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Ding X, Jin S, Tian W, Zhang Y, Xu L, Zhang T, Chen Z, Niu F, Li Q. ROLE OF CASPASE-1/CASPASE-11-HMGB1-RAGE/TLR4 SIGNALING IN THE EXACERBATION OF EXTRAPULMONARY SEPSIS-INDUCED LUNG INJURY BY MECHANICAL VENTILATION. Shock 2025; 63:299-311. [PMID: 39228020 DOI: 10.1097/shk.0000000000002471] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/05/2024]
Abstract
ABSTRACT Background: Mechanical ventilation (MV) is a clinically important measure for respiratory support in critically ill patients. Although moderate tidal volume MV does not cause lung injury, it can further exacerbate lung injury in a pathological state such as sepsis. This pathological process is known as the "two-hit" theory, whereby an initial lung injury (e.g., infection, trauma, or sepsis) triggers an inflammatory response that activates immune cells, presenting the lung tissue in a fragile state and rendering it more susceptible to subsequent injury. The second hit occurs when MV is applied to lung tissue in a fragile state, and it is noteworthy that this MV is harmless to healthy lung tissue, further aggravating preexisting lung injury through unknown mechanisms. This interaction between initial injury and subsequent MV develops a malignant cycle significantly exacerbating lung injury and severely hampering patient prognosis. The two-hit theory is critical to understanding the complicated mechanisms of ventilator-associated lung injury and facilitates the subsequent development of targeted therapeutic strategies. Methods and Results: The cecum ligation and perforation mice model was used to mimic clinical sepsis patients. After 12 h, the mice were mechanically ventilated for 2 to 6 h. MV by itself did not lead to HMGB1 release, but significantly strengthened HMGB1 in plasma and cytoplasm of lung tissue in septic mice. Plasma and lung tissue activation of cytokines and chemokines, mitogen-activated protein kinase signaling pathway, neutrophil recruitment, and acute lung injury were progressively decreased in LysM HMGB1 -/- (Hmgb1 deletion in myeloid cells) and iHMGB1 -/- mice (inducible HMGB1 -/- mouse strain where the Hmgb1 gene was globally deleted after tamoxifen treatment). Compared with C57BL/6 mice, although EC-HMGB1 -/- (Hmgb1 deletion in endothelial cells) mice did not have lower levels of inflammation, neutrophil recruitment and lung injury were reduced. Compared with LysM HMGB1 -/- mice, EC-HMGB1 -/- mice had higher levels of inflammation but significantly lower neutrophil recruitment and lung injury. Overall, iHMGB1 -/- mice had the lowest levels of all the above indicators. The level of inflammation, neutrophil recruitment, and the degree of lung injury were decreased in RAGE -/- mice, and even the above indices were further decreased in TLR4/RAGE -/- mice. Levels of inflammation and neutrophil recruitment were decreased in caspase-11 -/- and caspase-1/11 -/- mice, but there was no statistical difference between these two gene knockout mice. Conclusions: These data show for the first time that the caspase-1/caspase-11-HMGB1-TLR4/RAGE signaling pathway plays a key role in mice model of sepsis-induced lung injury exacerbated by MV. Different species of HMGB1 knockout mice have different lung-protective mechanisms in the two-hit model, and location is the key to function. Specifically, LysM HMGB1 -/- mice due to the deletion of HMGB1 in myeloid cells resulted in a pulmonary-protective mechanism that was associated with a downregulation of the inflammatory response. EC-HMGB1 -/- mice are deficient in HMGB1 owing to endothelial cells, resulting in a distinct pulmonary-protective mechanism independent of the inflammatory response and more relevant to the improvement of alveolar-capillary permeability. iHMGB1 -/- mice, which are systemically HMGB1-deficient, share both of these lung-protective mechanisms.
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Affiliation(s)
| | | | - Weitian Tian
- Department of Anesthesiology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Yizhe Zhang
- Department of Anesthesiology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | | | - Tong Zhang
- Department of Anesthesiology, Shanghai Pulmonary Hospital, Tongji University, Shanghai, China
| | - Zhixia Chen
- Department of Anesthesiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China
| | - Fangfang Niu
- Department of Anesthesiology, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Quan Li
- Department of Anesthesiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China
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Ding N, Xiao H, Zhen L, Li H, Zhang Z, Ge J. Imp7 siRNA nanoparticles protect against mechanical ventilation-associated liver injury by inhibiting HMGB1 production and NETs formation. Biochim Biophys Acta Mol Basis Dis 2024; 1870:167085. [PMID: 38369216 DOI: 10.1016/j.bbadis.2024.167085] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Revised: 01/16/2024] [Accepted: 02/15/2024] [Indexed: 02/20/2024]
Abstract
Mechanical ventilation (MV) has the potential to induce extra-pulmonary organ damage by adversely affecting the lungs and promoting the secretion of inflammatory cytokines. High-mobility group box 1 protein (HMGB1) is a pro-inflammatory mediator in ventilator-induced lung injury (VILI), but its effect on MV-associated liver injury and the mechanisms are poorly understood. In the present study, mice were subjected to high-volume MV (20 ml/kg) to induce VILI. MV-induced HMGB1 prompted neutrophil extracellular traps (NETs) formation and PANoptosis within the liver. Inhibiting NETs formation by DNase I or PAD4 inhibitor, or by HMGB1 neutralizing ameliorated the liver injury. HMGB1 activated neutrophils to form NETs through TLR4/MyD88/TRAF6 pathway. Importantly, Importin7 siRNA nanoparticles inhibited HMGB1 release and protected against MV-associated liver injury. These data provide evidence of MV-induced HMGB1 prompted NETs formation and PANoptosis in the liver via the TLR4/MyD88/TRAF6 pathway. HMGB1 is a potential therapeutic target for MV-associated liver injury.
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Affiliation(s)
- Ning Ding
- Department of Anesthesiology, Shandong Provincial Third Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250031, China; Shandong Provincial Key Medical and Health Laboratory of Intensive Care Rehabilitation, Shandong Provincial Third Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250031, China.
| | - Hui Xiao
- Shandong Provincial Key Medical and Health Laboratory of Intensive Care Rehabilitation, Shandong Provincial Third Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250031, China
| | - Lixiao Zhen
- Shandong Provincial Key Medical and Health Laboratory of Intensive Care Rehabilitation, Shandong Provincial Third Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250031, China
| | - Huiqing Li
- Department of Anesthesiology, Shandong Provincial Third Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250031, China; Shandong Provincial Key Medical and Health Laboratory of Intensive Care Rehabilitation, Shandong Provincial Third Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250031, China
| | - Zengzhen Zhang
- Department of Anesthesiology, Shandong Provincial Third Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250031, China; Shandong Provincial Key Medical and Health Laboratory of Intensive Care Rehabilitation, Shandong Provincial Third Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250031, China
| | - Junke Ge
- Shandong Provincial Key Medical and Health Laboratory of Intensive Care Rehabilitation, Shandong Provincial Third Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250031, China; Department of Intensive Care Medicine, Shandong Provincial Third Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250031, China
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Delrue C, Speeckaert R, Delanghe JR, Speeckaert MM. Breath of fresh air: Investigating the link between AGEs, sRAGE, and lung diseases. VITAMINS AND HORMONES 2024; 125:311-365. [PMID: 38997169 DOI: 10.1016/bs.vh.2024.01.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/14/2024]
Abstract
Advanced glycation end products (AGEs) are compounds formed via non-enzymatic reactions between reducing sugars and amino acids or proteins. AGEs can accumulate in various tissues and organs and have been implicated in the development and progression of various diseases, including lung diseases. The receptor of advanced glycation end products (RAGE) is a receptor that can bind to advanced AGEs and induce several cellular processes such as inflammation and oxidative stress. Several studies have shown that both AGEs and RAGE play a role in the pathogenesis of lung diseases, such as chronic obstructive pulmonary disease, asthma, idiopathic pulmonary fibrosis, cystic fibrosis, and acute lung injury. Moreover, the soluble form of the receptor for advanced glycation end products (sRAGE) has demonstrated its ability to function as a decoy receptor, possessing beneficial characteristics such as anti-inflammatory, antioxidant, and anti-fibrotic properties. These qualities make it an encouraging focus for therapeutic intervention in managing pulmonary disorders. This review highlights the current understanding of the roles of AGEs and (s)RAGE in pulmonary diseases and their potential as biomarkers and therapeutic targets for preventing and treating these pathologies.
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Affiliation(s)
- Charlotte Delrue
- Department of Nephrology, Ghent University Hospital, Ghent, Belgium
| | | | - Joris R Delanghe
- Department of Diagnostic Sciences, Ghent University, Ghent, Belgium
| | - Marijn M Speeckaert
- Department of Nephrology, Ghent University Hospital, Ghent, Belgium; Research Foundation-Flanders (FWO), Brussels, Belgium.
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Liu X, Qian N, Zhu L, Fan L, Fu G, Ma M, Bao J, Cao C, Liang X. Geniposide ameliorates acute kidney injury via enhancing the phagocytic ability of macrophages towards neutrophil extracellular traps. Eur J Pharmacol 2023; 957:176018. [PMID: 37634840 DOI: 10.1016/j.ejphar.2023.176018] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2023] [Revised: 08/22/2023] [Accepted: 08/24/2023] [Indexed: 08/29/2023]
Abstract
Acute kidney injury (AKI) is a clinically serious disorder associated with high mortality rates and an increased risk of progression to end-stage renal disease. As an essential supportive treatment for patients with respiratory failure, mechanical ventilation not only save many critically ill patients, but also affect glomerular filtration function by changing renal hemodynamics, neurohumoral and positive end-expiratory pressure, eventually leading to AKI. AMP-activated protein kinase (AMPK), a crucial energy homeostasis regulator, could enhance macrophage phagocytic ability and inhibit inflammation, but whether it can engulf neutrophil extracellular traps (NETs) and alleviate mechanical ventilation-associated AKI is still unclear. In this study, we found that geniposide significantly ameliorated histopathological damage, reduced serum Cre and BUN levels. Besides, geniposide can also induce AMPK activation and enhance macrophage phagocytic ability toward NETs. Moreover, geniposide can markedly reduce the levels of high mobility group box 1 (HMGB1), and these effects were dependent on AMPK-PI3K/Akt signaling. Altogether, these results indicated that geniposide promoted macrophage efferocytosis by inducing AMPK-PI3K/Akt signaling activation, clearing NETs and ameliorating AKI.
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Affiliation(s)
- Xiaodong Liu
- Department of Nephrology, Sir Run Run Hospital, Nanjing Medical University, Nanjing, 211100, Jiangsu, China; The Second People's Hospital of Lianyungang, Affiliated to Kangda College of Nanjing Medical University, Lianyungang, 222006, Jiangsu, China
| | - Na Qian
- The Second People's Hospital of Lianyungang, Affiliated to Kangda College of Nanjing Medical University, Lianyungang, 222006, Jiangsu, China
| | - Li Zhu
- Department of Nephrology, Sir Run Run Hospital, Nanjing Medical University, Nanjing, 211100, Jiangsu, China
| | - Li Fan
- Department of Nephrology, Sir Run Run Hospital, Nanjing Medical University, Nanjing, 211100, Jiangsu, China; Department of Nephrology, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, Jiangsu, China
| | - Guanghao Fu
- The Second People's Hospital of Lianyungang, Affiliated to Kangda College of Nanjing Medical University, Lianyungang, 222006, Jiangsu, China
| | - Mengqing Ma
- Department of Nephrology, Sir Run Run Hospital, Nanjing Medical University, Nanjing, 211100, Jiangsu, China
| | - Jiaxin Bao
- Department of Nephrology, Sir Run Run Hospital, Nanjing Medical University, Nanjing, 211100, Jiangsu, China
| | - Changchun Cao
- Department of Nephrology, Sir Run Run Hospital, Nanjing Medical University, Nanjing, 211100, Jiangsu, China.
| | - Xiubin Liang
- Department of Pathophysiology, Nanjing Medical University, Nanjing, 211166, Jiangsu, China.
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Yamaguchi K, Iwamoto H, Sakamoto S, Horimasu Y, Masuda T, Miyamoto S, Nakashima T, Fujitaka K, Hamada H, Hattori N. Association of the RAGE/RAGE-ligand axis with interstitial lung disease and its acute exacerbation. Respir Investig 2022; 60:531-542. [PMID: 35504814 DOI: 10.1016/j.resinv.2022.04.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 03/10/2022] [Accepted: 04/12/2022] [Indexed: 06/14/2023]
Abstract
The receptor for advanced glycation end product (RAGE) is a transmembrane receptor highly expressed in type 1 pneumocytes of healthy lungs. RAGE is considered to play a homeostatic role in the lung, as RAGE knockout mice develop lung fibrosis as they age. In contrast, RAGE can bind numerous ligands, including high-mobility group box 1 (HMGB1). These interactions initiate pro-inflammatory signaling associated with the pathogenesis of lung injury and interstitial lung disease (ILD), including idiopathic pulmonary fibrosis (IPF). ILD is a broad category of diffuse parenchymal lung disease characterized by various extents of lung fibrosis and inflammation, and IPF is a common and progressive ILD of unknown cause. The prognosis of patients with IPF is poor, and acute exacerbation of IPF (AE-IPF) is one of the main causes of death. Recent reports indicate that acute exacerbations can occur in other ILDs (AE-ILD). Notably, ILD is frequently observed in patients with lung cancer, and AE-ILD after surgical procedures or the initiation of chemotherapy for concomitant lung cancer are clinically important due to their association with increased mortality. In this review, we summarize the associations of RAGE/soluble RAGE (sRAGE)/RAGE ligands with the pathogenesis and clinical course of ILD, including IPF and AE-IPF. Additionally, the potential use of sRAGE and RAGE ligands as predictive markers of AE-IPF and cancer treatment-triggered AE-ILD is also discussed.
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Affiliation(s)
- Kakuhiro Yamaguchi
- Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, 734-8551, Hiroshima, Japan.
| | - Hiroshi Iwamoto
- Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, 734-8551, Hiroshima, Japan
| | - Shinjiro Sakamoto
- Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, 734-8551, Hiroshima, Japan
| | - Yasushi Horimasu
- Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, 734-8551, Hiroshima, Japan
| | - Takeshi Masuda
- Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, 734-8551, Hiroshima, Japan
| | - Shintaro Miyamoto
- Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, 734-8551, Hiroshima, Japan
| | - Taku Nakashima
- Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, 734-8551, Hiroshima, Japan
| | - Kazunori Fujitaka
- Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, 734-8551, Hiroshima, Japan
| | - Hironobu Hamada
- Department of Physical Analysis and Therapeutic Sciences, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Noboru Hattori
- Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, 734-8551, Hiroshima, Japan
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Yu S, Qian L, Ma J. Genetic alterations, RNA expression profiling and DNA methylation of HMGB1 in malignancies. J Cell Mol Med 2022; 26:4322-4332. [PMID: 35765707 PMCID: PMC9344825 DOI: 10.1111/jcmm.17454] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 05/31/2022] [Accepted: 06/07/2022] [Indexed: 11/27/2022] Open
Abstract
The high mobility group box 1 (HMGB1) is a potential biomarker and therapeutic target in various human diseases. However, a systematic, comprehensive pan‐cancer analysis of HMGB1 in human cancers remains to be reported. This study analysed the genetic alteration, RNA expression profiling and DNA methylation of HMGB1 in more than 30 types of tumours. It is worth noting that HMGB1 is overexpressed in malignant tissues, including lymphoid neoplasm diffuse large B‐cell lymphoma (DLBC), pancreatic adenocarcinoma (PAAD) and thymoma (THYM). Interestingly, there is a positive correlation between the high expression of HMGB1 and the high survival prognosis of THYM. Finally, this study comprehensively evaluates the genetic variation of HMGB1 in human malignant tumours. As a prospective biomarker of COVID‐19, the role that HMGB1 plays in THYM is highlighted.
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Affiliation(s)
- Shoukai Yu
- Hongqiao International Institue of Medicine & Clinical Research Center, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lingmei Qian
- Hongqiao International Institue of Medicine & Clinical Research Center, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jun Ma
- Hongqiao International Institue of Medicine & Clinical Research Center, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Neutrophils and Asthma. Diagnostics (Basel) 2022; 12:diagnostics12051175. [PMID: 35626330 PMCID: PMC9140072 DOI: 10.3390/diagnostics12051175] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Revised: 05/04/2022] [Accepted: 05/05/2022] [Indexed: 02/04/2023] Open
Abstract
Although eosinophilic inflammation is characteristic of asthma pathogenesis, neutrophilic inflammation is also marked, and eosinophils and neutrophils can coexist in some cases. Based on the proportion of sputum cell differentiation, asthma is classified into eosinophilic asthma, neutrophilic asthma, neutrophilic and eosinophilic asthma, and paucigranulocytic asthma. Classification by bronchoalveolar lavage is also performed. Eosinophilic asthma accounts for most severe asthma cases, but neutrophilic asthma or a mixture of the two types can also present a severe phenotype. Biomarkers for the diagnosis of neutrophilic asthma include sputum neutrophils, blood neutrophils, chitinase-3-like protein, and hydrogen sulfide in sputum and serum. Thymic stromal lymphoprotein (TSLP)/T-helper 17 pathways, bacterial colonization/microbiome, neutrophil extracellular traps, and activation of nucleotide-binding oligomerization domain-like receptor family, pyrin domain-containing 3 pathways are involved in the pathophysiology of neutrophilic asthma and coexistence of obesity, gastroesophageal reflux disease, and habitual cigarette smoking have been associated with its pathogenesis. Thus, targeting neutrophilic asthma is important. Smoking cessation, neutrophil-targeting treatments, and biologics have been tested as treatments for severe asthma, but most clinical studies have not focused on neutrophilic asthma. Phosphodiesterase inhibitors, anti-TSLP antibodies, azithromycin, and anti-cholinergic agents are promising drugs for neutrophilic asthma. However, clinical research targeting neutrophilic inflammation is required to elucidate the optimal treatment.
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Zhu CJ, Yang WG, Li DJ, Song YD, Chen SY, Wang QF, Liu YN, Zhang Y, Cheng B, Wu ZW, Cui ZC. Calycosin attenuates severe acute pancreatitis-associated acute lung injury by curtailing high mobility group box 1 - induced inflammation. World J Gastroenterol 2021; 27:7669-7686. [PMID: 34908806 PMCID: PMC8641048 DOI: 10.3748/wjg.v27.i44.7669] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 07/09/2021] [Accepted: 09/10/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Acute lung injury (ALI) is a common and life-threatening complication of severe acute pancreatitis (SAP). There are currently limited effective treatment options for SAP and associated ALI. Calycosin (Cal), a bioactive constituent extracted from the medicinal herb Radix Astragali exhibits potent anti-inflammatory properties, but its effect on SAP and associated ALI has yet to be determined.
AIM To identify the roles of Cal in SAP-ALI and the underlying mechanism.
METHODS SAP was induced via two intraperitoneal injections of L-arg (4 g/kg) and Cal (25 or 50 mg/kg) were injected 1 h prior to the first L-arg challenge. Mice were sacrificed 72 h after the induction of SAP and associated ALI was examined histologically and biochemically. An in vitro model of lipopolysaccharide (LPS)-induced ALI was established using A549 cells. Immunofluorescence analysis and western blot were evaluated in cells. Molecular docking analyses were conducted to examine the interaction of Cal with HMGB1.
RESULTS Cal treatment substantially reduced the serum amylase levels and alleviated histopathological injury associated with SAP and ALI. Neutrophil infiltration and lung tissue levels of neutrophil mediator myeloperoxidase were reduced in line with protective effects of Cal against ALI in SAP. Cal treatment also attenuated the serum levels and mRNA expression of pro-inflammatory cytokines tumor necrosis factor-α, interleukin-6, IL-1β, HMGB1 and chemokine (CXC motif) ligand 1 in lung tissue. Immunofluorescence and western blot analyses showed that Cal treatment markedly suppressed the expression of HMGB1 and phosphorylated nuclear factor-kappa B (NF-κB) p65 in lung tissues and an in vitro model of LPS-induced ALI in A549 cells suggesting a role for HGMB1 in the pathogenesis of ALI. Furthermore, molecular docking analysis provided evidence for the direct interaction of Cal with HGMB1.
CONCLUSION Cal protects mice against L-arg-induced SAP and associated ALI by attenuating local and systemic neutrophil infiltration and inflammatory response via inhibition of HGMB1 and the NF-κB signaling pathway.
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Affiliation(s)
- Chang-Ju Zhu
- Henan Medical Key Laboratory of Emergency and Trauma Research, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
- Key Laboratory of Hepatobiliary and Pancreatic Surgery and Digestive Organ Transplantation of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Wan-Guang Yang
- Henan Medical Key Laboratory of Emergency and Trauma Research, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
- Key Laboratory of Hepatobiliary and Pancreatic Surgery and Digestive Organ Transplantation of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - De-Jian Li
- Henan Medical Key Laboratory of Emergency and Trauma Research, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
- Key Laboratory of Hepatobiliary and Pancreatic Surgery and Digestive Organ Transplantation of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Yao-Dong Song
- Henan Medical Key Laboratory of Emergency and Trauma Research, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - San-Yang Chen
- Henan Medical Key Laboratory of Emergency and Trauma Research, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
- Key Laboratory of Hepatobiliary and Pancreatic Surgery and Digestive Organ Transplantation of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Qiao-Fang Wang
- Henan Medical Key Laboratory of Emergency and Trauma Research, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
- Key Laboratory of Hepatobiliary and Pancreatic Surgery and Digestive Organ Transplantation of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Yan-Na Liu
- Henan Medical Key Laboratory of Emergency and Trauma Research, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
- Key Laboratory of Hepatobiliary and Pancreatic Surgery and Digestive Organ Transplantation of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Yan Zhang
- Henan Medical Key Laboratory of Emergency and Trauma Research, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Bo Cheng
- Henan Medical Key Laboratory of Emergency and Trauma Research, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Zhong-Wei Wu
- Henan Medical Key Laboratory of Emergency and Trauma Research, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Zong-Chao Cui
- Henan Medical Key Laboratory of Emergency and Trauma Research, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
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Lai Y, Huang Y. Mechanisms of Mechanical Force Induced Pulmonary Vascular Endothelial Hyperpermeability. Front Physiol 2021; 12:714064. [PMID: 34671268 PMCID: PMC8521004 DOI: 10.3389/fphys.2021.714064] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Accepted: 08/30/2021] [Indexed: 12/27/2022] Open
Abstract
Mechanical ventilation is a supportive therapy for patients with acute respiratory distress syndrome (ARDS). However, it also inevitably produces or aggravates the original lung injury with pathophysiological changes of pulmonary edema caused by increased permeability of alveolar capillaries which composed of microvascular endothelium, alveolar epithelium, and basement membrane. Vascular endothelium forms a semi-selective barrier to regulate body fluid balance. Mechanical ventilation in critically ill patients produces a mechanical force on lung vascular endothelium when the endothelial barrier was destructed. This review aims to provide a comprehensive overview of molecular and signaling mechanisms underlying the endothelial barrier permeability in ventilator-induced lung jury (VILI).
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Affiliation(s)
- Yan Lai
- State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Department of Critical Care Medicine, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Yongbo Huang
- State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Department of Critical Care Medicine, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
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Sekiya Y, Shimada K, Takahashi H, Kuga C, Komachi S, Miwa K, Kotani T. Evaluation of a simultaneous adsorption device for cytokines and platelet-neutrophil complexes in vitro and in a rabbit acute lung injury model. Intensive Care Med Exp 2021; 9:49. [PMID: 34568985 PMCID: PMC8473513 DOI: 10.1186/s40635-021-00414-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Accepted: 08/29/2021] [Indexed: 11/21/2022] Open
Abstract
Background Platelet–neutrophil complexes (PNCs) readily migrate into tissues and induce tissue damage via cytokine or other pathogenic factors release. These actions are involved in onset and progression of acute respiratory distress syndrome (ARDS). Thus, simultaneous removal of cytokines and activated neutrophils, including PNCs by blood purification may prevent development of ARDS and enhance drug effects. The goal of this study was to examine the effect of a newly developed adsorption column (NOA-001) that eliminates cytokines and activated neutrophils in a lung injury model. Results Adsorption of cytokines, such as IL-8, IL-6 and HMGB-1, and PNCs was first measured in vitro. Lung injury was induced by HCl and lipopolysaccharide intratracheal infusion in rabbits ventilated at a low tidal volume (7–8 mL/kg) and PEEP (2.5 cmH2O) for lung protection. Arterial blood gas, hematologic values, plasma IL-8, blood pressure and heart rate were measured, and lung damage was evaluated histopathologically in animals treated with 8-h direct hemoperfusion with or without use of NOA-001. The in vitro adsorption rates for IL-8, IL-6, HMGB-1, activated granulocytes and PNCs were 99.5 (99.4–99.5)%, 63.9 (63.4–63.9)%, 57.6 (57.4–62.1)%, 9.9 (-4.4–21.3)% and 60.9 (49.0–67.6)%, respectively. Absorption of PNCs onto fibers was confirmed microscopically. These adsorption effects were associated with several improvements in the rabbit model. In respiratory function, the PaO2/FIO2 ratios at 8 h were 314 ± 55 mmHg in the NOA-001 group and 134 ± 41 mmHg in the sham group. The oxygenation index and PaCO2 at 8 h were 9.6 ± 3.1 and 57.0 ± 9.6 mmHg in the sham group and 3.0 ± 0.8 and 40.4 ± 4.5 mmHg in the NOA-001 group, respectively (p < 0.05). Blood pH at 8 h reached 7.18 ± 0.06 in the sham group, but was maintained at 7.36 ± 0.03 (within the normal range) in the NOA-001 group (p < 0.05). In lung histopathology, fewer hyaline membrane and inflammatory cells were observed in the NOA-001 group. Conclusion A column for simultaneous removal of cytokines and PNCs showed efficacy for improvement of pulmonary function in an animal model. This column may be effective in support of treatment of ARDS. Supplementary Information The online version contains supplementary material available at 10.1186/s40635-021-00414-7.
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Affiliation(s)
- Yumiko Sekiya
- Medical Devices & Materials Research Lab., Advanced Materials Research Labs., Toray Industries, Inc., Shiga, Japan.
| | - Kaoru Shimada
- Medical Devices & Materials Research Lab., Advanced Materials Research Labs., Toray Industries, Inc., Shiga, Japan
| | - Hiroshi Takahashi
- Medical Devices & Materials Research Lab., Advanced Materials Research Labs., Toray Industries, Inc., Shiga, Japan
| | - Chisa Kuga
- Medical Devices & Materials Research Lab., Advanced Materials Research Labs., Toray Industries, Inc., Shiga, Japan
| | - Shunsuke Komachi
- Medical Devices & Materials Research Lab., Advanced Materials Research Labs., Toray Industries, Inc., Shiga, Japan
| | - Keishi Miwa
- Medical Devices & Materials Research Lab., Advanced Materials Research Labs., Toray Industries, Inc., Shiga, Japan
| | - Toru Kotani
- Department of Intensive Care Medicine, Showa University School of Medicine, Tokyo, Japan
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11
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Predictive role of circulatory HMGB1 in postoperative acute exacerbation of interstitial lung disease in lung cancer patients. Sci Rep 2021; 11:10105. [PMID: 33980944 PMCID: PMC8115343 DOI: 10.1038/s41598-021-89663-w] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Accepted: 04/29/2021] [Indexed: 12/25/2022] Open
Abstract
Postoperative acute exacerbation of interstitial lung disease (AE-ILD) can be fatal in patients with lung cancer concomitant with ILD. We aimed to elucidate the predictive potential of high-mobility group box 1 (HMGB1), which is associated with the development and severity of lung injury, for evaluating the risk of this complication. We included 152 patients with lung cancer and ILD who underwent radical surgery between January 2011 and August 2019. We evaluated the preoperative levels of serum HMGB1 and its predictive potential for postoperative AE-ILD. Postoperative AE-ILD developed in 17 patients. Serum levels of HMGB1 were significantly higher in patients with postoperative AE-ILD than in those without (median [interquartile range]: 5.39 [3.29–11.70] ng/mL vs. 3.55 [2.07–5.62] ng/mL). Univariate and multivariate logistic regression analyses revealed that higher HMGB1 levels were significantly associated with the development of postoperative AE-ILD in entire studied patients (n = 152). In the subgroup analysis, higher HMGB1 levels were associated with a significantly increased risk of this complication in patients who underwent lobectomy (n = 77) than in those who underwent sublobar resection (n = 75). Serum HMGB1 could be a promising marker for evaluating the risk of postoperative AE-ILD, specifically in patients who underwent lobectomy.
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12
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Monjezi M, Jamaati H, Noorbakhsh F. Attenuation of ventilator-induced lung injury through suppressing the pro-inflammatory signaling pathways: A review on preclinical studies. Mol Immunol 2021; 135:127-136. [PMID: 33895577 DOI: 10.1016/j.molimm.2021.04.007] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Revised: 03/28/2021] [Accepted: 04/06/2021] [Indexed: 10/21/2022]
Abstract
Mechanical ventilation (MV) is a relatively common medical intervention in ICU patients. The main side effect of MV is the so-called "ventilator-induced lung injury" (VILI). The pathogenesis of VILI is not completely understood; however, it has been reported that MV might be associated with up-regulation of various inflammatory mediators within the lung tissue and that these mediators might act as pathogenic factors in lung tissue injury. One potential mechanism for the generation of inflammatory mediators is through the release of endogenous molecules known as damage associated molecular patterns (DAMPs). These molecules are released from injured tissues and can bind to pattern recognition receptors (PRRs). PRR activation generally leads to the production and release of inflammation-related molecules including innate immune cytokines and chemokines. It has been suggested that blocking DAMP/PRR signaling pathways might diminish the progression of VILI. Herein, we review the latest findings with regard to the effects of DAMP/PRRs and their blockade, as well as the potential therapeutic targets and future research directions in VILI. Results of studies performed on human samples, animal models of disease, as well as relevant in vitro systems will be discussed.
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Affiliation(s)
- Mojdeh Monjezi
- Chronic Respiratory Diseases Research Center (CRDRC), National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hamidreza Jamaati
- Chronic Respiratory Diseases Research Center (CRDRC), National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Farshid Noorbakhsh
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
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Li B, Peng X, Li H, Chen F, Chen Y, Zhang Y, Le K. The performance of the alarmin HMGB1 in pediatric diseases: From lab to clinic. Immun Inflamm Dis 2021; 9:8-30. [PMID: 33140586 PMCID: PMC7860603 DOI: 10.1002/iid3.370] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Revised: 10/10/2020] [Accepted: 10/21/2020] [Indexed: 12/13/2022] Open
Abstract
INTRODUCTION The ubiquitously expressed nonhistone nuclear protein high-mobility group box protein 1 (HMGB1) has different functions related to posttranslational modifications and cellular localization. In the nucleus, HMGB1 modulates gene transcription, replication and DNA repair as well as determines chromosomal architecture. When the post-transcriptional modified HMGB1 is released into the extracellular space, it triggers several physiological and pathological responses and initiates innate immunity through interacting with its reciprocal receptors (i.e., TLR4/2 and RAGE). The effect of HMGB1-mediated inflammatory activation on different systems has received increasing attention. HMGB1 is now considered to be an alarmin and participates in multiple inflammation-related diseases. In addition, HMGB1 also affects the occurrence and progression of tumors. However, most studies involving HMGB1 have been focused on adults or mature animals. Due to differences in disease characteristics between children and adults, it is necessary to clarify the role of HMGB1 in pediatric diseases. METHODS AND RESULTS Through systematic database retrieval, this review aimed to first elaborate the characteristics of HMGB1 under physiological and pathological conditions and then discuss the clinical significance of HMGB1 in the pediatric diseases according to different systems. CONCLUSIONS HMGB1 plays an important role in a variety of pediatric diseases and may be used as a diagnostic biomarker and therapeutic target for new strategies for the prevention and treatment of pediatric diseases.
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Affiliation(s)
- Bo Li
- Department of CardiologyChildren's Hospital of Hebei Province Affiliated to Hebei Medical UniversityShijiazhuangHebeiChina
| | - Xin Peng
- Department of OtolaryngologyThe Affiliated Children's Hospital of Nanchang UniversityNanchangJiangxiChina
| | - He Li
- Department of Urology SurgeryQilu Children's Hospital of Shandong UniversityJinanShandongChina
| | - Fei Chen
- Department of Child Health CareQilu Children's Hospital of Shandong UniversityJinanShandongChina
| | - Yuxia Chen
- Ministry of Education Key Laboratory of Child Development and Disorders, and Chongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory Disorders, and Rehabilitation Centre, Children's HospitalChongqing Medical UniversityChongqingYuzhongChina
| | - Yingqian Zhang
- Department of CardiologyChildren's Hospital of Hebei Province Affiliated to Hebei Medical UniversityShijiazhuangHebeiChina
| | - Kai Le
- Department of Rehabilitation MedicineThe First Affiliated Hospital of Nanchang UniversityNanchangJiangxiChina
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14
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Sitapara RA, Gauthier AG, Patel VS, Lin M, Zur M, Ashby CR, Mantell LL. The α7 nicotinic acetylcholine receptor agonist GTS-21 improves bacterial clearance in mice by restoring hyperoxia-compromised macrophage function. Mol Med 2020; 26:98. [PMID: 33126860 PMCID: PMC7596622 DOI: 10.1186/s10020-020-00224-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2020] [Accepted: 10/07/2020] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Mechanical ventilation, in combination with supraphysiological concentrations of oxygen (i.e., hyperoxia), is routinely used to treat patients with respiratory distress, such as COVID-19. However, prolonged exposure to hyperoxia compromises the clearance of invading pathogens by impairing macrophage phagocytosis. Previously, we have shown that the exposure of mice to hyperoxia induces the release of the nuclear protein high mobility group box-1 (HMGB1) into the pulmonary airways. Furthermore, extracellular HMGB1 impairs macrophage phagocytosis and increases the mortality of mice infected with Pseudomonas aeruginosa (PA). The aim of this study was to determine whether GTS-21 (3-(2,4-dimethoxybenzylidene) anabaseine), an α7 nicotinic acetylcholine receptor (α7nAChR) agonist, could (1) inhibit hyperoxia-induced HMGB1 release into the airways; (2) enhance macrophage phagocytosis and (3) increase bacterial clearance from the lungs in a mouse model of ventilator-associated pneumonia. METHOD GTS-21 (0.04, 0.4, and 4 mg/kg) or saline were administered by intraperitoneal injection to mice that were exposed to hyperoxia (≥ 99% O2) and subsequently challenged with PA. RESULTS The systemic administration of 4 mg/kg i.p. of GTS-21 significantly increased bacterial clearance, decreased acute lung injury and decreased accumulation of airway HMGB1 compared to the saline control. To determine the mechanism of action of GTS-21, RAW 264.7 cells, a macrophage-like cell line, were incubated with different concentrations of GTS-21 in the presence of 95% O2. The phagocytic activity of macrophages was significantly increased by GTS-21 in a dose-dependent manner. In addition, GTS-21 significantly inhibited the cytoplasmic translocation and release of HMGB1 from RAW 264.7 cells and attenuated hyperoxia-induced NF-κB activation in macrophages and mouse lungs exposed to hyperoxia and infected with PA. CONCLUSIONS Our results indicate that GTS-21 is efficacious in improving bacterial clearance and reducing acute lung injury via enhancing macrophage function by inhibiting the release of nuclear HMGB1. Therefore, the α7nAChR represents a possible pharmacological target to improve the clinical outcome of patients on ventilators by augmenting host defense against bacterial infections.
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Affiliation(s)
- Ravikumar A Sitapara
- Department of Pharmaceutical Sciences, St. John's University College of Pharmacy and Health Sciences, 8000 Utopia Parkway, Queens, NY, 11439, USA
| | - Alex G Gauthier
- Department of Pharmaceutical Sciences, St. John's University College of Pharmacy and Health Sciences, 8000 Utopia Parkway, Queens, NY, 11439, USA
| | - Vivek S Patel
- Department of Pharmaceutical Sciences, St. John's University College of Pharmacy and Health Sciences, 8000 Utopia Parkway, Queens, NY, 11439, USA
| | - Mosi Lin
- Department of Pharmaceutical Sciences, St. John's University College of Pharmacy and Health Sciences, 8000 Utopia Parkway, Queens, NY, 11439, USA
| | - Michelle Zur
- Department of Pharmaceutical Sciences, St. John's University College of Pharmacy and Health Sciences, 8000 Utopia Parkway, Queens, NY, 11439, USA
| | - Charles R Ashby
- Department of Pharmaceutical Sciences, St. John's University College of Pharmacy and Health Sciences, 8000 Utopia Parkway, Queens, NY, 11439, USA
| | - Lin L Mantell
- Department of Pharmaceutical Sciences, St. John's University College of Pharmacy and Health Sciences, 8000 Utopia Parkway, Queens, NY, 11439, USA. .,The Feinstein Institute for Medical Research, Northwell Health System, Manhasset, NY, 11030, USA.
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15
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Kurokawa C, Araújo Júnior J, Pires R, Carpi M, Moraes M, Medeiros L, Fioretto J. HMGB1 and inflammatory cytokines in experimental acute lung injury induced in rabbits. ARQ BRAS MED VET ZOO 2020. [DOI: 10.1590/1678-4162-11499] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
ABSTRACT The aim of this work was to measure HMGB1, TNF-alpha, and IL-8 in bronchoalveolar lavage (BAL), serum and TLR2 and TLR4mRNA expression in lung tissue of rabbits with two grades of acute lung injury (ALI). The animals were randomly assigned to groups with severe (S) and mild/moderate (MM) ALI, induced with warm saline, and a control group. HMGB1, TNF-alpha, IL-8, TLR2mRNA and TLR4mRNA were measured after ALI induction. The results showed increased levels of IL-8, TNF-alpha, HMGB1 and TLR4mRNA in the ALI groups. HMGB1, IL-8 and TNF-alpha concentrations in BAL were higher in S compared MM. Increased TLR4mRNA was observed in S and MM versus control. The results suggest an early participation of HMGB1 in ALI together with IL-8 and TNF-alpha and association with severity. TLR4 has early expression and role in ALI pathophysiology but is not associated with severity.
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16
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Relja B, Land WG. Damage-associated molecular patterns in trauma. Eur J Trauma Emerg Surg 2020; 46:751-775. [PMID: 31612270 PMCID: PMC7427761 DOI: 10.1007/s00068-019-01235-w] [Citation(s) in RCA: 119] [Impact Index Per Article: 23.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2019] [Accepted: 09/27/2019] [Indexed: 12/13/2022]
Abstract
In 1994, the "danger model" argued that adaptive immune responses are driven rather by molecules released upon tissue damage than by the recognition of "strange" molecules. Thus, an alternative to the "self versus non-self recognition model" has been provided. The model, which suggests that the immune system discriminates dangerous from safe molecules, has established the basis for the future designation of damage-associated molecular patterns (DAMPs), a term that was coined by Walter G. Land, Seong, and Matzinger. The pathological importance of DAMPs is barely somewhere else evident as in the posttraumatic or post-surgical inflammation and regeneration. Since DAMPs have been identified to trigger specific immune responses and inflammation, which is not necessarily detrimental but also regenerative, it still remains difficult to describe their "friend or foe" role in the posttraumatic immunogenicity and healing process. DAMPs can be used as biomarkers to indicate and/or to monitor a disease or injury severity, but they also may serve as clinically applicable parameters for optimized indication of the timing for, i.e., secondary surgeries. While experimental studies allow the detection of these biomarkers on different levels including cellular, tissue, and circulatory milieu, this is not always easily transferable to the human situation. Thus, in this review, we focus on the recent literature dealing with the pathophysiological importance of DAMPs after traumatic injury. Since dysregulated inflammation in traumatized patients always implies disturbed resolution of inflammation, so-called model of suppressing/inhibiting inducible DAMPs (SAMPs) will be very briefly introduced. Thus, an update on this topic in the field of trauma will be provided.
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Affiliation(s)
- Borna Relja
- Experimental Radiology, Department of Radiology and Nuclear Medicine, Otto von Guericke University Magdeburg, Magdeburg, Germany.
- Department of Trauma, Hand and Reconstructive Surgery, University Hospital Frankfurt, Goethe University Frankfurt am Main, 60590, Frankfurt, Germany.
| | - Walter Gottlieb Land
- Molecular ImmunoRheumatology, INSERM UMR_S1109, Laboratory of Excellence Transplantex, University of Strasbourg, Strasbourg, France
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Sitapara RA, Gauthier AG, Valdés-Ferrer SI, Lin M, Patel V, Wang M, Martino AT, Perron JC, Ashby CR, Tracey KJ, Pavlov VA, Mantell LL. The α7 nicotinic acetylcholine receptor agonist, GTS-21, attenuates hyperoxia-induced acute inflammatory lung injury by alleviating the accumulation of HMGB1 in the airways and the circulation. Mol Med 2020; 26:63. [PMID: 32600307 PMCID: PMC7322715 DOI: 10.1186/s10020-020-00177-z] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Accepted: 04/29/2020] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND Oxygen therapy, using supraphysiological concentrations of oxygen (hyperoxia), is routinely administered to patients who require respiratory support including mechanical ventilation (MV). However, prolonged exposure to hyperoxia results in acute lung injury (ALI) and accumulation of high mobility group box 1 (HMGB1) in the airways. We previously showed that airway HMGB1 mediates hyperoxia-induced lung injury in a mouse model of ALI. Cholinergic signaling through the α7 nicotinic acetylcholine receptor (α7nAChR) attenuates several inflammatory conditions. The aim of this study was to determine whether 3-(2,4 dimethoxy-benzylidene)-anabaseine dihydrochloride, GTS-21, an α7nAChR partial agonist, inhibits hyperoxia-induced HMGB1 accumulation in the airways and circulation, and consequently attenuates inflammatory lung injury. METHODS Mice were exposed to hyperoxia (≥99% O2) for 3 days and treated concurrently with GTS-21 (0.04, 0.4 and 4 mg/kg, i.p.) or the control vehicle, saline. RESULTS The systemic administration of GTS-21 (4 mg/kg) significantly decreased levels of HMGB1 in the airways and the serum. Moreover, GTS-21 (4 mg/kg) significantly reduced hyperoxia-induced acute inflammatory lung injury, as indicated by the decreased total protein content in the airways, reduced infiltration of inflammatory monocytes/macrophages and neutrophils into the lung tissue and airways, and improved lung injury histopathology. CONCLUSIONS Our results indicate that GTS-21 can attenuate hyperoxia-induced ALI by inhibiting extracellular HMGB1-mediated inflammatory responses. This suggests that the α7nAChR represents a potential pharmacological target for the treatment regimen of oxidative inflammatory lung injury in patients receiving oxygen therapy.
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Affiliation(s)
- Ravikumar A. Sitapara
- Department of Pharmaceutical Sciences, St, College of Pharmacy and Health Sciences, St. John’s University College of Pharmacy and Health Sciences, St. Albert Hall, 8000 Utopia Parkway, Queens, New York, 11439 USA
| | - Alex G. Gauthier
- Department of Pharmaceutical Sciences, St, College of Pharmacy and Health Sciences, St. John’s University College of Pharmacy and Health Sciences, St. Albert Hall, 8000 Utopia Parkway, Queens, New York, 11439 USA
| | - Sergio I. Valdés-Ferrer
- Feinstein Institutes for Medical Research, Northwell Health System, 350 Community Drive, Manhasset, New York, 11030 USA
| | - Mosi Lin
- Department of Pharmaceutical Sciences, St, College of Pharmacy and Health Sciences, St. John’s University College of Pharmacy and Health Sciences, St. Albert Hall, 8000 Utopia Parkway, Queens, New York, 11439 USA
| | - Vivek Patel
- Department of Pharmaceutical Sciences, St, College of Pharmacy and Health Sciences, St. John’s University College of Pharmacy and Health Sciences, St. Albert Hall, 8000 Utopia Parkway, Queens, New York, 11439 USA
| | - Mao Wang
- Department of Pharmaceutical Sciences, St, College of Pharmacy and Health Sciences, St. John’s University College of Pharmacy and Health Sciences, St. Albert Hall, 8000 Utopia Parkway, Queens, New York, 11439 USA
| | - Ashley T. Martino
- Department of Pharmaceutical Sciences, St, College of Pharmacy and Health Sciences, St. John’s University College of Pharmacy and Health Sciences, St. Albert Hall, 8000 Utopia Parkway, Queens, New York, 11439 USA
| | - Jeanette C. Perron
- Department of Pharmaceutical Sciences, St, College of Pharmacy and Health Sciences, St. John’s University College of Pharmacy and Health Sciences, St. Albert Hall, 8000 Utopia Parkway, Queens, New York, 11439 USA
| | - Charles R. Ashby
- Department of Pharmaceutical Sciences, St, College of Pharmacy and Health Sciences, St. John’s University College of Pharmacy and Health Sciences, St. Albert Hall, 8000 Utopia Parkway, Queens, New York, 11439 USA
| | - Kevin J. Tracey
- Feinstein Institutes for Medical Research, Northwell Health System, 350 Community Drive, Manhasset, New York, 11030 USA
| | - Valentin A. Pavlov
- Feinstein Institutes for Medical Research, Northwell Health System, 350 Community Drive, Manhasset, New York, 11030 USA
| | - Lin L. Mantell
- Department of Pharmaceutical Sciences, St, College of Pharmacy and Health Sciences, St. John’s University College of Pharmacy and Health Sciences, St. Albert Hall, 8000 Utopia Parkway, Queens, New York, 11439 USA
- Feinstein Institutes for Medical Research, Northwell Health System, 350 Community Drive, Manhasset, New York, 11030 USA
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Wu MQ, Li C, Zhang LN, Lin J, He K, Niu YW, Che CY, Jiang N, Jiang JQ, Zhao GQ. High-mobility group box1 as an amplifier of immune response and target for treatment in Aspergillus fumigatus keratitis. Int J Ophthalmol 2020; 13:708-717. [PMID: 32420216 DOI: 10.18240/ijo.2020.05.03] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Accepted: 03/12/2020] [Indexed: 12/16/2022] Open
Abstract
AIM To determine the roles of high-mobility group box1 (HMGB1) in pro-inflammation, host immune response and its potential target for treatment in Aspergillus fumigatus (A.fumigatus) keratitis. METHODS Expression of HMGB1 was tested in C57BL/6 normal and infected corneas. Dual immunostaining tested co-expression of HMGB1 with TLR4 or LOX-1. C57BL/6 mice were pretreated with Box A or PBS and then infected. Clinical scores, polymerase chain reaction, ELISA, and MPO assay were used to assess the disease response. Flow cytometry were used to test the effect of Box A on reactive oxygen species (ROS) expression after A.fumigatus stimulation in polymorphonuclear neutrophilic leukocytes (PMN). C57BL/6 peritoneal macrophages were pretreated with Box B before A.fumigatus stimulation, and MIP-2, IL-1β, TNF-α, HMGB1 and LOX-1 were measured. Macrophages were pretreated with Box B or Box B combined with Poly(I) (an inhibitor of LOX-1) before stimulating with A.fumigatus, and MIP-2, IL-1β, TNF-α, LOX-1, p38-MAPK, p-p38-MAPK were measured. RESULTS HMGB1 levels were elevated in C57BL/6 mice after infection. HMGB1 co-expressed with TLR4, and LOX-1 in infiltrated cells. Box A vs PBS treated C57BL/6 mice had lower clinical scores and down-regulated corneal HMGB1, MIP-2, IL-1β expression and neutrophil influx. Box B treatment amplified expression of MIP-2, IL-1β, TNF-α, HMGB1 and LOX-1 that induced by A.fumigatus in macrophage. Compared to the treatment of Box B only, the protein expression of IL-1β, TNF-α showed inhibition of Box B combined with Poly(I), which also reduced the A.fumigatus-evoked protein level of LOX-1 and phosphorylation level of p38-MAPK. The production of A.fumigatus-stimulated ROS was significantly declined after Box A pretreatment in PMN. CONCLUSION Blocking HMGB1 reduces the disease response in C57BL/6 mice. HMGB1 can amplify the host immune response through p38-MAPK, and is a target for treatment of A.fumigatus keratitis.
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Affiliation(s)
- Meng-Qi Wu
- Department of Ophthalmology, the Affiliated Hospital of Qingdao University, Qingdao 266003, Shandong Province, China
| | - Cui Li
- Department of Ophthalmology, the Affiliated Hospital of Qingdao University, Qingdao 266003, Shandong Province, China
| | - Li-Na Zhang
- Department of Ophthalmology, the Affiliated Hospital of Qingdao University, Qingdao 266003, Shandong Province, China
| | - Jing Lin
- Department of Ophthalmology, the Affiliated Hospital of Qingdao University, Qingdao 266003, Shandong Province, China
| | - Kun He
- Department of Ophthalmology, the Affiliated Hospital of Qingdao University, Qingdao 266003, Shandong Province, China
| | - Ya-Wen Niu
- Department of Ophthalmology, the Affiliated Hospital of Qingdao University, Qingdao 266003, Shandong Province, China
| | - Cheng-Ye Che
- Department of Ophthalmology, the Affiliated Hospital of Qingdao University, Qingdao 266003, Shandong Province, China
| | - Nan Jiang
- Department of Ophthalmology, the Affiliated Hospital of Qingdao University, Qingdao 266003, Shandong Province, China
| | - Jia-Qian Jiang
- Department of Ophthalmology, the Affiliated Hospital of Qingdao University, Qingdao 266003, Shandong Province, China
| | - Gui-Qiu Zhao
- Department of Ophthalmology, the Affiliated Hospital of Qingdao University, Qingdao 266003, Shandong Province, China
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Andersson U, Ottestad W, Tracey KJ. Extracellular HMGB1: a therapeutic target in severe pulmonary inflammation including COVID-19? Mol Med 2020; 26:42. [PMID: 32380958 PMCID: PMC7203545 DOI: 10.1186/s10020-020-00172-4] [Citation(s) in RCA: 167] [Impact Index Per Article: 33.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Accepted: 04/23/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The 2019 novel coronavirus disease (COVID-19) causes for unresolved reasons acute respiratory distress syndrome in vulnerable individuals. There is a need to identify key pathogenic molecules in COVID-19-associated inflammation attainable to target with existing therapeutic compounds. The endogenous damage-associated molecular pattern (DAMP) molecule HMGB1 initiates inflammation via two separate pathways. Disulfide-HMGB1 triggers TLR4 receptors generating pro-inflammatory cytokine release. Extracellular HMGB1, released from dying cells or secreted by activated innate immunity cells, forms complexes with extracellular DNA, RNA and other DAMP or pathogen-associated molecular (DAMP) molecules released after lytic cell death. These complexes are endocytosed via RAGE, constitutively expressed at high levels in the lungs only, and transported to the endolysosomal system, which is disrupted by HMGB1 at high concentrations. Danger molecules thus get access to cytosolic proinflammatory receptors instigating inflammasome activation. It is conceivable that extracellular SARS-CoV-2 RNA may reach the cellular cytosol via HMGB1-assisted transfer combined with lysosome leakage. Extracellular HMGB1 generally exists in vivo bound to other molecules, including PAMPs and DAMPs. It is plausible that these complexes are specifically removed in the lungs revealed by a 40% reduction of HMGB1 plasma levels in arterial versus venous blood. Abundant pulmonary RAGE expression enables endocytosis of danger molecules to be destroyed in the lysosomes at physiological HMGB1 levels, but causing detrimental inflammasome activation at high levels. Stress induces apoptosis in pulmonary endothelial cells from females but necrosis in cells from males. CONCLUSION Based on these observations we propose extracellular HMGB1 to be considered as a therapeutic target for COVID-19.
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Affiliation(s)
- Ulf Andersson
- Department of Women’s and Children’s Health, Karolinska Institutet at Karolinska University Hospital, Tomtebodavägen 18A, 171 77 Stockholm, Sweden
| | - William Ottestad
- Air Ambulance department, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Kevin J. Tracey
- Center for Biomedical Science and Bioelectronic Medicine, Feinstein Institutes for Medical Research, Northwell Health, 350 Community Drive, Manhasset, NY 11030 USA
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, 500 Hofstra University, Hempstead, New York, 11030 USA
- Department of Surgery, North Shore University Hospital, Northwell Health, 300 Community Drive, Manhasset, NY 11030 USA
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20
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Manzoor S, Mariappan N, Zafar I, Wei CC, Ahmad A, Surolia R, Foote JB, Agarwal A, Ahmad S, Athar M, Antony VB, Ahmad A. Cutaneous lewisite exposure causes acute lung injury. Ann N Y Acad Sci 2020; 1479:210-222. [PMID: 32329907 DOI: 10.1111/nyas.14346] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Revised: 03/11/2020] [Accepted: 03/17/2020] [Indexed: 12/12/2022]
Abstract
Lewisite is a strong vesicating and chemical warfare agent. Because of the rapid transdermal absorption, cutaneous exposure to lewisite can also elicit severe systemic injury. Lewisite (2.5, 5.0, and 7.5 mg/kg) was applied to the skin of Ptch1+/- /SKH-1 mice and acute lung injury (ALI) was assessed after 24 hours. Arterial blood gas measurements showed hypercapnia and hypoxemia in the lewisite-exposed group. Histological evaluation of lung tissue revealed increased levels of proinflammatory neutrophils and a dose-dependent increase in structural changes indicative of injury. Increased inflammation was also confirmed by altered expression of cytokines, including increased IL-33, and a dose-dependent elevation of CXCL1, CXCL5, and GCSF was observed in the lung tissue. In the bronchoalveolar lavage fluid of lewisite-exposed animals, there was a significant increase in HMGB1, a damage-associated molecular pattern molecule, as well as elevated CXCL1 and CXCL5, which coincided with an influx of neutrophils to the lungs. Complete blood cell analysis revealed eosinophilia and altered neutrophil-lymphocyte ratios as a consequence of lewisite exposure. Mean platelet volume and RBC distribution width, which are predictors of lung injury, were also increased in the lewisite group. These data demonstrate that cutaneous lewisite exposure causes ALI and may contribute to mortality in exposed populations.
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Affiliation(s)
- Shajer Manzoor
- Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, Birmingham, Alabama
| | - Nithya Mariappan
- Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, Birmingham, Alabama
| | - Iram Zafar
- Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, Birmingham, Alabama
| | - Chih-Chang Wei
- Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, Birmingham, Alabama
| | - Aamir Ahmad
- Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, Birmingham, Alabama
| | - Ranu Surolia
- Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama
| | - Jeremy B Foote
- Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama
| | - Anupam Agarwal
- Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama
| | - Shama Ahmad
- Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, Birmingham, Alabama
| | - Mohammad Athar
- Department of Dermatology, University of Alabama at Birmingham, Birmingham, Alabama
| | - Veena B Antony
- Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama
| | - Aftab Ahmad
- Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, Birmingham, Alabama
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21
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Mariappan N, Husain M, Zafar I, Singh V, Smithson KG, Crowe DR, Pittet JF, Ahmad S, Ahmad A. Extracellular nucleic acid scavenging rescues rats from sulfur mustard analog-induced lung injury and mortality. Arch Toxicol 2020; 94:1321-1334. [PMID: 32157350 DOI: 10.1007/s00204-020-02699-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2020] [Accepted: 03/02/2020] [Indexed: 01/08/2023]
Abstract
Sulfur mustard (SM) is a highly toxic war chemical that causes significant morbidity and mortality and lacks any effective therapy. Rats exposed to aerosolized CEES (2-chloroethyl ethyl sulfide; 10% in ethanol), an analog of SM, developed acute respiratory distress syndrome (ARDS), which is characterized by increased inflammation, hypoxemia and impaired gas exchange. We observed elevated levels of extracellular nucleic acids (eNA) in the bronchoalveolar lavage fluid (BALF) of CEES-exposed animals. eNA can induce inflammation, coagulation and barrier dysfunction. Treatment with hexadimethrine bromide (HDMBr; 10 mg/kg), an eNA neutralizing agent, 2 h post-exposure, reduced lung injury, inhibited disruption of alveolar-capillary barrier, improved blood oxygenation (PaO2/FiO2 ratio), thus reversing ARDS symptoms. HDMBr treatment also reduced lung inflammation in the CEES-exposed animals by decreasing IL-6, IL-1A, CXCL-1 and CCL-2 mRNA levels in lung tissues and HMGB1 protein in BALF. Furthermore, HDMBr treatment also reduced levels of lung tissue factor and plasminogen activator inhibitor-1 indicating reduction in clot formation and increased fibrinolysis. Fibrin was reduced in BALF of the HDMBr-treated animals. This was further confirmed by histology that revealed diminished airway fibrin, epithelial sloughing and hyaline membrane in the lungs of HDMBr-treated animals. HDMBr completely rescued the CEES-associated mortality 12 h post-exposure when the survival rate in CEES-only group was just 50%. Experimental eNA treatment of cells caused increased inflammation that was reversed by HDMBr. These results demonstrate a role of eNA in the pathogenesis of CEES/SM-induced injury and that its neutralization can serve as a potential therapeutic approach in treating SM toxicity.
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Affiliation(s)
- Nithya Mariappan
- Division of Molecular and Translational Biomedicine, Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, 901 19th St. South, Birmingham, AL, 35294, USA
| | - Maroof Husain
- Division of Molecular and Translational Biomedicine, Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, 901 19th St. South, Birmingham, AL, 35294, USA
| | - Iram Zafar
- Division of Molecular and Translational Biomedicine, Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, 901 19th St. South, Birmingham, AL, 35294, USA
| | - Vinodkumar Singh
- Division of Molecular and Translational Biomedicine, Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, 901 19th St. South, Birmingham, AL, 35294, USA
| | - Kenneth G Smithson
- Division of Molecular and Translational Biomedicine, Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, 901 19th St. South, Birmingham, AL, 35294, USA
| | - David R Crowe
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Jean-Francois Pittet
- Division of Molecular and Translational Biomedicine, Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, 901 19th St. South, Birmingham, AL, 35294, USA
| | - Shama Ahmad
- Division of Molecular and Translational Biomedicine, Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, 901 19th St. South, Birmingham, AL, 35294, USA
| | - Aftab Ahmad
- Division of Molecular and Translational Biomedicine, Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, 901 19th St. South, Birmingham, AL, 35294, USA.
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22
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Cai W, Shen Y, Han N, Chen H, Zhang M. Evaluation of lipopolysaccharide-induced acute lung injury attenuation in mice by Glycyrrhiza glabra. Pharmacogn Mag 2020. [DOI: 10.4103/pm.pm_189_19] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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23
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JAK2/STAT1-mediated HMGB1 translocation increases inflammation and cell death in a ventilator-induced lung injury model. J Transl Med 2019; 99:1810-1821. [PMID: 31467427 DOI: 10.1038/s41374-019-0308-8] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2018] [Revised: 06/03/2019] [Accepted: 06/14/2019] [Indexed: 01/06/2023] Open
Abstract
Janus kinase 2/signal transducer and activators of transcription 1 (JAK2/STAT1) signaling is a common pathway that contributes to numerous inflammatory disorders, including different forms of acute lung injury (ALI). However, the role of JAK2/STAT1 in ventilator-induced lung injury (VILI) and its underlying mechanism remain unclear. In this study, using lipopolysaccharide (LPS) inhalation plus mechanical ventilation as VILI mouse model, we found that the administration of JAK2 inhibitor AZD1480 markedly attenuated lung destruction, diminished protein leakage, and inhibited cytokine release. In addition, when mouse macrophage-like RAW 264.7 cells were exposed to LPS and cyclic stretch (CS), AZD1480 prevented cell autophagy, reduced apoptosis, and suppressed lactate dehydrogenase release by downregulating JAK2/STAT1 phosphorylation levels and inducing HMGB1 translocation from the nucleus to the cytoplasm. Furthermore, HMGB1 and STAT1 knockdown attenuated LPS+CS-induced autophagy and apoptosis in RAW 264.7 cells. In conclusion, these findings reveal the connection between the JAK2/STAT1 pathway and HMGB1 translocation in mediating lung inflammation and cell death in VILI, suggesting that these molecules may serve as novel therapeutic targets for VILI.
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24
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Liu Y, Chen N, Chang C, Lin S, Kao K, Hu H, Chang G, Li L. Ethyl pyruvate attenuates ventilation-induced diaphragm dysfunction through high-mobility group box-1 in a murine endotoxaemia model. J Cell Mol Med 2019; 23:5679-5691. [PMID: 31339670 PMCID: PMC6652995 DOI: 10.1111/jcmm.14478] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2019] [Revised: 04/12/2019] [Accepted: 05/22/2019] [Indexed: 01/05/2023] Open
Abstract
Mechanical ventilation (MV) can save the lives of patients with sepsis. However, MV in both animal and human studies has resulted in ventilator-induced diaphragm dysfunction (VIDD). Sepsis may promote skeletal muscle atrophy in critically ill patients. Elevated high-mobility group box-1 (HMGB1) levels are associated with patients requiring long-term MV. Ethyl pyruvate (EP) has been demonstrated to lengthen survival in patients with severe sepsis. We hypothesized that the administration of HMGB1 inhibitor EP or anti-HMGB1 antibody could attenuate sepsis-exacerbated VIDD by repressing HMGB1 signalling. Male C57BL/6 mice with or without endotoxaemia were exposed to MV (10 mL/kg) for 8 hours after administrating either 100 mg/kg of EP or 100 mg/kg of anti-HMGB1 antibody. Mice exposed to MV with endotoxaemia experienced augmented VIDD, as indicated by elevated proteolytic, apoptotic and autophagic parameters. Additionally, disarrayed myofibrils and disrupted mitochondrial ultrastructures, as well as increased HMGB1 mRNA and protein expression, and plasminogen activator inhibitor-1 protein, oxidative stress, autophagosomes and myonuclear apoptosis were also observed. However, MV suppressed mitochondrial cytochrome C and diaphragm contractility in mice with endotoxaemia (P < 0.05). These deleterious effects were alleviated by pharmacologic inhibition with EP or anti-HMGB1 antibody (P < 0.05). Our data suggest that EP attenuates endotoxin-enhanced VIDD by inhibiting HMGB1 signalling pathway.
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Affiliation(s)
- Yung‐Yang Liu
- Chest DepartmentTaipei Veterans General HospitalTaipeiTaiwan
- Institutes of Clinical MedicineSchool of MedicineNational Yang‐Ming UniversityTaipeiTaiwan
| | - Ning‐Hung Chen
- Department of Internal Medicine, Division of Pulmonary and Critical Care MedicineChang Gung Memorial HospitalTaoyuanTaiwan
- Department of Internal MedicineChang Gung UniversityTaoyuanTaiwan
- Department of Respiratory TherapyChang Gung Memorial HospitalTaoyuanTaiwan
| | - Chih‐Hao Chang
- Department of Internal Medicine, Division of Pulmonary and Critical Care MedicineChang Gung Memorial HospitalTaoyuanTaiwan
- Department of Internal MedicineChang Gung UniversityTaoyuanTaiwan
| | - Shih‐Wei Lin
- Department of Internal Medicine, Division of Pulmonary and Critical Care MedicineChang Gung Memorial HospitalTaoyuanTaiwan
- Department of Internal MedicineChang Gung UniversityTaoyuanTaiwan
- Department of Respiratory TherapyChang Gung Memorial HospitalTaoyuanTaiwan
| | - Kuo‐Chin Kao
- Department of Internal Medicine, Division of Pulmonary and Critical Care MedicineChang Gung Memorial HospitalTaoyuanTaiwan
- Department of Internal MedicineChang Gung UniversityTaoyuanTaiwan
- Department of Respiratory TherapyChang Gung Memorial HospitalTaoyuanTaiwan
- Department of Respiratory Care, College of MedicineChang Gung UniversityTaoyuanTaiwan
| | - Han‐Chung Hu
- Department of Internal Medicine, Division of Pulmonary and Critical Care MedicineChang Gung Memorial HospitalTaoyuanTaiwan
- Department of Internal MedicineChang Gung UniversityTaoyuanTaiwan
- Department of Respiratory TherapyChang Gung Memorial HospitalTaoyuanTaiwan
- Department of Respiratory Care, College of MedicineChang Gung UniversityTaoyuanTaiwan
| | - Gwo‐Jyh Chang
- Graduate Institute of Clinical Medical SciencesChang Gung UniversityTaoyuanTaiwan
| | - Li‐Fu Li
- Department of Internal Medicine, Division of Pulmonary and Critical Care MedicineChang Gung Memorial HospitalTaoyuanTaiwan
- Department of Internal MedicineChang Gung UniversityTaoyuanTaiwan
- Department of Respiratory TherapyChang Gung Memorial HospitalTaoyuanTaiwan
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25
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Therapeutic Role of Recombinant Human Soluble Thrombomodulin for Acute Exacerbation of Idiopathic Pulmonary Fibrosis. ACTA ACUST UNITED AC 2019; 55:medicina55050172. [PMID: 31137593 PMCID: PMC6571552 DOI: 10.3390/medicina55050172] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2019] [Revised: 03/11/2019] [Accepted: 05/15/2019] [Indexed: 12/24/2022]
Abstract
Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is an acute respiratory worsening of unidentifiable cause that sometimes develops during the clinical course of IPF. Although the incidence of AE-IPF is not high, prognosis is poor. The pathogenesis of AE-IPF is not well understood; however, evidence suggests that coagulation abnormalities and inflammation are involved. Thrombomodulin is a transmembranous glycoprotein found on the cell surface of vascular endothelial cells. Thrombomodulin combines with thrombin, regulates coagulation/fibrinolysis balance, and has a pivotal role in suppressing excess inflammation through its inhibition of high-mobility group box 1 protein and the complement system. Thus, thrombomodulin might be effective in the treatment of AE-IPF, and we and other groups found that recombinant human soluble thrombomodulin improved survival in patients with AE-IPF. This review summarizes the existing evidence and considers the therapeutic role of thrombomodulin in AE-IPF.
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26
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Feng Z, Wang JW, Wang Y, Dong WW, Xu ZF. Propofol Protects Lung Endothelial Barrier Function by Suppression of High-Mobility Group Box 1 (HMGB1) Release and Mitochondrial Oxidative Damage Catalyzed by HMGB1. Med Sci Monit 2019; 25:3199-3211. [PMID: 31040263 PMCID: PMC6507496 DOI: 10.12659/msm.915417] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Background The processes of mechanical ventilation-induced lung injury (VILI) triggers the release of high-mobility group box 1 (HMGB1), a prominent damage-associated molecular pattern (DAMP) family member, which can cause damage to pulmonary vascular endothelial cells. We aimed to determine whether propofol protected against endothelial cell injury induced by HMGB1 in vitro and in vivo. Material/Methods ICR mice (male) were mechanically ventilated for 4 h after anesthetization at both low tidal volume (LVT, 6 ml/kg) and high tidal volume (HVT, 30 ml/kg). A propofol bolus (10 mg/kg) was administered to the animals prior to the onset of ventilation, followed by infusion at 5 mg/(kg·h). We obtained confluent cultures of mouse lung vascular endothelial cells (MLVECs) and then performed cyclic stretching at 20% stretch for 4 h with or without propofol. Results HMGB1 reduced the expression of tight junctions between endothelial cells, including VE-cadherin and ZO-1, and increased endothelial permeability, and both were blocked by propofol. We found that MLVECs exhibited mitochondrial oxidative damage by HMGB1, which was successfully suppressed through administration of MnTBAP as well as propofol. Propofol ameliorated HVT-associated lung vascular hyperpermeability and HMGB1 production in vivo. Propofol also inhibited HMBG1 release caused by cyclic stretching in MLVECs in vitro. Conclusions Our results prove that the cyto-protective function of propofol protects against lung ventilation-induced dysfunction of the lung endothelial barrier. This function of propofol is mediated through inhibition of HMGB1 release caused by mechanical stretching and mitochondrial oxidative damage triggered by HMGB1.
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Affiliation(s)
- Zhou Feng
- Department of Anesthesiology, International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (mainland)
| | - Jian-Wei Wang
- Department of Anesthesiology, International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (mainland)
| | - Yan Wang
- Department of Anesthesiology and Surgical Intensive Care Unit, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (mainland)
| | - Wen-Wen Dong
- Department of Anesthesiology and Surgical Intensive Care Unit, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (mainland)
| | - Zi-Feng Xu
- Department of Anesthesiology, International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (mainland)
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27
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Koutsogiannaki S, Shimaoka M, Yuki K. The Use of Volatile Anesthetics as Sedatives for Acute Respiratory Distress Syndrome. ACTA ACUST UNITED AC 2019; 6:27-38. [PMID: 30923729 PMCID: PMC6433148 DOI: 10.31480/2330-4871/084] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Acute respiratory distress syndrome (ARDS) remains to pose a high morbidity and mortality without any targeted therapies. Sedation, usually given intravenously, is an important part of clinical practice in intensive care unit (ICU), and the effect of sedatives on patients’ outcomes has been studied intensively. Although volatile anesthetics are not routine sedatives in ICU, preclinical and clinical studies suggested their potential benefit in pulmonary pathophysiology. This review will summarize the current knowledge of ARDS and the role of volatile anesthetic sedation in this setting from both clinical and mechanistic standpoints. In addition, we will review the infrastructure to use volatile anesthetics.
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Affiliation(s)
- Sophia Koutsogiannaki
- Department of Anaesthesia, Harvard Medical School, Boston, Massachusetts, USA.,Department of Anesthesiology, Critical Care and Pain Medicine, Cardiac Anesthesia Division, Boston Children's Hospital, Boston, Massachusetts, USA
| | - Motomu Shimaoka
- Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, Tsushi, Mie, Japan
| | - Koichi Yuki
- Department of Anaesthesia, Harvard Medical School, Boston, Massachusetts, USA.,Department of Anesthesiology, Critical Care and Pain Medicine, Cardiac Anesthesia Division, Boston Children's Hospital, Boston, Massachusetts, USA
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28
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Abstract
This review summarizes a short list of currently discussed trauma-induced danger-associated molecular patterns (DAMP). Due to the bivalent character and often pleiotropic effects of a DAMP, it is difficult to describe its "friend or foe" role in post-traumatic inflammation and regeneration, both systemically as well locally in tissues. DAMP can be used as biomarkers to indicate or monitor disease or injury severity, but also may serve as clinically applicable parameters for better indication and timing of surgery. Due to the inflammatory processes at the local tissue level or the systemic level, the precise role of DAMP is not always clear to define. While in vitro and experimental studies allow for the detection of these biomarkers at the different levels of an organism-cellular, tissue, circulation-this is not always easily transferable to the human setting. Increased knowledge exploring the dual role of DAMP after trauma, and concentrating on their nuclear functions, transcriptional targets, release mechanisms, cellular sources, multiple functions, their interactions and potential therapeutic targeting is warranted.
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Affiliation(s)
- Borna Relja
- Department of Trauma, Hand and Reconstructive Surgery, University Hospital Frankfurt, Goethe University, 60590, Frankfurt, Germany.
| | - Katharina Mörs
- Department of Trauma, Hand and Reconstructive Surgery, University Hospital Frankfurt, Goethe University, 60590, Frankfurt, Germany
| | - Ingo Marzi
- Department of Trauma, Hand and Reconstructive Surgery, University Hospital Frankfurt, Goethe University, 60590, Frankfurt, Germany
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29
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Maca J, Holub M, Bursa F, Ihnat P, Reimer P, Svagera Z, Burda M, Sevcik P. Alarmins as biomarkers of gastrointestinal surgical injury - a pilot study. APMIS 2018; 126:152-159. [PMID: 29700911 DOI: 10.1111/apm.12798] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2017] [Accepted: 11/12/2017] [Indexed: 12/21/2022]
Abstract
The dysregulation of inflammatory response to surgical injury affects outcomes. Alarmins, the earliest bioactive substances from damaged cells, play a crucial role in initiating the inflammation. We analyzed serum levels of alarmins (S100A8, S100A12, high mobility group box, and heat shock protein 70) after major abdominal surgery (MAS) in surgical (S) (n = 82) and nonsurgical (NS) groups (n = 35). The main objective was determining a role of selected alarmins in host response to MAS. The secondary objectives were (i) evaluation of the relationship among alarmins and selected biomarkers (C-reactive protein, interleukin-6), (ii) influence of the place of gastrointestinal resection, and (iii) role of alarmins in MAS for cancer. Except for HMGB1, the levels of all alarmins were higher in the S group compared with the NS group. In the S group, positive correlations were found between S100A8 and both IL-6 and CRP. Additionally, the S100A8 level was higher (p < 0.01) in patients who underwent upper gastrointestinal tract (GIT) surgery compared to middle and lower GIT resections. Alarmins levels did not differ between cancer and noncancer patients. MAS is able to elicit increase in alarmin levels. S100A8 can be considered a potential biomarker of surgical injury, especially in the upper part of the GIT.
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Affiliation(s)
- Jan Maca
- Faculty of Medicine, Department of Intensive Care Medicine and Forensic Studies, University of Ostrava, Ostrava-Poruba, Czech Republic.,Department of Anesthesiology and Intensive Care Medicine, University Hospital Ostrava, Ostrava-Poruba, Czech Republic.,First Faculty of Medicine, Department of Infectious Diseases, Charles University in Prague and Military University Hospital, Prague, Czech Republic
| | - Michal Holub
- First Faculty of Medicine, Department of Infectious Diseases, Charles University in Prague and Military University Hospital, Prague, Czech Republic
| | - Filip Bursa
- Faculty of Medicine, Department of Intensive Care Medicine and Forensic Studies, University of Ostrava, Ostrava-Poruba, Czech Republic.,Department of Anesthesiology and Intensive Care Medicine, University Hospital Ostrava, Ostrava-Poruba, Czech Republic
| | - Peter Ihnat
- Department of Surgery, University Hospital Ostrava, Ostrava-Poruba, Czech Republic
| | - Petr Reimer
- Faculty of Medicine, Department of Intensive Care Medicine and Forensic Studies, University of Ostrava, Ostrava-Poruba, Czech Republic.,Department of Anesthesiology and Intensive Care Medicine, University Hospital Ostrava, Ostrava-Poruba, Czech Republic
| | - Zdenek Svagera
- Institute of Laboratory Diagnostics, University Hospital Ostrava, Ostrava-Poruba, Czech Republic
| | - Michal Burda
- Institute for Research and Applications of Fuzzy Modeling, Centre of Excellence IT4Innovations, University of Ostrava, Ostrava-Poruba, Czech Republic
| | - Pavel Sevcik
- Faculty of Medicine, Department of Intensive Care Medicine and Forensic Studies, University of Ostrava, Ostrava-Poruba, Czech Republic.,Department of Anesthesiology and Intensive Care Medicine, University Hospital Ostrava, Ostrava-Poruba, Czech Republic
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30
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Effects of Dexmedetomidine Infusion on Inflammatory Responses and Injury of Lung Tidal Volume Changes during One-Lung Ventilation in Thoracoscopic Surgery: A Randomized Controlled Trial. Mediators Inflamm 2018; 2018:2575910. [PMID: 29853785 PMCID: PMC5952437 DOI: 10.1155/2018/2575910] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2017] [Accepted: 02/26/2018] [Indexed: 12/18/2022] Open
Abstract
One-lung ventilation in thoracic surgery provokes profound systemic inflammatory responses and injury related to lung tidal volume changes. We hypothesized that the highly selective a2-adrenergic agonist dexmedetomidine attenuates these injurious responses. Sixty patients were randomly assigned to receive dexmedetomidine or saline during thoracoscopic surgery. There is a trend of less postoperative medical complication including that no patients in the dexmedetomidine group developed postoperative medical complications, whereas four patients in the saline group did (0% versus 13.3%, p = 0.1124). Plasma inflammatory and injurious biomarkers between the baseline and after resumption of two-lung ventilation were particularly notable. The plasma high-mobility group box 1 level decreased significantly from 51.7 (58.1) to 33.9 (45.0) ng.ml−1 (p < 0.05) in the dexmedetomidine group, which was not observed in the saline group. Plasma monocyte chemoattractant protein 1 [151.8 (115.1) to 235.2 (186.9) pg.ml−1, p < 0.05] and neutrophil elastase [350.8 (154.5) to 421.9 (106.1) ng.ml−1, p < 0.05] increased significantly only in the saline group. In addition, plasma interleukin-6 was higher in the saline group than in the dexmedetomidine group at postoperative day 1 [118.8 (68.8) versus 78.5 (58.8) pg.ml−1, p = 0.0271]. We conclude that dexmedetomidine attenuates one-lung ventilation-associated inflammatory and injurious responses by inhibiting alveolar neutrophil recruitment in thoracoscopic surgery.
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31
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Zhu XD, Lei XP, Dong WB. Resveratrol as a potential therapeutic drug for respiratory system diseases. DRUG DESIGN DEVELOPMENT AND THERAPY 2017; 11:3591-3598. [PMID: 29290681 PMCID: PMC5736354 DOI: 10.2147/dddt.s148868] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Respiratory system diseases are common and major ailments that seriously endanger human health. Resveratrol, a polyphenolic phytoalexin, is considered an anti-inflammatory, antioxidant, and anticancer agent. Thanks to its wide range of biological activities, resveratrol has become a hotspot in many fields, including respiratory system diseases. Indeed, research has demonstrated that resveratrol is helpful to relieve pulmonary function in the general population. Meanwhile, growing evidence indicates that resveratrol plays a protective role in respiratory system diseases. This review aimed to summarize the main protective effects of resveratrol in respiratory system diseases, including its anti-inflammatory, antiapoptotic, antioxidant, antifibrotic, antihypertensive, and anticancer activities. We found that resveratrol plays a protective role in the respiratory system through a variety of mechanisms, and so it may become a new drug for the treatment of respiratory system diseases.
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Affiliation(s)
- Xiao-Dan Zhu
- Department of Newborn Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People's Republic of China
| | - Xiao-Ping Lei
- Department of Newborn Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People's Republic of China
| | - Wen-Bin Dong
- Department of Newborn Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People's Republic of China
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32
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Role of monocytes and macrophages in regulating immune response following lung transplantation. Curr Opin Organ Transplant 2017; 21:239-45. [PMID: 26977996 DOI: 10.1097/mot.0000000000000313] [Citation(s) in RCA: 85] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
PURPOSE OF REVIEW Advances in the field of monocyte and macrophage biology have dramatically changed our understanding of their role during homeostasis and inflammation. Here we review the role of these important innate immune effectors in the lung during inflammatory challenges including lung transplantation. RECENT FINDINGS Neutrophil extravasation into lung tissue and the alveolar space have been shown to be pathogenic during acute lung injury as well as primary graft dysfunction following lung transplantation. Recent advances in lung immunology have demonstrated the remarkable plasticity of both monocytes and macrophages and demonstrated their importance as mediators of neutrophil recruitment and transendothelial migration during inflammation. SUMMARY Monocytes and macrophages are emerging as key players in mediating both the pathogen response and sterile lung inflammation, including that arising from barotrauma and ischemia-reperfusion injury. Ongoing studies will establish the mechanisms by which these monocytes and macrophages initiate a variety of immune response that lay the fundamental basis of injury response in the lung.
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Wang X, Zhang R, Tong Y, Ding X, Jin S, Zhao X, Zong J, Chen Z, Billiar TR, Li Q. High-mobility group box 1 protein is involved in the protective effect of Saquinavir on ventilation-induced lung injury in mice. Acta Biochim Biophys Sin (Shanghai) 2017; 49:907-915. [PMID: 28981603 DOI: 10.1093/abbs/gmx085] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2017] [Indexed: 01/07/2023] Open
Abstract
Saquinavir (SQV) is the first FDA approved HIV protease inhibitor. Previous studies showed that SQV can limit Toll-like receptor-4 (TLR4)-mediated inflammatory pathway and nuclear factor-κB (NF-κB) activation, thereby playing a protective role in many kinds of diseases. High-mobility group box 1 (HMGB1) has been identified as an inflammatory mediator and it might express its toxicity in a short period of time in ventilator-induced lung injury (VILI). In this study, C57BL/6 mice were randomly divided into four groups (n = 10): control group and control with SQV group (Con + SQV) were spontaneous breath. HTV group (HTV) received high tidal volume ventilation (HTV) for 4 h. HTV with SQV group (HTV + SQV) were pretreated with 5 mg/kg of SQV for 7 days before HTV. Mice were sacrificed after 4 h of HTV. Lung wet/dry weight (W/D) ratio, alveolar-capillary permeability to Evans blue albumin (EBA), cell counts, total proteins in bronchoalveolar lavage fluid (BALF), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) level in BALF and lung tissue, and lung histopathology were examined. Our results showed that HTV caused significant lung injury and NF-κB activation, which was correlated with the increase of TNF-α and IL-6 levels in BALF and plasma. SQV pretreatment significantly attenuated pulmonary inflammatory injury, as well as NF-κB activation. These findings indicate that the protective effect of SQV may be associated with the inhibition of NF-κB activation and HMGB1 expression in mice.
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Affiliation(s)
- Xin Wang
- Department of Anesthesiology, East Hospital, Tongji University School of Medicine, Shanghai 200120, China
- Department of Anesthesiology, The First Clinical Medical College of Nanjing Medical University, Nanjing 210029, China
| | - Renlingzi Zhang
- Department of Anesthesiology, East Hospital, Tongji University School of Medicine, Shanghai 200120, China
| | - Yao Tong
- Department of Anesthesiology, East Hospital, Tongji University School of Medicine, Shanghai 200120, China
| | - Xibing Ding
- Department of Anesthesiology, East Hospital, Tongji University School of Medicine, Shanghai 200120, China
| | - Shuqing Jin
- Department of Anesthesiology, East Hospital, Tongji University School of Medicine, Shanghai 200120, China
| | - Xiang Zhao
- Department of Anesthesiology, East Hospital, Tongji University School of Medicine, Shanghai 200120, China
| | - Jiaying Zong
- Department of Anesthesiology, East Hospital, Tongji University School of Medicine, Shanghai 200120, China
- Department of Anesthesiology, The First Clinical Medical College of Nanjing Medical University, Nanjing 210029, China
| | - Zhixia Chen
- Department of Anesthesiology, East Hospital, Tongji University School of Medicine, Shanghai 200120, China
| | - Timothy R Billiar
- Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15260, USA
| | - Quan Li
- Department of Anesthesiology, East Hospital, Tongji University School of Medicine, Shanghai 200120, China
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Abstract
The receptor for advanced glycation end-products (RAGE) is involved in inflammatory response during acute respiratory distress syndrome (ARDS). Growing body of evidence support strategies of RAGE inhibition in experimental lung injury, but its modalities and effects remain underinvestigated. Anesthetised C57BL/6JRj mice were divided in four groups; three of them underwent orotracheal instillation of acid and were treated with anti-RAGE monoclonal antibody (mAb) or recombinant soluble RAGE (sRAGE), acting as a decoy receptor. The fourth group served as a control. Lung injury was assessed by the analysis of blood gases, alveolar permeability, histology, AFC, and cytokines. Lung expression and distribution epithelial channels ENaC, Na,K-ATPase, and aquaporin (AQP)−5 were assessed. Treatment with either anti-RAGE mAb or sRAGE improved lung injury, arterial oxygenation and decreased alveolar inflammation in acid-injured animals. Anti-RAGE therapies were associated with restored AFC and increased lung expression of AQP-5 in alveolar cell. Blocking RAGE had potential therapeutic effects in a translational mouse model of ARDS, possibly through a decrease in alveolar type 1 epithelial cell injury as shown by restored AFC and lung AQP-5 expression. Further mechanistic studies are warranted to describe intracellular pathways that may control such effects of RAGE on lung epithelial injury and repair.
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Takahashi Y, Matsutani N, Dejima H, Nakayama T, Uehara H, Kawamura M. Nuclear factor-kappa B influences early phase of compensatory lung growth after pneumonectomy in mice. J Biomed Sci 2017; 24:41. [PMID: 28679393 PMCID: PMC5499001 DOI: 10.1186/s12929-017-0350-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2017] [Accepted: 06/27/2017] [Indexed: 02/08/2023] Open
Abstract
Background Compensatory lung growth (CLG) is a well-established lung regeneration model. However, the sequential mechanisms, including unknown molecular triggers or regulators, remain unclear. Nuclear factor- kappa B (NF-κB) is known to be essential for inflammation and tissue regeneration; therefore, we investigated the role of NF-κB in CLG. Methods C57BL/6 J mice underwent either a left pneumonectomy or a thoracotomy (n = 77). Gene microarray analysis was performed to detect genes that were upregulated at 12 h after pneumonectomy. NF-κB protein expression was examined by immunohistochemistry and Western blot. To investigate the influence of NF-κB on CLG, either an NF-κB inhibitor SN50 or saline was administered following pneumonectomy and the degree of CLG was evaluated in each group by measuring the lung dry weight index (LDWI) and the mean linear intercept. Results Gene microarray analysis identified 11 genes that were significantly but transiently increased at 12 h after pneumonectomy. Among the 11 genes, NF-κB was selected based on its reported functions. Western blot analysis showed that NF-κB protein expression after pneumonectomy was significantly higher at 12 h compared to 48 h. Additionally, NF-κB protein expression at 12 h after pneumonectomy was significantly higher than at both 12 and 48 h after thoracotomy (p < 0.029 for all). NF-κB protein expression, evaluated through immunohistochemistry, was expressed mainly in type 2 alveolar epithelial cells and was significant increased 12 h after pneumonectomy compared to 48 h after pneumonectomy and both 12 and 48 h after thoracotomy (p < 0.001 for all). SN50 administration following pneumonectomy induced a significant decrease in NF-κB expression (p = 0.004) and LDWI compared to the vehicle administration (p = 0.009). Conclusions This is the first report demonstrating that NF-κB signaling may play a key role in CLG. Given its pathway is crucial in tissue regeneration of various organs, NF-κB may shed light on identification of molecular triggers or clinically usable key regulators of CLG.
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Affiliation(s)
- Yusuke Takahashi
- Department of General Thoracic Surgery, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi, Tokyo, 173-8606, Japan.
| | - Noriyuki Matsutani
- Department of General Thoracic Surgery, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi, Tokyo, 173-8606, Japan
| | - Hitoshi Dejima
- Department of General Thoracic Surgery, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi, Tokyo, 173-8606, Japan
| | - Takashi Nakayama
- Department of General Thoracic Surgery, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi, Tokyo, 173-8606, Japan
| | - Hirofumi Uehara
- Department of General Thoracic Surgery, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi, Tokyo, 173-8606, Japan
| | - Masafumi Kawamura
- Department of General Thoracic Surgery, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi, Tokyo, 173-8606, Japan
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Therapeutic potential of recombinant thrombomodulin for lung injury after pneumonectomy via inhibition of high-mobility group box 1 in mice. J Trauma Acute Care Surg 2017; 81:868-875. [PMID: 27504958 DOI: 10.1097/ta.0000000000001208] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
BACKGROUND Surgical acute respiratory distress syndrome (ARDS) is an extremely critical condition which may occur after major lung resection. Despite advances in minimally invasive surgical procedures and progress in the therapeutic management of this disease, prognosis remains poor. In this study, we investigated the contribution of high-mobility group box 1 (HMGB1) in a surgical ARDS model and evaluated the possible therapeutic effect of recombinant thrombomodulin (rTM) for the treatment of surgical ARDS. METHODS C57BL/6J mice underwent left pneumonectomy. rTM was injected at 12 hours before surgery, followed by 12 hours for 3 days after surgery. Lipopolysaccharide (LPS) was administered at 2 hours after surgery. We conducted a histologic analysis and measured HMGB1, IL-6, IL-1β, and TNF-α in bronchoalveolar lavage fluid on day 3 after pneumonectomy. Data were compared between the treatment groups. RESULTS On histologic analysis, left pneumonectomy followed by LPS administration induced both severe inflammatory cellular infiltration and alveolar wall congestion with hemorrhage. rTM administration rescued these histologic changes. The level of HMGB1, IL-6, IL-1β, and TNF-α in bronchoalveolar lavage fluid was significantly increased by LPS administration after pneumonectomy and significantly decreased by rTM administration with LPS and pneumonectomy (p < 0.001). Also, LPS alone showed no statistical differences in HMGB1 or proinflammatory cytokine level compared with pneumonectomy (PNX) group. In addition, the survival outcome was also improved by rTM administration. CONCLUSIONS LPS administration after left pneumonectomy could induce the severe lung injury. PNX and LPS have similar contribution to this model and may play a synergistic role in this process. rTM may have the potential therapeutic effect for surgical ARDS via suppression of HMGB1 and the secretion of proinflammatory cytokines induced by the administration of LPS after left pneumonectomy.
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Wang F, Yin J, Ma Y, Jiang H, Li Y. Vitexin alleviates lipopolysaccharide‑induced islet cell injury by inhibiting HMGB1 release. Mol Med Rep 2017; 15:1079-1086. [PMID: 28098903 PMCID: PMC5367348 DOI: 10.3892/mmr.2017.6114] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2015] [Accepted: 11/15/2016] [Indexed: 12/23/2022] Open
Abstract
Diabetes mellitus (DM) is a chronic metabolic disease, where the predominant pathogenesis is pancreatic β‑cells dysfunction or injury. It has been well established that inflammation leads to a gradual exhaustion of pancreatic β‑cell function with decreased β‑cell mass likely resulting from pancreatic β‑cells apoptosis or death. Vitexin, a major bioactive flavonoid compound in plants has numerous pharmacological properties, including antioxidant, anti‑inflammatory and antimyeloperoxidase. Whether vitexin can protect pancreatic β‑cells against lipopolysaccharide (LPS)‑induced pro‑inflammatory cytokine production and apoptosis has received little attention. The present study investigated the potential effects of vitexin on LPS‑induced pancreatic β‑cell injury and apoptosis. It was revealed that apoptosis and damage induced by LPS in islet tissue of rats and INS‑1 cells was significantly decreased in response to vitexin treatment. In addition, pretreatment with vitexin decreased the levels of the pro‑inflammatory cytokines tumor necrosis factor‑α and high mobility group box 1 (HMGB1) in LPS‑induced rats. Further experiments demonstrated that vitexin pretreatment suppressed the activation of P38 mitogen‑activated protein kinase signaling pathways in LPS‑induced INS‑1 cells. In conclusion, the results indicated that vitexin prevented LPS‑induced islet tissue damage in rats, and INS‑1 cells injury and apoptosis by inhibiting HMGB1 release. Therefore, the present study provided clear evidence indicating that vitexin may be a viable therapeutic strategy for the treatment of DM.
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Affiliation(s)
- Feifei Wang
- Department of Endocrinology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Jiajing Yin
- Department of Endocrinology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Yujin Ma
- Department of Endocrinology, The First Affiliated Hospital of Henan University of Science and Technology, Luoyang, Henan 471003, P.R. China
| | - Hongwei Jiang
- Department of Endocrinology, The First Affiliated Hospital of Henan University of Science and Technology, Luoyang, Henan 471003, P.R. China
| | - Yanbo Li
- Department of Endocrinology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
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Abstract
Danger-associated molecular patterns (DAMPs) that are released by injured, threatened, or dead cells, or that originate from the extracellular matrix, influence the immune system. This is of great relevance in critically ill patients, in whom trauma or surgery-related cell damage, hypoxia, ischemia, and infections can result in extensive release of DAMPs. As many patients at the intensive care unit suffer from immune system-related complications, DAMPs could serve as markers for the prognosis of these patients and represent possible therapeutic targets. In the present review, we provide an overview of several well known DAMPs (high-mobility group box 1, heat-shock proteins, s100 proteins, nucleic acids, and hyaluronan) and their effects on the immune system. Furthermore, we discuss the role of DAMPs as markers or therapeutic targets in several conditions frequently encountered in critically ill patients, such as sepsis, trauma, ventilator-induced lung injury, and cardiac arrest.
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Quan H, Hur YH, Xin C, Kim JM, Choi JI, Kim MY, Bae HB. Stearoyl lysophosphatidylcholine enhances the phagocytic ability of macrophages through the AMP-activated protein kinase/p38 mitogen activated protein kinase pathway. Int Immunopharmacol 2016; 39:328-334. [DOI: 10.1016/j.intimp.2016.07.014] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2016] [Revised: 07/13/2016] [Accepted: 07/16/2016] [Indexed: 11/26/2022]
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Máca J, Burša F, Ševčík P, Sklienka P, Burda M, Holub M. Alarmins and Clinical Outcomes After Major Abdominal Surgery-A Prospective Study. J INVEST SURG 2016; 30:152-161. [PMID: 27689623 DOI: 10.1080/08941939.2016.1231855] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
PURPOSE Tissue injury causing immune response is an integral part of surgical procedure. Evaluation of the degree of surgical trauma could help to improve postoperative management and determine the clinical outcomes. MATERIALS AND METHODS We analyzed serum levels of alarmins, including S100A5, S100A6, S100A8, S100A9, S100A11, and S100A12; high-mobility group box 1; and heat-shock protein 70, after elective major abdominal surgery (n = 82). Blood samples were collected for three consecutive days after surgery. The goals were to evaluate the relationships among the serum levels of alarmins and selected surgical characteristics and to test potential of alarmins to predict the clinical outcomes. RESULTS Significant, positive correlations were found for high-mobility group box 1 with the length of surgery, blood loss, and intraoperative fluid intake for all three days of blood sampling. The protein S100A8 serum levels showed positive correlations with intensive care unit length of stay, 28-day and in-hospital mortality. The protein S100A12 serum levels had significant, positive correlations with intensive care unit length of stay, 28-day mortality, and in-hospital mortality. We did not find significant differences in alarmin levels between cancer and noncancer subjects. CONCLUSION The high-mobility group box 1 serum levels reflect the degree of surgical injury, whereas proteins S100A8 and S100A12 might be considered good predictors of major abdominal surgery morbidity and mortality.
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Affiliation(s)
- Jan Máca
- a University of Ostrava , Ostrava , Czech Republic.,b University Hospital of Ostrava , Ostrava , Czech Republic
| | - Filip Burša
- a University of Ostrava , Ostrava , Czech Republic.,b University Hospital of Ostrava , Ostrava , Czech Republic
| | - Pavel Ševčík
- a University of Ostrava , Ostrava , Czech Republic.,b University Hospital of Ostrava , Ostrava , Czech Republic
| | - Peter Sklienka
- a University of Ostrava , Ostrava , Czech Republic.,b University Hospital of Ostrava , Ostrava , Czech Republic
| | - Michal Burda
- c University of Ostrava , Institute for Research and Applications of Fuzzy Modeling , Ostrava , Czech Republic
| | - Michal Holub
- d Univerzita Karlova v Praze , First Faculty Of Medicine , Praha , Czech Republic.,e Military Hospital of Prague , Prague , Czech Republic
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Waseda K, Miyahara N, Taniguchi A, Kurimoto E, Ikeda G, Koga H, Fujii U, Yamamoto Y, Gelfand EW, Yamamoto H, Tanimoto M, Kanehiro A. Emphysema requires the receptor for advanced glycation end-products triggering on structural cells. Am J Respir Cell Mol Biol 2016; 52:482-91. [PMID: 25188021 DOI: 10.1165/rcmb.2014-0027oc] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Pulmonary emphysema is characterized by persistent inflammation and progressive alveolar destruction. The receptor for advanced glycation end-products (RAGE) is a multiligand cell surface receptor reported to be involved in the process of acute alveolar epithelial cell injury. However, studies that address the role of RAGE in pulmonary emphysema are inconclusive. We investigated the role of RAGE in the development of elastase-induced pulmonary inflammation and emphysema in mice. RAGE-sufficient (RAGE(+/+)) mice and RAGE-deficient (RAGE(-/-)) mice were treated with intratracheal elastase on Day 0. Airway inflammation, static lung compliance, lung histology, and the levels of neutrophil-related chemokine and proinflammatory cytokines in bronchoalveolar lavage fluid were determined on Days 4 and 21. Neutrophilia in bronchoalveolar lavage fluid, seen in elastase-treated RAGE(+/+) mice, was reduced in elastase-treated RAGE(-/-) mice on Day 4, and was associated with decreased levels of keratinocyte chemoattractant, macrophage inflammatory protein-2, and IL-1β. Static lung compliance values and emphysematous changes in the lung tissue were decreased in RAGE(-/-) mice compared with RAGE(+/+) mice on Day 21 after elastase treatment. Experiments using irradiated, bone marrow-chimeric mice showed that the mice expressing RAGE on radioresistant structural cells, but not hematopoietic cells, developed elastase-induced neutrophilia and emphysematous change in the lung. In contrast, mice expressing RAGE on hematopoietic cells, but not radioresistant structural cells, showed reduced neutrophilia and emphysematous change in the lung. These data identify the importance of RAGE expressed on lung structural cells in the development of elastase-induced pulmonary inflammation and emphysema. Thus, RAGE represents a novel therapeutic target for preventing pulmonary emphysema.
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Affiliation(s)
- Koichi Waseda
- 1 Department of Hematology, Oncology, Allergy and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
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Preconditioning of physiological cyclic stretch attenuated HMGB1 expression in pathologically mechanical stretch-activated A549 cells and ventilator-induced lung injury rats through inhibition of IL-6/STAT3/SOCS3. Int Immunopharmacol 2016; 31:66-73. [DOI: 10.1016/j.intimp.2015.12.017] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2015] [Revised: 12/11/2015] [Accepted: 12/12/2015] [Indexed: 01/24/2023]
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Ma L, Zeng J, Mo B, Wang C, Huang J, Sun Y, Yu Y, Liu S. High mobility group box 1: a novel mediator of Th2-type response-induced airway inflammation of acute allergic asthma. J Thorac Dis 2015; 7:1732-41. [PMID: 26623095 DOI: 10.3978/j.issn.2072-1439.2015.10.18] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022]
Abstract
BACKGROUND High mobility group box 1 (HMGB1) is an inflammatory mediator involved into the advanced stage of systemic inflammatory response syndrome (SIRS), and is over-expressed in bacterial sepsis and hemorrhagic shock. Recently, it has been found that the HMGB1 was abnormally expressed in induced sputum and plasma of asthmatic patients. However, the precise role of HMGB1 in the acute allergic asthma is unclear. Therefore, we aim to investigate the role HMGB1 in regulating airway inflammation of acute allergic asthma and its possible mechanism in this study. METHODS Forty-eight BALB/c female mice were randomly divided into four groups: control group (Control), asthma group (Asthma), HMGB1 group (HMGB1) and anti-HMGB1 (HMGB1 monoclonal antibody of mice) group (Anti-HMGB1). Acute allergic asthma mice models were established by ovalbumin (OVA)-challenge. Then, we measured the levels of HMGB1 in bronchoalveolar lavage fluid (BALF) and lung tissue of mice. Finally, after exogenous HMGB1 and/or anti-HMGB1 administration, pulmonary function test, histological analysis, Western blot, cytological analysis and ELISA assay were performed to explore the effect of HMGB1 in acute allergic asthma. RESULTS The levels of HMGB1 in BALF and lung tissue and the expression of HMGB1 protein in the lung tissue of asthma group were significantly higher than those in control group, respectively (P<0.01). Moreover, the HMGB1 group was showed an increased mucus secretion and infiltration of eosinophils and neutrophils in the airway of asthma mice, and a decrease of pulmonary function, compared to control group (P<0.01, respectively). Meanwhile, exogenous HMGB1 could increase the levels of IL-4, IL-5, IL-6, IL-8 and IL-17, whereas could reduce the IFN-γ in the BALF and lung tissue (P<0.05, respectively). Exogenous HMGB1 could enhance GATA3 expression of Th2 cells and attenuate the T-bet expression of Th1 cells (P<0.05, respectively), which could be abrogated after inhibiting HMGB1. CONCLUSIONS HMGB1 could aggravate eosinophilic inflammation in the airway of acute allergic asthma through inducing a dominance of Th2-type response and promoting the neutrophilic inflammation.
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Affiliation(s)
- Libing Ma
- 1 Department of Respiratory Medicine, the Affiliated Hospital of Guilin Medical University, Guilin 541001, China ; 2 Institute of Respiratory Diseases, Guilin Medical University, Guilin 541001, China ; 3 Key Laboratory of Respiratory Diseases of Colleges and Universities Affiliated Education Department of Guangxi Zhuang Autonomous Region, Guilin 541001, China ; 4 Department of Respiratory Medicine, the Second Xiangya Hospital, Central South University, Changsha 410011, China
| | - Jinrong Zeng
- 1 Department of Respiratory Medicine, the Affiliated Hospital of Guilin Medical University, Guilin 541001, China ; 2 Institute of Respiratory Diseases, Guilin Medical University, Guilin 541001, China ; 3 Key Laboratory of Respiratory Diseases of Colleges and Universities Affiliated Education Department of Guangxi Zhuang Autonomous Region, Guilin 541001, China ; 4 Department of Respiratory Medicine, the Second Xiangya Hospital, Central South University, Changsha 410011, China
| | - Biwen Mo
- 1 Department of Respiratory Medicine, the Affiliated Hospital of Guilin Medical University, Guilin 541001, China ; 2 Institute of Respiratory Diseases, Guilin Medical University, Guilin 541001, China ; 3 Key Laboratory of Respiratory Diseases of Colleges and Universities Affiliated Education Department of Guangxi Zhuang Autonomous Region, Guilin 541001, China ; 4 Department of Respiratory Medicine, the Second Xiangya Hospital, Central South University, Changsha 410011, China
| | - Changming Wang
- 1 Department of Respiratory Medicine, the Affiliated Hospital of Guilin Medical University, Guilin 541001, China ; 2 Institute of Respiratory Diseases, Guilin Medical University, Guilin 541001, China ; 3 Key Laboratory of Respiratory Diseases of Colleges and Universities Affiliated Education Department of Guangxi Zhuang Autonomous Region, Guilin 541001, China ; 4 Department of Respiratory Medicine, the Second Xiangya Hospital, Central South University, Changsha 410011, China
| | - Jianwei Huang
- 1 Department of Respiratory Medicine, the Affiliated Hospital of Guilin Medical University, Guilin 541001, China ; 2 Institute of Respiratory Diseases, Guilin Medical University, Guilin 541001, China ; 3 Key Laboratory of Respiratory Diseases of Colleges and Universities Affiliated Education Department of Guangxi Zhuang Autonomous Region, Guilin 541001, China ; 4 Department of Respiratory Medicine, the Second Xiangya Hospital, Central South University, Changsha 410011, China
| | - Yabing Sun
- 1 Department of Respiratory Medicine, the Affiliated Hospital of Guilin Medical University, Guilin 541001, China ; 2 Institute of Respiratory Diseases, Guilin Medical University, Guilin 541001, China ; 3 Key Laboratory of Respiratory Diseases of Colleges and Universities Affiliated Education Department of Guangxi Zhuang Autonomous Region, Guilin 541001, China ; 4 Department of Respiratory Medicine, the Second Xiangya Hospital, Central South University, Changsha 410011, China
| | - Yuanyuan Yu
- 1 Department of Respiratory Medicine, the Affiliated Hospital of Guilin Medical University, Guilin 541001, China ; 2 Institute of Respiratory Diseases, Guilin Medical University, Guilin 541001, China ; 3 Key Laboratory of Respiratory Diseases of Colleges and Universities Affiliated Education Department of Guangxi Zhuang Autonomous Region, Guilin 541001, China ; 4 Department of Respiratory Medicine, the Second Xiangya Hospital, Central South University, Changsha 410011, China
| | - Shaokun Liu
- 1 Department of Respiratory Medicine, the Affiliated Hospital of Guilin Medical University, Guilin 541001, China ; 2 Institute of Respiratory Diseases, Guilin Medical University, Guilin 541001, China ; 3 Key Laboratory of Respiratory Diseases of Colleges and Universities Affiliated Education Department of Guangxi Zhuang Autonomous Region, Guilin 541001, China ; 4 Department of Respiratory Medicine, the Second Xiangya Hospital, Central South University, Changsha 410011, China
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Dong WW, Liu YJ, Lv Z, Mao YF, Wang YW, Zhu XY, Jiang L. Lung endothelial barrier protection by resveratrol involves inhibition of HMGB1 release and HMGB1-induced mitochondrial oxidative damage via an Nrf2-dependent mechanism. Free Radic Biol Med 2015; 88:404-416. [PMID: 25979658 DOI: 10.1016/j.freeradbiomed.2015.05.004] [Citation(s) in RCA: 63] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2015] [Revised: 04/10/2015] [Accepted: 05/04/2015] [Indexed: 12/12/2022]
Abstract
High-mobility group box 1 (HMGB1) contributes to lung vascular hyperpermeability during ventilator-induced lung injury. We aimed to determine whether the natural antioxidant resveratrol protected against HMGB1-induced endothelial hyperpermeability both in vitro and in vivo. We found that HMGB1 decreased vascular endothelial (VE)-cadherin expression and increased endothelial permeability, leading to mitochondrial oxidative damage in primary cultured mouse lung vascular endothelial cells (MLVECs). Both the mitochondrial superoxide dismutase 2 mimetic MnTBAP and resveratrol blocked HMGB1-induced mitochondrial oxidative damage, VE-cadherin downregulation, and endothelial hyperpermeability. In in vivo studies, anesthetized male ICR mice were ventilated for 4h using low tidal volume (6 ml/kg) or high tidal volume (HVT; 30 ml/kg) ventilation. The mice were injected intraperitoneally with resveratrol immediately before the onset of ventilation. We found that resveratrol attenuated HVT-associated lung vascular hyperpermeability and HMGB1 production. HVT caused a significant increase in nuclear factor-erythroid 2-related factor 2 (Nrf2) nuclear translocation and Nrf2 target gene expression in lung tissues, which was further enhanced by resveratrol treatment. HMGB1 had no effect on Nrf2 activation, whereas resveratrol treatment activated the Nrf2 signaling pathway in HMGB1-treated MLVECs. Moreover, Nrf2 knockdown reversed the inhibitory effects of resveratrol on HMGB1-induced mitochondrial oxidative damage and endothelial hyperpermeability. The inhibitory effect of resveratrol on cyclic stretch-induced HMGB1 mRNA expression in primary cultured MLVECs was also abolished by Nrf2 knockdown. In summary, this study demonstrates that resveratrol protects against lung endothelial barrier dysfunction initiated by HVT. Lung endothelial barrier protection by resveratrol involves inhibition of mechanical stretch-induced HMGB1 release and HMGB1-induced mitochondrial oxidative damage. These protective effects of resveratrol might be mediated through an Nrf2-dependent mechanism.
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Affiliation(s)
- Wen-Wen Dong
- Department of Anesthesiology and Surgical Intensive Care Unit, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, Peoples׳ Republic of China; School of Kinesiology, Key Laboratory of Exercise and Health Sciences, Ministry of Education, Shanghai University of Sport, Shanghai 200438, Peoples׳ Republic of China
| | - Yu-Jian Liu
- School of Kinesiology, Key Laboratory of Exercise and Health Sciences, Ministry of Education, Shanghai University of Sport, Shanghai 200438, Peoples׳ Republic of China
| | - Zhou Lv
- Department of Anesthesiology and Surgical Intensive Care Unit, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, Peoples׳ Republic of China
| | - Yan-Fei Mao
- Department of Anesthesiology and Surgical Intensive Care Unit, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, Peoples׳ Republic of China
| | - Ying-Wei Wang
- Department of Anesthesiology and Surgical Intensive Care Unit, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, Peoples׳ Republic of China.
| | - Xiao-Yan Zhu
- Department of Physiology and Key Laboratory of Molecular Neurobiology, Ministry of Education, Second Military Medical University, Shanghai 200433, Peoples׳ Republic of China.
| | - Lai Jiang
- Department of Anesthesiology and Surgical Intensive Care Unit, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, Peoples׳ Republic of China.
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Jabaudon M, Blondonnet R, Roszyk L, Bouvier D, Audard J, Clairefond G, Fournier M, Marceau G, Déchelotte P, Pereira B, Sapin V, Constantin JM. Soluble Receptor for Advanced Glycation End-Products Predicts Impaired Alveolar Fluid Clearance in Acute Respiratory Distress Syndrome. Am J Respir Crit Care Med 2015; 192:191-9. [PMID: 25932660 DOI: 10.1164/rccm.201501-0020oc] [Citation(s) in RCA: 112] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
RATIONALE Levels of the soluble form of the receptor for advanced glycation end-products (sRAGE) are elevated during acute respiratory distress syndrome (ARDS) and correlate with severity and prognosis. Alveolar fluid clearance (AFC) is necessary for the resolution of lung edema but is impaired in most patients with ARDS. No reliable marker of this process has been investigated to date. OBJECTIVES To verify whether sRAGE could predict AFC during ARDS. METHODS Anesthetized CD-1 mice underwent orotracheal instillation of hydrochloric acid. At specified time points, lung injury was assessed by analysis of blood gases, alveolar permeability, lung histology, AFC, and plasma/bronchoalveolar fluid measurements of proinflammatory cytokines and sRAGE. Plasma sRAGE and AFC rates were also prospectively assessed in 30 patients with ARDS. MEASUREMENTS AND MAIN RESULTS The rate of AFC was inversely correlated with sRAGE levels in the plasma and the bronchoalveolar fluid of acid-injured mice (Spearman's ρ = -0.73 and -0.69, respectively; P < 10(-3)), and plasma sRAGE correlated with AFC in patients with ARDS (Spearman's ρ = -0.59; P < 10(-3)). Similarly, sRAGE levels were significantly associated with lung injury severity, and decreased over time in mice, whereas AFC was restored and lung injury resolved. CONCLUSIONS Our results indicate that sRAGE levels could be a reliable predictor of impaired AFC during ARDS, and should stimulate further studies on the pathophysiologic implications of RAGE axis in the mechanisms leading to edema resolution. Clinical trial registered with www.clinicaltrials.gov (NCT 00811629).
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Affiliation(s)
- Matthieu Jabaudon
- 1 Intensive Care Unit, Department of Anesthesiology, Critical Care and Perioperative Medicine, Estaing University Hospital.,2 Clermont Université, Université d'Auvergne, Clermont-Ferrand, France
| | - Raiko Blondonnet
- 1 Intensive Care Unit, Department of Anesthesiology, Critical Care and Perioperative Medicine, Estaing University Hospital.,2 Clermont Université, Université d'Auvergne, Clermont-Ferrand, France
| | - Laurence Roszyk
- 3 Department of Medical Biochemistry and Molecular Biology.,2 Clermont Université, Université d'Auvergne, Clermont-Ferrand, France
| | - Damien Bouvier
- 3 Department of Medical Biochemistry and Molecular Biology.,2 Clermont Université, Université d'Auvergne, Clermont-Ferrand, France
| | - Jules Audard
- 1 Intensive Care Unit, Department of Anesthesiology, Critical Care and Perioperative Medicine, Estaing University Hospital
| | - Gael Clairefond
- 2 Clermont Université, Université d'Auvergne, Clermont-Ferrand, France
| | | | - Geoffroy Marceau
- 3 Department of Medical Biochemistry and Molecular Biology.,2 Clermont Université, Université d'Auvergne, Clermont-Ferrand, France
| | | | - Bruno Pereira
- 6 Department of Clinical Research and Innovation, CHU Clermont-Ferrand, Clermont-Ferrand, France; and
| | - Vincent Sapin
- 3 Department of Medical Biochemistry and Molecular Biology.,2 Clermont Université, Université d'Auvergne, Clermont-Ferrand, France
| | - Jean-Michel Constantin
- 1 Intensive Care Unit, Department of Anesthesiology, Critical Care and Perioperative Medicine, Estaing University Hospital.,2 Clermont Université, Université d'Auvergne, Clermont-Ferrand, France
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Pribis JP, Al-Abed Y, Yang H, Gero D, Xu H, Montenegro MF, Bauer EM, Kim S, Chavan SS, Cai C, Li T, Szoleczky P, Szabo C, Tracey KJ, Billiar TR. The HIV Protease Inhibitor Saquinavir Inhibits HMGB1-Driven Inflammation by Targeting the Interaction of Cathepsin V with TLR4/MyD88. Mol Med 2015; 21:749-757. [PMID: 26349060 DOI: 10.2119/molmed.2015.00197] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2015] [Accepted: 09/02/2015] [Indexed: 12/18/2022] Open
Abstract
Extracellular high-mobility group box 1 (HMGB1) (disulfide form), via activation of toll-like receptor 4 (TLR4)-dependent signaling, is a strong driver of pathologic inflammation in both acute and chronic conditions. Identification of selective inhibitors of HMGB1-TLR4 signaling could offer novel therapies that selectively target proximal endogenous activators of inflammation. A cell-based screening strategy led us to identify first generation HIV-protease inhibitors (PI) as potential inhibitors of HMGB1-TLR4 driven cytokine production. Here we report that the first-generation HIV-PI saquinavir (SQV), as well as a newly identified mammalian protease inhibitor STO33438 (334), potently block disulfide HMGB1-induced TLR4 activation, as assayed by the production of TNF-α by human monocyte-derived macrophages (THP-1). We further report on the identification of mammalian cathepsin V, a protease, as a novel target of these inhibitors. Cellular as well as recombinant protein studies show that the mechanism of action involves a direct interaction between cathepsin V with TLR4 and its adaptor protein MyD88. Treatment with SQV, 334 or the known cathepsin inhibitor SID26681509 (SID) significantly improved survival in murine models of sepsis and reduced liver damage following warm liver ischemia/reperfusion (I/R) models, both characterized by strong HMGB1-TLR4 driven pathology. The current study demonstrates a novel role for cathepsin V in TLR4 signaling and implicates cathepsin V as a novel target for first-generation HIV-PI compounds. The identification of cathepsin V as a target to block HMGB1-TLR4-driven inflammation could allow for a rapid transition of the discovery from the bench to the bedside. Disulfide HMGB1 drives pathologic inflammation in many models by activating signaling through TLR4. Cell-based screening identified the mammalian protease cathepsin V as a novel therapeutic target to inhibit TLR4-mediated inflammation induced by extracellular HMGB1 (disulfide form). We identified two protease inhibitors (PIs) that block cathepsin V and thereby inhibit disulfide HMGB1-induced TLR4 activation: saquinavir (SQV), a first-generation PI targeting viral HIV protease and STO33438 (334), targeting mammalian proteases. We discovered that cathepsin V binds TLR4 under basal and HMGB1-stimulated conditions, but dissociates in the presence of SQV over time. Thus cathepsin V is a novel target for first-generation HIV PIs and represents a potential therapeutic target of pathologic inflammation.
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Affiliation(s)
- John P Pribis
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.,Integrative Molecular and Biomedical Sciences Graduate Program, Baylor College of Medicine, Houston, Texas, United States of America
| | - Yousef Al-Abed
- Laboratory of Biomedical Science, The Feinstein Institute for Medical Research, Manhasset, New York, United States of America.,Department of Medicinal Chemistry, The Feinstein Institute for Medical Research, Manhasset, New York, United States of America
| | - Huan Yang
- Laboratory of Biomedical Science, The Feinstein Institute for Medical Research, Manhasset, New York, United States of America
| | - Domokos Gero
- Department of Anesthesiology, University of Texas Medical Branch, Galveston, Texas, United States of America
| | - Hongbo Xu
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.,The Third Xiangya Hospital, Central South University, Hunan, China
| | - Marcelo F Montenegro
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
| | - Eileen M Bauer
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
| | - Sodam Kim
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
| | - Sangeeta S Chavan
- Laboratory of Biomedical Science, The Feinstein Institute for Medical Research, Manhasset, New York, United States of America
| | - Changchun Cai
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
| | - Tunliang Li
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.,The Third Xiangya Hospital, Central South University, Hunan, China
| | - Petra Szoleczky
- Department of Anesthesiology, University of Texas Medical Branch, Galveston, Texas, United States of America
| | - Csaba Szabo
- Department of Anesthesiology, University of Texas Medical Branch, Galveston, Texas, United States of America
| | - Kevin J Tracey
- Laboratory of Biomedical Science, The Feinstein Institute for Medical Research, Manhasset, New York, United States of America
| | - Timothy R Billiar
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
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Stearoyl lysophosphatidylcholine prevents lipopolysaccharide-induced extracellular release of high mobility group box-1 through AMP-activated protein kinase activation. Int Immunopharmacol 2015. [DOI: 10.1016/j.intimp.2015.07.010] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
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Ramani V, Awasthi S. Toll-like receptor 4-interacting SPA4 peptide suppresses the NLRP3 inflammasome in response to LPS and ATP stimuli. J Leukoc Biol 2015; 98:1037-48. [PMID: 26254306 DOI: 10.1189/jlb.3a1114-570r] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2014] [Accepted: 07/18/2015] [Indexed: 12/18/2022] Open
Abstract
Inflammation is induced because of interplay among multiple signaling pathways and molecules during infectious and noninfectious tissue injuries. Crosstalk between Toll-like receptor-4 signaling and the neuronal apoptosis inhibitor protein, major histocompatibility class 2 transcription activator, incompatibility locus protein from Podospora anserina, and telomerase-associated protein (NACHT), leucine-rich repeat (LRR), and pyrin domain-containing protein 3 (NLRP3) inflammasome against pathogen- or damage-associated molecular patterns can cause exaggerated inflammation. We previously established that the Toll-like receptor-4-interacting SPA4 peptide suppresses gram-negative bacterial lipopolysaccharide (Toll-like receptor-4 ligand)-induced nuclear factor-κB and inflammatory response. In the present study, we hypothesized that the SPA4 peptide exerts its anti-inflammatory effects by suppressing the crosstalk between Toll-like receptor-4 signaling and the NLRP3 inflammasome. We evaluated binding of the lipopolysaccharide-ligand to cell-surface Toll-like receptor-4 in the presence or absence of adenosine triphosphate (an NLRP3 inflammasome inducer) by flow cytometry. The expression and activity of NLRP3 inflammasome-related parameters were studied in cells challenged with lipopolysaccharide and adenosine triphosphate using molecular and immunologic methods. The cells were challenged with lipopolysaccharide and treated with SPA4 peptide before (pre-adenosine triphosphate) or after (post-adenosine triphosphate) secondary challenge with adenosine triphosphate. Our data demonstrate that the Toll-like receptor-4-interacting SPA4 peptide does not affect the binding of lipopolysaccharide to Toll-like receptor-4 in the presence or absence of adenosine triphosphate. We also found that the SPA4 peptide inhibits mRNA and cellular protein levels of pro-interleukin-1β and NLRP3, formation of the NLRP3 inflammasome, caspase activity, and release of interleukin-1β. Furthermore, the SPA4 peptide treatment reduced the secreted levels of interleukin-1β from cells overexpressing Toll-like receptor-4 compared with cells expressing the dominant-negative form of Toll-like receptor-4. Together our results suggest that the SPA4 peptide exerts its anti-inflammatory activity by suppressing Toll-like receptor-4-priming of the NLRP3 inflammasome.
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Affiliation(s)
- Vijay Ramani
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
| | - Shanjana Awasthi
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
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Müller-Redetzky HC, Lienau J, Witzenrath M. The Lung Endothelial Barrier in Acute Inflammation. THE VERTEBRATE BLOOD-GAS BARRIER IN HEALTH AND DISEASE 2015. [PMCID: PMC7123850 DOI: 10.1007/978-3-319-18392-3_8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
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Kuipers MT, Aslami H, Tuinman PR, Tuip-de Boer AM, Jongsma G, van der Sluijs KF, Choi G, Wolthuis EK, Roelofs JJ, Bresser P, Schultz MJ, van der Poll T, Wieland CW. The receptor for advanced glycation end products in ventilator-induced lung injury. Intensive Care Med Exp 2014. [PMID: 26215707 PMCID: PMC4678142 DOI: 10.1186/s40635-014-0022-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
Background Mechanical ventilation (MV) can cause ventilator-induced lung injury (VILI). The innate immune response mediates this iatrogenic inflammatory condition. The receptor for advanced glycation end products (RAGE) is a multiligand receptor that can amplify immune and inflammatory responses. We hypothesized that RAGE signaling contributes to the pro-inflammatory state induced by MV. Methods RAGE expression was analyzed in lung brush and lavage cells obtained from ventilated patients and lung tissue of ventilated mice. Healthy wild-type (WT) and RAGE knockout (KO) mice were ventilated with relatively low (approximately 7.5 ml/kg) or high (approximately 15 ml/kg) tidal volume. Positive end-expiratory pressure was set at 2 cm H2O during both MV strategies. Also, WT and RAGE KO mice with lipopolysaccharide (LPS)-induced lung injury were ventilated with the above described ventilation strategies. In separate experiments, the contribution of soluble RAGE, a RAGE isoform that may function as a decoy receptor, in ventilated RAGE KO mice was investigated. Lung wet-to-dry ratio, cell and neutrophil influx, cytokine and chemokine concentrations, total protein levels, soluble RAGE, and high-mobility group box 1 (HMGB1) presence in lung lavage fluid were analyzed. Results MV was associated with increased RAGE mRNA levels in both human lung brush samples and lung tissue of healthy mice. In healthy high tidal volume-ventilated mice, RAGE deficiency limited inflammatory cell influx. Other VILI parameters were not affected. In our second set of experiments where we compared RAGE KO and WT mice in a 2-hit model, we observed higher pulmonary cytokine and chemokine levels in RAGE KO mice undergoing LPS/high tidal volume MV as compared to WT mice. Third, in WT mice undergoing the LPS/high tidal volume MV, we observed HMGB1 presence in lung lavage fluid. Moreover, MV increased levels of soluble RAGE in lung lavage fluid, with the highest levels found in LPS/high tidal volume-ventilated mice. Administration of soluble RAGE to LPS/high tidal volume-ventilated RAGE KO mice attenuated the production of inflammatory mediators. Conclusions RAGE was not a crucial contributor to the pro-inflammatory state induced by MV. However, the presence of sRAGE limited the production of pro-inflammatory mediators in our 2-hit model of LPS and high tidal volume MV. Electronic supplementary material The online version of this article (doi:10.1186/s40635-014-0022-1) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Maria T Kuipers
- Laboratory of Experimental Intensive Care and Anesthesiology (L.E.I.C.A), Academic Medical Centre, University of Amsterdam, room M0-220, Meibergdreef 9, Amsterdam, 1105 AZ, The Netherlands,
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