The Role of the Inflammasome in Ventilator-induced Lung Injury

Santos, Claudia C. dos

doi:10.1164/rccm.201204-0649ed

Cited by 9 publications

(11 citation statements)

References 28 publications

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“…It was found that the NF-κB signaling pathway and NF-κB p65 nuclear translocation were clearly activated by 5% CSE. Furthermore, it has also been pointed out that the nucleotide-binding oligomerization domain-like receptor 3 (NLRP3) inflammasome is closely related to the pathological process of COPD 16, 36, and NLRP3 KO significantly inhibits the expression levels of IL-1α and IL-1β in the lung tissue of COPD mice 37. Similar results were found in our study.…”

Section: Discussionsupporting

confidence: 91%

“…Pharmacological inhibitors of the NF-κB pathway in endothelial cells have potential therapeutic value in treating inflammatory diseases and cancers 15. In COPD and other pulmonary inflammatory diseases, the main function of the NLRP3 inflammatory corpuscle and its products is to initiate a primary immune response and prevent pathogen invasion 16. However, when the NLRP3 inflammasome is excessively activated, leading to the excessive release of IL-1 beta and IL-18, the inflammatory response persists, leading to COPD-related pathophysiological changes, which results in airflow limitation and breathing difficulties 17-20.…”

Section: Introductionmentioning

confidence: 99%

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The Antioxidant MitoQ Protects Against CSE-Induced Endothelial Barrier Injury and Inflammation by Inhibiting ROS and Autophagy in Human Umbilical Vein Endothelial Cells

et al. 2019

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Chronic obstructive pulmonary disease (COPD) is a common disease characterized by persistent airflow limitation. Pulmonary vascular endothelial barrier injury and inflammation are increasingly considered to be important pathophysiological processes in cigarette smoke extract (CSE)-induced COPD, but the mechanism remains unclear. To identify the cellular mechanism of endothelial barrier injury and inflammation in CSE-treated human umbilical vein endothelial cells (HUVECs), we investigated the effect of the mitochondrion-targeting antioxidant mitoquinone (MitoQ) on endothelial barrier injury and inflammation. We demonstrated that MitoQ restored endothelial barrier integrity by preventing VE-cadherin disassembly and actin cytoskeleton remodeling, as well as decreased inflammation by the NF-κB and NLRP3 inflammasome pathways in endothelial cells. In addition, MitoQ also maintained mitochondrial function by reducing the production of ROS and excess autophagy. Inhibition of autophagy by 3-MA protected against cytotoxicity that was induced by CSE in HUVECs. Overall, our study indicated that mitochondrial damage is a key promoter in the induction of endothelial barrier dysfunction and inflammation by CSE. The protective effect of MitoQ is related to the inhibition of ROS and excess autophagy in CSE-induced HUVEC injury.

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

The Antioxidant MitoQ Protects Against CSE-Induced Endothelial Barrier Injury and Inflammation by Inhibiting ROS and Autophagy in Human Umbilical Vein Endothelial Cells

et al. 2019

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“…Second, while we demonstrated the crucial involvement of IL-1β in the development of VILI/ALI by treating mice with anti-IL-1β mAb at the same point as LPS administration, we did not test the effect of late administration of anti-IL-1β mAb (i.e., anti-IL-1β antibody administration after LPS treatment) from a translational point of view. However, since the onset of VILI is predictable, and early mediators such as IL-1β and TNF-α can be modulated preventively (69,70), prophylactic treatment against VILI may be the clue for a successful approach. In this context, a cytokinetargeting strategy, including anti-IL-1β, may be promising in the management of VILI, although a number of clinical trials in (predominantly sepsis) patients targeting a specific cytokine failed to show the effectiveness (69).…”

Section: Discussionmentioning

confidence: 99%

Autophagy Protects Against Developing Increased Lung Permeability and Hypoxemia by Down Regulating Inflammasome Activity and IL-1β in LPS Plus Mechanical Ventilation-Induced Acute Lung Injury

et al. 2020

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Targeting inflammasome activation to modulate interleukin (IL)-1β is a promising treatment strategy against acute respiratory distress syndrome and ventilator-induced lung injury (VILI). Autophagy is a key regulator of inflammasome activation in macrophages. Here, we investigated the role of autophagy in the development of acute lung injury (ALI) induced by lipopolysaccharide (LPS) and mechanical ventilation (MV). Two hours before starting MV, 0.2 mg/kg LPS was administered to mice intratracheally. Mice were then placed on high-volume MV (30 ml/kg with 3 cmH 2 O positive end-expiratory pressure for 2.5 h without additional oxygen application). Mice with myeloid-specific deletion of the autophagic protein ATG16L1 (Atg16l1 fl/fl LysM Cre ) suffered severe hypoxemia (adjusted p < 0.05) and increased lung permeability (p < 0.05, albumin level in bronchoalveolar lavage fluid) with significantly higher IL-1β release into alveolar space (p < 0.05). Induction of autophagy by fasting-induced starvation led to improved arterial oxygenation (adjusted p < 0.0001) and lung permeability (p < 0.05), as well as significantly suppressed IL-1β production (p < 0.01). Intratracheal treatment with anti-mouse IL-1β monoclonal antibody (mAb; 2.5 mg/kg) significantly improved arterial oxygenation (adjusted p < 0.01) as well as lung permeability (p < 0.05). On the other hand, deletion of IL-1α gene or use of anti-mouse IL-1α mAb (2.5 mg/kg) provided no significant protection, suggesting that the LPS and MV-induced ALI is primarily dependent on IL-1β, but independent of IL-1α. These observations suggest that autophagy has a protective role in controlling inflammasome activation and production of IL-1β, which plays a critical role in developing hypoxemia and increased lung permeability in LPS plus MV-induced acute lung injury.

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“…Recent studies demonstrate that sterile inflammation in response to MV is NLRP3-dependent. In mice, MV increases inflammasome gene expression in lung tissue and AMs ( 160 , 163 – 165 ). Concomitantly, MV enhances IL-Iβ and L-18 protein levels in the lung and bronchoalveolar lavage.…”

Section: Contribution Of Inflammasomes To Specific Organ Dysfunctionsmentioning

confidence: 99%

Inflammasomes in Tissue Damages and Immune Disorders After Trauma

2018

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Trauma remains a leading cause of death worldwide. Hemorrhagic shock and direct injury to vital organs are responsible for early mortality whereas most delayed deaths are secondary to complex pathophysiological processes. These processes result from imbalanced systemic reactions to the multiple aggressions associated with trauma. Trauma results in the uncontrolled local and systemic release of endogenous mediators acting as danger signals [damage-associated molecular patterns (DAMPs)]. Their recognition by the innate immune system triggers a pro-inflammatory immune response paradoxically associated with concomitant immunosuppression. These responses, ranging in intensity from inappropriate to overwhelming, promote the propagation of injuries to remote organs, leading to multiple organ failure and death. Some of the numerous DAMPs released after trauma trigger the assembly of intracellular multiprotein complexes named inflammasomes. Once activated by a ligand, inflammasomes lead to the activation of a caspase. Activated caspases allow the release of mature forms of interleukin-1β and interleukin-18 and trigger a specific pro-inflammatory cell death termed pyroptosis. Accumulating data suggest that inflammasomes, mainly NLRP3, NLRP1, and AIM2, are involved in the generation of tissue damage and immune dysfunction after trauma. Following trauma-induced DAMP(s) recognition, inflammasomes participate in multiple ways in the development of exaggerated systemic and organ-specific inflammatory response, contributing to organ damage. Inflammasomes are involved in the innate responses to traumatic brain injury and contribute to the development of acute respiratory distress syndrome. Inflammasomes may also play a role in post-trauma immunosuppression mediated by dysregulated monocyte functions. Characterizing the involvement of inflammasomes in the pathogenesis of post-trauma syndrome is a key issue as they may be potential therapeutic targets. This review summarizes the current knowledge on the roles of inflammasomes in trauma.

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The Role of the Inflammasome in Ventilator-induced Lung Injury

Cited by 9 publications

References 28 publications

The Antioxidant MitoQ Protects Against CSE-Induced Endothelial Barrier Injury and Inflammation by Inhibiting ROS and Autophagy in Human Umbilical Vein Endothelial Cells

The Antioxidant MitoQ Protects Against CSE-Induced Endothelial Barrier Injury and Inflammation by Inhibiting ROS and Autophagy in Human Umbilical Vein Endothelial Cells

Autophagy Protects Against Developing Increased Lung Permeability and Hypoxemia by Down Regulating Inflammasome Activity and IL-1β in LPS Plus Mechanical Ventilation-Induced Acute Lung Injury

Inflammasomes in Tissue Damages and Immune Disorders After Trauma

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