Caspase-1 Inhibition Attenuates Hyperoxia-induced Lung and Brain Injury in Neonatal Mice

Dapaah‐Siakwan, Fredrick; Zambrano, Ronald; Luo, Shihua; Duncan, Matthew R.; Kerr, Nadine; Donda, Keyur; Vaccari, Juan Pablo de Rivero; Keane, Robert W.; Dietrich, W. Dalton; Benny, Merline; Young, Karen; Wu, Shu

doi:10.1165/rcmb.2018-0192oc

Cited by 41 publications

(36 citation statements)

References 61 publications

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“…The main action of inflammasome activation is the maturation and release of pro-inflammatory cytokines, with IL-1β constituting the most decisive in the context of BPD, along with the activation of caspases such as caspase-8, with cell death induction as the key effector function [51]. Treatment of mice exposed to hyperoxia with the irreversible caspase-1 inhibitor Ac-YVAD-CMK markedly reduced lung injury, with improved alveolar and vascular development, along with reduced IL-1β production [52].…”

Section: Inflammatory Responsementioning

confidence: 99%

Oxygen Toxicity to the Immature Lung—Part I: Pathomechanistic Understanding and Preclinical Perspectives

Choi

Rekers

Dong

et al. 2021

IJMS

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In utero, the fetus and its lungs develop in a hypoxic environment, where HIF-1α and VEGFA signaling constitute major determinants of further development. Disruption of this homeostasis after preterm delivery and extrauterine exposure to high fractions of oxygen are among the key events leading to bronchopulmonary dysplasia (BPD). Reactive oxygen species (ROS) production constitutes the initial driver of pulmonary inflammation and cell death, altered gene expression, and vasoconstriction, leading to the distortion of further lung development. From preclinical studies mainly performed on rodents over the past two decades, the deleterious effects of oxygen toxicity and the injurious insults and downstream cascades arising from ROS production are well recognized. This article provides a concise overview of disease drivers and different therapeutic approaches that have been successfully tested within experimental models. Despite current studies, clinical researchers are still faced with an unmet clinical need, and many of these strategies have not proven to be equally effective in clinical trials. In light of this challenge, adapting experimental models to the complexity of the clinical situation and pursuing new directions constitute appropriate actions to overcome this dilemma. Our review intends to stimulate research activities towards the understanding of an important issue of immature lung injury.

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Section: Inflammatory Responsementioning

confidence: 99%

Oxygen Toxicity to the Immature Lung—Part I: Pathomechanistic Understanding and Preclinical Perspectives

Choi

Rekers

Dong

et al. 2021

IJMS

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“…30,31 The current study demonstrates that constant hyperoxia treatment results in proliferation inhibition and membrane damage of pulmonary epithelial cells and destruction of alveolus, accompanied by inflammatory response. In addition, Dapaah-Siakwan et al 32 found that inhibition of caspase-1 declines IL-1b activation in hyperoxia-challenged lungs. Similarly, in this study, long-term treatment of hyperoxia was verified to accelerate the inflammatory cytokine expression and release in MLE-12, and the analogous changes in proinflammatory cytokine expressions of IL-1b and IL-18 were exhibited in the mice model experiment.…”

Section: Discussionmentioning

confidence: 99%

Knockdown of Long Noncoding RNAs of Maternally Expressed 3 Alleviates Hyperoxia-Induced Lung Injury via Inhibiting Thioredoxin-Interacting Protein–Mediated Pyroptosis by Binding to miR-18a

Zou

Zhou

et al. 2020

The American Journal of Pathology

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Long-term hyperoxia exposure may cause lung damage with characteristic inflammation. Long noncoding RNA of maternally expressed 3 (MEG3) is up-regulated in lung tissues exposed to hyperoxia; however, the underlying mechanism is unclear. Hyperoxia-induced cells and mouse models were used to study these mechanisms. Molecular assays were used to detect cell viability, cytotoxicity, and expression of miR-18a, MEG3, and inflammatory cytokines. The interaction among MEG3, miR-18a, and thioredoxin-interacting protein (TXNIP) was verified; and pyroptosis-related proteins were analyzed. The in vivo model was established by exposing MEG3 knockdown mice to hyperoxia. Hematoxylin and eosin staining was used to assess pathologic alterations of lung tissues. Hyperoxia suppressed cell viability, induced cell damage, and exacerbated the secretion of IL-1b and IL-18. Hyperoxia inhibited miR-18a, with increased expression of MEG3, TXNIP, and nonobese diabeticelike receptor family pyrin domain containing 3 (NLRP3). MEG3 aggravated TXNIP expression by binding to miR-18a. Knockdown of MEG3 rescued hyperoxia-induced pyroptosis by up-regulating miR-18a. Furthermore, knockdown of MEG3 inhibited NLRP3 inflammasome activity and caspase-1 signaling by miR-18a. In vivo knockdown of MEG3 and overexpression of miR-18a relieved hyperoxia-induced lung injury via restraining NLRP3 inflammasomemediated pyroptosis, whereas miR-18a inhibition reversed these effects. In conclusion, knockdown of MEG3 inhibits pyroptosis to alleviate hyperoxia lung injury by suppressing NLRP3 inflammasome and caspase-1 signaling via regulating miR-18aeTXNIP axis.

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“…Caspase family members have different regulatory mechanisms and functions [34]. Activation of Caspase1 and Gsdmd is essential in inducing cell pyroptosis[28], inhibition of Caspase1 activity, IL-1β release and Gsdmd expression [35]. Caspase11 is a mouse gene, human caspase-4/5 has the highest homology with Caspase11.…”

Section: Discussionmentioning

confidence: 99%

Isopropyl 3-(3, 4-Dihydroxyphenyl)-2-Hydroxypropanoate, A Novel Metabolite From Salvia Miltiorrhiza, Protects Against LPS-Induced Acute Lung Injury in Mice by Attenuating the Canonical and Non-Canonical Inflammatory Pathway of Pyroptosis

Zhang¹,

Meng²,

Chen

et al. 2021

Preprint

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Background: The pathological characteristics of acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) are pulmonary edema resulting from pulmonary permeability increasing. The main cause is uncontrolled inflammatory response leading to the damage of pulmonary vascular endothelial and alveolar epithelial barriers. However, there has not been effective drugs against ALI. In this study, we investigated the function of Isopropyl 3-(3, 4-dihydroxypheny l)-2-hydroxypropanoate (IDHP), a novel metabolite of Danshen dripping pill having anti-inflammatory effect, in lipopolysaccharide (LPS) induced ALI in mice, and its underlying mechanisms.Methods: Pretreatment of IDHP in LPS-induced acute lung injury in mice were observed on survival rate, pulmonary morphologic changes, total protein content in bronchoalveolar lavage fluid (BALF), and inflammatory cytokines in lung tissue and BALF. To further explore its mechanism on ALI, THP-1 macrophages was studied to analyse propotosis related proteins and co-culture with epithelial or endothelial cells to assess protection function of IDHP in vitro.Results: As revealed by survival study, pretreatment with high dose of IDHP reduced the mortality of mice from ALI. IDHP pretreatment significantly improved LPS-induced lung pathological changes, reduced protein leakage and lung myeloperoxidase activity. IDHP also inhibited the release of inflammatory mediators TNFα, IL-1β, IL-6 and IL-18 in BALF and lung tissue. Meanwhile, IDHP decreased the expression of active-caspase1 (in canonical pyroptosis pathway), caspase4/5 (non-canonical pyroptosis pathway), Nrlp3, mature IL-1β, mature IL-18, Asc speck formation, and cleaved Gsdmd, all these are required for pyroptosis, in LPS stimulated THP-1 macrophages. Moreover, IDHP also decreased ROS production in LPS-stimulated THP-1 macrophages, inhibited the expression of tight junction proteins (Occludin, Zo-1) in endothelial cells, and decreased lactate dehydrogenase activity in supernatants of epithelial or endothelial cells, co-cultured with LPS-stimulated THP-1 macrophages. Conclusions: Pretreatment of IDHP improves survival rate and ameliorates LPS-induced ALI in mice possibly via inhibiting canonical and non-canonical pyroptosis pathways.

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Caspase-1 Inhibition Attenuates Hyperoxia-induced Lung and Brain Injury in Neonatal Mice

Cited by 41 publications

References 61 publications

Oxygen Toxicity to the Immature Lung—Part I: Pathomechanistic Understanding and Preclinical Perspectives

Oxygen Toxicity to the Immature Lung—Part I: Pathomechanistic Understanding and Preclinical Perspectives

Knockdown of Long Noncoding RNAs of Maternally Expressed 3 Alleviates Hyperoxia-Induced Lung Injury via Inhibiting Thioredoxin-Interacting Protein–Mediated Pyroptosis by Binding to miR-18a

Isopropyl 3-(3, 4-Dihydroxyphenyl)-2-Hydroxypropanoate, A Novel Metabolite From Salvia Miltiorrhiza, Protects Against LPS-Induced Acute Lung Injury in Mice by Attenuating the Canonical and Non-Canonical Inflammatory Pathway of Pyroptosis

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