Protective Effect of Oxytocin on Ventilator-Induced Lung Injury Through NLRP3-Mediated Pathways

Yang, Xiaomei; An, Xiaona; Wang, Cheng; Gao, Feng; Lin, Yu-Min; Chen, Wenjing; Deng, Qi; Xu, Dongsheng; Li, Shengqiang; Zhang, Peng; Sun, Bo; Hou, Yuedong; Wu, Jianbo

doi:10.3389/fphar.2021.722907

Cited by 11 publications

(9 citation statements)

References 36 publications

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“…37 The canonical pyroptosis pathway is induced by an NLRP3 inflammasome sensor that can detect the DAMPs released after ICH. 7,15 NLRP3 binds adaptor protein ASC and subsequently activates caspase-1. Cl-caspase-1 enables the maturation of the pro–IL-1β and pro–IL-18 and the activation of GSDMD.…”

Section: Discussionmentioning

confidence: 99%

“…14 In the ventilator-induced lung injury model, OXT was effective in alleviating the pyroptosis of lung tissue. 15 With the plentiful health benefits, OXT was considered a promising pharmaceutical for treating some diseases, including inflammation, aging-related neurocognitive decline, autism spectrum disorders, and pain. 11,13 Endogenous OXT level has also been shown to be decreased in several neurological diseases.…”

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confidence: 99%

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Oxytocin Improves Intracerebral Hemorrhage Outcomes by Suppressing Neuronal Pyroptosis and Mitochondrial Fission

Yang

Deng

Jiang

et al. 2023

Stroke

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Background: Intracerebral hemorrhage (ICH) causes severe sensorimotor dysfunction and cognitive decline which are aggravated by secondary brain injury, yet there are no effective management to alleviate these outcomes. Pyroptosis is strongly related to neuroinflammation, which plays a crucial role in the pathophysiological processes of secondary brain injury after ICH. OXT (oxytocin), as a pleiotropic neuropeptide, has multiple functions including anti-inflammation and antioxidation. This study aims to investigate the role of OXT in improving ICH outcomes and the underlying mechanisms. Methods: C57BL/6 mice were used to establish the ICH model by autologous blood injection. OXT was administered intranasally (0.2 μg/g) after ICH. Combing behavioral tests, Western blot, immunofluorescence staining, electron microscopy, and pharmacological approaches, we evaluated the effect of intranasal OXT application on neurological outcomes after ICH and explored the underlying mechanism. Results: Endogenous OXT level was decreased, whereas OXTR (oxytocin receptor) expression was increased after ICH. OXT treatment improved the short-term and long-term neurological functions and alleviated neuronal pyroptosis and neuroinflammation. In addition, OXT reduced excessive mitochondrial fission and mitochondrial-derived oxidative stress 3 days after ICH. OXT decreased the expression of pyroptotic and proinflammatory factors including NLRP3 (NOD-like receptor protein 3), ASC (apoptosis-associated speck-like protein containing a CARD), GSDMD (gasdermin D), caspase-1, IL (interleukin)-1β, and IL-18 and increased the expression of p-PKA (phospho-protein kinase A) and p-DRP1 (S637; DRP1 [dynamin-related protein 1] phosphorylation at Ser637). OXT-induced neuroprotective effects were blocked by either OXTR inhibitor or PKA inhibitor. Conclusions: Intranasal application of OXT can ameliorate neurological deficits and alleviate neural pyroptosis, inflammation, and excessive mitochondrial fission via OXTR/p-PKA/DRP1 signaling pathway after ICH. Thus, OXT administration may be a potential therapeutic strategy to improve the prognosis of ICH.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Oxytocin Improves Intracerebral Hemorrhage Outcomes by Suppressing Neuronal Pyroptosis and Mitochondrial Fission

Yang

Deng

Jiang

et al. 2023

Stroke

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“…Noncardiogenic pulmonary edema is the most visible manifestation of VILI. Its fundamental causes are destruction of alveolar membrane integrity and increased pulmonary capillary permeability [28,29]. In this study, we used HE staining and lung injury scores to assess the pathological changes in lung tissues and the lung W/D ratio to describe the extent of pulmonary edema in a mouse model of VILI and aerobic exercise.…”

Section: Discussionmentioning

confidence: 99%

Aerobic exercise alleviates ventilator-induced lung injury by inhibiting NLRP3 inflammasome activation

et al. 2022

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Background Ventilator-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. Methods To 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. Results NLRP3, 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. Conclusion PKC 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.

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“…Non-cardiogenic pulmonary edema is the most visible manifestation of VILI, its fundamental causes are the destruction of alveolar membrane integrity and the increase of pulmonary capillary permeability [28,29] . In this study, we used HE staining and lung injury scores to assess the pathological changes in lung tissues, and lung W/D ratio to describe the extent of pulmonary edema in mice model of VILI and aerobic exercise.…”

Section: Discussionmentioning

confidence: 99%

Aerobic exercise alleviates ventilator-induced lung injury due to activation of NLRP3 inflammasome

Liu

Yan

Wang

2022

Preprint

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BackgroundVentilator-induced lung injury (VILI) is a type of lung injury caused by stretch stimulation and other reasons for mechanical ventilation. NOD-like receptor protein 3(NLRP3) is an important ingredient of innate immunity and is strongly associated with VILI. This paper aims to investigate the effect of aerobic exercise on VILI and the role of NLRP3.MethodsC57BL/6 male mice (7-week-old, 19~23g) were pre‐treated with Bisindolylmaleimide I (specific and highly efficient inhibitor of PKC) . Then the mice were subjected to mechanical ventilation at a high tidal volume. For another study, the mice were randomly divided into the following four groups:control group (C group), mechanical ventilation group (MV group), exercise group (EX group) and exercise + mechanical ventilation group (EX+MV group) which were subjected to mechanical ventilation or 5 weeks of aerobic exercise training. At the end of ventilation, hematoxylin-eosin (HE) staining and wet/dry weight ratio were used to access the pathophysiological changes of lung tissues. The expression of PKCɑ, P-PKCɑ,ASC,Procaspase-1,caspase-1,ProIL-1β,IL-1β,NLRP3 and tight junction protein occludin in lung tissues were determined by Western blot. The contents of IL-6 in alveolar lavage fluid were determined by ELISA.ResultsMechanical ventilation could increase the levels of NLRP3, P-PKCɑ, PKCɑ, while these changes could be reversed by Bisindolylmaleimide I. Inhibited the PKC production can prevented the activation of NLRP3. Moreover, mechanical ventilation also could increase the levels of ASC,Procaspase-1,caspase-1,ProIL-1β,IL1β and decrease the levels of occludin, while these changes could be alleviated by aerobic exercise. HE staining and lung injury scores all confirmed that no obvious lung injury to group C and EX, while the severity of lung injury was the severest in group MV but was improved on group EX+MV.Taken together, these findings suggest that mechanical ventilation activated the NLRP3 inflammasome by activating PKCɑ, induced the degradation of occludin; while aerobic exercise attenuated activation of NLRP3 inflammasome and PKCɑ and mitigated the decrease in occludin expression caused by mechanical stretch.ConclusionActivation of NLRP3 leads to acute lung injury. Aerobic exercise can reduce lung injury by inhibiting activation of PKCɑ and NLRP3, suggesting a potential preventive measure for the clinical treatment of VILI.

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Protective Effect of Oxytocin on Ventilator-Induced Lung Injury Through NLRP3-Mediated Pathways

Cited by 11 publications

References 36 publications

Oxytocin Improves Intracerebral Hemorrhage Outcomes by Suppressing Neuronal Pyroptosis and Mitochondrial Fission

Oxytocin Improves Intracerebral Hemorrhage Outcomes by Suppressing Neuronal Pyroptosis and Mitochondrial Fission

Aerobic exercise alleviates ventilator-induced lung injury by inhibiting NLRP3 inflammasome activation

Aerobic exercise alleviates ventilator-induced lung injury due to activation of NLRP3 inflammasome

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