PICK1 Deficiency Induces Autophagy Dysfunction via Lysosomal Impairment and Amplifies Sepsis-Induced Acute Lung Injury

Mo, Yunchang; Lou, Yingying; Zhang, Anqi; Zhang, Jingjing; Zhu, Congying; Zheng, Bo; Li, Dan; Zhang, Mingyuan; Jin, Wenjun; Zhang, Lei; Wang, Junlu

doi:10.1155/2018/6757368

Cited by 28 publications

(17 citation statements)

References 49 publications

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“…ALI has been found to be associated with inflammatory responses, neutrophil infiltration, oxidative stress and the accumulation of pro-tein-rich fluid in the lung (Kissoon et al, 2016). As previously reported, patients with sepsis-induced ALI have a poor outcome, with mortality rates of more than 40% (Mo et al, 2018). Currently available treatments for ALI, antibiotics and pulmonary supportive measures, can hardly improve the outcome of the patients (Aziz et al, 2018).…”

Section: Introductionmentioning

confidence: 89%

High expression of miR-483-5p aggravates sepsis-induced acute lung injury

et al. 2020

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Sepsis-induced acute lung injury (ALI) has high morbidity and mortality rates, and there remains a need for therapeutic methods to improve the outcome of ALI patients. miR-483-5p is an important regulator for the development of various diseases such as sepsis. Nevertheless, it is not known whether miR-483-5p has an effect on sepsis-induced ALI. To explore this issue, this study used cecal ligation and puncture (CLP)-treated mice and lipopolysaccharide (LPS)-treated pulmonary microvascular endothelial cells (PMVECs) cells to simulate the models of sepsis-induced ALI in vivo and in vitro. Pathological and histological changes of lungs from sepsis-induced ALI mice were detected by Hematoxylin-eosin staining. The detection levels of caspase-3, interleukin (IL)-6 and IL-1β were used to reflect the effect of miR-483-5p on apoptosis and inflammation of sepsis-induced ALI. The detection level of lactate dehydrogenase (LDH) in PMVECs cells was used to reflect the severe extent of sepsis-induced injury. The expression of miR-483-5p in lung tissues of sepsis-induced ALI mice was determined by qRT-PCR. In addition, the interaction of miR-483-5p with PIAS1 was identified and validated by Targetscan website and luciferase reporter assay, respectively. The results showed that miR-483-5p was up-regulated in the lung tissues of sepsis-induced ALI mice. Knockdown of miR-483-5p effectively ameliorated lung injury in mice with sepsis-induced ALI and inhibited inflammation and apoptosis of LPS-treated PMVECs cells. Furthermore, in vitro experiment revealed that PIAS1 was a potential target of miR-483-5p. Moreover, miR-483-5p could suppress PIAS1 expression to aggravate inflammation and apoptosis of LPS-treated PMVECs cells. These findings suggest miR-483-5p is a potential therapeutic and diagnostic biomarker for sepsis-induced ALI and provide a new insight for understanding the molecular mechanism of sepsisinduced ALI.

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Section: Introductionmentioning

confidence: 89%

High expression of miR-483-5p aggravates sepsis-induced acute lung injury

et al. 2020

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“…In vivo experiments also found that PICK1 deficiency caused a disruption of autophagy progress and amplified the damage in sepsis-induced ALIs. Lysosomal damage caused by PICK1 deficiency may be responsible for the impediment of autophagy flux (Mo et al, 2018). Another experiment found that the AMPK activator might improve lung recovery through the activation of mitochondrial biogenesis via the increased expression of PGC-1α.…”

Section: Mechanism Of Action Of Autophagy In Different Organsmentioning

confidence: 99%

The Role of Autophagy in Sepsis: Protection and Injury to Organs

et al. 2019

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Sepsis is a systemic inflammatory disease with infection, and autophagy has been shown to play an important role in sepsis. This review summarizes the main regulatory mechanisms of autophagy in sepsis and its latest research. Recent studies have shown that autophagy can regulate innate immune processes and acquired immune processes, and the regulation of autophagy in different immune cells is different. Mitophagy can select damaged mitochondria and remove it to deal with oxidative stress damage. The process of mitophagy is regulated by other factors. Non-coding RNA is also an important factor in the regulation of autophagy. In addition, more and more studies in recent years have shown that autophagy plays different roles in different organs. It tends to be protective in the lungs, heart, kidneys, and brain, and tends to be damaging in skeletal muscle. We also mentioned that some drugs can regulate autophagy. The process of modulating autophagy through drug intervention appears to be a new potential hope for the treatment of sepsis.

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“…Studies have proved that cytokine bursts caused by uncontrolled inflammatory responses could induce severe damage in tissue and organ, even causing death [17]. Acute organ dysfunction is a common respiratory and cardiovascular complication of sepsis [18]. The lung is the easiest infection target in sepsis, which also plays a critical role in the secretion and release of inflammatory mediators [19].…”

Section: Discussionmentioning

confidence: 99%

miR-128-3p enhances the protective effect of dexmedetomidine on acute lung injury in septic mice by targeted inhibition of MAPK14

Ding¹,

Gao²,

Yu³

et al. 2020

J Bioenerg Biomembr

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Background: To investigate the role of miR-128-3p and MAPK14 in the dexmedetomidine treatment of acute lung injury in septic mice. Methods: SPF C57BL/6 mice were divided into 8 groups. The pathological changes and wet/dry weight ratio (W/D), PaO 2 , PaCO 2 , MDA, SOD and MPO levels in lung tissue and the serum levels of inflammation factors were observed. Dual luciferase reporter assay was used to detect the targeting relationship of miR-128-3p and MAPK14, and qPCR and WB were used to detect the expression of miR-128-3p and MAPK14. Results: Compared with the Normal group, other groups had lower MDA, MPO, inflammatory factors levels and the expression level of MAPK14, while the content of SOD and the expression level of miR-128-3p was significantly decreased (all p < 0.05). Compared with the Model group, the contents of MDA, MPO, inflammatory factors in the DEX group and miR-128-3p mimic group were significantly decreased, and the content SOD was significantly increased, however, opposite results were occurred in oe-MAPK14 group (all p < 0.05). Compared with the DEX group, all the indicators in miR-128-3p mimic+DEX group showed significant improvement (all p < 0.05). Compared with the miR-128-3p mimic group, all the indicators were deteriorated in the miR-128-3p mimic+oe-MAPK14 group (all p < 0.05). The combination of DEX and oe-MAPK14 blocked the protective effect of dexmedetomidine on acute lung injury in septic mice. Conclusion: miR-128-3p can further enhance the protective effect of dexmedetomidine on acute lung injury in septic mice by targeting and inhibiting MAPK14 expression.

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PICK1 Deficiency Induces Autophagy Dysfunction via Lysosomal Impairment and Amplifies Sepsis-Induced Acute Lung Injury

Cited by 28 publications

References 49 publications

High expression of miR-483-5p aggravates sepsis-induced acute lung injury

High expression of miR-483-5p aggravates sepsis-induced acute lung injury

The Role of Autophagy in Sepsis: Protection and Injury to Organs

miR-128-3p enhances the protective effect of dexmedetomidine on acute lung injury in septic mice by targeted inhibition of MAPK14

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