinflammatory and profibrosis cytokines and by accelerating the metabolism of extracellular matrix. Therefore, STY39 may be an effective therapy for preventing PF.


Assuntos
Anti-Inflamatórios/uso terapêutico , Bleomicina/toxicidade , Pneumonia/tratamento farmacológico , Fibrose Pulmonar/tratamento farmacológico , alfa-MSH/análogos & derivados , Animais , Imuno-Histoquímica , Interleucina-6/metabolismo , Metaloproteinase 1 da Matriz/metabolismo , Camundongos , Pneumonia/induzido quimicamente , Pneumonia/metabolismo , Reação em Cadeia da Polimerase , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/metabolismo , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
11.
Brain Res ; 1337: 104-12, 2010 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-20417627

RESUMO

Gabapentin, an anticonvulsant, is widely accepted as an alternative therapeutic agent for neuropathic pain and has proved to produce analgesic effects in a mouse model of visceral pain. However, it is unknown whether gabapentin is also analgesically effective in chronic pancreatitis. The aim of the present study was to investigate the role and underlying mechanisms of gabapentin in a rat model of chronic pancreatitis. Chronic pancreatitis induced by dibutyltin dichloride (DBTC) produced a marked increase in mechanical sensitivity of the abdomen after the establishment of the model. During the first day to the sixth day in the fourth week, Gabapentin was administered intraperitoneally daily at a dose of 100mg/kg. The behavioral test began 1h after drug administration. The analgesic effect of gabapentin was not evident with a single injection, but gabapentin significantly reduced the responsive frequencies to mechanical stimulation in rats with chronic pancreatitis from the third day to the end of the experiment. To explore the underlying mechanisms, the expression of alpha(2)delta-1 calcium channel subunit was examined in the thoracic spinal cord (T8-11). There was no significant change in alpha(2)delta-1 level of T8-11 following the first injection. But after the sixth injection, the alpha(2)delta-1 level of T8-11 in rats with chronic pancreatitis was declined. Taken together, the present study suggested that repeated administration of gabapentin daily could reduce mechanical hypersensitivity in the upper abdomen and produce an analgesic effect in a rat model of chronic pancreatitis. The down-regulation of alpha(2)delta-1 calcium channel subunit might be one of the mechanisms underlying the analgesic effect of gabapentin.


Assuntos
Aminas/farmacologia , Canais de Cálcio/biossíntese , Ácidos Cicloexanocarboxílicos/farmacologia , Dor/tratamento farmacológico , Ácido gama-Aminobutírico/farmacologia , Analgésicos/uso terapêutico , Animais , Canais de Cálcio/genética , Canais de Cálcio Tipo L , Modelos Animais de Doenças , Gabapentina , Imunossupressores/efeitos adversos , Masculino , Compostos Orgânicos de Estanho/efeitos adversos , Medição da Dor/efeitos dos fármacos , Pancreatite Crônica/induzido quimicamente , Pancreatite Crônica/tratamento farmacológico , Pancreatite Crônica/fisiopatologia , Ratos , Ratos Endogâmicos WF
12.
Immunopharmacol Immunotoxicol ; 32(1): 110-5, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19811108

RESUMO

BACKGROUND AND AIM: The effects of methanol extract of Phellodendri cortex on acute airway inflammation induced by intranasal administration of lipopolysaccharide (LPS, 300mug/kg) were investigated in female BALB/c mice. MATERIALS AND METHODS: At 2 h after LPS exposure, mice were treated orally with methanol extract of Phellodendri cortex (100, 200 and 400 mg/kg). At the end of this study, bronchoalveolar lavage fluids (BALF) were collected and number of total cells, macrophages and neutrophils, protein concentration were analyzed. Tumor necrosis factor-alpha (TNF-alpha), macrophage inflammatory protein (MIP-2), IL-10 levels and nitric oxide (NO) production in BALF were also determined. RESULTS: Methanol extract of Phellodendri cortex dose-dependently alleviated LPS-induced acute airway inflammation via decreasing the infiltration of inflammatory cells and the release of inflammatory mediators. CONCLUSION: The relief of airway inflammation provides a possible therapeutic application of Phellodendri cortex for the treatment of infectious pulmonary diseases.


Assuntos
Phellodendron , Fitoterapia , Extratos Vegetais/uso terapêutico , Pneumonia/tratamento farmacológico , Doença Aguda , Animais , Relação Dose-Resposta a Droga , Feminino , Lipopolissacarídeos/toxicidade , Camundongos , Camundongos Endogâmicos BALB C
13.
Eur J Pharmacol ; 630(1-3): 152-7, 2010 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-20035747

RESUMO

Impaired lung function is the primary contributor to most deaths associated with severe acute pancreatitis. It is widely accepted that oxidative stress plays a central role in the pathogenesis of pancreatitis and associated complications. Therefore, in the present study, we investigated whether therapeutic treatment with the free radical scavenger edaravone could protect rats against acute pancreatitis and the associated lung injury. Acute pancreatitis was induced by infusion of 1ml/kg of sodium taurocholate (3% solution) into the biliopancreatic duct. Edaravone (8mg/kg) was administered 1h and 13h after inducing pancreatitis, the severity of pancreatic and pulmonary injuries was evaluated 24h after inducing pancreatitis. Edaravone treatment significantly reduced the elevated malondialdehyde levels in rat lungs after acute pancreatitis, suggesting an important role for free radicals in acute pancreatitis-associated lung injury. In addition, edaravone showed significant protective effects against neutrophil infiltration and tissue injury in both pancreas and lung, as demonstrated by serum amylase levels, myeloperoxidase activity and histopathological analysis. Edaravone treatment also attenuated the elevated mRNA levels of pro-inflammatory cytokines interleukin (IL)-6 and tumor necrosis factor alpha (TNF-alpha) in rat lungs after acute pancreatitis. In conclusion, edaravone protects rats against acute pancreatitis-associated lung injury, probably through its antioxidant and anti-inflammatory effects. Thus, edaravone shows promise as a treatment for lung injury in patients with acute pancreatitis.


Assuntos
Lesão Pulmonar Aguda/etiologia , Antipirina/análogos & derivados , Depuradores de Radicais Livres/farmacologia , Pancreatite/complicações , Substâncias Protetoras/farmacologia , Animais , Antipirina/farmacologia , Modelos Animais de Doenças , Edaravone , Masculino , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley
14.
Eur J Pharmacol ; 615(1-3): 61-5, 2009 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-19358840

RESUMO

Peripheral nerve injury, which gives rise to persistent chronic pain, has become an area of intense research activity, largely because it represents a disorder with a high unmet medical need. In this study, serum biomarkers of the spinal nerve ligation model were successfully investigated with the metabolomic method. The regulatory effect of gabapentin, a novel clinical antineuralgia drug, on biomarker levels in serum was also investigated. Rat serum extract samples were analyzed by ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS). A method of supervised multivariate analysis, the partial least squares-discrimination analysis (PLS-DA), was used to validate metabolic changes. In addition, another multivariate method, the orthogonal partial least-squares analysis (OPLS), was used to monitor the real biological variability and to detect potential biomarkers in the spinal nerve ligation model. The results demonstrated that the spinal nerve ligation model had several discriminating ions compared with the control model. Among the detectable metabolites, levels of norepinephrine were increased in the spinal nerve ligation model and were decreased to control levels by gabapentin.


Assuntos
Aminas/farmacologia , Analgésicos/farmacologia , Biomarcadores/sangue , Ácidos Cicloexanocarboxílicos/farmacologia , Doenças do Sistema Nervoso Periférico/sangue , Nervos Espinhais/lesões , Ácido gama-Aminobutírico/farmacologia , Animais , Cromatografia Líquida de Alta Pressão , Modelos Animais de Doenças , Gabapentina , Injeções Intraperitoneais , Ligadura , Masculino , Metabolômica , Análise Multivariada , Norepinefrina/sangue , Doenças do Sistema Nervoso Periférico/etiologia , Ratos , Ratos Sprague-Dawley , Soro , Espectrometria de Massas em Tandem
15.
Biochem Biophys Res Commun ; 381(4): 602-5, 2009 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-19249288

RESUMO

OBJECTIVE: Hydrogen has been reported to selectively reduce the hydroxyl radical, the most cytotoxic of reactive oxygen species. In this study we investigated the effects of hydrogen-rich saline on the prevention of lung injury induced by intestinal ischemia/reperfusion (I/R) in rats. METHODS: Male Sprague-Dawley rats (n=30, 200-220g) were divided randomly into three experimental groups: sham operated, intestinal I/R plus saline treatment (5ml/kg, i.v.), and intestinal I/R plus hydrogen-rich saline treatment (5ml/kg, i.v.) groups. Intestinal I/R was produced by 90min of intestinal ischemia followed by a 4h of reperfusion. RESULTS: Hydrogen-rich saline treatment decreased the neutrophil infiltration, the lipid membrane peroxidation, NF-kappaB activation and the pro-inflammatory cytokine interleukin IL-1beta and TNF-alpha in the lung tissues compared with those in saline-treated rat. CONCLUSION: Hydrogen-rich saline attenuates lung injury induced by intestinal I/R.


Assuntos
Hidrogênio/uso terapêutico , Lesão Pulmonar/prevenção & controle , Cloreto de Sódio/uso terapêutico , Animais , Membrana Celular , Interleucina-1beta/metabolismo , Intestinos/irrigação sanguínea , Peroxidação de Lipídeos , Lesão Pulmonar/etiologia , Lesão Pulmonar/patologia , Masculino , NF-kappa B/metabolismo , Neutrófilos , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/complicações , Fator de Necrose Tumoral alfa/metabolismo
16.
Zhong Xi Yi Jie He Xue Bao ; 7(2): 130-4, 2009 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-19216855

RESUMO

OBJECTIVE: To study the effects of salidroside-pretreatment on changes of neuroethology in rats with global cerebral ischemia-reperfusion injury so as to investigate its probable mechanism. METHODS: Sixty SD male rats were randomly divided into sham-operated group, untreated group and salidroside-pretreated group. The rats in salidroside-pretreated group were intraperitoneally administered with salidroside for seven days. The dose of salidroside was 12 mg/(kg.d). Thirty minutes after the last administration, the acute global cerebral ischemia-reperfusion in rats of the untreated group and the salidroside-pretreated group was induced by using the modified Pulsinelli's 4-vessel occlusion method. Five rats in each group were killed to obtain their brains 24 hours after reperfusion. The water content in the right brain was measured by calculating the ratio of dry weight to wet weight of the right brain. Activity of superoxide dismutase (SOD) and content of malondialdehyde (MDA) in hippocampus of the rats were measured. Then neurological severity scores (NSSs) of the other 15 rats in each group were observed respectively before and 6, 12, 24, 48 and 96 h after reperfusion. At the fifth day after reperfusion, the test of Morris water maze was carried out to examine the memories and learning abilities of the rats. RESULTS: The content of MDA, the activity of SOD, the NSS, the mean incubation period and the ratio of time in the second quadrant in the untreated group were significant different from those in the sham-operated group (P<0.05). Compared with the untreated group, the brain water content, the content of MDA and the NSS degraded, and the mean incubation period shortened in salidroside-pretreated group. The activity of SOD and the ratio of residence time in the second quadrant increased in salidroside-pretreated group as compared with the untreated group (P<0.05). CONCLUSION: Salidroside can reduce the degree of cerebral edema of rats with global cerebral ischemia-reperfusion injury, relieve the metabolism abnormity of free radical and improve the function of cognition.


Assuntos
Isquemia Encefálica/patologia , Glucosídeos/uso terapêutico , Precondicionamento Isquêmico/métodos , Aprendizagem em Labirinto/efeitos dos fármacos , Fenóis/uso terapêutico , Traumatismo por Reperfusão/patologia , Animais , Encéfalo/metabolismo , Isquemia Encefálica/psicologia , Masculino , Malondialdeído/metabolismo , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/psicologia , Superóxido Dismutase/metabolismo
17.
Brain Res ; 1248: 68-75, 2009 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-19028459

RESUMO

Recent studies indicate that reactive oxygen species (ROS) are involved in persistent pain, including neuropathic and inflammatory pain. Edaravone, a free radical scavenger, which is widely used clinically in Japan for acute cerebral infarction to prevent ischemia reperfusion injury, has been shown to inhibit inflammatory-induced pain in rats. However, it is unknown whether edaravone is effective on neuropathic pain. In the present study, we used the spinal nerve ligation (SNL)-induced neuropathic pain model of rats to investigate the role of edaravone in the generation or development of neuropathic pain. Edaravone was administrated intraperitoneally per day at a dose of 4 mg/kg. We found that preemptive treatment of edaravone had analgesic effects on SNL-induced chronic pain without inducing any behavioral side-effects or motor disturbances at the dose given. By contrast, when administered on the third day after SNL surgery, edaravone cannot reverse the established pain but only produced tenuous analgesic effects on the rats of neuropathic pain. To explore the underlying mechanisms, effects of edaravone on the excitability of dorsal root ganglion (DRG) neurons and activation of JNK in DRG were observed. We found that preemptive edaravone treatment can decrease the H(2)O(2)-induced depolarization in the acutely dissociated DRG neurons. Furthermore, we found that preemptive edaravone treatment can reduce the SNL-induced pJNK expression in the ipsilateral DRG. Taken together, the present study indicated that edaravone could prevent the development of SNL-induced neuropathic pain but had little effects on the established neuropathic pain. The inhibition of the signaling pathway of JNK cascade or suppression of the possible ROS-induced hyper-excitability of DRG neurons might be, at least in part, mechanisms underlying the effects of edaravone on SNL-induced neuropathic pain.


Assuntos
Analgésicos/farmacologia , Antipirina/análogos & derivados , Neuralgia/tratamento farmacológico , Animais , Antipirina/administração & dosagem , Antipirina/farmacologia , Western Blotting , Células Cultivadas , Doença Crônica , Edaravone , Depuradores de Radicais Livres/administração & dosagem , Depuradores de Radicais Livres/farmacologia , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/fisiopatologia , Janus Quinases/metabolismo , Neuralgia/prevenção & controle , Medição da Dor , Limiar da Dor/efeitos dos fármacos , Técnicas de Patch-Clamp , Ratos , Ratos Sprague-Dawley , Nervos Espinhais/lesões
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