Abstract:-Increasing evidence shows that hyperoxia is a serious complication of oxygen therapy in acutely ill patients that causes excessive production of free radicals leading to hyperoxia-induced acute lung injury (HALI). Our previous studies have shown that P2X7 receptor activation is required for inflammasome activation during HALI. However, the role of P2X7 in HALI is unclear. The main aim of this study was to determine the effect of P2X7 receptor gene deletion on HALI. Wild-type (WT) and P2X7 knockout (P2X7 KO) m… Show more
“…An increasing number of researchers believe that the NLRP3 inflammasome is essential for the development of ALI induced by LPS, mechanical ventilation, hyperoxia or burn (26–29). Inhibition of NLRP3 with various methods could alleviate ALI (30, 31). However, the effect of EETs on activation of NLRP3 inflammasome is poor understood.…”
Acute lung injury (ALI) is characterized by rapid alveolar injury, vascular leakage, lung inflammation, neutrophil accumulation, and induced cytokines production leading to lung edema. The mortality rate of patients suffering from ALI remains high. Epoxyeicosatrienoic acids (EETs) are cytochrome P450-dependent derivatives of polyunsaturated fatty acid (PUFA) with anti-hypertensive, profibrinolytic and anti-inflammatory functions. EETs are rapidly hydrated by soluble epoxide hydrolase (sEH) to their less potent diols. The aim of this study was to investigate the role of sEH inhibitor TPPU and EETs in lipopolysaccharide (LPS)-induced ALI of mice. Our studies revealed that inhibition of sEH with TPPU attenuated the morphological changes in mice, decreased the neutrophil infiltration to the lung, pro-inflammatory cytokine levels (IL-1β and TNF-α) in serum and bronchoalveolar lavage fluid (BALF), and alveolar capillary leakage (lung wet/dry ratio and total protein concentration in BALF). TPPU improved the survival rate of LPS-induced ALI. In addition, in vitro experiments revealed that both TPPU and EETs (11,12-EET and 14,15-EET) suppressed the expression of IL-1β and TNF-α, and LDH release in RAW264.7 cells. These results indicate that EETs play a role in dampening LPS-induced acute lung inflammation, and suggest that sEH could be a valuable candidate for treatment of ALI.
“…An increasing number of researchers believe that the NLRP3 inflammasome is essential for the development of ALI induced by LPS, mechanical ventilation, hyperoxia or burn (26–29). Inhibition of NLRP3 with various methods could alleviate ALI (30, 31). However, the effect of EETs on activation of NLRP3 inflammasome is poor understood.…”
Acute lung injury (ALI) is characterized by rapid alveolar injury, vascular leakage, lung inflammation, neutrophil accumulation, and induced cytokines production leading to lung edema. The mortality rate of patients suffering from ALI remains high. Epoxyeicosatrienoic acids (EETs) are cytochrome P450-dependent derivatives of polyunsaturated fatty acid (PUFA) with anti-hypertensive, profibrinolytic and anti-inflammatory functions. EETs are rapidly hydrated by soluble epoxide hydrolase (sEH) to their less potent diols. The aim of this study was to investigate the role of sEH inhibitor TPPU and EETs in lipopolysaccharide (LPS)-induced ALI of mice. Our studies revealed that inhibition of sEH with TPPU attenuated the morphological changes in mice, decreased the neutrophil infiltration to the lung, pro-inflammatory cytokine levels (IL-1β and TNF-α) in serum and bronchoalveolar lavage fluid (BALF), and alveolar capillary leakage (lung wet/dry ratio and total protein concentration in BALF). TPPU improved the survival rate of LPS-induced ALI. In addition, in vitro experiments revealed that both TPPU and EETs (11,12-EET and 14,15-EET) suppressed the expression of IL-1β and TNF-α, and LDH release in RAW264.7 cells. These results indicate that EETs play a role in dampening LPS-induced acute lung inflammation, and suggest that sEH could be a valuable candidate for treatment of ALI.
“…OXIDATIVE STRESS IS A COMMON complication of numerous pathologies including cancer, diabetes, and Alzheimer's disease, and is occasionally the outcome of oxygen therapy when administered at concentrations of FI O 2 Ͼ 0.8 (13,21). Furthermore, it is well documented and widely known that oxidative stress is a precursor to elevated levels of reactive oxygen species (ROS) (19,29).…”
In this perspective, we summarize and discuss critical advancements in the study of 4-hydroxy-2-nonenal (4-HNE) as it relates to diseases and clinical complications either caused or exacerbated by oxidative stress. Since its identification in 1980, 4-HNE has been extensively studied with an emphasis on its formation, its role in pathology, and its targets. As a reactive aldehyde, and a product of lipid peroxidation, studies corroborate its ability to disrupt signal transduction and protein activity, as well as induce inflammation and trigger cellular apoptosis in conditions of oxidative stress. Notably, we discuss the role of natural enzymes involved in the regulation of 4-HNE, and how they can be applied to its detoxification in various physiological conditions.
“…In addition, NLRP3 inflammasome can not only affect the body’s immune defense system, but also take part in the occurrence and development of various diseases, such as acute lung injury [4], diabetes mellitus [5], and atherosclerosis [6]. Recent researches have confirmed that inhibition of NLRP3 inflammasome could relieve bronchopulmonary dysplasia and hyperoxia-induced acute lung injury [7, 8], indicating that NLRP3 inflammasome may be a therapeutic target for hyperoxia-induced acute lung injury.…”
Background/Aims: Dexmedetomidine (Dex), a specific agonist of α2-adrenoceptor, has been reported to have extensive pharmacological effects. In this study, we focused on the protective effect of Dex on hyperoxia-induced acute lung injury and further explored its possible molecular mechanisms. Methods: The model of hyperoxia-induced acute lung injury was established by continuous inhalation of oxygen (FiO2= 0.90) for 7 d in neonatal rats in vivo. The in vitro experiments were carried out in LPS/ATP or hyperoxia-treated RAW264.7 cells. ELISA, western blot, TUNEL staining, and immunohistochemistry staining assays were performed and the commercial kits were used to assess the beneficial effect of Dex on hyperoxia-induced acute lung injury. Results: According to our results, Dex treatment attenuated hyperoxia-induced acute lung injury via decreasing the lung wet/dry(W/D) weight ratio and mitigating pathomorphologic changes. Moreover, the oxidative stress injury, inflammatory reaction, and apoptosis in lung epithelial cells were inhibited by Dex treatment. In addition, the activation of NLRP3 inflammasome was restrained by Dex both in lung tissue in vivo and RAW264.7 cells in vitro. Conclusion: These data provide evidence that Dex may ameliorate hyperoxia-induced acute lung injury, which suggests a potential clinical application of Dex in long-term supplemental oxygen therapy.
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