Dataset Information

Overexpression of CXCL14 Alleviates Ventilator-Induced Lung Injury through the Downregulation of PKM2-Mediated Cytokine Production.

ABSTRACT: Ventilator-induced lung injury (VILI) is one of the most common complications of mechanical ventilation (MV), which strongly impacts the outcome of ventilated patients. Current evidences indicated that inflammation is a major contributor to the pathogenesis of VILI. Our results showed that MV induced excessive proinflammatory cytokine productions together with decreased CXCL14 and increased PKM2 expressions in injured lungs. In addition, CXCL14 overexpression downregulated PKM2 expression and attenuated VILI with reduced inflammation. Moreover, the overexpression of PKM2 markedly diminished the protective effects of CXCL14 against VILI as reflected by worsened morphology and increased cytokine production, whereas PKM2 knockdown decreased cytokine production and attenuated VILI. Collectively, these results suggested that CXCL14 overexpression attenuates VILI through the downregulation of PKM2-mediated proinflammatory cytokine production.

SUBMITTER: Zhu R

PROVIDER: S-EPMC7396076 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Overexpression of CXCL14 Alleviates Ventilator-Induced Lung Injury through the Downregulation of PKM2-Mediated Cytokine Production.

Zhu Rui R Lei Yan-Qing YQ Zhao Dong-Chi DC

Mediators of inflammation 20200723

Ventilator-induced lung injury (VILI) is one of the most common complications of mechanical ventilation (MV), which strongly impacts the outcome of ventilated patients. Current evidences indicated that inflammation is a major contributor to the pathogenesis of VILI. Our results showed that MV induced excessive proinflammatory cytokine productions together with decreased CXCL14 and increased PKM2 expressions in injured lungs. In addition, CXCL14 overexpression downregulated PKM2 expression and at ...[more]

PMID: 32774150

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Project description:BackgroundVentilator-induced lung injury (VILI) is caused by stretch stimulation and other factors related to mechanical ventilation (MV). NOD-like receptor protein 3 (NLRP3), an important innate immune component, is strongly associated with VILI. This study aimed to investigate the effect and mechanisms of aerobic exercise (EX) on VILI.MethodsTo test the effects of the PKC inhibitor bisindolylmaleimide I on PKC and NLRP3, male C57BL/6 mice (7 weeks old, 19 ~ 23 g) were randomly divided into four groups: control group(C), bisindolylmaleimide I-pretreated group(B), MV group, and bisindolylmaleimide I-pretreated + MV (B + MV) group. The mice were pretreated with bisindolylmaleimide I through intraperitoneal injection (0.02 mg/kg) 1 h before MV. MV was performed at a high tidal volume (30 ml/kg). To explore the ameliorative effect of EX on VILI, the mice were randomly divided into C group, MV group, EX group and EX + MV group and subjected to either MV or 5 weeks of EX training. After ventilation, haematoxylin-eosin (HE) staining and wet/dry weight ratio was used to assess lung pathophysiological changes. PKCɑ, P-PKCɑ, ASC, procaspase-1, caspase-1, pro-IL-1β, IL-1β, NLRP3 and occludin (tight junction protein) expression in lung tissues was determined by Western blotting. The level of IL-6 in alveolar lavage fluid was determined by ELISA.ResultsNLRP3, P-PKCɑ, and PKCɑ levels were inceased in MV group, but bisindolylmaleimide I treatment reversed these changes. Inhibition of PKC production prevented NLRP3 activation. Moreover, MV increased ASC, procaspase-1, caspase-1, pro-IL-1β, and IL1β levels and decreased occludin levels, but EX alleviated these changes. HE staining and lung injury scoring confirmed an absence of obvious lung injury in C group and EX group. Lung injury was most severe in MV group but was improved in EX + MV group. Overall, these findings suggest that MV activates the NLRP3 inflammasome by activating PKCɑ and inducing occludin degradation, while Exercise attenuates NLRP3 inflammasome and PKCɑ activation. Besides, exercise improves cyclic stretch-induced degradation of occludin.ConclusionPKC activation can increase the level of NLRP3, which can lead to lung injury. Exercise can reduce lung injury by inhibiting PKCɑ and NLRP3 activation. Exercise maybe a potential measure for clinical prevention of VILI.

Project description:Apoptosis is a critical event in the pathogenesis of lung ischemia/reperfusion (I/R) injury. Sirtuin 3 (SIRT3), an important deacetylase predominantly localized in mitochondria, regulates diverse physiological processes, including apoptosis. However, the detailed mechanisms by which SIRT3 regulates lung I/R injury remain unclear. Many polyphenols strongly regulate the sirtuin family. In this study, we found that a polyphenol compound, procyanidin B2 (PCB2), activated SIRT3 in mouse lungs. Due to this effect, PCB2 administration attenuated histological lesions, relieved pulmonary dysfunction, and improved the survival rate of the murine model of lung I/R injury. Additionally, this treatment inhibited hypoxia/reoxygenation (H/R)-induced A549 cell apoptosis and rescued Bcl-2 expression. Using Sirt3-knockout mice and specific SIRT3 knockdown in vitro, we further found that SIRT3 strongly protects against lung I/R injury. Sirt3 deficiency or enzymatic inactivation substantially aggravated lung I/R-induced pulmonary lesions, promoted apoptosis, and abolished PCB2-mediated protection. Mitochondrial pyruvate kinase M2 (PKM2) inhibits apoptosis by stabilizing Bcl-2. Here, we found that PKM2 accumulates and is hyperacetylated in mitochondria upon lung I/R injury. By screening the potential sites of PKM2 acetylation, we found that SIRT3 deacetylates the K433 residue of PKM2 in A549 cells. Transfection with a deacetylated mimic plasmid of PKM2 noticeably reduced apoptosis, while acetylated mimic transfection abolished the protective effect of PKM2. Furthermore, PKM2 knockdown or inhibition in vivo significantly abrogated the antiapoptotic effects of SIRT3 upregulation. Collectively, this study provides the first evidence that the SIRT3/PKM2 pathway is a protective target for the suppression of apoptosis in lung I/R injury. Moreover, this study identifies K433 deacetylation of PKM2 as a novel modification that regulates its anti-apoptotic activity. In addition, PCB2-mediated modulation of the SIRT3/PKM2 pathway may significantly protect against lung I/R injury, suggesting a novel prophylactic strategy for lung I/R injury.

Dataset Information

Overexpression of CXCL14 Alleviates Ventilator-Induced Lung Injury through the Downregulation of PKM2-Mediated Cytokine Production.

Publications

Overexpression of CXCL14 Alleviates Ventilator-Induced Lung Injury through the Downregulation of PKM2-Mediated Cytokine Production.

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