Dihydromyricetin Alleviates Sepsis-Induced Acute Lung Injury through Inhibiting NLRP3 Inflammasome-Dependent Pyroptosis in Mice Model

Wang, Yuchang; Liu, Qinxin; Zheng, Qiang; Liu, Tao; Xie, Xia; Liu, Xinghua; Bai, Xiangjun; Li, Zhanfei

doi:10.1007/s10753-019-00990-7

Cited by 85 publications

(41 citation statements)

References 37 publications

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“…It was reported that DHM ameliorated lung pathological changes and lung edema in ALI mice challenged by LPS or CLP, which was associated with its inhibition of secretion of inflammatory cytokines TNF-α, IL1-β, IL-6 and IL-18. The responsible mechanism involved DHM activating PPAR-α expression as well as blocking the MAPK signaling pathway [ 167 ] and NLRP3 inflammasome [ 168 ]. Moreover, DHM had similar effects to 5 mg/kg DEX.…”

Section: Natural Compounds That Exert Anti-ali Effectsmentioning

confidence: 99%

Natural product derived phytochemicals in managing acute lung injury by multiple mechanisms

Zhou

et al. 2021

Pharmacological Research

224

121

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Section: Natural Compounds That Exert Anti-ali Effectsmentioning

confidence: 99%

Natural product derived phytochemicals in managing acute lung injury by multiple mechanisms

Zhou

et al. 2021

Pharmacological Research

224

121

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“…By revisiting [25] a two hit model (Poly(I:C)-MTV) of acute lung injury noted to be TLR4 independent, we have detected an additional stimulus, e.g. systemic endotoxemia; as a result of gut-lung axis, both noncanonical caspase-11 (via presumptive cytosolic endotoxemia [28]) and canonical (via NLRP3 in ammasome [38,39]) and their interactions led to pyroptosis in alveolar macrophages, disruption of alveolar capillary barrier and proin ammatory state within lung. Pharmacologic strategies at disrupting communication between gut and lung, inhibition of in ammasomes or effector molecules (GSDMD) in pyroptosis may be useful in acute lung injury.…”

Section: Discussionmentioning

confidence: 94%

“…Nonetheless, excessive activation is implicated in human diseases including sepsis [37]. For example, dihydromyricetin, an inhibitor of NLRP3, alleviated cecal ligation and puncture-induced lung histopathologic injury in mice [38]. As cell death, per se, and in ammatory mediators are essential components of disruption of alveolar capillary barrier in ALI and ARDS, insight into relevant pathways may be informative of pathogenesis and therapeutic strategies.…”

Section: Discussionmentioning

confidence: 99%

Mechanical Ventilation Exacerbates Poly (I:C) Induced Acute Lung Injury: Central Role for Caspase-11 and Gut-Lung Axis

Jin

Ding

Yang

et al. 2020

Preprint

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Background: The mechanisms by which moderate tidal volume ventilation (MTV) may exacerbate preexisting lung injury remain unclear. We hypothesized that in two hit model (polyinosinic-polycytidylic acid (Poly(I:C)), a synthetic analog of dsRNA and MTV), systemic endotoxemia via gut-lung axis would lead to non-canonical (i.e. caspase-11 dependent) and canonical (caspase-1 dependent) inflammasome activation and programmed necrotic cell death (pyroptosis) contributing to acute lung injury (ALI) in intact mice.Methods: Anesthetized mice were administered Poly(I:C) intratracheally and then 6 h later, they were mechanically ventilated for 4 h with otherwise non-injurious MTV (10ml/kg). Changes in intestinal and alveolar capillary permeability were measured. Further documentation of ALI was assessed by evans blue albumin permeability, protein and IL-1 family concentration in bronchoalveolar lavage fluid (BALF) or plasma, and histopathology in cohorts of wildtype, whole body genetically ablated caspase-11 (caspase-11-/-), caspase-1/caspase-11 double knockout (caspase-1/11-/-), gasdermin D (GSDMD-/-), and NLRP3-/- mice. Results: Non-injurious MTV exacerbated mild Poly(I:C) lung injury including disruption of alveolar-capillary barrier and increased levels of IL-6, HMGB1, IL-1β in BALF and IL-18 in plasma. Combined (Poly(I:C)-MTV) injury was associated with increase in gastrointestinal permeability and endotoxin in plasma and BALF. Poly(I:C)-MTV injury was sensitive to caspase-11 deletion with no further contribution of caspase-1 except for maturation and release of IL-18 (that itself was sensitive to deletion of NLRP3). Combined injury led to large increases in pro-caspase-11 and its cleaved product as well as cleaved product of caspase-1. Genetic ablation of GSDMD attenuated alveolar-capillary disruption and maturation and release of cytokines in combined injury model.Conclusions: The previously noted TLR-4 independent exacerbation of mild Poly(I:C)-induced ALI by otherwise non-injurious MTV is associated with an increase in gut permeability resulting in systemic endotoxemia. The gut-lung axis resulted in activation of pulmonary non-canonical (cytosolic mediated caspase-11 activation) and canonical (caspase-1) inflammasome (NLRP3) mediated ALI in this two hit model resulting in GSDMD sensitive alveolar capillary barrier disruption, pyroptosis (in alveolar macrophages) and cytokine maturation and release (IL-1β; IL-18). Pharmacologic strategies at disrupting communication between gut and lung, inhibition of inflammasomes or effector molecule (GSDMD) in pyroptosis may be useful in ALI.

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“…If not effectively cleared, the increased pyroptotic macrophages and released cytokines may results in the uncontrolled lung in ammation among patients with ARDS [22]. Thus, suppression of pyroptotic macrophages through molecular intervention might be an effective therapeutic strategy in the treatment of the uncontrolled lung in ammation in ARDS patients [23][24][25].…”

Section: Discussionmentioning

confidence: 99%

STAT6 attenuated murine acute lung injury through NLRP3/p38 MAPK/NF-kappaB signaling in macrophages

Shao

Pan

et al. 2021

Preprint

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Signal transducer and activator of transcription 6 (STAT6) is an intracellular transcription factor, it remained unclear whether STAT6 affects murine acute lung injury (ALI) through modulation of macrophage subtypes and NLRP3/p38 MAPK/NF-kappaB signaling. We in this study, intratracheal treated wild-type (WT) and STAT6-/- mice with 5 mg/kg LPS. Lung tissues and bronchoalveolar lavage (BAL) were collected 2 days after the treatment. The results showed that lack of STAT6 in STAT6-/- mice caused more severe lung inflammation, neutrophil influx, and the expression of TNF-α, IL-6 and IL-1β in the inflamed lung tissues. Flow cytometry analysis showed Siglec F-CD206- biased polarization of M1 subtype macrophages in the LPS-treated STAT6-/- mice. In addition, lack of STAT6 increased the expression of NLRP3, p-p38 M APK, TNF-α, IL-1β and Calreticulin in the lung tissues of LPS-treated mice and STAT6-/- bone marrow-derived macrophages (BMDMs). However, Glibenclamide, PDTC and SB203580 effectively reversed the up-regulated pro-inflammatory cytokines in STAT6-/- BMDMs. Thereby, STAT6 defciency increased ALI severity, possibly through increasing polarization of M1 subtype macrophages and NLRP3/p38 MAPK/NF-kappaB signaling. NLRP3/p38 MAPK/NF-kappaB signaling may particiupate in the polarizatin of M1 subtype macrophages. Modulation of macrophages subtypes by molecular intervention of STAT6 signaling would be a promising therapeutic approach in the treatment of ALI.

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Dihydromyricetin Alleviates Sepsis-Induced Acute Lung Injury through Inhibiting NLRP3 Inflammasome-Dependent Pyroptosis in Mice Model

Cited by 85 publications

References 37 publications

Natural product derived phytochemicals in managing acute lung injury by multiple mechanisms

Natural product derived phytochemicals in managing acute lung injury by multiple mechanisms

Mechanical Ventilation Exacerbates Poly (I:C) Induced Acute Lung Injury: Central Role for Caspase-11 and Gut-Lung Axis

STAT6 attenuated murine acute lung injury through NLRP3/p38 MAPK/NF-kappaB signaling in macrophages

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