A Novel Anti-Histone H1 Monoclonal Antibody, SSV Monoclonal Antibody, Improves Lung Injury and Survival in a Mouse Model of Lipopolysaccharide-Induced Sepsis-Like Syndrome

Background. Histones play important roles in both host defenses and inflammation related to microbial infection. A peptide mimotope (SSV) was identified from a novel histone H1 monoclonal antibody (16G9 mAb) that was shown to inhibit the mixed lymphocyte reaction. In the present study, an anti-SSV producing hybridoma was established. We investigated the effects of SSV mAb in a mouse acute inflammation model induced by intraperitoneal injection of lipopolysaccharide (LPS).Methods. SSV mAb was generated and characterized. Mice were treated with SSV mAb or a control IgG antibody prior to LPS injection. Evaluation of survival rate and lung tissue on histological score was performed. The levels of inflammatory cytokines and histones H1, H3, and H4 in plasma and lung tissue were measured by ELISA.Results. Competitive ELISA revealed that SSV mAb binds to histone H1. SSV mAb improved lung injury and prolonged the survival of LPS-injected mice. Increased levels of histones H1, H3, and H4 and inflammatory cytokines (TNF-α, IL-1β, and IL-6) in plasma and lung tissue after LPS injection were ameliorated by SSV mAb.Conclusion. SSV mAb is shown to have anti-inflammatory activity and organ-protective effects, highlighting the importance of controlling histone H1 as well as H3 and H4 levels during inflammation.

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Protectin conjugates in tissue regeneration 1 restores lipopolysaccharide-induced pulmonary endothelial glycocalyx loss via ALX/SIRT1/NF-kappa B axis

Respiratory Research ◽

10.1186/s12931-021-01793-x ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Xin-Yang Wang ◽

Xin-Yu Li ◽

Cheng-Hua Wu ◽

Yu Hao ◽

Pan-Han Fu ◽

...

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Inflammatory Cytokines ◽

Tissue Regeneration ◽

Umbilical Vein ◽

Endothelial Glycocalyx ◽

Lipid Mediator ◽

Protective Effects ◽

Pulmonary Vascular Permeability

Abstract Background Endothelial glycocalyx loss is integral to increased pulmonary vascular permeability in sepsis-related acute lung injury. Protectin conjugates in tissue regeneration 1 (PCTR1) is a novel macrophage-derived lipid mediator exhibiting potential anti-inflammatory and pro-resolving benefits. Methods PCTR1 was administrated intraperitoneally with 100 ng/mouse after lipopolysaccharide (LPS) challenged. Survival rate and lung function were used to evaluate the protective effects of PCTR1. Lung inflammation response was observed by morphology and inflammatory cytokines level. Endothelial glycocalyx and its related key enzymes were measured by immunofluorescence, ELISA, and Western blot. Afterward, related-pathways inhibitors were used to identify the mechanism of endothelial glycocalyx response to PCTR1 in mice and human umbilical vein endothelial cells (HUVECs) after LPS administration. Results In vivo, we show that PCTR1 protects mice against lipopolysaccharide (LPS)-induced sepsis, as shown by enhanced the survival and pulmonary function, decreased the inflammatory response in lungs and peripheral levels of inflammatory cytokines such as tumor necrosis factor-α, interleukin-6, and interleukin-1β. Moreover, PCTR1 restored lung vascular glycocalyx and reduced serum heparin sulphate (HS), syndecan-1 (SDC-1), and hyaluronic acid (HA) levels. Furthermore, we found that PCTR1 downregulated heparanase (HPA) expression to inhibit glycocalyx degradation and upregulated exostosin-1 (EXT-1) protein expression to promote glycocalyx reconstitution. Besides, we observed that BAY11-7082 blocked glycocalyx loss induced by LPS in vivo and in vitro, and BOC-2 (ALX antagonist) or EX527 (SIRT1 inhibitor) abolished the restoration of HS in response to PCTR1. Conclusion PCTR1 protects endothelial glycocalyx via ALX receptor by regulating SIRT1/NF-κB pathway, suggesting PCTR1 may be a significant therapeutic target for sepsis-related acute lung injury.

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The Protection Effect of Ulinastatin on Freshwater Instillation-Induced Acute Lung Injury in Rabbits

10.21203/rs.3.rs-137414/v1 ◽

2021 ◽

Author(s):

Shaosong Xi ◽

Le Huan ◽

Hongyan Wu ◽

Ying Zhu ◽

Wei Hu ◽

...

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Inflammatory Cytokines ◽

Large Dose ◽

Weight Ratio ◽

Endothelial Permeability ◽

Potential Candidate ◽

Protective Effects ◽

Arterial Blood ◽

Vegf Pathway

Abstract Background: Drowning is an important cause of accidental death in humans. The main cause of death following drowning is pulmonary oedema or lung injury, eventually leading to acute respiratory distress syndrome. The present study aimed to determine the protective effects of Ulinastatin on freshwater-induced acute drowning lung injury. Methods: Rabbits were randomly divided into a control, freshwater, freshwater + small-dose Ulinastatin, freshwater + medium-dose Ulinastatin, freshwater + large-dose Ulinastatin group. The arterial blood gas analysis was performed before modelling (baseline) and at various time points after freshwater instillation. And then, the wet-to-dry weight ratio lung permeability index were measured to detect the effect of Ulinastatin on lung endothelial permeability. Furthermore, histopathological staining and ELISAs were used to analyse the histological changes and inflammatory cytokines expression resulted from lung injury, respectively. Western blotting and Quantitative real-time polymerase chain reaction were used to measure the protein and mRNA levels of Hypoxia inducible factor-lα (HIF-1α)/ Vascular endothelial growth factor (VEGF) in the lung tissues. Results: By inhibiting the HIF-1α/VEGF pathway, treatment with Ulinastatin at a large dose could markedly attenuate changes in the PaO2/FiO2 (P/F), lung endothelial permeability, histopathology, and the expression of inflammatory cytokines induced by freshwater instillation. Conclusion: Ulinastatin is a potential candidate treatment for freshwater drowning-induced acute lung injury that targets the HIF-1α/VEGF pathway.

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Roflumilast, a phosphodiesterase-4 inhibitor, improves hyperoxia-induced lung injury via anti-inflammation

Undersea and Hyperbaric Medicine ◽

10.22462/04.06.2020.3 ◽

2020 ◽

Vol 47 (2) ◽

pp. 189-196

Author(s):

Hong-Ying Cao ◽

◽

Tian-Hua Yu ◽

Cui-Hong Han ◽

Wen-Wu Liu ◽

...

Keyword(s):

Lung Injury ◽

Inflammatory Cytokines ◽

Pure Oxygen ◽

Control Group ◽

Lung Edema ◽

Lung Pathology ◽

Protective Effects ◽

Lactate Dehydrogenase Activity ◽

Phosphodiesterase 4 ◽

Hyperoxia Exposure

Roflumilast is an inhibitor of phosphodiesterase-4 (PDE4) and can suppress the hydrolysis of cAMP in inflammatory cells, conferring anti-inflammatory effects. This study aimed to investigate the protective effects of roflumilast on hyperoxia-induced acute lung injury (HALI) in a rat model. Male Sprague-Dawley rats were randomly assigned into: control group; HALI group; 2.5 mg/kg roflumilast group; and 5 mg/kg roflumilast group. Rats were pressurized to 250 kPa with pure oxygen to induce lung injury. In the roflumilast groups, rats were orally administered with roflumilast at 2.5 or 5 mg/kg once before hyperoxia exposure and once daily for two days after exposure. Rats were sacrificed 72 hours after hyperoxia exposure. The lung tissues were collected for the detection of lung water content, inflammatory cytokines and NF-κB/p-NF-κB protein expression, and the bronchoalveolar lavage fluid was harvested for the measurement of protein concentration and lactate dehydrogenase activity. Results showed roflumilast at different doses could significantly reduce lung edema, improve lung pathology and reduce the expression of inflammatory cytokines in the lung. The protective effects seemed to be related to the dose of roflumilast. Our study indicates roflumilast has the potential as a medication for the treatment of HALI.

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Curcumin therapy: Immune booster in present and post-pandemic (COVID-19) Era

International Journal of Research in Pharmaceutical Sciences ◽

10.26452/ijrps.v12i4.4906 ◽

2021 ◽

Vol 12 (4) ◽

pp. 2566-2572

Author(s):

Shubha P ◽

Shyamsundar S ◽

Manjunatha H B

Keyword(s):

Lung Injury ◽

Inflammatory Cytokines ◽

Lung Tissue ◽

Therapeutic Agent ◽

Tissue Injury ◽

Curcuma Longa ◽

Clinical Feature ◽

World Population ◽

Human Beings ◽

Healthy Human

COVID-19 pandemic, which has traumatized the world population, in principle, is an inflammatory lung disease secondary to SARS-COV2 virus infection. Inflammatory lung injury progressing to Acute Respiratory Distress Syndrome (ARDS) is a recognized clinical feature of the disease. Inflammatory cytokines released in response to COVID-19 activate the transcription factor - the nuclear factor-қB (NF-қB) and series of pro-inflammatory cytokines, which are responsible for lung injury. Accurate yet precise treatment of coronavirus disease still remains inconclusive, and intervention is mainly symptomatic treatment, respiratory support, antiviral therapies and vaccination. Currently, the major focus of therapy is on reducing lung inflammation by elevating the host immunity. In this scenario, NF-қB inhibition can be conceptualized as a promising approach to down-regulate the overproduction of cytokines, such that inflammatory lung tissue injury could be prevented in COVID-19 infected patients. Towards this, curcumin from Curcuma longa (Turmeric) would play a vital role in the intervention and suppress NF-қB activation via translocation of p65 into the nucleus. Moreover, Curcumin is a proven therapeutic agent against various inflammatory pathologies as it also has the potential to inhibit the expression of certain genes that are critical for the regulation of inflammation. Keeping this phenomenon and the current medical significance in view, we have explored and computed the anti-inflammatory properties of curcumin to develop it as a potent therapeutic agent to prevent NF-қB induced lung tissue injury in COVID-19 with the main goal of elevating immunity in the post-covid-19 situations as well as in healthy human beings.

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Amentoflavone prevents sepsis-associated acute lung injury through Nrf2-GCLc-mediated upregulation of glutathione

Acta Biochimica Polonica ◽

10.18388/abp.2016_1296 ◽

2016 ◽

Vol 64 (1) ◽

Cited By ~ 7

Author(s):

Yuan Zong ◽

Huali Zhang

Keyword(s):

Oxidative Stress ◽

Acute Lung Injury ◽

Lung Injury ◽

Lung Tissue ◽

Medical Problem ◽

Binding Activity ◽

Content Increase ◽

Protective Effects ◽

Sod Activity ◽

Buthionine Sulphoximine

Sepsis is a serious medical problem that is one of the main causes of high mortality in intensive care units. Fifty percent of patients with severe sepsis will develop acute lung injury (ALI). Amentoflavone (AMF) is a polyphenolic compound possessing potent anti-inflammatory activities. The present study was designed to explore the protective effects of AMF against ALI in CLP-induced septic rats. The results showed that AMF administration protected against septic ALI, as reflected by marked amelioration of histological injury of lung tissues and decrease of pulmonary edema in CLP-treated rats. AMF ameliorated CLP-induced increase of systemic and lung TNF-α and IL-1β and the binding activity of p65 NF-κB, indicating the inhibition of inflammation induced by CLP. Moreover, AMF prevented CLP-induced oxidative stress, as evidenced by increase of oxygen consumption rate, decrease of TBARS content, increase of SOD activity and GSH level in lung tissue of CLP-treated rats. CLP resulted in significant decrease of mRNA expression of Nrf2 and GCLc, which was inhibited by AMF. AMF-induced protective effects on ALI, inflammation, and oxidative stress were inhibited by lentivirus-mediated shRNA of Nrf2 and buthionine sulphoximine (BSO), an inhibitor of GSH synthesis. AMF increased Nrf2-binding activity with GCLc promoters in lung tissue of CLP-treated rats. The results suggested that AMF protected against ALI in septic rats through upregulation of Nrf2-GCLc signaling, enhancement of GSH antioxidant defense, reduction of oxidative stress and final amelioration of inflammation and histological injury of lung. The data provide new therapeutic options for the treatment of sepsis-associated ALI.

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Protective effects of ulinastatin and methylprednisolone against radiation-induced lung injury in mice

Journal of Radiation Research ◽

10.1093/jrr/rrw036 ◽

2016 ◽

Vol 57 (5) ◽

pp. 505-511 ◽

Cited By ~ 4

Author(s):

Yu Sun ◽

Yu-Jun Du ◽

Hui Zhao ◽

Guo-Xing Zhang ◽

Ni Sun ◽

...

Keyword(s):

Lung Injury ◽

Lung Tissue ◽

Transforming Growth Factor ◽

Lavage Fluid ◽

Protective Effects ◽

Pathological Changes ◽

Tnf Α ◽

Methylprednisolone Treatment ◽

Radiation Induced ◽

Tgf Β1

Abstract The effectiveness of ulinastatin and methylprednisolone in treating pathological changes in mice with radiation-induced lung injury (RILI) was evaluated. Forty C57BL/6 female mice received whole-chest radiation (1.5 Gy/min for 12 min) and were randomly allocated into Group R (single radiation, n = 10), Group U (ulinastatin treatment, n = 10), Group M (methylprednisolone treatment, n = 10), or Group UM (ulinastatin and methylprednisolone treatment, n = 10). Another 10 untreated mice served as controls (Group C). Pathological changes in lung tissue, pulmonary interstitial area density (PIAD) and expression levels of transforming growth factor β1 (TGF-β1) and tumor necrosis factor α (TNF-α) in lung tissue, serum and bronchoalveolar lavage fluid were determined. Alleviation of pathological changes in lung tissue was observed in Groups U, M and UM. Treatment with ulinastatin, methylprednisolone or both effectively delayed the development of fibrosis at 12 weeks after radiation. Ulinastatin, methylprednisolone or both could alleviate the radiation-induced increase in the PIAD ( P < 0.05 or P < 0.01). Treatment with ulinastatin, methylprednisolone or both significantly reduced the expression of TNF-α, but not TGF-β1, at 9 weeks after radiation compared with Group R ( P < 0.01). Ulinastatin and / or methylprednisolone effectively decreased the level of TNF-α in lung tissue after RILI and inhibited both the inflammatory response and the development of fibrosis.

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IL-6 knockout alleviates inflammatory response and improve acute lung injury via regulating macrophage polarization in sepsis

10.21203/rs.3.rs-618570/v2 ◽

2021 ◽

Author(s):

Jinxin Zhang ◽

Kuo Shen ◽

Jiangang Xie ◽

Shanshou Liu ◽

Xiaozhi Bai ◽

...

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Western Blot ◽

Bronchoalveolar Lavage ◽

Inflammatory Cytokines ◽

Lung Tissue ◽

General Condition ◽

Death Rate ◽

Bronchoalveolar Lavage Fluid ◽

Lavage Fluid

Abstract BackgroundSepsis is a fatal disease with a high rate of morbidity and mortality, during which acute lung injury is the earliest and most serious complication. Macrophage plays a crucial role in the initiation and progress of sepsis. This study meant to explore the effect of IL-6 knockout in CLP induced sepsis.MethodsIn this study, cecal ligation and puncture (CLP) was performed on wildtype and interleukin 6 (IL-6) knockout C57 mice. General condition and death rate of sepsis mice were observed. organ samples (lungs, livers, kidneys and hearts) and serum were collected for histology observation and inflammatory cytokine detection. Lung tissue injury detection were conducted via lung injury score, wet/dry ration and protein concentrations measurement of Bronchoalveolar lavage fluid (BALF). In in vivo studies, RAW264.7 macrophages were transfected with IL-6 specific siRNA and treated with LPS. After exposed to IL-6 specific siRNA and LPS, expression of inflammatory cytokines interleukin 1 (IL-1), tumor necrosis factor- (TNF-), IL-6 and interleukin 10 (IL-10) were detected by RT-qPCR, concentration of IL-1 and TNF- in culture supernatant were detected by ELISA and M1 and M2 markers were detected by western blot and flow cytometry.ResultsWe constructed CLP induced sepsis models and found that inhibition of IL-6 could improve general condition and death rate of sepsis mice. Mice in IL-6 knockout group display improved tissue damage, especially in the lung tissue. IL-6 knockout relieved inflammatory cytokines storm in both serum and bronchoalveolar lavage fluid while polarized macrophage to an anti-inflammatory M2 phenotype. In cell model, inhibition of IL-6 could alleviate LPS induced expression of inflammatory cytokines IL-1, TNF-, and IL-6 in macrophages. Western blot and Flow cytometry results indicated that expression of M1 markers (iNOS and CD86) in LPS stimulated macrophages were significantly declined while M2 (Arg-1 and CD206) were enhanced when expression of IL-6 was blocked.Conclusion Inhibition of IL-6 alleviated LPS induced inflammation and exerted protective effect in sepsis via regulating macrophage function and polarization.

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Protectin Conjugates in Tissue Regeneration 1 Restores Lipopolysaccharide-Induced Pulmonary Endothelial Glycocalyx Loss via ALX/SIRT1/NF-kappa B Axis

10.21203/rs.3.rs-102371/v1 ◽

2020 ◽

Author(s):

Xin-Yang Wang ◽

Xin-Yu Li ◽

Cheng-Hua Wu ◽

Yu Hao ◽

Pan-Han Fu ◽

...

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Inflammatory Cytokines ◽

Tissue Regeneration ◽

Umbilical Vein ◽

Endothelial Glycocalyx ◽

Lipid Mediator ◽

Protective Effects ◽

Pulmonary Vascular Permeability

Abstract Background: Endothelial glycocalyx loss is integral to increased pulmonary vascular permeability in sepsis-related acute lung injury. Protectin conjugates in tissue regeneration 1 (PCTR1) is a novel macrophage-derived lipid mediator exhibiting potential anti-inflammatory and pro-resolving benefits. Methods: PCTR1 was administrated intraperitoneally with 100 ng/mouse after lipopolysaccharide (LPS) challenged. Survival rate and lung function were used to evaluate the protective effects of PCTR1. Lung inflammation response was observed by morphology and inflammatory cytokines level. Endothelial glycocalyx and its related key enzymes were measured by immunofluorescence, ELISA, and Western blot. Afterward, related-pathways inhibitors were used to identify the mechanism of endothelial glycocalyx response to PCTR1 in mice and human umbilical vein endothelial cells (HUVECs) after LPS administration.Results: In vivo, we show that PCTR1 protects mice against lipopolysaccharide (LPS)-induced sepsis, as shown by enhanced the survival and pulmonary function, decreased the inflammatory response in lungs and peripheral levels of inflammatory cytokines such as tumor necrosis factor-α, interleukin-6, and interleukin-1β. Moreover, PCTR1 restored lung vascular glycocalyx and reduced serum heparin sulphate (HS), syndecan-1 (SDC-1), and hyaluronic acid (HA) levels. Furthermore, we found that PCTR1 downregulated heparanase (HPA) expression to inhibit glycocalyx degradation and upregulated exostosin-1 (EXT-1) protein expression to promote glycocalyx reconstitution. Besides, we observed that BAY11-7082 blocked glycocalyx loss induced by LPS in vivo and in vitro, and BOC-2（ALX antagonist） or EX527（SIRT1 inhibitor） abolished the restoration of HS in response to PCTR1. Conclusion: PCTR1 protects endothelial glycocalyx via ALX receptor by regulating SIRT1/NF-κB pathway, suggesting PCTR1 may be a significant therapeutic target for sepsis-related acute lung injury.

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Therapeutic Efficacy of Excretory-Secretory Products of Trichinella spiralis Adult Worms on Sepsis-Induced Acute Lung Injury in a Mouse Model

Frontiers in Cellular and Infection Microbiology ◽

10.3389/fcimb.2021.653843 ◽

2021 ◽

Vol 11 ◽

Author(s):

Huihui Li ◽

Dapeng Qiu ◽

Huijuan Yang ◽

Yuan Yuan ◽

Lingqin Wu ◽

...

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Therapeutic Effect ◽

Inflammatory Cytokines ◽

Lung Tissue ◽

Therapeutic Efficacy ◽

Trichinella Spiralis ◽

Inflammatory Diseases ◽

Secretory Products ◽

Pro Inflammatory Cytokines

Acute lung injury (ALI) is a common complication of systemic inflammation or sepsis with high morbidity and mortality. Although many studies have confirmed that helminth-derived proteins had strong immunomodulatory functions and could be used to treat inflammatory diseases, there is no report on the therapeutic effect of excretory-secretory products of Trichinella spiralis adult worms (Ts-AES) on sepsis-induced ALI. In this study, the therapeutic efficacy of Ts-AES on sepsis-induced ALI and the underlying immunological mechanism and the signaling pathway were investigated. The results indicated that after being treated with Ts-AES, the survival rate of mice with CLP-induced sepsis was significantly increased to 50% for 72 hours after CLP surgery compared to PBS control group with all mice died. The sepsis-induced ALI was largely mitigated characterized by reduced inflammation cell infiltration and pathological changes in lung tissue, with decreased lung injury scores and lung wet/dry weight ratio. The therapeutic efficacy of Ts-AES is associated with stimulated Tregs response with increased regulatory cytokines IL-10 and TGF-β and downregulated pro-inflammatory cytokines (TNF-α, IL-6, IL-1β). The expression of HMGB1, TLR2 and MyD88 in lung tissue was inhibited after treatment of Ts-AES. Our results demonstrated that Ts-AES play an important role in immunomodulation and confer a therapeutic effect on sepsis-induced ALI through inhibiting pro-inflammatory cytokines. The activation of Tregs and increased level of regulatory cytokines IL-10 and TGF-β are possibly involved in the immunomodulatory functions of Ts-AES through HMGB1/TLR2/MyD88 signal pathway. The findings suggest Ts-AES is a potential therapeutic agent for prevention and treatment of sepsis-induced ALI and other inflammatory diseases.

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HMGB1 and inflammatory cytokines in experimental acute lung injury induced in rabbits

Arquivo Brasileiro de Medicina Veterinária e Zootecnia ◽

10.1590/1678-4162-11499 ◽

2020 ◽

Vol 72 (4) ◽

pp. 1329-1338

Author(s):

C.S. Kurokawa ◽

J.P. Araújo Júnior ◽

R.B. Pires ◽

M.F. Carpi ◽

M.A. Moraes ◽

...

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Bronchoalveolar Lavage ◽

Inflammatory Cytokines ◽

Lung Tissue ◽

Tnf Alpha ◽

Control Group ◽

Early Expression

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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