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Chen Y, Peng S, Liang J, Wei K. SIRT1 in acute lung injury: unraveling its pleiotropic functions and therapeutic development prospects. Mol Cell Biochem 2025; 480:1449-1464. [PMID: 39269678 DOI: 10.1007/s11010-024-05111-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Accepted: 08/27/2024] [Indexed: 09/15/2024]
Abstract
Acute lung injury (ALI) is a continuum of lung changes caused by multiple lung injuries, often associated with severe complications and even death. In ALI, macrophages, alveolar epithelial cells and vascular endothelial cells in the lung are damaged to varying degrees and their function is impaired. Research in recent years has focused on the use of SIRT1 for the treatment of ALI. In this paper, we reviewed the role of SIRT1 in ALI in terms of its cellular and molecular mechanism, targeting of SIRT1 by non-coding RNAs and drug components, as well as pointing out the value of SIRT1 for clinical diagnosis and prognosis. Based on the current literature, SIRT1 exhibits diverse functionalities and possesses significant therapeutic potential. Targeting SIRT1 may provide new therapeutic ideas for the treatment of ALI.
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Affiliation(s)
- Yina Chen
- Medical School, Hunan University of Chinese Medicine, Changsha, 410208, China
| | - Shuangyan Peng
- Medical School, Hunan University of Chinese Medicine, Changsha, 410208, China
| | - Junjie Liang
- Medical School, Hunan University of Chinese Medicine, Changsha, 410208, China
| | - Ke Wei
- Medical School, Hunan University of Chinese Medicine, Changsha, 410208, China.
- Hunan Province Key Laboratory of Integrative Pathogen Biology, Hunan University of Chinese Medicine, Changsha, 410208, Hunan, China.
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Neutrophil extracellular traps-triggered impaired autophagic flux via METTL3 underlies sepsis-associated acute lung injury. Cell Death Dis 2022; 8:375. [PMID: 36030287 PMCID: PMC9420153 DOI: 10.1038/s41420-022-01166-3] [Citation(s) in RCA: 57] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Revised: 08/05/2022] [Accepted: 08/11/2022] [Indexed: 11/29/2022]
Abstract
Neutrophil extracellular traps (NETs) assist pathogen clearance, while excessive NETs formation is associated with exacerbated inflammatory responses and tissue injury in acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). Autophagy is generally considered to be a protective process, but autophagy dysfunction is harmful. Whether and how NETs affect autophagic flux during sepsis-induced ALI are currently unknown. Here, we confirmed that the level of NETs was increased in ARDS patients and mice models, which led to impairment of autophagic flux and deterioration of the disease. Mechanistically, NETs activated METTL3 mediated m6A methylation of Sirt1 mRNA in alveolar epithelial cells, resulting in abnormal autophagy. These findings provide new insights into how NETs contribute to the development of sepsis-associated ALI/ARDS.
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Han J, Liu X, Wang L. Dexmedetomidine protects against acute lung injury in mice via the DUSP1/MAPK/NF-κB axis by inhibiting miR-152-3p. Pulm Pharmacol Ther 2022:102131. [PMID: 35551994 DOI: 10.1016/j.pupt.2022.102131] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 04/07/2022] [Accepted: 05/01/2022] [Indexed: 10/18/2022]
Abstract
OBJECTIVE Acute lung injury (ALI) is a debilitating condition in clinics. Dexmedetomidine (Dex) is known for its anti-apoptotic and anti-inflammatory properties. This study attempted to investigate the protective mechanism of Dex in ALI mice. METHODS Mice were pretreated with Dex before model establishment by tracheal injection of lipopolysaccharide (LPS). Pulmonary function indexes and wet-to-dry (W/D) ratio were measured. Pulmonary pathological changes were observed through HE staining, CD31+-positive mouse pulmonary microvascular endothelial cells (MPMVECs) were counted through immunofluorescence staining, and apoptosis was detected through TUNEL staining. miR-152-3p mimic, sh-DUSP1, or p38 MAPK inhibitor was delivered into MPMVECs, followed by combined treatment of Dex and LPS. miR-152-3p expression, apoptosis, levels of apoptosis- and MAPK/NF-κB pathway-associated proteins, and inflammatory factors were measured through RT-qPCR, flow cytometry, Western blot, and ELISA. The binding relationship of miR-152-3p and DUSP1 was verified through bioinformatics software and dual-luciferase assay. ALI mouse model was established after injection of miR-152-3p antagomir. RESULTS Dex improved ALI mouse pulmonary function and mitigated injury in mice and MPMVECs. miR-125-3p overexpression or sh-DUSP1 partially abolished the protection of Dex on MPMVECs. miR-152-3p targeted DUSP1. sh-DUSP1 partially averted the protection of Dex on MPMVECs. Dex inhibited the activation of the MAPK/NF-κB pathway in MPMVECs mediated by LPS, which was partially reversed by sh-DUSP1. The p38 MAPK inhibitor SB203580 antagonized the protective effect of Dex on MPMVECs mediated by sh-DUSP1. Similarly, downregulation of miR-152-3p mitigated ALI via the DUSP1/MAPK/NF-κB axis in vivo. CONCLUSION Dex relieved ALI in mice via the DUSP1/MAPK/NF-κB axis by down-regulating miR-152-3p.
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Affiliation(s)
- Jieran Han
- Department of Anesthesiology, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, 471003, China
| | - Xiao Liu
- Department of Anesthesiology, The First Affiliated Hospital of Henan University of Science and Technology, Luoyang, 471003, China
| | - Ling Wang
- Department of Anesthesiology, 989 Hospital of JOINT Logistic Support Force of PLA, Luoyang, 471031, China.
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Cai W, Shen K, Ji P, Jia Y, Han S, Zhang W, Hu X, Yang X, Han J, Hu D. The Notch pathway attenuates burn-induced acute lung injury in rats by repressing reactive oxygen species. BURNS & TRAUMA 2022; 10:tkac008. [PMID: 35441079 PMCID: PMC9014447 DOI: 10.1093/burnst/tkac008] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Revised: 02/02/2022] [Indexed: 12/21/2022]
Abstract
Background Acute lung injury (ALI) is a common complication following severe burns. The underlying mechanisms of ALI are incompletely understood; thus, available treatments are not sufficient to repair the lung tissue after ALI. Methods To investigate the relationship between the Notch pathway and burn-induced lung injury, we established a rat burn injury model by scalding and verified lung injury via lung injury evaluations, including hematoxylin and eosin (H&E) staining, lung injury scoring, bronchoalveolar lavage fluid and wet/dry ratio analyses, myeloperoxidase immunohistochemical staining and reactive oxygen species (ROS) accumulation analysis. To explore whether burn injury affects Notch1 expression, we detected the expression of Notch1 and Hes1 after burn injury. Then, we extracted pulmonary microvascular endothelial cells (PMVECs) and conducted Notch pathway inhibition and activation experiments, via a γ-secretase inhibitor (GSI) and OP9-DLL1 coculture, respectively, to verify the regulatory effect of the Notch pathway on ROS accumulation and apoptosis in burn-serum-stimulated PMVECs. To investigate the regulatory effect of the Notch pathway on ROS accumulation, we detected the expression of oxidative-stress-related molecules such as superoxide dismutase, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) 2, NOX4 and cleaved caspase-3. NOX4-specific small interfering RNA (siRNA) and the inhibitor GKT137831 were used to verify the regulatory effect of the Notch pathway on ROS via NOX4. Results We successfully established a burn model and revealed that lung injury, excessive ROS accumulation and an inflammatory response occurred. Notch1 detection showed that the expression of Notch1 was significantly increased after burn injury. In PMVECs challenged with burn serum, ROS and cell death were elevated. Moreover, when the Notch pathway was suppressed by GSI, ROS and cell apoptosis levels were significantly increased. Conversely, these parameters were reduced when the Notch pathway was activated by OP9-DLL1. Mechanistically, the inhibition of NOX4 by siRNA and GKT137831 showed that the Notch pathway reduced ROS production and cell apoptosis by downregulating the expression of NOX4 in PMVECs. Conclusions The Notch pathway reduced ROS production and apoptosis by downregulating the expression of NOX4 in burn-stimulated PMVECs. The Notch-NOX4 pathway may be a novel therapeutic target to treat burn-induced ALI.
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Affiliation(s)
- Weixia Cai
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
| | - Kuo Shen
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
| | - Peng Ji
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
| | - Yanhui Jia
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
| | - Shichao Han
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
| | - Wanfu Zhang
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
| | - Xiaolong Hu
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
| | - Xuekang Yang
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
| | - Juntao Han
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
| | - Dahai Hu
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
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Zhang Y, Zhang J, Fu Z. Molecular hydrogen is a potential protective agent in the management of acute lung injury. Mol Med 2022; 28:27. [PMID: 35240982 PMCID: PMC8892414 DOI: 10.1186/s10020-022-00455-y] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Accepted: 02/14/2022] [Indexed: 11/21/2022] Open
Abstract
Acute lung injury (ALI) and acute respiratory distress syndrome, which is a more severe form of ALI, are life-threatening clinical syndromes observed in critically ill patients. Treatment methods to alleviate the pathogenesis of ALI have improved to a great extent at present. Although the efficacy of these therapies is limited, their relevance has increased remarkably with the ongoing pandemic caused by the novel coronavirus disease 2019 (COVID-19), which causes severe respiratory distress syndrome. Several studies have demonstrated the preventive and therapeutic effects of molecular hydrogen in the various diseases. The biological effects of molecular hydrogen mainly involve anti-inflammation, antioxidation, and autophagy and cell death modulation. This review focuses on the potential therapeutic effects of molecular hydrogen on ALI and its underlying mechanisms and aims to provide a theoretical basis for the clinical treatment of ALI and COVID-19.
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Affiliation(s)
- Yan Zhang
- Department of Anesthesiology, Shengjing Hospital of China Medical University, Shenyang, 110004 People’s Republic of China
| | - Jin Zhang
- Department of Anesthesiology, Shengjing Hospital of China Medical University, Shenyang, 110004 People’s Republic of China
| | - Zhiling Fu
- Department of Anesthesiology, Shengjing Hospital of China Medical University, Shenyang, 110004 People’s Republic of China
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Human Umbilical Cord-Derived Mesenchymal Stem Cells Alleviate Acute Lung Injury Caused by Severe Burn via Secreting TSG-6 and Inhibiting Inflammatory Response. Stem Cells Int 2022; 2022:8661689. [PMID: 35222649 PMCID: PMC8881119 DOI: 10.1155/2022/8661689] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Revised: 01/28/2022] [Accepted: 01/29/2022] [Indexed: 12/13/2022] Open
Abstract
Objectives To investigate whether hUC-MSCs attenuated severe burn-induced ALI and the effects were based on TSG-6 secreted from hUC-MSCs. Method A rat model was established and evaluated as follows: cytokine expression was measured by ELISA, and both inflammatory cell infiltration and lung injury were assessed by immunohistochemistry assay. Results In vitro, TSG-6 levels in serum from the burn group were significantly increased compared with those from the sham group. In vivo, TSG-6 levels of lung tissues and serum in the burn+hUC-MSC group were significantly increased compared with those in the burn group. Both in lung tissues and in serum, increased levels of proinflammatory cytokines (TNF-α, IL-1β, and IL-6) were remarkably decreased, but the anti-inflammatory cytokine IL-10 increased after hUC-MSC administration (p < 0.05). These significant positive effects after hUC-MSC transplantation did not occur in the burn+siTSG-6 group. Conclusion The intratracheal implantation of hUC-MSCs has been an effective treatment for severe burn-induced ALI via promoting TSG-6 secretion and inhibiting inflammatory reaction in lung tissue.
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Zhang Q, Wang Z, Zhu J, Peng Z, Tang C. Ferulic acid regulates miR-17/PTEN axis to inhibit LPS-induced pulmonary microvascular endothelial cells apoptosis through activation of PI3K/Akt pathway. J Toxicol Sci 2022; 47:61-69. [PMID: 35110471 DOI: 10.2131/jts.47.61] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Affiliation(s)
- Qinqin Zhang
- Department of Critical Care Medicine, Nantong Hospital of Traditional Chinese Medicine, Nantong Hospital Affiliated to Nanjing University of Chinese Medicine, China
| | - Zhilan Wang
- Department of Critical Care Medicine, Nantong Hospital of Traditional Chinese Medicine, Nantong Hospital Affiliated to Nanjing University of Chinese Medicine, China
| | - Jinfei Zhu
- Department of pneumology, Nantong Hospital of Traditional Chinese Medicine, Nantong Hospital Affiliated to Nanjing University of Chinese Medicine, China
| | - Zhili Peng
- Department of Critical Care Medicine, Rugao Hospital of Traditional Chinese Medicine, China
| | - Cheng Tang
- Department of Critical Care Medicine, The Affiliated Suqian First People's Hospital of Nanjing Medical University, China
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Li X, Tong J, Liu J, Wang Y. Down-regulation of ROCK2 alleviates ethanol-induced cerebral nerve injury partly by the suppression of the NF-κB signaling pathway. Bioengineered 2021; 11:779-790. [PMID: 32684089 PMCID: PMC8291877 DOI: 10.1080/21655979.2020.1795404] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Chronic alcohol consumption leads to hippocampal neuronal impairment, which related to neuronal death, oxidative stress, and inflammatory response. Rho-associated protein kinase 2 (ROCK2) is a major regulator in the central nervous system injury. However, the effects of ROCK2 in ethanol-induced brain injury have not been explored. In this work, we investigated the neuroprotective effects and the mechanism of ROCK2 inhibition in vivo. Wistar rats were exposed to 37% ethanol for 8 weeks to establish brain injury models. Morris water maze test was performed to evaluate cognitive function, and we found that the down-regulation of ROCK2 reduced the escape latency and increased the passing times and percentage of time spent in the target quadrant of rats. The results of H&E staining and Nissl staining showed that ROCK2 inhibition alleviated the pathological injury induced by ethanol. PI staining and Western blot confirmed that inhibiting ROCK2 attenuated the neuronal death and apoptosis as reflected by the reduced PI-positive neurons and the decreased expression of cleaved-caspase-3 and cleaved-caspase-9. Furthermore, the down-regulation of ROCK2 ameliorated the oxidative stress and inflammatory response induced by ethanol in rats as reflected by the up-regulation of IL-10, SOD, and GSH and reduction of TNF-α, IL-6, and MDA respectively. Additionally, Western blot and EMSA analysis revealed that the down-regulation of ROCK2 suppressed the nuclear transfer of NF-κB p65. In conclusion, our data suggested that ROCK2 inhibition ameliorated ethanol-mediated hippocampal neuronal impairment by anti-apoptotic, anti-inflammatory, anti-oxidative effects at least partially through the suppression of the NF-κB pathway.
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Affiliation(s)
- Xinguo Li
- Department of Neurosurgery, The First Hospital of China Medical University , Shenyang, People's Republic of China
| | - Jing Tong
- Department of Gastroenterology, The First Hospital of China Medical University , Shenyang, People's Republic of China
| | - Jihui Liu
- Department of Neurosurgery, The First Hospital of China Medical University , Shenyang, People's Republic of China
| | - Yibao Wang
- Department of Neurosurgery, The First Hospital of China Medical University , Shenyang, People's Republic of China
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Wang H, Wang S, Huang S. MiR-494-3p alleviates acute lung injury through regulating NLRP3 activation by targeting CMPK2. Biochem Cell Biol 2021; 99:286-295. [PMID: 34037470 DOI: 10.1139/bcb-2020-0243] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
Acute lung injury (ALI) is a severe respiratory disorder with a high rate of mortality, and is characterized by excessive cell apoptosis and inflammation. MicroRNAs (miRNAs) play pivotal roles in ALI. This study examined the biological function of miR-494-3p in cell apoptosis and inflammatory response in ALI. For this, mice were injected with lipopolysaccharide (LPS) to generate an in-vivo model of ALI (ALI mice), and WI-38 cells were stimulated with lipopolysaccharide (LPS) to generate an in-vitro model of ALI. We found that miR-494-3p was significantly downregulated in the ALI mice and in the in-vitro model. Overexpression of miR-494-3p inhibited inflammation and cell apoptosis in the LPS-induced WI-38 cells, and improved the symptoms of lung injury in the ALI mice. We then identified cytidine/uridine monophosphate kinase 2 (CMPK2) as a novel target of miR-494-3p in the WI-38 cells. Furthermore, miR-494-3p suppressed cell apoptosis and the inflammatory response in LPS-treated WI-38 cells through targeting CMPK2. The NLRP3 inflammasome is reportedly responsible for the activation of inflammatory processes. In our study, CMPK2 was confirmed to activate the NLRP3 inflammasome in LPS-treated WI-38 cells. In conclusion, miR-494-3p attenuates ALI through inhibiting cell apoptosis and the inflammatory response by targeting CMPK2, which suggests the value of miR-494-3p as a target for the treatment for ALI.
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Affiliation(s)
- Hong Wang
- Operating Room, Qilu Hospital of Shandong University, Jinan 250012, Shandong, China
| | - Shuqin Wang
- Department of Anesthesiology, Qilu Hospital of Shandong University, Jinan 250012, Shandong, China
| | - Shanshan Huang
- Department of Anesthesiology, Qilu Hospital of Shandong University, Jinan 250012, Shandong, China
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Sun Z, Wang X, Xu Z. SIRT1 provides new pharmacological targets for polydatin through its role as a metabolic sensor. Biomed Pharmacother 2021; 139:111549. [PMID: 33901876 DOI: 10.1016/j.biopha.2021.111549] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Revised: 03/14/2021] [Accepted: 03/24/2021] [Indexed: 12/29/2022] Open
Abstract
The SIRT family of proteins constitutes highly conserved deacetylases with diverse and extensive functions. These proteins have specific biological functions, including regulation of transcription, cell cycle, cell differentiation, apoptosis, stress, metabolism, and genomic stability. Polydatin is a monocrystalline compound isolated from a Chinese herb, Polygonum cuspidatum. The pharmacological mechanisms of polydatin are mostly unclear but involve members of the SIRT protein family, among which SIRT1 plays a vital role. Polydatin is usually considered a potential SIRT1 activator. This review summarizes the signaling mechanism of polydatin involving SIRT1 and discusses the roles of related signal molecules such as PGC-1α, Nrf2, p38-MAPK, NLPR3 inflammasome, and p53. Further, we describe the metabolic regulation of related biological macromolecules and demonstrate that SIRT1, as a metabolic sensor, may act as a new pharmacological target for polydatin.
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Affiliation(s)
- Zhicheng Sun
- Department of Spine Surgery, Xiangya Hospital, Central South University, Changsha 410008, Hunan, People's Republic of China; Hunan Engineering Laboratory of Advanced Artificial Osteo-Materials, Xiangya Hospital, Central South University, Changsha 410008, Hunan, People's Republic of China.
| | - Xiyang Wang
- Department of Spine Surgery, Xiangya Hospital, Central South University, Changsha 410008, Hunan, People's Republic of China; Hunan Engineering Laboratory of Advanced Artificial Osteo-Materials, Xiangya Hospital, Central South University, Changsha 410008, Hunan, People's Republic of China.
| | - Zhenchao Xu
- Department of Spine Surgery, Xiangya Hospital, Central South University, Changsha 410008, Hunan, People's Republic of China; Hunan Engineering Laboratory of Advanced Artificial Osteo-Materials, Xiangya Hospital, Central South University, Changsha 410008, Hunan, People's Republic of China.
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Atypical p38 Signaling, Activation, and Implications for Disease. Int J Mol Sci 2021; 22:ijms22084183. [PMID: 33920735 PMCID: PMC8073329 DOI: 10.3390/ijms22084183] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 03/29/2021] [Accepted: 04/13/2021] [Indexed: 02/07/2023] Open
Abstract
The mitogen-activated protein kinase (MAPK) p38 is an essential family of kinases, regulating responses to environmental stress and inflammation. There is an ever-increasing plethora of physiological and pathophysiological conditions attributed to p38 activity, ranging from cell division and embryonic development to the control of a multitude of diseases including retinal, cardiovascular, and neurodegenerative diseases, diabetes, and cancer. Despite the decades of intense investigation, a viable therapeutic approach to disrupt p38 signaling remains elusive. A growing body of evidence supports the pathological significance of an understudied atypical p38 signaling pathway. Atypical p38 signaling is driven by a direct interaction between the adaptor protein TAB1 and p38α, driving p38 autophosphorylation independent from the classical MKK3 and MKK6 pathways. Unlike the classical MKK3/6 signaling pathway, atypical signaling is selective for just p38α, and at present has only been characterized during pathophysiological stimulation. Recent studies have linked atypical signaling to dermal and vascular inflammation, myocardial ischemia, cancer metastasis, diabetes, complications during pregnancy, and bacterial and viral infections. Additional studies are required to fully understand how, when, where, and why atypical p38 signaling is induced. Furthermore, the development of selective TAB1-p38 inhibitors represents an exciting new opportunity to selectively inhibit pathological p38 signaling in a wide array of diseases.
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Yin Q, Wang JF, Xu XH, Xie H. Effect of lycopene on pain facilitation and the SIRT1/mTOR pathway in the dorsal horn of burn injury rats. Eur J Pharmacol 2020; 889:173365. [PMID: 32712090 DOI: 10.1016/j.ejphar.2020.173365] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Revised: 06/18/2020] [Accepted: 07/09/2020] [Indexed: 12/12/2022]
Abstract
To explore the effect of intrathecal injection of lycopene on pain facilitation, glial activation, and the SIRT1/mTOR pathway in the dorsal horn of rats with burn injury pain (BIP). Here we found that the mechanical pain threshold increased in the lycopene group compared with that of the control group, (P < 0.05). Compared with expression in the sham group, mTOR, pS6, p4EBP, GFAP, and Iba-1 decreased and SIRT1 increased in the lycopene group (P < 0.01). Glial activation in the spinal dorsal horn of BIP rats was alleviated by lycopene (P < 0.01). The SIRT1 and mTOR were mainly distributed in neurons in the spinal dorsal horn in the BIP model. Intrathecal injection of 3-MA (a mTOR agonist) or EX-527 (an inhibitor of Sirt1) partially antagonized lycopene-induced analgesia. Intrathecal injection of rapamycin (an mTOR inhibitor) or SRT1720 (an agonist of Sirt1) induced analgesia in BIP rats. 3-MA abrogated the SRT1720-induced analgesic effects. The present data indicated that the SIRT1/mTOR pathway changed in the spinal dorsal horn of BIP rats; Lycopene alleviated the pain sensitization of BIP rats by regulating the SIRT1/mTOR pathway and glial activation in the spinal dorsal horn.
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Affiliation(s)
- Qin Yin
- The Second Affliated Hospital of Soochow University, No. 1055, Sanxiang Road, Suzhou 215004, China; The Affiliated Hospital of Xuzhou Medical University, Xuzhou 221002, PR China
| | | | - Xiao-Hua Xu
- The People's Hospital of Kizilsu Kirghiz Autonomous Prefecture, Xinjiang 845350, PR China
| | - Hong Xie
- The Second Affliated Hospital of Soochow University, No. 1055, Sanxiang Road, Suzhou 215004, China.
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Hui Q, Zhang Q, Li X, Wang K, Zhang J, Zhou Z. Down-regulation of miR-133a-3p protects lung tissue against sepsis-induced acute respiratory distress syndrome by up-regulating SIRT1. Arch Med Sci 2020; 20:289-301. [PMID: 38414466 PMCID: PMC10895959 DOI: 10.5114/aoms.2020.94410] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Accepted: 11/09/2019] [Indexed: 02/29/2024] Open
Abstract
Introduction MicroRNA-133a-3p (miR-133a-3p) is a potential gene regulator having an important role in the process of inflammation and lung injury. The present work studied the role of miR-133a-3p in sepsis-mediated acute respiratory distress syndrome (ARDS) and the mechanism involved. Material and methods C57BL/6 mice were selected for the study. Protein expression of Bcl-2, cleaved caspase-3 and Bax was assessed by western blot analysis. Expression of mRNA was assessed by RT-PCR. Effects of inflammation were studied by myeloperoxidase (MPO) activity. Quantification of albumin was done by measuring the albumin conjugated with Evan's blue. The alveolar macrophages were separated from the lungs of mice by the bronchoalveolar lavage procedure and were submitted to sepsis challenge in vitro; the macrophages were treated with lipopolysaccharide (LPS). Results Treatment of LPS resulted in upregulation of miR-133a-3p in alveolar macrophages. Suppression of miR-133a-3p halted the over-expression of inflammatory cytokines in macrophages and caused remission of histopathologic changes. The ARDS lungs showed a decrease in levels of proinflammatory cytokines and an increase in levels of apoptotic protein, establishing the protective role for miR-133a-3p. The results suggested sirtuin 1 (SIRT1) as a potential target of miR-133a-3p in the macrophages, also showing that expression of SIRT1 was inversely associated with expression of miR-133a-3p. The protective effect of miR-133a-3p down-regulation in LPS-mediated alveolar macrophages and sepsis-induced ARDS could be corrected by a SIRT1 inhibitor. Conclusions Down-regulation of miR-133a-3p may exert a protective effect on lung tissue against sepsis-mediated ARDS by up-regulating the levels of SIRT1 via suppressing the inflammatory response and inhibiting the cellular apoptosis in lung tissues.
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Affiliation(s)
- Qin Hui
- Department of Pediatrics, China-Japan Friendship Hospital, Chaoyang District, Beijing, China
- Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Qi Zhang
- Department of Pediatrics, China-Japan Friendship Hospital, Chaoyang District, Beijing, China
| | - Xuan Li
- Department of Pediatrics, China-Japan Friendship Hospital, Chaoyang District, Beijing, China
| | - Kundi Wang
- Department of Pediatrics, China-Japan Friendship Hospital, Chaoyang District, Beijing, China
| | - Jing Zhang
- Department of Pediatrics, China-Japan Friendship Hospital, Chaoyang District, Beijing, China
| | - Zhongshu Zhou
- Department of Pediatrics, China-Japan Friendship Hospital, Chaoyang District, Beijing, China
- Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
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Zhang X, Liu N, Shao Y, Jiang T, Cui C, Chen X. MiR-132 represses sepsis-induced myocardial injury in rats by regulating SIRT1 expression. Panminerva Med 2020; 63:565-566. [PMID: 32231180 DOI: 10.23736/s0031-0808.20.03886-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Affiliation(s)
- Xiaoying Zhang
- Department of Emergency Internal Medicine, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Nan Liu
- Department of Critical Care Medicine, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yanmei Shao
- Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Tao Jiang
- Department of Emergency Internal Medicine, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Cangxing Cui
- Department of Emergency Internal Medicine, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Xiaoxue Chen
- Health Management Center, The Affiliated Hospital of Qingdao University, Qingdao, China -
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15
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Badamjav R, Sonom D, Wu Y, Zhang Y, Kou J, Yu B, Li F. The protective effects of Thalictrum minus L. on lipopolysaccharide-induced acute lung injury. JOURNAL OF ETHNOPHARMACOLOGY 2020; 248:112355. [PMID: 31669667 DOI: 10.1016/j.jep.2019.112355] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/27/2019] [Revised: 10/12/2019] [Accepted: 10/24/2019] [Indexed: 06/10/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Thalictrum minus L., a Mongolian folk medicinal plant, was applied for the treatment of bacterial and fungal infection, tuberculosis and lung inflammation. AIM OF THE STUDY The present work aims to elucidate the protective effects of Thalictrum minus L.(TML) against lipopolysaccharide (LPS)-induced acute lung injury and the underlying mechanisms. METHODS The mice model of acute lung injury was induced by LPS via endotracheal drip, and TML (10, 20, 40 mg/kg) were administered orally 1 h prior to LPS. The efficacy and molecular mechanisms in the presence or absence of TML were investigated. RESULTS We demonstrated that treatment with TML aqueous extract protected the mice from acute lung injury induced by LPS administration. TML significantly inhibited weight loss in mice, decreased the lung wet to dry weight (W/D) ratios and attenuated lung histopathological changes, such as infiltration of inflammatory cells and coagulation, pulmonary edema. Furthermore, we found that TML markedly reduced the LPS-induced inflammatory cytokines including tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), decreased nitric oxide (NO), and increased superoxide dismutase (SOD) in bronchoalveolar lavage fluid (BALF), and effectively ameliorated LPS-induced increased total protein, leukocyte and macrophages in BALF. In addition, TML pronouncedly suppressed the activation of the MAPKs p38-NLRP3/caspase-1 and COX2, increased the expression of p-AMPK-Nrf2, and suppressed the expression of KEAP, apoptotic-related protein as well as autophagy. CONCLUSIONS These results suggested that TML ameliorated LPS-induced acute lung injury by inhibiting the release of inflammatory cytokines and reducing oxidative damage associated with the MAPKs p38-NLRP3/caspase-1 and COX2 signaling pathways, AMPK-Nrf2/KEAP signaling pathways, as well as apoptosis and autophagy.
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Affiliation(s)
- Rentsen Badamjav
- Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Research Center for Traceability and Standardization of TCMs, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, 211198, China.
| | - Dolgor Sonom
- Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Research Center for Traceability and Standardization of TCMs, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, 211198, China.
| | - Yunhao Wu
- Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Research Center for Traceability and Standardization of TCMs, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, 211198, China.
| | - Yuanyuan Zhang
- Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Research Center for Traceability and Standardization of TCMs, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, 211198, China.
| | - Junping Kou
- Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Research Center for Traceability and Standardization of TCMs, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, 211198, China.
| | - Boyang Yu
- Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Research Center for Traceability and Standardization of TCMs, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, 211198, China.
| | - Fang Li
- Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Research Center for Traceability and Standardization of TCMs, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, 211198, China.
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16
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Son B, Lee S, Kim H, Kang H, Kim J, Youn H, Nam SY, Youn B. Low dose radiation attenuates inflammation and promotes wound healing in a mouse burn model. J Dermatol Sci 2019; 96:81-89. [DOI: 10.1016/j.jdermsci.2019.10.004] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2019] [Revised: 09/28/2019] [Accepted: 10/17/2019] [Indexed: 02/07/2023]
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17
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Curtis BJ, Shults JA, Boe DM, Ramirez L, Kovacs EJ. Mesenchymal stem cell treatment attenuates liver and lung inflammation after ethanol intoxication and burn injury. Alcohol 2019; 80:139-148. [PMID: 30217504 DOI: 10.1016/j.alcohol.2018.09.001] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2018] [Revised: 08/31/2018] [Accepted: 09/06/2018] [Indexed: 12/25/2022]
Abstract
Cutaneous burn injury is one of the most devastating injuries one can obtain, with tissue damage extending beyond the skin wound to distal organs, including the gastrointestinal tract, liver, and lungs. Multiple organ failure is a leading cause of death after burn injury, resulting in excessive systemic and localized inflammation directly contributing to end organ damage. We postulated that the gut-liver-lung inflammatory axis underscores multiple organ failure in the context of burn injury and is hyper-activated when ethanol intoxication precedes burn. Mesenchymal stem cells (MSCs) are regenerative and anti-inflammatory, and MSC treatment has been shown to be beneficial in several immune disorders and injury models. Our objective was to determine whether intravenous infusion of exogenous bone marrow-derived MSCs could reduce post-burn and intoxication pulmonary, hepatic, and systemic inflammation. Vehicle- or ethanol- (1.6 g/kg) treated mice were subjected to sham or 15% total body surface area scald burn. One hour post-injury, mice were given 5 × 105 CFSE-labeled MSCs or phosphate-buffered saline intravenously (i.v.) and were euthanized 24 h later. We assessed circulating biomarkers of inflammation and liver damage, measured cytokine and chemokine production, and quantified apoptosis in lung and liver tissue. Compared to intoxicated and burned mice, those treated with MSCs had less cellularity, limited apoptosis, and a slight reduction in the pro-inflammatory cytokine interleukin-6 (IL-6) and the neutrophil chemokine, KC (CXCL1) in lung tissue. Mice with MSCs treatment had more dramatic anti-inflammatory effects on systemic and hepatic inflammation, as serum IL-6 levels were diminished by 43%, and il6 and kc expression in liver tissue were markedly reduced, as were biomarkers of liver damage, aspartate transaminase (AST) and alanine transaminase (AST), compared with intoxicated and burned mice. Taken together, our results suggest intravenous MSCs treatment can diminish systemic inflammation, lessen hepatic damage, and decrease liver and lung apoptosis and inflammation, indicating MSCs as a novel therapy for restoring homeostasis of multiple organ systems in intoxicated burn patients.
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Affiliation(s)
- Brenda J Curtis
- Burn Research and Alcohol Research Programs, Department of Surgery, Division of GI, Trauma and Endocrine Surgery, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, United States
| | - Jill A Shults
- Alcohol Research Program, Burn and Shock Trauma Research Institute, Department of Surgery, Loyola University Chicago, Health Sciences Campus, Stritch School of Medicine, Maywood, IL, United States
| | - Devin M Boe
- Burn Research and Alcohol Research Programs, Department of Surgery, Division of GI, Trauma and Endocrine Surgery, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, United States
| | - Luis Ramirez
- Alcohol Research Program, Burn and Shock Trauma Research Institute, Department of Surgery, Loyola University Chicago, Health Sciences Campus, Stritch School of Medicine, Maywood, IL, United States
| | - Elizabeth J Kovacs
- Burn Research and Alcohol Research Programs, Department of Surgery, Division of GI, Trauma and Endocrine Surgery, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, United States.
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Feng Y, Fang Z, Liu B, Zheng X. p38MAPK plays a pivotal role in the development of acute respiratory distress syndrome. Clinics (Sao Paulo) 2019; 74:e509. [PMID: 31411275 PMCID: PMC6683303 DOI: 10.6061/clinics/2019/e509] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2018] [Accepted: 04/25/2019] [Indexed: 01/11/2023] Open
Abstract
Acute respiratory distress syndrome (ARDS) is a life-threatening illness characterized by a complex pathophysiology, involving not only the respiratory system but also nonpulmonary distal organs. Although advances in the management of ARDS have led to a distinct improvement in ARDS-related mortality, ARDS is still a life-threatening respiratory condition with long-term consequences. A better understanding of the pathophysiology of this condition will allow us to create a personalized treatment strategy for improving clinical outcomes. In this article, we present a general overview p38 mitogen-activated protein kinase (p38MAPK) and recent advances in understanding its functions. We consider the potential of the pharmacological targeting of p38MAPK pathways to treat ARDS.
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Affiliation(s)
- Ying Feng
- Department of Intensive Care Unit, Taihe Hospital, Hubei University of Medicine, Shiyan 442000, Hubei Province, China
- Institute of Biomedical Research, Taihe Hospital, Hubei University of Medicine, Shiyan 442000, Hubei Province, China
- *Corresponding author. E-mail:
| | - Zhicheng Fang
- Department of Intensive Care Unit, Taihe Hospital, Hubei University of Medicine, Shiyan 442000, Hubei Province, China
- *Corresponding author. E-mail:
| | - Boyi Liu
- Department of Intensive Care Unit, Taihe Hospital, Hubei University of Medicine, Shiyan 442000, Hubei Province, China
| | - Xiang Zheng
- Department of Intensive Care Unit, Taihe Hospital, Hubei University of Medicine, Shiyan 442000, Hubei Province, China
- *Corresponding author. E-mail:
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Wild-type p53-modulated autophagy and autophagic fibroblast apoptosis inhibit hypertrophic scar formation. J Transl Med 2018; 98:1423-1437. [PMID: 30089855 DOI: 10.1038/s41374-018-0099-3] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2017] [Revised: 04/12/2018] [Accepted: 05/24/2018] [Indexed: 02/06/2023] Open
Abstract
Hypertrophic scarring is a serious fibrotic skin disease, and the abnormal activation of hypertrophic scar fibroblasts (HSFs) intensifies its pathogenesis. Our previous studies have demonstrated that the dysregulation of autophagy in HSFs is associated with fibrosis. However, knowledge regarding the regulation of HS fibrosis by p53-modulated autophagy is limited. Here, we investigated the effect of p53-modulated autophagy on HS fibrosis. The overexpression of wtp53 (Adp53) promoted autophagic capacity and inhibited collagen and α-SMA expression in HSFs. In contrast, LC3 (AdLC3) overexpression did not suppress Col 1, Col 3, or α-SMA expression, but LC3 (shLC3) knockdown downregulated collagen expression. Adp53-modulated autophagy altered Bcl-2 and Bcl-xL expression, but AdLC3 affected only Bcl-xL expression. Silencing Bcl-xL suppressed collagen expression, but autophagy was also inhibited. Flow cytometry showed that the silencing of Bcl-2 (sibcl-2), Bcl-xL (sibcl-xL), and Adp53 significantly increased apoptosis in the HSFs. Therefore, wtp53 inhibited fibrosis in the HSFs by modulating autophagic HSF apoptosis; moreover, the inhibition of autophagy by sibcl-xL had antifibrotic effects. In addition, treatment with Adp53, AdLC3, shLC3, sibcl-2, and sibcl-xL reduced scar formation in a rabbit ear scar model. These data confirm that wtp53-modulated autophagy and autophagic HSF apoptosis can serve as potential molecular targets for HS therapy.
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20
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Calpain inhibition ameliorates scald burn-induced acute lung injury in rats. BURNS & TRAUMA 2018; 6:28. [PMID: 30338266 PMCID: PMC6174571 DOI: 10.1186/s41038-018-0130-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/20/2018] [Accepted: 08/27/2018] [Indexed: 12/26/2022]
Abstract
Background The molecular pattern of severe burn-induced acute lung injury, characterized by cell structure damage and leukocyte infiltration, remains unknown. This study aimed to determine whether calpain, a protease involved in both processes, mediates severe burn-induced acute lung injury. Methods Rats received full-thickness scald burns covering 30% of the total body surface area, followed by instant fluid resuscitation. MDL28170 (Tocris Bioscience), an inhibitor of calpain, was given intravenously 1 h before or after the scald burn. The histological score, wet/dry weight ratio, and caspase-3 activity were examined to evaluate the degree of lung damage. Calpain activity and its source were detected by an assay kit and immunofluorescence staining. The proteolysis of membrane skeleton proteins α-fodrin and ankyrin-B, which are substrates of calpain, was measured by Western blot. Results Time-course studies showed that tissue damage reached a peak between 1 and 6 h post-scald burn and gradually diminished at 24 h. More importantly, calpain activity reached peak levels at 1 h and was maintained until 24 h, paralleled by lung damage to some extent. Western blot showed that the levels of the proteolyzed forms of α-fodrin and ankyrin-B correlated well with the degree of damage. MDL28170 at a dose of 3 mg/kg b. w. given 1 h before burn injury not only antagonized the increase in calpain activity but also ameliorated scald burn-induced lung injury, including the degradation of α-fodrin and ankyrin-B. Immunofluorescence images revealed calpain 1 and CD45 double-positive cells in the lung tissue of rats exposed to scald burn injury, suggesting that leukocytes were a dominant source of calpain. Furthermore, this change was blocked by MDL28170. Finally, MDL28170 given at 1 h post-scald burn injury significantly ameliorated the wet/dry weight ratio compared with burn injury alone. Conclusions Calpain, a product of infiltrating leukocytes, is a mediator of scald burn-induced acute lung injury that involves enhancement of inflammation and proteolysis of membrane skeleton proteins. Its late effects warrant further study.
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21
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Li D, Ren W, Jiang Z, Zhu L. Regulation of the NLRP3 inflammasome and macrophage pyroptosis by the p38 MAPK signaling pathway in a mouse model of acute lung injury. Mol Med Rep 2018; 18:4399-4409. [PMID: 30152849 PMCID: PMC6172370 DOI: 10.3892/mmr.2018.9427] [Citation(s) in RCA: 113] [Impact Index Per Article: 16.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2018] [Accepted: 07/25/2018] [Indexed: 01/06/2023] Open
Abstract
Acute lung injury and acute respiratory distress syndrome (ALI/ARDS) is characterized by uncontrolled progressive lung inflammation. Macrophages serve a key role in the pathogenesis of ALI/ARDS. Macrophage pyroptosis is a process of cell death releasing the proinflammatory cytokines interleukin (IL)‑1β and IL‑18. It was hypothesized that macrophage pyroptosis may partially account for the uncontrolled lung inflammation of ALI/ARDS. In the present study, greater macrophage pyroptosis in lipopolysaccharide (LPS)‑treated macrophages and the ALI/ARDS mouse model was observed. The expression of nucleotide‑binding domain, leucine‑rich‑containing family, pyrin domain‑containing (NLRP)3 and IL‑1β and cleavage of caspase‑1 were significantly elevated following LPS treatment accompanied by greater activation of p38 mitogen‑activated protein kinase (MAPK) signaling in vitro and in vivo. However, blocking p38 MAPK signaling through the inhibitor SB203580 significantly suppressed the acute lung injury and excessive lung inflammation in vivo, consistent with the reduced expression of the NLRP3 inflammasome and IL‑1β and cleavage of caspase‑1. Pretreatment of the rat NR8383 macrophage cell line with SB203580 significantly decreased the population of caspase‑1+PI+ pyroptotic cells and expression of NLRP3/IL‑1β. However, a larger population of Annexin V+PI‑ apoptotic cells was observed following blocking of the p38 MAPK signaling pathway. The results indicated that blockage of p38 MAPK signaling pathway skewed macrophage cell death from proinflammatory pyroptosis towards non‑inflammatory apoptosis. These effects may contribute to attenuated acute lung injury and excessive inflammation in the SB203580‑treated mice. The results may provide a novel therapeutic strategy for the treatment of uncontrolled lung inflammation in patients with ALI/ARDS.
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Affiliation(s)
- Dandan Li
- Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
| | - Weiying Ren
- Department of Gerontology, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
| | - Zhilong Jiang
- Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
| | - Lei Zhu
- Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
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The Role of SIRT1 in Autophagy in Lipopolysaccharide-Induced Mouse Type II Alveolar Epithelial Cells. Inflammation 2018; 41:2222-2235. [DOI: 10.1007/s10753-018-0865-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
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23
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Yang L, Zhang Z, Zhuo Y, Cui L, Li C, Li D, Zhang S, Cui N, Wang X, Gao H. Resveratrol alleviates sepsis-induced acute lung injury by suppressing inflammation and apoptosis of alveolar macrophage cells. Am J Transl Res 2018; 10:1961-1975. [PMID: 30093935 PMCID: PMC6079135] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2017] [Accepted: 10/10/2017] [Indexed: 06/08/2023]
Abstract
Sepsis is a major cause of death in intensive care units. The purpose of this study was to investigate the effect of resveratrol (RSV) on sepsis-induced acute lung injury (ALI). The underlying molecular mechanisms were deciphered by both in vitro and in vivo experiments. Polymicrobial sepsis was induced in C57BL/6 mice by cecal ligation and puncture (CLP). RSV pretreatment significantly attenuated CLP-induced acute lung injury, which was associated with enhanced expression of VEGF-B. The protective properties of RSV were assayed in lipopolysaccharide (LPS)-stimulated MH-S cells. We determine that RSV administration inhibited the increased production of TNF-α, IL-6, and IL-1β in LPS-stimulated MH-S cells, which was associated with inhibition of the nuclear factor-κB, P38, and ERK signaling pathways. We also provide evidence that RSV administration reduced LPS-induced apoptosis of MH-S cells by altering the unbalance of Bax/Bcl-2 and inhibiting LPS-induced autophagy. The inhibitory effects of RSV on cytokine levels and apoptosis of alveolar macrophages were both blocked by VEGF-B siRNA. Furthermore, RSV administration regulated LPS-induced C5aR and C5L2 expression, revealing an additional mechanism underlying RSV's anti-inflammatory and anti-apoptosis effects. Collectively, these results demonstrated that RSV was able to protect against sepsis-induced acute lung injury by activating the VEGF-B signaling pathway.
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Affiliation(s)
- Lei Yang
- Tianjin Institute of Acute Abdominal Disease of Integrated Traditional Chinese and Western MedicineTianjin 300100, China
| | - Zhen Zhang
- Graduate School of Tianjin Medical UniversityTianjin 300070, China
| | - Yuzhen Zhuo
- Tianjin Institute of Acute Abdominal Disease of Integrated Traditional Chinese and Western MedicineTianjin 300100, China
| | - Lihua Cui
- Tianjin Institute of Acute Abdominal Disease of Integrated Traditional Chinese and Western MedicineTianjin 300100, China
| | - Caixia Li
- Tianjin Institute of Acute Abdominal Disease of Integrated Traditional Chinese and Western MedicineTianjin 300100, China
| | - Dihua Li
- Tianjin Institute of Acute Abdominal Disease of Integrated Traditional Chinese and Western MedicineTianjin 300100, China
| | - Shukun Zhang
- Tianjin Institute of Acute Abdominal Disease of Integrated Traditional Chinese and Western MedicineTianjin 300100, China
| | - Naiqiang Cui
- Department of Surgery, Tianjin Hospital of Integrated Traditional Chinese and Western MedicineTianjin 300100, China
| | - Ximo Wang
- Graduate School of Tianjin Medical UniversityTianjin 300070, China
- Department of Surgery, Tianjin Hospital of Integrated Traditional Chinese and Western MedicineTianjin 300100, China
| | - Hongwei Gao
- Department of Anesthesiology, Perioperative & Pain Medicine, Brigham and Women’s Hospital, Harvard Medical SchoolBoston 02115, MA
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Luo J, Zhan J, You H, Cheng X. MicroRNA‑146a/Toll‑like receptor 4 signaling protects against severe burn‑induced remote acute lung injury in rats via anti‑inflammation. Mol Med Rep 2018; 17:8377-8384. [PMID: 29658581 DOI: 10.3892/mmr.2018.8877] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2017] [Accepted: 12/14/2017] [Indexed: 11/06/2022] Open
Abstract
The present study investigated the preventive effects of microRNA (miR)‑146a against severe burn‑induced remote acute lung injury (ALI) in rats and the underlying mechanism. The surface area of the skin was immersed in 100˚C water for 5‑10 sec on the dorsal surface. The expression level of miR‑146a was significantly downregulated in rats with burn‑induced ALI. Downregulation of miR‑146a increased inflammation, and inducible nitric oxide synthase (iNOS) and cyclooxygenase‑2 (COX‑2) expression in a model of ALI in vitro via the promotion of the Toll‑like receptor (TLR)4/nuclear factor (NF)‑κB signaling pathway. In addition, the overexpression of miR‑146a reduced inflammation, and iNOS and COX‑2 protein expression in the model of ALI in vitro via the suppression of the TLR4/NF‑κB signaling pathway. A TLR4 inhibitor reduced the function of anti‑miR‑146a on inflammation in the model of ALI. Collectively, the results of the present study demonstrated the preventive effects of miR‑146a against severe burn‑induced remote ALI in rats through the anti‑inflammatory‑regulated TLR4/NF‑κB signaling pathway.
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Affiliation(s)
- Jinhua Luo
- Department of Burns, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Jianhua Zhan
- Department of Burns, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Haoyuan You
- Department of Burns, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Xing Cheng
- Department of Burns, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
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Liu Y, Guan H, Zhang JL, Zheng Z, Wang HT, Tao K, Han SC, Su LL, Hu D. Acute downregulation of miR-199a attenuates sepsis-induced acute lung injury by targeting SIRT1. Am J Physiol Cell Physiol 2018; 314:C449-C455. [PMID: 29351405 DOI: 10.1152/ajpcell.00173.2017] [Citation(s) in RCA: 70] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
MicroRNA-199a (miR-199a) is a novel gene regulator with an important role in inflammation and lung injury. However, its role in the pathogenesis of sepsis-induced acute respiratory distress syndrome (ARDS) is currently unknown. Our study explored the role of miR-199a in sepsis-induced ARDS and its mechanism of action. First, we found that LPS could upregulate miR-199a in alveolar macrophages. Downregulation of miR-199a inhibited the upregulation of inflammatory cytokines in alveolar macrophages and induced the remission of histopathologic changes, the reduction of proinflammatory cytokines, and the upregulation of apoptosis protein expression in an ARDS lung, showing a protective role for miR-199a. We further identified sirtuin 1 (SIRT1) as a direct target of miR-199a in alveolar macrophages, and the expression of SIRT1 was negatively correlated with the level of miR-199a. The protective role of miR-199a downregulation in LPS-stimulated alveolar macrophages and sepsis-induced ARDS could be attenuated by SIRT1 inhibitor. Taken together, these results indicate that downregulation of miR-199a might protect lung tissue against sepsis-induced ARDS by upregulation of SIRT1 through the suppression of excessive inflammatory responses and the inhibition of cellular apoptosis in lung tissue, suggesting its potential therapeutic effects on sepsis-induced ARDS.
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Affiliation(s)
- Yang Liu
- Department of Burns and Cutaneous Surgery, Xijing Hospital, The Fourth Military Medical University , Xi'an, Shaanxi , China
| | - Hao Guan
- Department of Burns and Cutaneous Surgery, Xijing Hospital, The Fourth Military Medical University , Xi'an, Shaanxi , China
| | - Ju-Lei Zhang
- Department of Burns and Cutaneous Surgery, Xijing Hospital, The Fourth Military Medical University , Xi'an, Shaanxi , China
| | - Zhao Zheng
- Department of Burns and Cutaneous Surgery, Xijing Hospital, The Fourth Military Medical University , Xi'an, Shaanxi , China
| | - Hong-Tao Wang
- Department of Burns and Cutaneous Surgery, Xijing Hospital, The Fourth Military Medical University , Xi'an, Shaanxi , China
| | - Ke Tao
- Department of Burns and Cutaneous Surgery, Xijing Hospital, The Fourth Military Medical University , Xi'an, Shaanxi , China
| | - Shi-Chao Han
- Department of Burns and Cutaneous Surgery, Xijing Hospital, The Fourth Military Medical University , Xi'an, Shaanxi , China
| | - Lin-Lin Su
- Department of Burns and Cutaneous Surgery, Xijing Hospital, The Fourth Military Medical University , Xi'an, Shaanxi , China
| | - Dahai Hu
- Department of Burns and Cutaneous Surgery, Xijing Hospital, The Fourth Military Medical University , Xi'an, Shaanxi , China
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Cho RL, Lin WN, Wang CY, Yang CC, Hsiao LD, Lin CC, Yang CM. Heme oxygenase-1 induction by rosiglitazone via PKCα/AMPKα/p38 MAPKα/SIRT1/PPARγ pathway suppresses lipopolysaccharide-mediated pulmonary inflammation. Biochem Pharmacol 2018; 148:222-237. [PMID: 29309760 DOI: 10.1016/j.bcp.2017.12.024] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2017] [Accepted: 12/28/2017] [Indexed: 12/20/2022]
Abstract
HO-1 (heme oxygenase-1), an antioxidant enzyme, induced by rosiglitazone (PPAR ligands) can be a potential treatment of inflammation. However, the mechanisms of rosiglitazone-induced HO-1 expression in human pulmonary alveolar epithelial cells (HPAEpiCs) remain largely unknown. In this study, we found that upregulation of HO-1 in vitro or in vivo by rosiglitazone attenuated VCAM-1 gene expression and monocyte adhesion to HPAEpiCs challenged with lipopolysaccharide (LPS). The inhibitory effects of rosiglitazone on LPS-mediated responses were reversed by transfection with HO-1 siRNA. LPS-induced VCAM-1 expression was mediated through NF-κB activation which was attenuated by rosiglitazone via suppressing p65 activation and translocation into the nucleus. Moreover, pretreatment with the inhibitor of PKCs (H7), PKCα (Gö6976), AMPKα (Compound C), p38 MAPKα (p38i VIII), SIRT1 (Sirtinol), or PPARγ (T0070907) and transfection with siRNA of PKCα, AMPKα, p38 MAPKα, SIRT1, or PPARγ abolished the rosiglitazone-induced HO-1 expression in HPAEpiCs. Further studies indicated that rosiglitazone stimulated SIRT1 deacetylase leading to PGC1α translocation from the cytosol into the nucleus, promoting fragmentation of NCoR and phosphorylation of PPARγ. Subsequently, PPARγ was activated by phosphorylation of PKCα, AMPKα, p38 MAPKα, and SIRT1, which turned on transcription of HO-1 gene by binding to PPAR response element (PPRE) and enhancing PPARγ promoter activity. These results suggested that rosiglitazone-induced HO-1 expression is mediated through PKCα/AMPKα/p38 MAPKα/SIRT1-dependent deacetylation of Ac-PGC1α and fragmentation of NCoR/PPARγ activation in HPAEpiCs. Up-regulation of HO-1 protected against the inflammatory responses triggered by LPS, at least in part, through attenuation of NF-κB.
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Affiliation(s)
- Rou-Ling Cho
- Department of Physiology and Pharmacology and Health Ageing Research Center, College of Medicine, Chang Gung University, Kwei-San, Tao-Yuan, Taiwan
| | - Wei-Ning Lin
- Graduate Institute of Biomedical and Pharmaceutical Science, Fu Jen Catholic University, Xinzhuang, New Taipei City, Taiwan
| | - Chen-Yu Wang
- Department of Physiology and Pharmacology and Health Ageing Research Center, College of Medicine, Chang Gung University, Kwei-San, Tao-Yuan, Taiwan
| | - Chien-Chung Yang
- Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital at Tao-Yuan, Kwei-San, Tao-Yuan, Taiwan
| | - Li-Der Hsiao
- Department of Anesthetics, Chang Gung Memorial Hospital at Linkuo and Chang Gung University, Kwei-San, Tao-Yuan, Taiwan
| | - Chih-Chung Lin
- Department of Anesthetics, Chang Gung Memorial Hospital at Linkuo and Chang Gung University, Kwei-San, Tao-Yuan, Taiwan.
| | - Chuen-Mao Yang
- Department of Physiology and Pharmacology and Health Ageing Research Center, College of Medicine, Chang Gung University, Kwei-San, Tao-Yuan, Taiwan; Department of Anesthetics, Chang Gung Memorial Hospital at Linkuo and Chang Gung University, Kwei-San, Tao-Yuan, Taiwan; Research Center for Chinese Herbal Medicine and Research Center for Food and Cosmetic Safety, College of Human Ecology, Chang Gung University of Science and Technology, Tao-Yuan, Taiwan.
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Hyperoxia causes miR-34a-mediated injury via angiopoietin-1 in neonatal lungs. Nat Commun 2017; 8:1173. [PMID: 29079808 PMCID: PMC5660088 DOI: 10.1038/s41467-017-01349-y] [Citation(s) in RCA: 95] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2017] [Accepted: 09/11/2017] [Indexed: 01/07/2023] Open
Abstract
Hyperoxia-induced acute lung injury (HALI) is a key contributor to the pathogenesis of bronchopulmonary dysplasia (BPD) in neonates, for which no specific preventive or therapeutic agent is available. Here we show that lung micro-RNA (miR)-34a levels are significantly increased in lungs of neonatal mice exposed to hyperoxia. Deletion or inhibition of miR-34a improves the pulmonary phenotype and BPD-associated pulmonary arterial hypertension (PAH) in BPD mouse models, which, conversely, is worsened by miR-34a overexpression. Administration of angiopoietin-1, which is one of the downstream targets of miR34a, is able to ameliorate the BPD pulmonary and PAH phenotypes. Using three independent cohorts of human samples, we show that miR-34a expression is increased in type 2 alveolar epithelial cells in neonates with respiratory distress syndrome and BPD. Our data suggest that pharmacologic miR-34a inhibition may be a therapeutic option to prevent or ameliorate HALI/BPD in neonates.
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Wang CY, Sun ZN, Wang MX, Zhang C. SIRT1 mediates salidroside-elicited protective effects against MPP + -induced apoptosis and oxidative stress in SH-SY5Y cells: involvement in suppressing MAPK pathways. Cell Biol Int 2017; 42:84-94. [PMID: 28851138 DOI: 10.1002/cbin.10864] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2017] [Accepted: 08/26/2017] [Indexed: 12/31/2022]
Abstract
Parkinson's disease (PD) is a progressive neurodegenerative disease, leading to tremor, rigidity, bradykinesia, and gait impairment. Salidroside has been reported to exhibit antioxidative and neuroprotective properties in PD. However, the underlying neuroprotective mechanisms effects of salidroside are poorly understood. Recently, a growing body of evidences suggest that silent information regulator 1 (SIRT1) plays important roles in the pathophysiology of PD. Hence, the present study investigated the roles of SIRT1 in neuroprotective effect of salidroside against N-methyl-4-phenylpyridinium (MPP+ )-induced SH-SY5Y cell injury. Our findings revealed that salidroside attenuates MPP+ -induced neurotoxicity as evidenced by the increase in cell viability, and the decreases in the caspase-3 activity and apoptosis ratio. Simultaneously, salidroside pretreatment remarkably increased SIRT1 activity, SIRT1 mRNA and protein levels in MPP+ -treated SH-SY5Y cell. However, sirtinol, a SIRT1 activation inhibitor, significantly blocked the inhibitory effects of salidroside on MPP+ -induced cytotoxicity and apoptosis. In addition, salidroside abolished MPP+ -induced the production of reactive oxygen species (ROS), the up-regulation of NADPH oxidase 2 (NOX2) expression, the down-regulations of superoxide dismutase (SOD) activity and glutathione (GSH) level in SH-SY5Y cells, while these effects were also blocked by sirtinol. Finally, we found that the inhibition of salidroside on MPP+ -induced phosphorylation of p38, extracellular signal-regulated kinase (ERK) and c-Jun NH2-terminal kinase (JNK) were also reversed by sirtinol in SH-SY5Y cells. Taken together, these results indicated that SIRT1 contributes to the neuroprotection of salidroside against MPP+ -induced apoptosis and oxidative stress, in part through suppressing of mitogen-activated protein kinase (MAPK) pathways.
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Affiliation(s)
- Chun-Yang Wang
- Department of Science and Technology, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Zhao-Nan Sun
- Department of General surgery, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Ming-Xin Wang
- Department of Otolaryngological, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Chao Zhang
- Department of Neurology, Tianjin Medical University General Hospital, Tianjin 300052, China
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Autophagy protein LC3 regulates the fibrosis of hypertrophic scar by controlling Bcl-xL in dermal fibroblasts. Oncotarget 2017; 8:93757-93770. [PMID: 29212187 PMCID: PMC5706833 DOI: 10.18632/oncotarget.20771] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2017] [Accepted: 07/29/2017] [Indexed: 12/19/2022] Open
Abstract
Hypertrophic scar (HS) is a serious skin fibrotic disease characterized by excessive hypercellularity and extracellular matrix (ECM) component deposition. Autophagy is a tightly regulated physiological process essential for cellular maintenance, differentiation, development and homeostasis. However, during the formation of HS, whether and how autophagy is regulated in dermal fibroblasts are still far from elucidated. Here we detected the autophagic capacity in HS and normal skin (NS) counterparts, explored and verified the key regulatory molecules of autophagy in HS-derived fibroblasts (HSFs), and validated the data using rabbit ear scar model. Transmission electron microscopy (TEM) and immunostaining data showed that LC3-positive cells and autophagosomes in HS/HSFs were more intensive relative to those in NS/NSFs groups. Knockdown of LC3 (shLC3) could significantly block the expressionof type I collagen (Col 1, p < 0.01) and type III collagen (Col 3, p < 0.01) and thus inhibit the fibrosis of HSFs. shLC3 resistant to autophagy was shown to be Bcl-xL-, not Bcl-2-dependent, and silencing of Bcl-xL (sibcl-xL) significantly increased apoptosis of HSFs (p < 0.01). Immunofluorescence results showed that instead of inhibiting α-SMA protein expression, shLC3 could change its architecture arrangement in HSFs. sibcl-xL showed that Bcl-xL was a key signaling molecule involved in HSFs autophagy. More importantly, both shLC3 and sibcl-xL obviously improved the appearance and architecture of the rabbit ear scar, and reduced scar formation on the rabbit ear. Therefore, the aberration of LC3 protein processing compromised autophagy in HS might associate with its pathogenesis in wound repair. LC3 regulated HS fibrosis by controlling the expression of Bcl-xL in HSFs. Thus, Bcl-xL might serve as a potential molecular target, providing a novel strategy for HS therapy.
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Ren W, Wang Z, Wu Z, Hu Z, Dai F, Chang J, Li B, Liu H, Ruan Y. JAK2/STAT3 Pathway Was Associated with the Protective Effects of IL-22 On Aortic Dissection with Acute Lung Injury. DISEASE MARKERS 2017; 2017:1917804. [PMID: 28827891 PMCID: PMC5554575 DOI: 10.1155/2017/1917804] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/15/2017] [Revised: 03/24/2017] [Accepted: 04/05/2017] [Indexed: 01/06/2023]
Abstract
Patients with aortic dissection (AD) may present acute lung injury (ALI) that may affect the prognosis. In this study, we aim to investigate the roles and mechanism of IL-22 in the pathogenesis of AD complicated with ALI. Six hundred and twenty-one AD patients were included, and the incidence of ALI and pulmonary CT findings were analyzed. Mouse ALI model was established through AngII, and then IL-22 injection and AG490 were given. The pathological changes, infiltration of inflammatory cells, and expression of STAT3 were determined. For the in vitro experiment, cultivated pulmonary microvascular endothelial cells (PMVECs) were treated by angiotensin II (AngII), followed by treating with IL-22 and/or AG490. The expression and migration of STAT3 was determined. Flow cytometry was carried out to evaluate the apoptosis. IL-22 contributed to the expression of STAT3 in lung tissues and attenuation of ALI. IL-22 obviously inhibited the apoptosis of PMVECs mediated by AngII and downregulated the expression and intranuclear transmission of STAT3. Such phenomenon was completely inhibited upon administration of AG490, an inhibitor of JAK2. Our data showed IL-22 contributed to the inhibition of PMVEC apoptosis mediated by AngII through activating the JAK2/STAT3 signaling pathway, which may attenuate the ALI induced by AngII.
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Affiliation(s)
- Wei Ren
- Department of Cardiovascular Surgery, Renmin Hospital of Wuhan University, Wuhan 430060, China
- Hubei Key Laboratory of Cardiology, Wuhan 430060, China
| | - Zhiwei Wang
- Department of Cardiovascular Surgery, Renmin Hospital of Wuhan University, Wuhan 430060, China
- Hubei Key Laboratory of Cardiology, Wuhan 430060, China
| | - Zhiyong Wu
- Department of Cardiovascular Surgery, Renmin Hospital of Wuhan University, Wuhan 430060, China
- Hubei Key Laboratory of Cardiology, Wuhan 430060, China
| | - Zhipeng Hu
- Department of Cardiovascular Surgery, Renmin Hospital of Wuhan University, Wuhan 430060, China
- Hubei Key Laboratory of Cardiology, Wuhan 430060, China
| | - Feifeng Dai
- Department of Cardiovascular Surgery, Renmin Hospital of Wuhan University, Wuhan 430060, China
- Hubei Key Laboratory of Cardiology, Wuhan 430060, China
| | - Jinxing Chang
- Department of Cardiovascular Surgery, Renmin Hospital of Wuhan University, Wuhan 430060, China
- Hubei Key Laboratory of Cardiology, Wuhan 430060, China
| | - Bowen Li
- Department of Cardiovascular Surgery, Renmin Hospital of Wuhan University, Wuhan 430060, China
- Hubei Key Laboratory of Cardiology, Wuhan 430060, China
| | - Huagang Liu
- Department of Cardiovascular Surgery, Renmin Hospital of Wuhan University, Wuhan 430060, China
- Hubei Key Laboratory of Cardiology, Wuhan 430060, China
| | - Yongle Ruan
- Department of Cardiovascular Surgery, Renmin Hospital of Wuhan University, Wuhan 430060, China
- Hubei Key Laboratory of Cardiology, Wuhan 430060, China
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Sun Q, Han W, Hu H, Fan D, Li Y, Zhang Y, Lv Y, Li M, Pan S. Hydrogen alleviates hyperoxic acute lung injury related endoplasmic reticulum stress in rats through upregulation of SIRT1. Free Radic Res 2017; 51:622-632. [PMID: 28675985 DOI: 10.1080/10715762.2017.1351027] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Affiliation(s)
- Qiang Sun
- Department of Hyperbaric Oxygen, PLA Navy General Hospital, Beijing, China
| | - Wenjie Han
- Department of VIP Respiration Medicine, PLA Navy General Hospital, Beijing, China
| | - Huijun Hu
- Department of Hyperbaric Oxygen, PLA Navy General Hospital, Beijing, China
| | - Danfeng Fan
- Department of VIP Respiration Medicine, PLA Navy General Hospital, Beijing, China
| | - Yanbo Li
- Department of VIP General Medicine, PLA Navy General Hospital, Beijing, China
| | - Yu Zhang
- Department of Hyperbaric Oxygen, PLA Navy General Hospital, Beijing, China
| | - Yan Lv
- Department of Hyperbaric Oxygen, PLA Navy General Hospital, Beijing, China
| | - Mingxin Li
- Department of Hyperbaric Oxygen, PLA Navy General Hospital, Beijing, China
| | - Shuyi Pan
- Department of Hyperbaric Oxygen, PLA Navy General Hospital, Beijing, China
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He DS, Hu XJ, Yan YQ, Liu H. Underlying mechanism of Sirt1 on apoptosis and extracellular matrix degradation of osteoarthritis chondrocytes. Mol Med Rep 2017; 16:845-850. [DOI: 10.3892/mmr.2017.6659] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2016] [Accepted: 02/06/2017] [Indexed: 11/06/2022] Open
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Activation and overexpression of Sirt1 attenuates lung fibrosis via P300. Biochem Biophys Res Commun 2017; 486:1021-1026. [DOI: 10.1016/j.bbrc.2017.03.155] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2017] [Accepted: 03/28/2017] [Indexed: 01/03/2023]
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SIRT1 plays a neuroprotective role in traumatic brain injury in rats via inhibiting the p38 MAPK pathway. Acta Pharmacol Sin 2017; 38:168-181. [PMID: 28017962 DOI: 10.1038/aps.2016.130] [Citation(s) in RCA: 70] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2016] [Accepted: 10/18/2016] [Indexed: 12/23/2022]
Abstract
Traumatic brain injury (TBI) is a major cause of disability and death in patients who experience a traumatic injury. Mitochondrial dysfunction is one of the main factors contributing to secondary injury in TBI-associated brain damage. Evidence of compromised mitochondrial function after TBI has been, but the molecular mechanisms underlying the pathogenesis of TBI are not well understood. Silent information regulator family protein 1 (SIRT1), a member of the NAD+-dependent protein deacetylases, has been shown to exhibit neuroprotective activities in animal models of various pathologies, including ischemic brain injury, subarachnoid hemorrhage and several neurodegenerative diseases. In this study, we investigated whether SIRT1 also exert neuroprotective effect post-TBI, and further explored the possible regulatory mechanisms involved in TBI pathogenesis. A lateral fluid-percussion (LFP) brain injury model was established in rats to mimic the insults of TBI. The expression levels of SIRT1, p-p38, cleaved caspase-9 and cleaved caspase-3 were all markedly increased and reached a maximum at 12 h post-TBI. In addition, mitochondrial function was impaired, evidenced by the presence of swollen and irregularly shaped mitochondria with disrupted and poorly defined cristae, a relative increase of the percentage of neurons with low ΔΨm, the opening of mPTP, and a decrease in neuronal ATP content, especially at 12 h post-TBI. Pretreatment with the SIRT1 inhibitor sirtinol (10 mg/kg, ip) induced p-p38 activation, exacerbated mitochondrial damage, and promoted the activation of the mitochondrial apoptosis pathway. In contrast, pretreatment with the p38 inhibitor SB203580 (200 μg/kg, ip) significantly attenuated post-TBI-induced expression of both cleaved caspase-9 and cleaved caspase-3 and mitochondrial damage, whereas it had no effects on SIRT1 expression. Together, these results reveal that the 12 h after TBI may be a crucial time at which secondary damage occurs; the activation of SIRT1 expression and inhibition of the p38 MAPK pathway may play a neuroprotective role in preventing secondary damage post-TBI. For this reason, both SIRT1 and p38 are likely to be important targets to prevent secondary damage post-TBI.
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Bai XZ, He T, Gao JX, Liu Y, Liu JQ, Han SC, Li Y, Shi JH, Han JT, Tao K, Xie ST, Wang HT, Hu DH. Melatonin prevents acute kidney injury in severely burned rats via the activation of SIRT1. Sci Rep 2016; 6:32199. [PMID: 27599451 PMCID: PMC5013284 DOI: 10.1038/srep32199] [Citation(s) in RCA: 56] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2016] [Accepted: 08/03/2016] [Indexed: 01/09/2023] Open
Abstract
Acute kidney injury (AKI) is a common complication after severe burns. Melatonin has been reported to protect against multiple organ injuries by increasing the expression of SIRT1, a silent information regulator that regulates stress responses, inflammation, cellular senescence and apoptosis. This study aimed to investigate the protective effects of melatonin on renal tissues of burned rats and the role of SIRT1 involving the effects. Rat severely burned model was established, with or without the administration of melatonin and SIRT1 inhibitor. The renal function and histological manifestations were determined to evaluate the severity of kidney injury. The levels of acetylated-p53 (Ac-p53), acetylated-p65 (Ac-p65), NF-κB, acetylated-forkhead box O1 (Ac-FoxO1), Bcl-2 and Bax were analyzed to study the underlying mechanisms. Our results suggested that severe burns could induce acute kidney injury, which could be partially reversed by melatonin. Melatonin attenuated oxidative stress, inflammation and apoptosis accompanied by the increased expression of SIRT1. The protective effects of melatonin were abrogated by the inhibition of SIRT1. In conclusion, we demonstrate that melatonin improves severe burn-induced AKI via the activation of SIRT1 signaling.
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Affiliation(s)
- Xiao-Zhi Bai
- Department of Burns and Cutaneous Surgery, Xijing Hospital, The Fourth Military Medical University, 127 Changle West Road, Xi’an, Shaanxi 710032, China
| | - Ting He
- Department of Burns and Cutaneous Surgery, Xijing Hospital, The Fourth Military Medical University, 127 Changle West Road, Xi’an, Shaanxi 710032, China
| | - Jian-Xin Gao
- Department of Burns and Cutaneous Surgery, Xijing Hospital, The Fourth Military Medical University, 127 Changle West Road, Xi’an, Shaanxi 710032, China
| | - Yang Liu
- Department of Burns and Cutaneous Surgery, Xijing Hospital, The Fourth Military Medical University, 127 Changle West Road, Xi’an, Shaanxi 710032, China
| | - Jia-Qi Liu
- Department of Burns and Cutaneous Surgery, Xijing Hospital, The Fourth Military Medical University, 127 Changle West Road, Xi’an, Shaanxi 710032, China
| | - Shi-Chao Han
- Department of Burns and Cutaneous Surgery, Xijing Hospital, The Fourth Military Medical University, 127 Changle West Road, Xi’an, Shaanxi 710032, China
| | - Yan Li
- Department of Burns and Cutaneous Surgery, Xijing Hospital, The Fourth Military Medical University, 127 Changle West Road, Xi’an, Shaanxi 710032, China
| | - Ji-Hong Shi
- Department of Burns and Cutaneous Surgery, Xijing Hospital, The Fourth Military Medical University, 127 Changle West Road, Xi’an, Shaanxi 710032, China
| | - Jun-Tao Han
- Department of Burns and Cutaneous Surgery, Xijing Hospital, The Fourth Military Medical University, 127 Changle West Road, Xi’an, Shaanxi 710032, China
| | - Ke Tao
- Department of Burns and Cutaneous Surgery, Xijing Hospital, The Fourth Military Medical University, 127 Changle West Road, Xi’an, Shaanxi 710032, China
| | - Song-Tao Xie
- Department of Burns and Cutaneous Surgery, Xijing Hospital, The Fourth Military Medical University, 127 Changle West Road, Xi’an, Shaanxi 710032, China
| | - Hong-Tao Wang
- Department of Burns and Cutaneous Surgery, Xijing Hospital, The Fourth Military Medical University, 127 Changle West Road, Xi’an, Shaanxi 710032, China
| | - Da-Hai Hu
- Department of Burns and Cutaneous Surgery, Xijing Hospital, The Fourth Military Medical University, 127 Changle West Road, Xi’an, Shaanxi 710032, China
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Qiao YY, Liu XQ, Xu CQ, Zhang Z, Xu HW. Interleukin-22 ameliorates acute severe pancreatitis-associated lung injury in mice. World J Gastroenterol 2016; 22:5023-32. [PMID: 27275094 PMCID: PMC4886377 DOI: 10.3748/wjg.v22.i21.5023] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2016] [Revised: 04/11/2016] [Accepted: 05/04/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the potential protective effect of exogenous recombinant interleukin-22 (rIL-22) on L-arginine-induced acute severe pancreatitis (SAP)-associated lung injury and the possible signaling pathway involved. METHODS Balb/c mice were injected intraperitoneally with L-arginine to induce SAP. Recombinant mouse IL-22 was then administered subcutaneously to mice. Serum amylase levels and myeloperoxidase (MPO) activity in the lung tissue were measured after the L-arginine administration. Histopathology of the pancreas and lung was evaluated by hematoxylin and eosin (HE) staining. Expression of B cell lymphoma/leukemia-2 (Bcl-2), Bcl-xL and IL-22RA1 mRNAs in the lung tissue was detected by real-time PCR. Expression and phosphorylation of STAT3 were analyzed by Western blot. RESULTS Serum amylase levels and MPO activity in the lung tissue in the SAP group were significantly higher than those in the normal control group (P < 0.05). In addition, the animals in the SAP group showed significant pancreatic and lung injuries. The expression of Bcl-2 and Bcl-xL mRNAs in the SAP group was decreased markedly, while the IL-22RA1 mRNA expression was increased significantly relative to the normal control group (P < 0.05). Pretreatment with PBS did not significantly affect the serum amylase levels, MPO activity or expression of Bcl-2, Bcl-xL or IL-22RA1 mRNA (P > 0.05). Moreover, no significant differences in the degrees of pancreatic and lung injuries were observed between the PBS and SAP groups. However, the serum amylase levels and lung tissue MPO activity in the rIL-22 group were significantly lower than those in the SAP group (P < 0.05), and the injuries in the pancreas and lung were also improved. Compared with the PBS group, rIL-22 stimulated the expression of Bcl-2, Bcl-xL and IL-22RA1 mRNAs in the lung (P < 0.05). In addition, the ratio of p-STAT3 to STAT3 protein in the rIL-22 group was significantly higher than that in the PBS group (P < 0.05). CONCLUSION Exogenous recombinant IL-22 protects mice against L-arginine-induced SAP-associated lung injury by enhancing the expression of anti-apoptosis genes through the STAT3 signaling pathway.
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Cheng W, Wang JF, Yang CX, Wu L, Yin Q, Liu H, Fu ZJ. Intrathecal Injection of Resveratrol Attenuates Burn Injury Pain by Activating Spinal Sirtuin 1. Pharmacogn Mag 2016; 12:S201-5. [PMID: 27279707 PMCID: PMC4883079 DOI: 10.4103/0973-1296.182167] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2015] [Revised: 10/16/2015] [Indexed: 11/30/2022] Open
Abstract
Objective: The present study sought to detect spinal sirtuin 1 (SIRT1) and acetylation of histone H3 (Ac-H3) expression in rats with burn injury pain (BIP model). Procedures and Results: A BIP model was first established. BIP rats showed lower paw withdrawal threshold (PWT) from day 1, which persisted for 21 days following the burn injury. Spinal SIRT1/Ac-H3 expression increased following burn injury. The intrathecal use of resveratrol increased PWT and SIRT1 expression but induced down-regulation of Ac-H3 expression. We first demonstrated that the inhibition of SIRT1 significantly induced mechanical allodynia in naïve rats. The preinjection of SIRT1 inhibitor partly antagonized the analgesic effects of resveratrol in BIP rats. Conclusion: Inhibition of SIRT1 produces pain facilitation in the naïve rats. The expression of spinal SIRT1 increased after burn injury in the BIP model. The activation of spinal SIRT1 might mediate the resveratrol-induced analgesic effects. SUMMARY
Burn injury resulted in pain facilitation Resveratrol attenuates pain facilitation induced by burn injury Intrathecal injection of resveratrol attenuates burn injury pain by increasing spinal sirtuin 1 (SIRT1) expression Inhibition of SIRT1 by selisistat, an SIRT1 inhibitor attenuated analgesic effects of resveratrol Abbreviations used: SIRT1: Sirtuin 1, Ac-H3: Acetylation of histone H3, SD: Sprague-Dawley, EX527: Selisistat, an SIRT1 inhibitor, BIP: Burn injury pain, DMSO: Dimethyl sulfoxide, PWTs: Paw withdrawal thresholds
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Affiliation(s)
- Wei Cheng
- Department of Pain Management, Shandong Provincial Hospital Affiliated to Shandong University, Shandong University, Jinan, Shandong 250000, PR China; Department of Anesthesiology, Affiliated Hospital of Xuzhou Medical College, Jiangsu Province Key Laboratory of Anesthesiology and Center for Pain Research and Treatment, Jiangsu 221002, PR China
| | - Jin-Feng Wang
- Department of Anesthesiology, Affiliated Hospital of Xuzhou Medical College, Jiangsu Province Key Laboratory of Anesthesiology and Center for Pain Research and Treatment, Jiangsu 221002, PR China; Department of Anesthesiology, Xuzhou Central Hospital, Jiangsu 221002, PR China
| | - Cong-Xian Yang
- Department of Pain Management, Shandong Provincial Hospital Affiliated to Shandong University, Shandong University, Jinan, Shandong 250000, PR China
| | - Liang Wu
- Department of Anesthesiology, Affiliated Hospital of Xuzhou Medical College, Jiangsu Province Key Laboratory of Anesthesiology and Center for Pain Research and Treatment, Jiangsu 221002, PR China
| | - Qin Yin
- Department of Anesthesiology, Affiliated Hospital of Xuzhou Medical College, Jiangsu Province Key Laboratory of Anesthesiology and Center for Pain Research and Treatment, Jiangsu 221002, PR China
| | - He Liu
- Department of Pain Management, Shandong Provincial Hospital Affiliated to Shandong University, Shandong University, Jinan, Shandong 250000, PR China
| | - Zhi-Jian Fu
- Department of Pain Management, Shandong Provincial Hospital Affiliated to Shandong University, Shandong University, Jinan, Shandong 250000, PR China
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Notch1 Pathway Protects against Burn-Induced Myocardial Injury by Repressing Reactive Oxygen Species Production through JAK2/STAT3 Signaling. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2016; 2016:5638943. [PMID: 27057278 PMCID: PMC4736405 DOI: 10.1155/2016/5638943] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/28/2015] [Accepted: 11/09/2015] [Indexed: 12/21/2022]
Abstract
Oxidative stress plays an important role in burn-induced myocardial injury, but the cellular mechanisms that control reactive oxygen species (ROS) production and scavenging are not fully understood. This study demonstrated that blockade of Notch signaling via knockout of the transcription factor RBP-J or a pharmacological inhibitor aggravated postburn myocardial injury, which manifested as deteriorated serum CK, CK-MB, and LDH levels and increased apoptosis in vitro and in vivo. Interruption of Notch signaling increased intracellular ROS production, and a ROS scavenger reversed the exacerbated myocardial injury after Notch signaling blockade. These results suggest that Notch signaling deficiency aggravated postburn myocardial injury through increased ROS levels. Notch signaling blockade also decreased MnSOD expression in vitro and in vivo. Notably, Notch signaling blockade downregulated p-JAK2 and p-STAT3 expression. Inhibition of JAK2/STAT3 signaling with AG490 markedly decreased MnSOD expression, increased ROS production, and aggravated myocardial injury. AG490 plus GSI exerted no additional effects. These results demonstrate that Notch signaling protects against burn-induced myocardial injury through JAK2/STAT3 signaling, which activates the expression of MnSOD and leads to decreased ROS levels.
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ROS-Mediated NLRP3 Inflammasome Activity Is Essential for Burn-Induced Acute Lung Injury. Mediators Inflamm 2015. [PMID: 26576075 DOI: 10.1155/2015/720457(2015).] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
The NLRP3 inflammasome is necessary for initiating acute sterile inflammation. However, its role in the pathogenesis of burn-induced acute lung injury (ALI) is unknown. This study aimed to determine the role of the NLRP3 inflammasome and the signaling pathways involved in burn-induced ALI. We observed that the rat lungs exhibited enhanced inflammasome activity after burn, as evidenced by increased levels of NLRP3 expression and Caspase-1 activity and augmented inflammatory cytokines. Inhibition of NLRP3 inflammasome by BAY11-7082 attenuated burn-induced ALI, as demonstrated by the concomitant remission of histopathologic changes and the reduction of myeloperoxidase (MPO) activity, inflammatory cytokines in rat lung tissue, and protein concentrations in the bronchoalveolar lavage fluid (BALF). In the in vitro experiments, we used AMs (alveolar macrophages) challenged with burn serum to mimic the postburn microenvironment and noted that the serum significantly upregulated NLRP3 inflammasome signaling and reactive oxygen species (ROS) production. The use of ROS scavenger N-acetylcysteine (NAC) partially reversed NLRP3 inflammasome activity in cells exposed to burn serum. These results indicate that the NLRP3 inflammasome plays an essential role in burn-induced ALI and that burn-induced NLRP3 inflammasome activity is a partly ROS-dependent process. Targeting this axis may represent a promising therapeutic strategy for the treatment of burn-induced ALI.
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ROS-Mediated NLRP3 Inflammasome Activity Is Essential for Burn-Induced Acute Lung Injury. Mediators Inflamm 2015. [PMID: 26576075 DOI: 10.1155/2015/720457(2015)] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
The NLRP3 inflammasome is necessary for initiating acute sterile inflammation. However, its role in the pathogenesis of burn-induced acute lung injury (ALI) is unknown. This study aimed to determine the role of the NLRP3 inflammasome and the signaling pathways involved in burn-induced ALI. We observed that the rat lungs exhibited enhanced inflammasome activity after burn, as evidenced by increased levels of NLRP3 expression and Caspase-1 activity and augmented inflammatory cytokines. Inhibition of NLRP3 inflammasome by BAY11-7082 attenuated burn-induced ALI, as demonstrated by the concomitant remission of histopathologic changes and the reduction of myeloperoxidase (MPO) activity, inflammatory cytokines in rat lung tissue, and protein concentrations in the bronchoalveolar lavage fluid (BALF). In the in vitro experiments, we used AMs (alveolar macrophages) challenged with burn serum to mimic the postburn microenvironment and noted that the serum significantly upregulated NLRP3 inflammasome signaling and reactive oxygen species (ROS) production. The use of ROS scavenger N-acetylcysteine (NAC) partially reversed NLRP3 inflammasome activity in cells exposed to burn serum. These results indicate that the NLRP3 inflammasome plays an essential role in burn-induced ALI and that burn-induced NLRP3 inflammasome activity is a partly ROS-dependent process. Targeting this axis may represent a promising therapeutic strategy for the treatment of burn-induced ALI.
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ROS-Mediated NLRP3 Inflammasome Activity Is Essential for Burn-Induced Acute Lung Injury. Mediators Inflamm 2015; 2015:720457. [PMID: 26576075 PMCID: PMC4630408 DOI: 10.1155/2015/720457] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2015] [Accepted: 08/09/2015] [Indexed: 12/20/2022] Open
Abstract
The NLRP3 inflammasome is necessary for initiating acute sterile inflammation. However, its role in the pathogenesis of burn-induced acute lung injury (ALI) is unknown. This study aimed to determine the role of the NLRP3 inflammasome and the signaling pathways involved in burn-induced ALI. We observed that the rat lungs exhibited enhanced inflammasome activity after burn, as evidenced by increased levels of NLRP3 expression and Caspase-1 activity and augmented inflammatory cytokines. Inhibition of NLRP3 inflammasome by BAY11-7082 attenuated burn-induced ALI, as demonstrated by the concomitant remission of histopathologic changes and the reduction of myeloperoxidase (MPO) activity, inflammatory cytokines in rat lung tissue, and protein concentrations in the bronchoalveolar lavage fluid (BALF). In the in vitro experiments, we used AMs (alveolar macrophages) challenged with burn serum to mimic the postburn microenvironment and noted that the serum significantly upregulated NLRP3 inflammasome signaling and reactive oxygen species (ROS) production. The use of ROS scavenger N-acetylcysteine (NAC) partially reversed NLRP3 inflammasome activity in cells exposed to burn serum. These results indicate that the NLRP3 inflammasome plays an essential role in burn-induced ALI and that burn-induced NLRP3 inflammasome activity is a partly ROS-dependent process. Targeting this axis may represent a promising therapeutic strategy for the treatment of burn-induced ALI.
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