Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 4 de 4
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
J Adv Res ; 53: 175-186, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-36526145

RESUMO

INTRODUCTION: Pulmonary fibrosis is a major cause of the poor prognosis of acute respiratory distress syndrome (ARDS). While mechanical ventilation (MV) is an indispensable life-saving intervention for ARDS, it may cause the remodeling process in lung epithelial cells to become disorganized and exacerbate ARDS-associated pulmonary fibrosis. Piezo1 is a mechanosensitive ion channel that is known to play a role in regulating diverse physiological processes, but whether Piezo1 is necessary for MV-exacerbated ARDS-associated pulmonary fibrosis remains unknown. OBJECTIVES: This study aimed to explore the role of Piezo1 in MV-exacerbated ARDS-associated pulmonary fibrosis. METHODS: Human lung epithelial cells were stimulated with hydrochloric acid (HCl) followed by mechanical stretch for 48 h. A two-hitmodel of MV afteracidaspiration-inducedlunginjuryin mice was used. Mice were sacrificed after 14 days of MV. Pharmacological inhibition and knockout of Piezo1 were used to delineate the role of Piezo1 in MV-exacerbated ARDS-associated pulmonary fibrosis. In some experiments, ATP or the ATP-hydrolyzing enzyme apyrase was administered. RESULTS: The stimulation of human lung epithelial cells to HCl resulted in phenotypes of epithelial-mesenchymal transition (EMT), which were enhanced by mechanical stretching. MV exacerbated pulmonary fibrosis in mice exposed to HCl. Pharmacologicalinhibitionorknockout of Piezo1 attenuated the MV-exacerbated EMT process and lung fibrosis in vivo and in vitro. Mechanistically, the observed effects were mediated by Piezo1-dependent Ca2+ influx and ATP release in lung epithelial cells. CONCLUSIONS: Our findings identify a key role for Piezo1 in MV-exacerbated ARDS-associated pulmonary fibrosis that is mediated by increased ATP release in lung epithelial cells. Inhibiting Piezo1 may constitute a novelstrategyfor the treatment of MV-exacerbated ARDS-associated pulmonary fibrosis.


Assuntos
Fibrose Pulmonar , Síndrome do Desconforto Respiratório , Camundongos , Humanos , Animais , Respiração Artificial/efeitos adversos , Síndrome do Desconforto Respiratório/complicações , Canais Iônicos , Trifosfato de Adenosina
3.
Int Immunopharmacol ; 81: 106257, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32044659

RESUMO

The activation of NLRP3 inflammasome and NF-κB pathway, associating with oxidativestress, have been implicated in the development of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). NecroX-5 has been reported to exhibit theeffectsofanti-oxidation and anti-stress in various diseases. However, the role of NecroX-5 in ALI has not been explicitly demonstrated. The aim of this study was to explore the therapeutic effects and potential mechanism action of NecroX-5 on ALI. Here, we found that NecroX-5 pretreatment dramatically diminished the levels of IL-1ß, IL-18 and ROS in in RAW264.7 cells challenged with LPS and ATP. Furthermore, NecroX-5 suppressed the activation of NLRP3 inflammasome and NF-κB signalpathway. In addition, NecroX-5 also inhibited the thioredoxin-interacting protein (TXNIP) expression. In vivo, NecroX-5 reduced the LPS-induced lung histopathological injury, the number of TUNEL-positive cells, lung wet/dry (W/D) ratio, levels of total protein and inflammatory cytokines in the bronchoalveolar lavage fluid (BALF) in mice. Additionally, LPS-induced upregulation of myeloperoxidase (MPO), ROS production and malondialdehyde (MDA) were inhibited by NecroX-5 administration. Thus, our results demonstrate that NecroX-5 protects against LPS-induced ALI by inhibiting TXNIP/NLRP3 and NF-κB.


Assuntos
Anti-Inflamatórios/uso terapêutico , Proteínas de Transporte/metabolismo , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Pulmão/metabolismo , Síndrome do Desconforto Respiratório/tratamento farmacológico , Sulfonas/uso terapêutico , Tiorredoxinas/metabolismo , Animais , Proteínas de Transporte/genética , Modelos Animais de Doenças , Regulação da Expressão Gênica , Humanos , Lipopolissacarídeos/imunologia , Pulmão/patologia , Masculino , Camundongos , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Peroxidase/metabolismo , Células RAW 264.7 , Síndrome do Desconforto Respiratório/imunologia , Transdução de Sinais , Tiorredoxinas/genética
4.
Shock ; 44(4): 371-80, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26196844

RESUMO

Acute lung injury (ALI) is characterized by lung inflammation and diffuse infiltration of neutrophils. Neutrophil apoptosis is recognized as an important control point in the resolution of inflammation. Maresin 1 (MaR1) is a new docosahexaenoic acid-derived proresolving agent that promotes the resolution of inflammation. However, its function in neutrophil apoptosis is unknown. In this study, isolated human neutrophils were incubated with MaR1, the pan-caspase inhibitor z-VAD-fmk, and lipopolysaccharide (LPS) to determine the mechanism of neutrophil apoptosis. Acute lung injury was induced by intratracheal instillation of LPS. In addition, mice were treated with MaR1 intravenously at the peak of inflammation and administered z-VAD-fmk intraperitoneally. We found that culture of isolated human neutrophils with LPS dramatically delayed neutrophil apoptosis through the phosphorylation of AKT, ERK, and p38 to upregulate the expression of the antiapoptotic proteins Mcl-1 and Bcl-2, which was blocked by pretreatment with MaR1 in vitro. In mice, MaR1 accelerated the resolution of inflammation in LPS-induced ALI through attenuation of neutrophil accumulation, pathohistological changes, and pulmonary edema. Maresin 1 promoted resolution of inflammation by accelerating caspase-dependent neutrophil apoptosis. Moreover, MaR1 also reduced the LPS-induced production of proinflammatory cytokines and upregulated the production of the anti-inflammatory cytokine interleukin-10. In contrast, treatment with z-VAD-fmk inhibited the proapoptotic action of MaR1 and attenuated the protective effects of MaR1 in LPS-induced ALI. Taken together, MaR1 promotes the resolution of LPS-induced ALI by overcoming LPS-mediated suppression of neutrophil apoptosis.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Anti-Inflamatórios não Esteroides/uso terapêutico , Ácidos Docosa-Hexaenoicos/uso terapêutico , Neutrófilos/efeitos dos fármacos , Lesão Pulmonar Aguda/patologia , Clorometilcetonas de Aminoácidos/farmacologia , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/antagonistas & inibidores , Anti-Inflamatórios não Esteroides/farmacologia , Apoptose/efeitos dos fármacos , Líquido da Lavagem Broncoalveolar/citologia , Inibidores de Caspase/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Ácidos Docosa-Hexaenoicos/administração & dosagem , Ácidos Docosa-Hexaenoicos/antagonistas & inibidores , Ácidos Docosa-Hexaenoicos/farmacologia , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Lipopolissacarídeos/administração & dosagem , Lipopolissacarídeos/antagonistas & inibidores , Masculino , Camundongos Endogâmicos BALB C , Neutrófilos/patologia , Transdução de Sinais/efeitos dos fármacos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...