Ventilator-induced Lung Injury Is Mediated by the NLRP3 Inflammasome

Kuipers, Maria T.; Arazi, Hamid; Janczy, John R.; Sluijs, Koenraad F. van der; Vlaar, Alexander P.J.; Wolthuis, Esther K.; Choi, Goda; Roelofs, Joris J. T. H.; Flavell, Richard A.; Sutterwala, Fayyaz S.; Bresser, Paul; Leemans, Jaklien C.; Poll, Tom van der; Schultz, Marcus J.; Wieland, Catharina W.

doi:10.1097/aln.0b013e3182518bc0

Cited by 113 publications

(119 citation statements)

References 45 publications

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“…The translational relevance of NLR research is most evident in the novel therapeutic targets it has identified. Caspase-1, IL-1b, and IL-1 receptor antagonists, and the uric acid inhibitors, uricase and allopurinol, have been tested in animal models with varied success in combating deleterious NLR-mediated inflammation (57)(58)(59)(60). The next logical step for NLR research may incorporate environmental stressors (i.e., CS, ventilator support), with bacterial challenge, thus enhancing our understanding of NLRmediated antibacterial immunity within a framework relevant to human disease.…”

Section: Discussionmentioning

confidence: 99%

“…In this regard, mechanical ventilation up-regulated NLRP3 and ASC mRNA, caspase-1, and IL-1b in the lungs of mice and also increased NLRP3 expression in human and murine alveolar macrophages (59). VILI was reduced in the lungs of NLRP3 and ASC gene-deficient mice and in wildtype mice treated with an IL-1 receptor antagonist (59). Although these data strongly support a role for NLRP3 in VILI, the interplay between VILI, VAP, and NLRs is less clear.…”

Section: Nlrs In Multifactorial Diseasementioning

confidence: 95%

“…Mechanical ventilation can contribute to the injury of both healthy and previously injured lungs, that is, VILI. Even when lower tidal volumes are used to reduce barotrauma, in lungs with existing injury some areas may be collapsed, while others are intrinsically prone to hyperinflation and injury (59). VILI causes release from dying cells of DAMPs including uric acid, ATP, and hyaluronan, all known inducers of the NLRP3 inflammasome (59).…”

Section: Nlrs In Multifactorial Diseasementioning

confidence: 99%

“…Even when lower tidal volumes are used to reduce barotrauma, in lungs with existing injury some areas may be collapsed, while others are intrinsically prone to hyperinflation and injury (59). VILI causes release from dying cells of DAMPs including uric acid, ATP, and hyaluronan, all known inducers of the NLRP3 inflammasome (59). In this regard, mechanical ventilation up-regulated NLRP3 and ASC mRNA, caspase-1, and IL-1b in the lungs of mice and also increased NLRP3 expression in human and murine alveolar macrophages (59).…”

Section: Nlrs In Multifactorial Diseasementioning

confidence: 99%

“…VILI causes release from dying cells of DAMPs including uric acid, ATP, and hyaluronan, all known inducers of the NLRP3 inflammasome (59). In this regard, mechanical ventilation up-regulated NLRP3 and ASC mRNA, caspase-1, and IL-1b in the lungs of mice and also increased NLRP3 expression in human and murine alveolar macrophages (59). VILI was reduced in the lungs of NLRP3 and ASC gene-deficient mice and in wildtype mice treated with an IL-1 receptor antagonist (59).…”

Section: Nlrs In Multifactorial Diseasementioning

confidence: 99%

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Investigating the Role of Nucleotide-Binding Oligomerization Domain–Like Receptors in Bacterial Lung Infection

Zemans

Downey

Jeyaseelan

2014

Am J Respir Crit Care Med

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Lower respiratory tract infections (LRTIs) are a persistent and pervasive public health problem worldwide. Pneumonia and other LRTIs will be among the leading causes of death in adults, and pneumonia is the single largest cause of death in children. LRTIs are also an important cause of acute lung injury and acute exacerbations of chronic obstructive pulmonary disease. Because innate immunity is the first line of defense against pathogens, understanding the role of innate immunity in the pulmonary system is of paramount importance. Pattern recognition molecules (PRMs) that recognize microbial-associated molecular patterns are an integral component of the innate immune system and are located in both cell membranes and cytosol. Toll-like receptors and nucleotidebinding oligomerization domain-like receptors (NLRs) are the major sensors at the forefront of pathogen recognition. Although Toll-like receptors have been extensively studied in host immunity, NLRs have diverse and important roles in immune and inflammatory responses, ranging from antimicrobial properties to adaptive immune responses. The lung contains NLR-expressing immune cells such as leukocytes and nonimmune cells such as epithelial cells that are in constant and close contact with invading microbes. This pulmonary perspective addresses our current understanding of the structure and function of NLR family members, highlighting advances and gaps in knowledge, with a specific focus on immune responses in the respiratory tract during bacterial infection. Further advances in exploring cellular and molecular responses to bacterial pathogens are critical to develop improved strategies to treat and prevent devastating infectious diseases of the lung.

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Section: Discussionmentioning

confidence: 99%

Section: Nlrs In Multifactorial Diseasementioning

confidence: 95%

Section: Nlrs In Multifactorial Diseasementioning

confidence: 99%

Section: Nlrs In Multifactorial Diseasementioning

confidence: 99%

Section: Nlrs In Multifactorial Diseasementioning

confidence: 99%

See 3 more Smart Citations

Investigating the Role of Nucleotide-Binding Oligomerization Domain–Like Receptors in Bacterial Lung Infection

Zemans

Downey

Jeyaseelan

2014

Am J Respir Crit Care Med

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Regulation of cell proliferation and transdifferentiation compensates for ventilator‐induced lung injury mediated by NLRP3 inflammasome activation

Liu,

Yang,

Liu

2023

Immunity Inflam & Disease

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BackgroundMechanical ventilation is an important means of respiratory support and treatment for various diseases. However, its use can lead to serious complications, especially ventilator‐induced lung injury (VILI). The mechanisms underlying this disease are complex, but activation of inflammatory signalling pathways results in activation of cytokines and inflammatory mediators, which play key roles in VILI. Recent studies have demonstrated that nod‐like receptor protein 3 (NLRP3) inflammasome activation mediates VILI and also accompanied by cell proliferation and transdifferentiation to compensate for alveolar membrane damage. Type I alveolar epithelial cells (AECs I), which are involved in the formation of the blood‐air barrier, are vulnerable to damage but cannot proliferate by themselves; thus, replacing AECs I relies on type II alveolar epithelial cells (AECs II).ObjectiveThe review aims to introduce the mechanisms of NLRP3 inflammasome activation and its inhibitors, as well as the mechanisms that regulate cell proliferation and transdifferentiation.MethodsA large number of relevant literature was searched, then the key content was summarized and figures were also made.ResultsThe mechanism of NLRP3 inflammasome activation has been further explored, including but not limited to pathogenic and aseptic inflammatory signals, such as, pathogenic molecular patterns and host‐derived danger‐associated molecular patterns activate toll‐like receptor 4/nuclear factor‐kappaB pathway or reactive oxygen species, cyclic stretch, adenosine triphosphate induce K+ efflux through P2X7, Ca2+ inflow, mitochondrial damage, etc, eventually induce NIMA‐related kinase 7/NLRP3 binding and NLRP3 inflammasome activation. Not only that, the review also described in detail the inhibitors of NLRP3 inflammasome. And the mechanisms regulating cell proliferation and transdifferentiation are complex and unclear, including the Wnt/β‐catenin, Yap/Taz, BMP/Smad and Notch signalling pathways.ConclusionsNLRP3 inflammasome activation mediated VILI, and VILI is alleviated after interfering with its activation, and inflammation and repair exist simultaneously in VILI. Clarifying these mechanisms is expected to provide theoretical guidance for alleviating VILI by inhibiting the inflammatory response and accelerating alveolar epithelial cell regeneration in the early stage.

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Cells under stress: The mechanical environment shapes inflammasome responses to danger signals

Joshi

Morley

2019

Journal of Leukocyte Biology

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Many intracellular signals, such as host danger-associated molecules and bacterial toxins during infection, elicit inflammasome activation. However, the mechanical environment in tissues may also influence the sensitivity of various inflammasomes to activation. The cellular mechanical environment is determined by the extracellular tissue stiffness, or its inverse, tissue compliance. Tissue stiffness is sensed by the intracellular cytoskeleton through a process termed mechanotransduction. Thus, extracellular compliance and the intracellular cytoskeleton may regulate the sensitivity of inflammasome activation. Control of proinflammatory signaling by tissue compliance may contribute to the pathogenesis of diseases such as ventilator-induced lung injury during bacterial pneumonia and tissue fibrosis in inflammatory disorders. The responsible signaling cascades in inflammasome activation pathways and mechanotransduction crosstalk are not yet fully understood. This rather different immunomodulatory perspective will be reviewed and open questions discussed here. K E Y W O R D S cell adhesion, inflammasome, inflammation, integrins, mechanobiology, monocytes/macrophages

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Ventilator-induced Lung Injury Is Mediated by the NLRP3 Inflammasome

Abstract: Mechanical ventilation induced a NLRP3 inflammasome dependent pulmonary inflammatory response. NLRP3 inflammasome deficiency partially protected mice from VILI.

Cited by 113 publications

References 45 publications

Investigating the Role of Nucleotide-Binding Oligomerization Domain–Like Receptors in Bacterial Lung Infection

Investigating the Role of Nucleotide-Binding Oligomerization Domain–Like Receptors in Bacterial Lung Infection

Regulation of cell proliferation and transdifferentiation compensates for ventilator‐induced lung injury mediated by NLRP3 inflammasome activation

Cells under stress: The mechanical environment shapes inflammasome responses to danger signals

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