Lipopolysaccharide-induced lung injury: Role of P2X7 receptor

Monção-Ribeiro, Leonardo Campos; Cagido, Viviane Ramos; Lima-Murad, Graziela; Santana, Patrícia Teixeira; Riva, Douglas; Borojević, Radovan; Zin, Walter A.; Cavalcante, Moisés C.M.; Riça, Ingred; Brando-Lima, Aline C.; Takiya, Christina Maeda; Faffe, Débora S.; Coutinho‐Silva, Robson

doi:10.1016/j.resp.2011.09.015

Cited by 53 publications

(71 citation statements)

References 43 publications

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“…Previous studies have demonstrated the augmented NLRP3 inflammasome action and IL-1␤ levels in the presence of LPS in ALI mice (65). Furthermore, LPS increased P2X7 levels in lung parenchyma, while P2X7 knockout mice demonstrated decreased amount of immune response cells and collagen deposition (36). Our previous research on P2X7 with antagonist oxATP exhibited inhibitory action on hyperoxia-induced inflammasome activation (28).…”

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confidence: 61%

“…The precursors of IL-1␤ and IL-18 (i.e., pro-IL-1␤ and pro-IL-18) were, in turn, activated by caspase-1 (49). We further showed that hyperoxiainduced inflammasome complex formation was inhibited by P2X7 suppression (28).The membrane receptor P2X7 becomes activated by extracellular ATP, which then stimulates the NLRP3 inflammasome to mediate the production of 36). Previous studies have demonstrated the augmented NLRP3 inflammasome action and IL-1␤ levels in the presence of LPS in ALI mice (65).…”

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confidence: 88%

“…The membrane receptor P2X7 becomes activated by extracellular ATP, which then stimulates the NLRP3 inflammasome to mediate the production of IL-1␤ (14,36). Previous studies have demonstrated the augmented NLRP3 inflammasome action and IL-1␤ levels in the presence of LPS in ALI mice (65).…”

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confidence: 99%

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Deletion of P2X7 attenuates hyperoxia-induced acute lung injury via inflammasome suppression

Galam

Rajan

Failla

et al. 2016

American Journal of Physiology-Lung Cellular and Molecular Phys

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-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) mice were exposed to 100% O 2 for 72 h. P2X7 KO mice treated with hyperoxia had enhanced survival in 100% O 2 compared with the WT mice. Hyperoxia-induced recruitment of inflammatory cells and elevation of IL-1␤, TNF-␣, monocyte chemoattractant protein-1, and IL-6 levels were attenuated in P2X7 KO mice. P2X7 deletion decreased lung edema and alveolar protein content, which are associated with enhanced alveolar fluid clearance. In addition, activation of the inflammasome was suppressed in P2X7-deficient alveolar macrophages and was associated with suppression of IL-1␤ release. Furthermore, P2X7-deficient alveolar macrophage in type II alveolar epithelial cells (AECs) coculture model abolished protein permeability across mouse type II AEC monolayers. Deletion of P2X7 does not lead to a decrease in epithelial sodium channel expression in cocultures of alveolar macrophages and type II AECs. Taken together, these findings show that deletion of P2X7 is a protective factor and therapeutic target for the amelioration of hyperoxia-induced lung injury. acute lung injury; P2X7; NLRP3; inflammasome; hyperoxia ACUTE LUNG INJURY (ALI) IS a major clinical problem in the United States, accounting for one of the primary causes of in-hospital hypoxemic respiratory failure leading to morbidity and mortality (48). Prolonged exposure to hyperoxia has been conclusively demonstrated to cause ALI (22,58,62). Furthermore, numerous cardiovascular and pulmonary diseases require oxygen therapy (22, 28 -30, 58). Therefore, it is pertinent to understand the mechanism of damage in ALI, wherein the pathology manifests as alveolar damage from immune cell infiltration and pulmonary edema (31,63).Prolonged exposure to oxygen concentrations of FI O 2 Ͼ 0.8 has previously been shown to cause mortality in small animal and higher-order primate models (26). Hyperoxia-induced lung injury contributes to increasing the production of reactive oxygen species (ROS), inflammatory cytokines, as well as exudative pulmonary edema, collagen deposition, and damage to the alveolar epithelium (26, 32). Thus, using hyperoxia as a form of oxygen toxicity is clinically relevant to study the pathophysiology of ALI. In ALI, the disruption of the fine balance between proinflammatory and anti-inflammatory agents is the basic pathology with a concomitant activation of apoptotic signals (33, 59, 62). IL-1␤ was discovered to be one of the early inflammatory cytokines to appear in ALI patients and cause the release of additional cytokines (18). The caspase-1-mediated acti...

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confidence: 61%

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confidence: 88%

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Deletion of P2X7 attenuates hyperoxia-induced acute lung injury via inflammasome suppression

Galam

Rajan

Failla

et al. 2016

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…The negative effects of alcohol consumption have been linked to an increased inflammatory response, including increased cytokine release (14,15,37,38). Pro-inflammatory cytokines such as IL-1β, TNF, IL-6 and IL-8 have been identified as important contributors to the pathogenesis of organ damage, including lung as well as liver injury in models of acute inflammation (17)(18)(19)(39)(40)(41)(42). Together with IL-6, IL-8 binds to molecules that are involved in neutrophil activation, trafficking and infiltration of tissues in models of acute lung and liver injury (18,43).…”

Section: Discussionmentioning

confidence: 99%

Ethanol, ethyl and sodium pyruvate decrease the inflammatory responses of human lung epithelial cells via Akt and NF-κB in vitro but have a low impact on hepatocellular cells

Relja

Omid

Wagner

et al. 2015

International Journal of Molecular Medicine

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Abstract. Increases in pro-inflammatory cytokine levels and tissue-infiltrating leukocytes have been closely linked to increased systemic and local inflammation, which result in organ injury. Previously, we demonstrated the beneficial and hepatoprotective anti-inflammatory effects of acute ethanol (EtOH) ingestion in an in vivo model of acute inflammation. Due to its undesirable side-effects, however, EtOH does not represent a therapeutic option for treatment of acute inflammation. Therefore, in this study, we compared the effects of acute EtOH exposure with ethyl pyruvate (EtP) as an alternative anti-inflammatory drug in an in vitro model of hepatic and pulmonary inflammation. Human hepatocellular carcinoma cells Huh7 and alveolar epithelial cells A549 were stimulated with either interleukin (IL) IL-1β (1 ng/ml, 24 h) or tumor necrosis factor (TNF) (10 ng/ml, 4 h), and then treated with EtP (2.5-10 mM), sodium pyruvate (NaP, 10 mM) or EtOH (85-170 mM) for 1 h. IL-6 or IL-8 release from Huh7 or A549 cells, respectively, was measured by an enzyme-linked immunosorbent assay. Neutrophil adhesion to cell monolayers and CD54 expression were also analyzed. Bcl-2 and Bax gene expression was determined by RT-qPCR, and western blot analysis was performed to determine the mechanisms involved. Treating A549 cells with either EtOH or EtP significantly reduced the IL-1β-or TNF-induced IL-8 release, whereas treating Huh7 cells did not significantly alter IL-6 release. Similarly, neutrophil adhesion to stimulated A549 cells was significantly reduced by EtOH or EtP, whereas for Huh7 cells the tendency for reduced neutrophil adhesion rates by EtOH or EtP was not significant. CD54 expression was noticeably reduced in A549 cells, but this was not the case in Huh7 cells after treatment. The Bax/ Bcl-2 ratio was dose-dependently decreased by EtOH and by high-dose EtP in A549 cells, indicating a reduction in apoptosis, whereas this effect was not observed in Huh7 cells. The underlying mechanisms involve reduced phosphorylation of Akt and nuclear factor-κB (NF-κB) p65. We noted that as with EtP, EtOH reduced the inflammatory response in lung epithelial cells under acute inflammatory conditions. However, due to the low impact which EtP and EtOH had on the hepatocellular cells, our data suggest that both substances exerted different effects depending on the cellular entity. The possible underlying mechanisms involved the downregulation of Akt and the transcription factor NF-κB, but further research on this subject is required.

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“…Nitric oxide (NO) levels in peritoneal wash and in blood were estimated by using the Griess reagent method [18]. Briefly, samples were spun at 500 g for 15 min at room temperature and 100 µl of supernatant was added to 100 µl of the Griess reagent, consisting of 1% sulfanilamide (Sigma-Aldrich, USA) and 0.1% N-1-naftiletilenediamine in 5% H3PO.…”

Section: Methodsmentioning

confidence: 99%

The P2X7 Receptor Contributes to the Development of the Exacerbated Inflammatory Response Associated with Sepsis

Santana¹,

Benjamim²,

Martinez³

et al. 2015

J Innate Immun

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Background: Sepsis is associated with high mortality rates in intensive care units worldwide and represents a systemic inflammatory response to infection. P2X7 is an ionotropic purine receptor with known proinflammatory activity. Here, we investigated the role of the P2X7 receptor in sepsis induced by cecal ligation and puncture (CLP). Methods: Wild-type (WT) and P2X7KO (P2X7 null) mice were subjected to CLP and their survival was monitored for 7 days. Blood, peritoneal wash and lungs were collected 24 h after CLP and used to measure bacterial load, immune cell infiltration, nitric oxide (NO), cytokine levels, and peritoneal cell death and to assess lung injury. Results: P2X7KO mice showed significantly increased survival 7 days after CLP (30% compared to 60% in WT animals) accompanied by an overall attenuated inflammatory response, with decreased cell recruitment to the peritoneum, no or limited increases in the levels of NO and proinflammatory cytokines (IL-1β, IL-6, IL-12, IL-17, and IL-4), reduced peritoneal cell apoptosis, and less pronounced lung infiltration and morphological changes. Conclusions: Our data show the P2X7 receptor is required for the development of the inflammatory response associated with sepsis and support the notion that P2X7 receptor is a valid therapeutic target against inflammatory diseases.

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Lipopolysaccharide-induced lung injury: Role of P2X7 receptor

Cited by 53 publications

References 43 publications

Deletion of P2X7 attenuates hyperoxia-induced acute lung injury via inflammasome suppression

Deletion of P2X7 attenuates hyperoxia-induced acute lung injury via inflammasome suppression

Ethanol, ethyl and sodium pyruvate decrease the inflammatory responses of human lung epithelial cells via Akt and NF-κB in vitro but have a low impact on hepatocellular cells

The P2X7 Receptor Contributes to the Development of the Exacerbated Inflammatory Response Associated with Sepsis

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