PRKCA Promotes Mitophagy through the miR-15a-5p/PDK4 Axis to Relieve Sepsis-Induced Acute Lung Injury

Zhu, Qiujiao; Wang, Jian; Liu, Ying; Bai, Zhidong; Guo, Xu-Bei; Pan, Tao

doi:10.1128/iai.00465-22

Cited by 15 publications

(7 citation statements)

References 42 publications

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“…Additionally, miR-15a inhibits macrophage activation stimulated by lipopolysaccharide (LPS)/interferon. 36 Thus, it is plausible that miR-15a plays a pivotal role in the anti-inflammatory mechanism of action of EMO. On the other hand, a comprehensive total of 39 DEmiRNAs were detected when comparing plasma-SAP+EMO-Exo to plasma-SAP-Exo.…”

Section: Discussionmentioning

confidence: 99%

Emodin Ameliorates Severe Acute Pancreatitis-Associated Acute Lung Injury in Rats by Modulating Exosome-Specific miRNA Expression Profiles

Yang,

Luo,

et al. 2023

IJN

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Background: Numerous preclinical investigations have exhibited the beneficial impact of emodin (EMO) on the management of severe acute pancreatitis (SAP)-associated acute lung injury (ALI). However, the potential of EMO to mitigate organ damage through the modulation of exosome (Exo)-specific miRNA expression profiles remains unclear. Methods: The SAP rat model was established by retrograde injection of 5% sodium taurocholate into the pancreatic bile duct. Rats received intragastric administration of EMO at 2 h and 12 h post-modeling. Plasma and bronchoalveolar lavage fluid (BALF)-derived exosomes were isolated and purified from SAP rats treated with EMO. The therapeutic effects of these Exos in SAP rats were assessed using hematoxylin-eosin staining and measurement of inflammatory factor levels. MicroRNA (miRNA) sequencing was conducted on plasma and BALF-derived Exos, and rescue experiments were performed to investigate the function of NOVEL miR-29a-3p in the treatment of SAP using EMO. Results: EMO exhibits ameliorative effects on pancreatic and lung injury and inflammation in rats with SAP. Plasma/BALF-derived Exos from EMO-treated SAP rats also have therapeutic effects on SAP rats. The miRNA expression profile of plasma and BALFderived Exos in SAP rats underwent significant changes upon exposure to EMO. In particular, 34 differentially expressed miRNAs (DEmiRNAs) were identified when comparing BALF-SAP+EMO-Exo and BALF-SAP-Exo. 39 DEmiRNAs were identified when comparing plasma-SAP+EMO-Exo to plasma-SAP-Exo. We found that SAP rats treated with Exos derived from BALF exhibited a more potent therapeutic response than those treated with Exos derived from plasma. EMO may rely on NOVEL-rno-miR-29a-3p expression to prevent pulmonary injury in SAP rats. Conclusion:The mechanism of action of EMO is observed to have a significant impact on the miRNA expression profile of Exos derived from plasma and BALF in SAP rats. NOVEL-rno-miR-29a-3p, which is specific to Exos, and is derived from BALF, may play a crucial role in the therapeutic efficacy of EMO.

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Section: Discussionmentioning

confidence: 99%

Emodin Ameliorates Severe Acute Pancreatitis-Associated Acute Lung Injury in Rats by Modulating Exosome-Specific miRNA Expression Profiles

Yang,

Luo,

et al. 2023

IJN

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“…Zhu et al. ( 82 ) established an animal model of sepsis by cecal ligation perforation. They confirmed the binding of miR-152-3p to PDK4, which resulted in the downregulation of PDK4 expression.…”

Section: Regulation Of Macrophage Orientations By Pdkmentioning

confidence: 99%

“…MiR-15a-5p plays crucial functions in multiple diseases including endometriosis, sepsis, and acute myocardial infarction (80,81). Zhu et al (82) established an animal model of sepsis by cecal ligation perforation. They confirmed the binding of miR-152-3p to PDK4, which resulted in the downregulation of PDK4 expression.…”

Section: Regulation Of Macrophage Activation By Pdk4mentioning

confidence: 99%

Pyruvate dehydrogenase kinase regulates macrophage polarization in metabolic and inflammatory diseases

Li,

Liu,

Zhang

et al. 2023

Front. Immunol.

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Macrophages are highly heterogeneous and plastic, and have two main polarized phenotypes that are determined by their microenvironment, namely pro- and anti-inflammatory macrophages. Activation of pro-inflammatory macrophages is closely associated with metabolic reprogramming, especially that of aerobic glycolysis. Mitochondrial pyruvate dehydrogenase kinase (PDK) negatively regulates pyruvate dehydrogenase complex activity through reversible phosphorylation and further links glycolysis to the tricarboxylic acid cycle and ATP production. PDK is commonly associated with the metabolism and polarization of macrophages in metabolic and inflammatory diseases. This review examines the relationship between PDK and macrophage metabolism and discusses the mechanisms by which PDK regulates macrophage polarization, migration, and inflammatory cytokine secretion in metabolic and inflammatory diseases. Elucidating the relationships between the metabolism and polarization of macrophages under physiological and pathological conditions, as well as the regulatory pathways involved, may provide valuable insights into the etiology and treatment of macrophage-mediated inflammatory diseases.

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“…Consequently, ongoing research efforts are exploring the potential therapeutic benefits of PDK4 inhibitors in addressing these conditions [10,11]. Furthermore, basic research has uncovered the involvement of PDK4 in various aspects of acute lung injury [12][13][14].…”

Section: Introductionmentioning

confidence: 99%

Genetic Ablation of Pyruvate Dehydrogenase Kinase Isoform 4 Gene Enhances Recovery from Hyperoxic Lung Injury: Insights into Antioxidant and Inflammatory Mechanisms

Watanabe,

Kato,

Adachi

et al. 2024

Biomedicines

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Background: Pyruvate dehydrogenase kinase isoform 4 (PDK4) plays a pivotal role in the regulation of cellular proliferation and apoptosis. The objective of this study was to examine whether the genetic depletion of the PDK4 gene attenuates hyperoxia-induced lung injury in neonatal mice. Methods: Neonatal PDK4−/− mice and wild-type (WT) mice were exposed to oxygen concentrations of 21% (normoxia) and 95% (hyperoxia) for the first 4 days of life. Pulmonary histological assessments were performed, and the mRNA levels of lung PDK4, monocyte chemoattractant protein (MCP)-1 and interleukin (IL)-6 were assessed. The levels of inflammatory cytokines in lung tissue were quantified. Results: Following convalescence from neonatal hyperoxia, PDK4−/− mice exhibited improved lung alveolarization. Notably, PDK4−/− mice displayed significantly elevated MCP-1 protein levels in pulmonary tissues following 4 days of hyperoxic exposure, whereas WT mice showed increased IL-6 protein levels under similar conditions. Furthermore, neonatal PDK4−/− mice subjected to hyperoxia demonstrated markedly higher MCP-1 mRNA expression at 4 days of age compared to WT mice, while IL-6 mRNA expression remained unaffected in PDK4−/− mice. Conclusions: Newborn PDK4−/− mice exhibited notable recovery from hyperoxia-induced lung injury, suggesting the potential protective role of PDK4 depletion in mitigating lung damage.

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PRKCA Promotes Mitophagy through the miR-15a-5p/PDK4 Axis to Relieve Sepsis-Induced Acute Lung Injury

Abstract: Acute lung injury (ALI) caused by sepsis is a common respiratory critical illness with high morbidity and mortality. Protein kinase C-alpha (PRKCA) plays a protective role in sepsis-induced ALI.

Cited by 15 publications

References 42 publications

Emodin Ameliorates Severe Acute Pancreatitis-Associated Acute Lung Injury in Rats by Modulating Exosome-Specific miRNA Expression Profiles

Emodin Ameliorates Severe Acute Pancreatitis-Associated Acute Lung Injury in Rats by Modulating Exosome-Specific miRNA Expression Profiles

Pyruvate dehydrogenase kinase regulates macrophage polarization in metabolic and inflammatory diseases

Genetic Ablation of Pyruvate Dehydrogenase Kinase Isoform 4 Gene Enhances Recovery from Hyperoxic Lung Injury: Insights into Antioxidant and Inflammatory Mechanisms

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