RESUMO
ABSTRACT: Aquaporins (AQPs) are a group of membrane proteins related to water permeability. Studies have shown that AQPs play a vital role in various diseases. Whether AQPs participate in regulating vascular permeability after sepsis and whether the subtype of AQPs is related are unknown. Ss-31, as a new antioxidant, had protective effects on a variety of diseases. However, whether Ss-31 has a protective effect on pulmonary vascular permeability in sepsis and whether its effect is related to AQPs are unclear. Using the cecum ligation perforation-induced septic rat and LPS-treated pulmonary vein endothelial cells, the role of AQPs in the regulation of the permeability of pulmonary vascular and its relationship to Ss-31 were studied. The results showed that the pulmonary vascular permeability significantly increased after sepsis, meanwhile the expressions of AQP3, 4, and 12 increased. Among those, the AQP3 was closely correlated with pulmonary vascular permeability. The inhibition of AQP3 antagonized the increase of the permeability of monolayer pulmonary vein endothelial cells. Further study showed that the expression of caveolin-1 (Cav-1) increased and occludin decreased after sepsis. The inhibition of AQP3 antagonized the decrease of Cav-1 and the increase of occludin in sepsis. Antioxidant Ss-31 decreased the expression of AQP3 and ROS levels. At the same time, Ss-31 improved pulmonary vascular permeability and prolonged survival of sepsis rats. In conclusion, AQP3 participates in the regulation of pulmonary vascular permeability after sepsis, and the antioxidant Ss-31 has a protective effect on pulmonary vascular permeability by downregulating the expression of AQP3 and inhibiting ROS production.
Assuntos
Antioxidantes/farmacologia , Aquaporina 3/metabolismo , Permeabilidade Capilar/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Oligopeptídeos/farmacologia , Veias Pulmonares/efeitos dos fármacos , Sepse/tratamento farmacológico , Animais , Aquaporina 3/genética , Caveolina 1/metabolismo , Modelos Animais de Doenças , Células Endoteliais/metabolismo , Feminino , Lipopolissacarídeos/toxicidade , Masculino , Ocludina/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Veias Pulmonares/metabolismo , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Sepse/genética , Sepse/metabolismo , Sepse/microbiologia , Transdução de SinaisRESUMO
BACKGROUND: Vascular leakage is an important pathophysiological process of critical conditions such as shock and ischemia-reperfusion (I/R)-induced lung injury. Microparticles (MPs), including endothelial cell-derived microparticles (EMPs), platelet-derived microparticles (PMPs) and leukocyte-derived microparticles (LMPs), have been shown to participate in many diseases. Whether and which of these MPs take part in pulmonary vascular leakage and lung injury after I/R and whether these MPs have synergistic effect and the underlying mechanism are not known. METHODS: Using hemorrhage/transfusion (Hemo/Trans) and aorta abdominalis occlusion-induced I/R rat models, the role of EMPs, PMPs and LMPs and the mechanisms in pulmonary vascular leakage and lung injury were observed. RESULTS: The concentrations of EMPs, PMPs and LMPs were significantly increased after I/R. Intravenous administration of EMPs and PMPs but not LMPs induced pulmonary vascular leakage and lung injury. Furthermore, EMPs induced pulmonary sequestration of platelets and promoted more PMPs production, and played a synergistic effect on pulmonary vascular leakage. MiR-1, miR-155 and miR-542 in EMPs, and miR-126 and miR-29 in PMPs, were significantly increased after hypoxia/reoxygenation (H/R). Of which, inhibition of miR-155 in EMPs and miR-126 in PMPs alleviated the detrimental effects of EMPs and PMPs on vascular barrier function and lung injury. Overexpression of miR-155 in EMPs down-regulated the expression of tight junction related proteins such as ZO-1 and claudin-5, while overexpression of miR-126 up-regulated the expression of caveolin-1 (Cav-1), the trans-cellular transportation related protein such as caveolin-1 (Cav-1). Inhibiting EMPs and PMPs production with blebbistatin (BLE) and amitriptyline (AMI) alleviated I/R induced pulmonary vascular leakage and lung injury. CONCLUSIONS: EMPs and PMPs contribute to the pulmonary vascular leakage and lung injury after I/R. EMPs mediate pulmonary sequestration of platelets, producing more PMPs to play synergistic effect. Mechanically, EMPs carrying miR-155 that down-regulates ZO-1 and claudin-5 and PMPs carrying miR-126 that up-regulates Cav-1, synergistically mediate pulmonary vascular leakage and lung injury after I/R. Video Abstract.
Assuntos
Plaquetas/metabolismo , Micropartículas Derivadas de Células/metabolismo , Células Endoteliais/metabolismo , Lesão Pulmonar/etiologia , Lesão Pulmonar/metabolismo , Pulmão/irrigação sanguínea , Traumatismo por Reperfusão/complicações , Amitriptilina/farmacologia , Animais , Plaquetas/efeitos dos fármacos , Permeabilidade Capilar/efeitos dos fármacos , Caveolina 1/metabolismo , Micropartículas Derivadas de Células/efeitos dos fármacos , Claudina-5/metabolismo , Células Endoteliais/efeitos dos fármacos , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Leucócitos/efeitos dos fármacos , Leucócitos/metabolismo , Pulmão/patologia , MicroRNAs/genética , MicroRNAs/metabolismo , Ratos Sprague-Dawley , Proteína da Zônula de Oclusão-1/metabolismoRESUMO
Pericyte, a kind of pluripotent cell, may regulate the irrigation flow and permeability of microcirculation. Pericytes are similar to the smooth muscle cells, which express several kinds of contractile proteins and have contractility. The dysfunction of pericytes is related to many microvascular diseases, including hypoxia, hypertension, diabetic retinopathy, fibrosis, inflammation, Alzheimer's disease, multiple sclerosis, and tumor formation. For a long time, their existence and function have been neglected. The distribution, structure, biomarker, related signaling pathways as well as the roles of pericytes on vascular diseases will be introduced in this review.