Honokiol alleviates LPS-induced acute lung injury by inhibiting NLRP3 inflammasome-mediated pyroptosis via Nrf2 activation in vitro and in vivo

Abstract Background Honokiol (HKL) has been reported to ameliorate lipopolysaccharide (LPS)-induced acute lung injury (ALI). However, its potential mechanism of its protective effects remains unclear. In this study, the protective mechanism of HKL on LPS-induced ALI was explored in vivo and in vitro. Methods In vivo, the SD rats were intratracheally instilled with LPS (5 mg/kg) to establish an acute lung injury model and then treated with HKL (1.25/2.5/5 mg/kg) or ML385 (30 mg/kg) intraperitoneally. In vitro, the human bronchial epithelial cell line (BEAS-2B) was stimulated with LPS and ATP to induce pyroptosis and treated with HKL (12.5/25/50 μM). Small interfering RNA (siRNA) technique was used to knockdown Nrf2 in BEAS-2B cells. The protein and mRNA expression levels of Nrf2, HO-1, NLRP3, ASC, CASP1, and GSDMD in cells and lung tissues were detected by western blot and real time-PCR. The expression levels of interleukin (IL)-1β, IL-18, MPO, MDA, and SOD in bronchoalveolar lavage fluid (BALF) and supernatant were determined by ELISA. The degree of pathological injury of lung tissue was evaluated by H&E staining. Results The results showed that HKL could alleviate oxidative stress and inflammatory responses by regulating the levels of MPO, MDA, SOD, IL-1β, IL-18 in supernatant. And it could also inhibit the expression levels of NLRP3, ASC, CASP1, GSDMD via activation of Nrf2 in BEAS-2B cells. Further studies revealed that HKL could attenuate the pathological injury in LPS-induced ALI rats, and the molecular mechanism was consistent with the results in vitro. Conclusions Our study demonstrated that HKL could alleviate LPS-induced ALI by reducing the oxidative stress and inhibiting NLRP3 inflammasome-mediated pyroptosis, which was partly dependent on the Nrf2 activation. Graphical Abstract

Download Full-text

Honokiol alleviates LPS-induced acute lung injury by inhibiting NLRP3 inflammasome-mediated pyroptosis via Nrf2 activation in vitro and in vivo

10.21203/rs.3.rs-917410/v1 ◽

2021 ◽

Author(s):

yuhan liu ◽

jiabin zhou ◽

yingying luo ◽

jinxiao li ◽

luorui shang ◽

...

Keyword(s):

Oxidative Stress ◽

Acute Lung Injury ◽

Lung Injury ◽

Nlrp3 Inflammasome ◽

Epithelial Cell Line ◽

Protective Mechanism ◽

Expression Levels ◽

Nrf2 Activation

Abstract Background Honokiol (HKL) has been reported to ameliorate lipopolysaccharide (LPS)-induced acute lung injury (ALI). However, its potential mechanism imparting the protective effects remains unclear. In this study, the protective mechanism of HKL on LPS-induced ALI was explored in vivo and in vitro. Methods In vivo, the SD rats were intratracheally instilled with LPS (5 mg/kg) to establish an acute lung injury model and then treated with HKL (1.25/2.5/5 mg/kg) or ML385 (30 mg/kg) intraperitoneally. In vitro, the human bronchial epithelial cell line (BEAS-2B) was stimulated with LPS and ATP to induce pyroptosis and treated with HKL (12.5/25/50 µM). Small interfering RNA (siRNA) technique was used to knockdown Nrf2 in BEAS-2B cells. The protein and mRNA expression levels of Nrf2, HO-1, NLRP3, ASC, CASP1, and GSDMD in cells and lung tissues were detected by western blot and real time-PCR. The expression levels of interleukin (IL)-1β, IL-18, MPO, MDA, and SOD in bronchoalveolar lavage fluid (BALF) and supernatant were determined by ELISA. The degree of pathological injury of lung tissue was evaluated by H&E staining. Results The results showed that HKL could alleviate the oxidative stress and inflammatory responses by regulating the levels of MPO, MDA, SOD, IL-1β, IL-18 in supernatant. And HKL inhibited the expression levels of NLRP3, ASC, CASP1, GSDMD via activation of Nrf2 in BEAS-2B cells. Further studies revealed that HKL could attenuate the pathological injury in LPS-induced ALI rats and the molecular mechanism was consistent with the results in vitro. Conclusions Our study demonstrated that HKL could alleviate LPS-induced ALI by reducing the oxidative stress and inhibiting NLRP3 inflammasome-mediated pyroptosis, which was partly dependent on the Nrf2 activation.

Download Full-text

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.

Download Full-text

Suppression of lncRNA NLRP3 inhibits NLRP3-triggered inflammatory responses in early acute lung injury

Cell Death and Disease ◽

10.1038/s41419-021-04180-y ◽

2021 ◽

Vol 12 (10) ◽

Author(s):

Deqiang Luo ◽

Wei Dai ◽

Xiaojin Feng ◽

Chengzhi Ding ◽

Qiang Shao ◽

...

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Inflammatory Response ◽

Nlrp3 Inflammasome ◽

Receptor Protein ◽

Luciferase Reporter ◽

Lung Pathology ◽

Caspase 1

AbstractAcute lung injury (ALI) is a common lung pathology that is accompanied by alveolar macrophage (AM) activation and inflammatory response. This study investigated the role of the long non-coding RNA NONRATT004344 (hereafter named lncRNA NLRP3) in regulating the Nod-like receptor protein 3 (NLRP3)-triggered inflammatory response in early ALI and the underlying mechanism as well. We established LPS-induced ALI models to explore their interactive mechanisms in vitro and in vivo. Luciferase reporter assays were performed to determine that miR-138-5p could bind to lncRNA NLRP3 and NLRP3. We observed increased lncRNA NLRP3 expression, decreased miR-138-5p expression, NLRP3 inflammasome activation, and upregulated caspase-1, IL-1β, and IL-18 expression in the LPS-induced ALI model. Furthermore, lncRNA NLRP3 overexpression activated the NLRP3 inflammasome and promoted IL-1β and IL-18 secretion; the miR-138-5p mimic abolished these effects in vivo and in vitro. Consistently, miR-138-5p inhibition reversed the effects of lncRNA NLRP3 silencing on the expression of NLRP3-related molecules and inhibition of the NLRP3/caspase-1/IL-1β signalling pathway. Mechanistically, lncRNA NLRP3 sponging miR-138-5p facilitated NLRP3 activation through a competitive endogenous RNA (ceRNA) mechanism. In summary, our results suggested that lncRNA NLRP3 binding miR-138-5p promotes NLRP3-triggered inflammatory response via lncRNA NLRP3/miR-138-5p/NLRP3 ceRNA network (ceRNET) and provides insights into the treatment of early ALI.

Download Full-text

Tanreqing Inhibits LPS-Induced Acute Lung Injury In Vivo and In Vitro Through Downregulating STING Signaling Pathway

Frontiers in Pharmacology ◽

10.3389/fphar.2021.746964 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yu-Qiong He ◽

Can-Can Zhou ◽

Jiu-Ling Deng ◽

Liang Wang ◽

Wan-Sheng Chen

Keyword(s):

Oxidative Stress ◽

Acute Lung Injury ◽

Lung Injury ◽

Signaling Pathway ◽

Inflammatory Responses ◽

Lung Edema ◽

Protective Effects ◽

And Oxidative Stress

Acute lung injury (ALI) is a common life-threatening lung disease, which is mostly associated with severe inflammatory responses and oxidative stress. Tanreqing injection (TRQ), a Chinese patent medicine, is clinically used for respiratory-related diseases. However, the effects and action mechanism of TRQ on ALI are still unclear. Recently, STING as a cytoplasmic DNA sensor has been found to be related to the progress of ALI. Here, we showed that TRQ significantly inhibited LPS-induced lung histological change, lung edema, and inflammatory cell infiltration. Moreover, TRQ markedly reduced inflammatory mediators release (TNF-α, IL-6, IL-1β, and IFN-β). Furthermore, TRQ also alleviated oxidative stress, manifested by increased SOD and GSH activities and decreased 4-HNE, MDA, LDH, and ROS activities. In addition, we further found that TRQ significantly prevented cGAS, STING, P-TBK, P-P65, P-IRF3, and P-IκBα expression in ALI mice. And we also confirmed that TRQ could inhibit mtDNA release and suppress signaling pathway mediated by STING in vitro. Importantly, the addition of STING agonist DMXAA dramatically abolished the protective effects of TRQ. Taken together, this study indicated that TRQ alleviated LPS-induced ALI and inhibited inflammatory responses and oxidative stress through STING signaling pathway.

Download Full-text

Fn14 Exacerbates Acute Lung Injury by Activating the NLRP3 Inflammasome in Mice

10.21203/rs.3.rs-1005882/v1 ◽

2021 ◽

Author(s):

Xin-Xin Guan ◽

Hui-Hui Yang ◽

Wen-Jing Zhong ◽

Jia-Xi Duan ◽

Chen-Yu Zhang ◽

...

Keyword(s):

Oxidative Stress ◽

Acute Lung Injury ◽

Survival Rate ◽

Lung Injury ◽

Nlrp3 Inflammasome ◽

Inflammasome Activation ◽

Inflammatory Factor ◽

Caspase 1 ◽

Primary Mouse

Abstract Background: Uncontrolled inflammation is an important factor in the occurrence and development of acute lung injury (ALI). Fibroblast growth factor-inducible 14 (Fn14) takes part in the pathological process of a variety of inflammatory diseases. However, the role of Fn14 in ALI has not yet been elucidated. Methods: C57BL/6J mice were used in this study. ALI model was induced by intratracheal injection of lipopolysaccharide (LPS, 5 mg/kg). The effects of Fn14 receptor blocker ATA (20 mg/kg) on lung injury, inflammatory cell infiltration, inflammatory factor secretion, and oxidative stress in mice were observed. The activation of NLRP3 inflammasome was detected by qPCR, Western blot, and ELISA. Prophylactic or therapeutic ATA was administered to observe its effect on the survival rate of ALI mice. In vitro, primary mouse peritoneal macrophages were used to activate the NLRP3 inflammasome by LPS or LPS+ATP. Fn14 was activated by recombinant TWEAK, or knockdown by lentivirus, and the effects on NLRP3 inflammasome activation was detected.Results: We found that ATA significantly downregulated the expression of Fn14 in the lungs and improved the survival rate of mice receiving a lethal dose of LPS. ATA also attenuated lung tissue damage by decreasing the infiltration of macrophages and neutrophils, reducing inflammation, and suppressing oxidative stress. Interestingly, we found that ATA strongly inhibited the activation of NLRP3 inflammasome in the lungs of ALI mice. Furthermore, in vitro, exogenous TWEAK, a natural ligand of Fn14, enhanced the levels of NLRP3 and Caspase-1 p10 and the maturation and secretion of IL-1β in the primary murine macrophages, eventually leading to the activation of NLRP3 inflammasome. In addition, the expression of Fn14, NLRP3, and Caspase-1 p10 and the production of IL-1β were effectively blocked by Fn14 shRNA in macrophages. In mechanism, the activation of Fn14 promoted the production of reactive oxygen species in activated macrophages. Conclusion：Our study first reports that the activation of Fn14 aggravates ALI by amplifying the activation of NLRP3 inflammasome. Therefore, blocking Fn14 may be a potential way to treat ALI.

Download Full-text

Downregulation of miR-497-5p Improves Sepsis-Induced Acute Lung Injury by Targeting IL2RB

BioMed Research International ◽

10.1155/2021/6624702 ◽

2021 ◽

Vol 2021 ◽

pp. 1-13

Author(s):

Wei Lou ◽

Jieping Yan ◽

Weisi Wang

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Inflammatory Cytokine ◽

Luciferase Reporter ◽

Normal Lung ◽

Epithelial Cell Line ◽

Protective Effects ◽

Inflammatory Reactions

Introduction. Acute lung injury (ALI) induced by sepsis is a process related to inflammatory reactions, which involves lung cell apoptosis and production of inflammatory cytokine. Here, lipopolysaccharide (LPS) was applied to stimulate the mouse or human normal lung epithelial cell line (BEAS-2B) to construct a sepsis model in vivo and in vitro, and we also investigated the effect of miR-497-5p on sepsis-induced ALI. Material and Methods. Before LPS treatment, miR-497-5p antagomir was injected intravenously into mice to inhibit miR-497-5p expression in vivo. Similarly, miR-497-5p was knocked down in BEAS-2B cells. Luciferase reporter assay was applied to predict and confirm the miR-497-5p target gene. Cell viability, apoptosis, the levels of miR-497-5p, IL2RB, SP1, inflammatory cytokine, and lung injury were assessed. Results. In BEAS-2B cells, a significant increase of apoptosis and inflammatory cytokine was shown after LPS stimulation. In septic mice, increased inflammatory cytokine production and apoptosis in lung cells and pulmonary morphological abnormalities were shown. The miR-497-5p inhibitor transfection showed antiapoptotic and anti-inflammatory effects on BEAS-2B cells upon LPS stimulation. In septic mice, the miR-497-5p antagomir injection also alleviated ALI, apoptosis, and inflammation caused by sepsis. The downregulation of IL2RB in BEAS-2B cells reversed the protective effects of the miR-497-5p inhibitor against ALI. Conclusion. In conclusion, downregulation of miR-497-5p reduced ALI caused by sepsis through targeting IL2RB, indicating the potential effect of miR-497-5p for improving ALI caused by sepsis.

Download Full-text

Emodin Attenuates LPS-Induced Acute Lung Injury by Inhibiting NLRP3 Inflammasome-Dependent Pyroptosis Signaling Pathway In vitro and In vivo

Inflammation ◽

10.1007/s10753-021-01581-1 ◽

2021 ◽

Author(s):

Yuhan Liu ◽

Luorui Shang ◽

Jiabin Zhou ◽

Guangtao Pan ◽

Fangyuan Zhou ◽

...

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Signaling Pathway ◽

Nlrp3 Inflammasome ◽

Quantitative Polymerase Chain Reaction ◽

Interleukin 1 ◽

Enzyme Linked Immunosorbent Assay ◽

Protective Effects

Abstract—Emodin, the effective component of the traditional Chinese medicine Dahuang, has anti-inflammatory effects. However, the protective effects and potential mechanisms of emodin are not clear. This study investigated the protective effects and potential mechanisms of emodin on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in vitro and in vivo. In vivo, we designed an LPS-induced ALI rat model. In vitro, we chose the J774A.1 cell line to establish an inflammatory cellular model, and knocked down NOD-like receptor family pyrin domain containing 3 (NLRP3) using small interfering RNA. The mRNA and protein expression of NLRP3, a C-terminal caspase recruitment domain (ASC), caspase 1 (CASP1), and gasdermin D (GSDMD) in cells and lung tissues were detected by western blot and real-time quantitative polymerase chain reaction (PCR). The expression levels of interleukin 1 beta (IL-1β) and IL-18 in the serum and supernatant were determined by the enzyme-linked immunosorbent assay. The degree of pathological injury in lung tissue was evaluated by hematoxylin and eosin (H&E) staining. In vitro, we demonstrated that emodin could inhibit NLRP3 and then inhibit the expression of ASC, CASP1, GSDMD, IL-1β, and IL-18. In vivo, we confirmed that emodin had protective effects on LPS-induced ALI and inhibitory effects on NLRP3 inflammasome -dependent pyroptosis. Emodin showed excellent protective effects against LPS-induced ALI by regulating the NLRP3 inflammasome-dependent pyroptosis signaling pathway.

Download Full-text

Dexmedetomidine Alleviates Hyperoxia-Induced Acute Lung Injury via Inhibiting NLRP3 Inflammasome Activation

Cellular Physiology and Biochemistry ◽

10.1159/000479609 ◽

2017 ◽

Vol 42 (5) ◽

pp. 1907-1919 ◽

Cited By ~ 32

Author(s):

Qiuyue Zhang ◽

Di Wu ◽

Yang Yang ◽

Tingting Liu ◽

Hongyu Liu

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Nlrp3 Inflammasome ◽

Lung Epithelial Cells ◽

Raw264.7 Cells ◽

Tunel Staining ◽

Inflammasome Activation ◽

Stress Injury

Background/Aims: Dexmedetomidine (Dex), a specific agonist of α2-adrenoceptor, has been reported to have extensive pharmacological effects. In this study, we focused on the protective effect of Dex on hyperoxia-induced acute lung injury and further explored its possible molecular mechanisms. Methods: The model of hyperoxia-induced acute lung injury was established by continuous inhalation of oxygen (FiO2= 0.90) for 7 d in neonatal rats in vivo. The in vitro experiments were carried out in LPS/ATP or hyperoxia-treated RAW264.7 cells. ELISA, western blot, TUNEL staining, and immunohistochemistry staining assays were performed and the commercial kits were used to assess the beneficial effect of Dex on hyperoxia-induced acute lung injury. Results: According to our results, Dex treatment attenuated hyperoxia-induced acute lung injury via decreasing the lung wet/dry(W/D) weight ratio and mitigating pathomorphologic changes. Moreover, the oxidative stress injury, inflammatory reaction, and apoptosis in lung epithelial cells were inhibited by Dex treatment. In addition, the activation of NLRP3 inflammasome was restrained by Dex both in lung tissue in vivo and RAW264.7 cells in vitro. Conclusion: These data provide evidence that Dex may ameliorate hyperoxia-induced acute lung injury, which suggests a potential clinical application of Dex in long-term supplemental oxygen therapy.

Download Full-text

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

Download Full-text

A Novel Protective Mechanism for Melatonin Against Acute Lung Injury: Preserving Mitochondrial Dynamic Equilibrium of Lung Epithelial Cells Through SIRT3-Dependent Deacetylation of SOD2

10.21203/rs.3.rs-1179197/v1 ◽

2022 ◽

Author(s):

Li Ning ◽

Xiong Rui ◽

Li Guorui ◽

Fu Tinglv ◽

Li Donghang ◽

...

Keyword(s):

Oxidative Stress ◽

Acute Lung Injury ◽

Epithelial Cells ◽

Lung Injury ◽

Dynamic Equilibrium ◽

Lung Epithelial Cells ◽

Mitochondrial Dynamic ◽

Lung Epithelial

Abstract Mitochondrial dynamic equilibrium of lung epithelial cells is disturbed during sepsis, which contributes to abnormal mitochondrial function and acute lung injury (ALI). Melatonin is one primary hormone secreted by the pineal gland, displaying favorable antioxidative actions in sepsis and cardiopulmonary disease. However, the potential roles and molecular basis of melatonin in lipopolysaccharide (LPS)-treated lung epithelial cells have not been explored and reported. Herein, we investigated whether melatonin could protect against sepsis-induced ALI and lipopolysaccharide (LPS)-treated lung epithelial cells through mitochondrial dynamic equilibrium as well as its possible molecular targets. Wild type and Sirt3 knockout mice were instilled with LPS intratracheally for 12 hours to construct an in vivo ALI model. And A549 lung epithelial cells were used to explore the possible roles of melatonin in vitro by incubating with small interfering RNA (siRNA) against Sirt3. To figure out the involvement of melatonin receptor, si Mtnr1b and luzindole were used in cells and mice. Melatonin pretreatment significantly inhibited pathological injury, inflammatory response, oxidative stress and apoptosis in LPS-treated lung tissues and LPS-treated lung epithelial cells. Meanwhile, melatonin also shifted the dynamic course of mitochondria from fission into fusion in LPS-treated lung epithelial cells in vivo and in vitro. However, SIRT3 inhibition abolished the protective roles of melatonin in ALI. Mechanistically, we found that melatonin increased the activity and expression of SIRT3, which further promoted the deacetylation of SOD2 at K122 and K68. More importantly, melatonin exerted pulmonary protection by activating MTNR1B but not MTNR1A in ALI. Collectively, melatonin could preserve mitochondrial dynamic equilibrium of lung epithelial cells through the deacetylation of SOD2 in a SIRT3-dependent manner, which eventually alleviated LPS-elicited injury, inflammation, oxidative stress, apoptosis. Thus, melatonin may serve as a promising candidate against ALI in the future.

Download Full-text