Anemoside B4 Protects against Acute Lung Injury by Attenuating Inflammation through Blocking NLRP3 Inflammasome Activation and TLR4 Dimerization

Acute lung injury (ALI) is an acute inflammatory process in the lung parenchyma. Anemoside B4 (B4) was isolated from Pulsatilla, a plant-based drug against inflammation and commonly applied in traditional Chinese medicine. However, the anti-inflammatory effect and the mechanisms of B4 are not clear. In this study, we explored the potential mechanisms and anti-inflammatory activity of B4 both in vitro and in vivo. The results indicated that B4 suppressed the expression of iNOS, COX-2, NLRP3, caspase-1, and IL-1β. The ELISA assay results showed that B4 significantly restrained the release of inflammatory cytokines like TNF-α, IL-6, and IL-1β in macrophage cells. In addition, B4 rescued mitochondrial membrane potential (MMP) loss in (lipopolysaccharide) LPS plus ATP stimulated macrophage cells. Co-IP and molecular docking results illustrated that B4 disrupted the dimerization of TLR4. For in vivo results, B4 exhibited a protective effect on LPS and bleomycin- (BLM-) induced ALI in mice through suppressing the lesions of lung tissues, the release of inflammatory cytokines, and the levels of white blood cells, neutrophils, and lymphoid cells in the blood. Collectively, B4 has a protective effect on ALI via blocking TLR4 dimerization and NLRP3 inflammasome activation, suggesting that B4 is a potential agent for the treatment of ALI.

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Protective effect of pteryxin on LPS-induced acute lung injury via modulating MAPK/NF-κB pathway and NLRP3 inflammasome activation

Journal of Ethnopharmacology ◽

10.1016/j.jep.2021.114924 ◽

2021 ◽

pp. 114924

Author(s):

Tian-qi Xuan ◽

Guohua Gong ◽

Huanhuan Du ◽

Chunyan Liu ◽

Yun Wu ◽

...

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Protective Effect ◽

Nlrp3 Inflammasome ◽

Inflammasome Activation ◽

Nlrp3 Inflammasome Activation

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Heat Shock Preconditioning Mesenchymal Stem Cells Attenuate Acute Lung Injury via Reducing NLRP3 Inflammasome Activation in Macrophages

10.21203/rs.3.rs-139954/v1 ◽

2021 ◽

Author(s):

Haijin Lv ◽

Xiaofeng Yuan ◽

Jiebin Zhang ◽

Tongyu Lu ◽

Jia Yao ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Acute Lung Injury ◽

Lung Injury ◽

Nlrp3 Inflammasome ◽

Inflammasome Activation ◽

Pathological Changes ◽

Nlrp3 Inflammasome Activation

Abstract Objectives: Acute lung injury (ALI) remains one of the common causes of morbidity and mortality worldwide, so far, without any effective therapeutic approach. Previous researches have revealed that topical administration of umbilical cord-derived mesenchymal stem cells (UC-MSCs) can attenuate pathological changes in experimental acute lung injury. Heat shock (HS) pretreatment has been identified as a method to enhance survival and function of cells. The present study aimed to assess whether HS-pretreated mesenchymal stem cells (MSCs) could strengthen the immunomodulation and recovery from ALI. Materials and Methods: HS pretreatment was defined 42℃ for 1h, the changes of biological characteristics and the secreted functions were detected. In the mouse model of ALI, we intranasally dripped the pretreated UC-MSCs in vivo, confirmed their therapeutic effects and detected the phenotypes of macrophages in bronchoalveolar lavage fluid (BALF). To elucidate their mechanisms, we co-cultured the pretreated UC-MSCs with macrophages in vitro, and the expression levels of inflammasome-related proteins in macrophages were assessed. Finally, Apoptozole was used for further determine the role of HSP70 in HS-pretreated UC-MSCs-based therapy. Results: The data showed that UC-MSCs did not represented significant changes in viability and biological characterizations after received HS pretreatment. Administration of HS-pretreated UC-MSCs into the ALI model, improved pathological changes and lung damage-related indexes, reduced of the levels of pro-inflammatory cytokines and modulated the balance of M1/M2. Mechanistically, both in vivo and in vitro studies demonstrated that HS pretreatment enhanced the protein level of HSP70 in UC-MSCs and subsequently upregulated the synthesis and secretion of PGE2, which negatively modulated the NLRP3 inflammasome activation of alveolar macrophages. And these effects was partially reversed by Apoptozole. Conclusion: HS pretreatment can strengthen the beneficial effects of UC-MSCs on inhibiting NLRP3 inflammasome activation of macrophages in ALI. The mechanism may be contributed to the upregulated expression of HSP70 to further induce PGE2 synthesis and secretion.

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Heat shock preconditioning mesenchymal stem cells attenuate acute lung injury via reducing NLRP3 inflammasome activation in macrophages

Stem Cell Research & Therapy ◽

10.1186/s13287-021-02328-3 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Haijin Lv ◽

Xiaofeng Yuan ◽

Jiebin Zhang ◽

Tongyu Lu ◽

Jia Yao ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Acute Lung Injury ◽

Lung Injury ◽

Nlrp3 Inflammasome ◽

Inflammasome Activation ◽

Pathological Changes ◽

Nlrp3 Inflammasome Activation

Abstract Objectives Acute lung injury (ALI) remains a common cause of morbidity and mortality worldwide, and to date, there is no effective treatment for ALI. Previous studies have revealed that topical administration of mesenchymal stem cells (MSCs) can attenuate the pathological changes in experimental acute lung injury. Heat shock (HS) pretreatment has been identified as a method to enhance the survival and function of cells. The present study aimed to assess whether HS-pretreated MSCs could enhance immunomodulation and recovery from ALI. Materials and methods HS pretreatment was performed at 42 °C for 1 h, and changes in biological characteristics and secretion functions were detected. In an in vivo mouse model of ALI, we intranasally administered pretreated umbilical cord-derived MSCs (UC-MSCs), confirmed their therapeutic effects, and detected the phenotypes of the macrophages in bronchoalveolar lavage fluid (BALF). To elucidate the underlying mechanisms, we cocultured pretreated UC-MSCs with macrophages in vitro, and the expression levels of inflammasome-related proteins in the macrophages were assessed. Results The data showed that UC-MSCs did not exhibit significant changes in viability or biological characteristics after HS pretreatment. The administration of HS-pretreated UC-MSCs to the ALI model improved the pathological changes and lung damage-related indexes, reduced the proinflammatory cytokine levels, and modulated the M1/M2 macrophage balance. Mechanistically, both the in vivo and in vitro studies demonstrated that HS pretreatment enhanced the protein level of HSP70 in UC-MSCs, which negatively modulated NLR family pyrin domain containing 3 (NLRP3) inflammasome activation in alveolar macrophages. These effects were partially reversed by knocking down HSP70 expression. Conclusion HS pretreatment can enhance the beneficial effects of UC-MSCs in inhibiting NLRP3 inflammasome activation in macrophages during ALI. The mechanism may be related to the upregulated expression of HSP70. Graphical abstract

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Wolf–Hirschhorn syndrome candidate 1 facilitates alveolar macrophage pyroptosis in sepsis-induced acute lung injury through NEK7-mediated NLRP3 inflammasome activation

Innate Immunity ◽

10.1177/17534259211035426 ◽

2021 ◽

pp. 175342592110354

Author(s):

Caixia Liu ◽

Benlong Cai ◽

Dan Li ◽

Yuan Yao

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Alveolar Macrophage ◽

Cancer Progression ◽

Nlrp3 Inflammasome ◽

Inflammasome Activation ◽

Nlrp3 Inflammasome Activation ◽

Incidence And Mortality

Sepsis is a complex clinical syndrome with high incidence and mortality. Acute lung injury (ALI) is a common complication of sepsis. At present, there is no effective therapeutic strategy to treat ALI. The SET domain–containing histone methyltransferase Wolf–Hirschhorn syndrome candidate 1 (WHSC1) regulates cancer progression, while its role in sepsis-induced ALI remains unclear. Thus, this study aimed to study the effect of WHSC1 on sepsis-induced ALI and to explore the potential mechanism of action. In the study, LPS treatment induced lung injury. WHSC1 was highly expressed in LPS-induced ALI. Knockdown of WHSC1 attenuated LPS-induced ALI and pyroptosis in vivo. Besides, knockdown of WHSC1 attenuated LPS-induced alveolar macrophage pyroptosis in vitro. Furthermore, NIMA-related kinase-7 (NEK7) expression could be regulated by WHSC1, and NEK7 bound to NLRP3 in alveolar macrophages. Moreover, WHSC1 regulated alveolar macrophage pyroptosis through modulating NEK7-mediated NLRP3 inflammasome activation. In conclusion, WHSC1 was highly expressed in LPS-induced ALI. WHSC1 facilitated alveolar macrophage pyroptosis in sepsis-induced ALI through NEK7-mediated NLRP3 inflammasome activation. WHSC1 may be a valuable target for the therapy of sepsis-induced ALI.

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Glycyrrhetinic acid alleviates acute lung injury by PI3K/AKT suppressing macrophagic Nlrp3 inflammasome activation

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2020.08.044 ◽

2020 ◽

Vol 532 (4) ◽

pp. 555-562

Author(s):

Kai Wang ◽

Yi Zhang ◽

Yue Cao ◽

Zhimian Shi ◽

Yike Lin ◽

...

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Nlrp3 Inflammasome ◽

Glycyrrhetinic Acid ◽

Inflammasome Activation ◽

Nlrp3 Inflammasome Activation

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Astragaloside IV Suppresses High Glucose-Induced NLRP3 Inflammasome Activation by Inhibiting TLR4/NF-κB and CaSR

Mediators of Inflammation ◽

10.1155/2019/1082497 ◽

2019 ◽

Vol 2019 ◽

pp. 1-16 ◽

Cited By ~ 10

Author(s):

Bin Leng ◽

Yingjie Zhang ◽

Xinran Liu ◽

Zhen Zhang ◽

Yang Liu ◽

...

Keyword(s):

Nlrp3 Inflammasome ◽

High Glucose ◽

Inflammasome Activation ◽

Astragaloside Iv ◽

Caspase 1 ◽

Endothelial Inflammation ◽

Nlrp3 Inflammasome Activation ◽

Anti Inflammatory

Long-term exposure to high glucose induces vascular endothelial inflammation that can result in cardiovascular disease. Astragaloside IV (As-IV) is widely used for anti-inflammatory treatment of cardiovascular diseases. However, its mechanism of action is still not fully understood. In this study, we investigated the effect of As-IV on high glucose-induced endothelial inflammation and explored its possible mechanisms. In vivo, As-IV (40 and 80 mg/kg/d) was orally administered to rats for 8 weeks after a single intraperitoneal injection of streptozotocin (STZ, 65 mg/kg). In vitro, human umbilical vein endothelial cells (HUVECs) were treated with high glucose (33 mM glucose) in the presence or absence of As-IV, NPS2143 (CaSR inhibitor), BAY 11-7082 (NF-κB p65 inhibitor), and INF39 (NLRP3 inhibitor), and overexpression of CaSR was induced by infection of CaSR-overexpressing lentiviral vectors to further discuss the anti-inflammatory property of As-IV. The results showed that high glucose increased the expression of interleukin-18 (IL-18), interleukin-1β (IL-1β), NLRP3, caspase-1, and ASC, as well as the protein level of TLR4, nucleus p65, and CaSR. As-IV can reverse these changes in vivo and in vitro. Meanwhile, NPS2143, BAY 11-7082, and INF39 could significantly abolish the high glucose-enhanced NLRP3, ASC, caspase-1, IL-18, and IL-1β expression in vitro. In addition, both NPS2143 and BAY 11-7082 attenuated high glucose-induced upregulation of NLRP3, ASC, caspase-1, IL-18, and IL-1β expression. In conclusion, this study suggested that As-IV could inhibit high glucose-induced NLRP3 inflammasome activation and subsequent secretion of proinflammatory cytokines via inhibiting TLR4/NF-κB signaling pathway and CaSR, which provides new insights into the anti-inflammatory activity of As-IV.

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