Role of Toll-Like Receptor 4 on Lupus Lung Injury and Atherosclerosis in LPS-Challenge ApoE−/−Mice

To investigate the pathologic mechanisms of toll-like receptor 4 (TLR4) in lung injury and atherosclerosis, ApoE−/−or wild-type mice were intraperitoneally administered saline, lipopolysaccharides (LPS), or LPS plus TAK-242 (TLR4 inhibitor), respectively, twice a week for 4 weeks. Serum autoantibody of antinuclear antibody (ANA), anti-double-stranded DNA (anti-dsDNA), and cytokines of interferon-gamma (IFN-γ), tumor necrosis factor (TNF-α), and interleukin-1 (IL-1β) were assessed by ELISA. Hematoxylin and eosin (HE) and Perl's stains for lung pathomorphology as well as HE staining for atherosclerosis were employed. TLR4 in macrophages was detected by double immunofluorescent staining. While protein expressions of TLR4, nuclear factor-kappa B p65 (NF-κB p65), and B cell activating factor belonging to the TNF family (BAFF) were examined by immunohistochemistry. We found that serum autoantibody (ANA and anti-dsDNA), cytokines (IFN-γ, TNF-α, IL-1β), lung inflammation, and intima-media thickness in brachiocephalic artery were obviously increased after LPS challenge in both genotypes, but to a lesser extent in wild-type strains. And those alterations were alleviated by coadministration of LPS and TAK-242. Mechanistically, upregulation of TLR4, NF-κb, and BAFF was involved. We concluded that TLR4/NF-κb/BAFF in macrophages might be a possible common autoimmune pathway that caused lung injury and atherosclerosis. TLR4 signal will be a therapeutic target in atherosclerosis and immune-mediated lung injury.

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Toll-Like Receptor 4 Mediates Heme Induced Acute Lung Injury: Preclinical Study of Resatorvid in Sickle Cell Disease

Blood ◽

10.1182/blood.v118.21.2113.2113 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2113-2113 ◽

Cited By ~ 2

Author(s):

Samit Ghosh ◽

Olufolake Adisa ◽

Yu Yang ◽

Fang Tan ◽

Solomon F Ofori-Acquah

Keyword(s):

Acute Lung Injury ◽

Sickle Cell Disease ◽

Lung Injury ◽

Sickle Cell ◽

Acute Chest Syndrome ◽

Toll Like Receptor ◽

Wild Type ◽

Cell Disease ◽

Toll Like Receptor 4 ◽

Breath Rate

Abstract Abstract 2113 Sickle cell disease (SCD) is characterized by multiple exacerbating events that cause intravascular hemolysis. Heme released into the circulation is scavenged by multiple plasma proteins and delivered to the liver for degradation. Our recent data indicate that this process is impaired in SCD resulting in excess protein-free plasma heme (PFPH) that triggers a lethal form of acute lung injury (ALI) in mice. In this study, we tested the hypothesis that toll-like receptor 4 (TLR4) mediates heme-induced ALI. Wild-type and two TLR4 mutant strains (B6.B10ScN-Tlr4lps-del/JthJ and C3H/HeJ) were intravenously injected with a dose range of ferric heme (0–210 micromoles/kg) and respiratory function monitored using a pulse oximeter. Excess PFPH was associated with reductions in oxygen saturation (SpO2) and breath rate in the wild-type mice but not in the TLR4 variants. Lungs of heme-treated wild-type mice were congested, edematous, hemorrhagic, and had thickened alveolar walls, while no histological abnormalities were found in the TLR4 variants. All heme-treated wild-type mice succumbed within 2 hours, while all TLR4 variants survived. Transgenic mice expressing exclusively human sickle hemoglobin (SS) were intravenously injected with a small molecule TLR4 inhibitor (resatorvid/TAK-242), or a lipid vehicle prior to induction of lung injury with heme (35 micromoles/kg). TAK-242 preserved lung function in the majority of SS mice that failed to scavenge excess PFPH, while both SpO2 and breath rate deteriorated in vehicle treated mice. The unique response to heme by TAK-242 and vehicle-treated SS mice was supported by histological analysis and survival (TAK-242; 76.9% vehicle; 23.5%, n=13–17; log-rank survival test, p<0.01). We provide the first evidence that the interaction between heme and TLR4 can be pathological, specifically causing a lethal form of ALI. Our data on TAK-242, a phase II drug, offers an attractive option to explore TLR4 inhibition as a novel therapeutic strategy to limit progression of acute chest syndrome. Disclosures: Ofori-Acquah: Emory University: Patents & Royalties.

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Reduced thromboxane biosynthesis in carriers of toll-like receptor 4 polymorphisms in vivo

Blood ◽

10.1182/blood-2005-12-4811 ◽

2006 ◽

Vol 107 (9) ◽

pp. 3572-3574 ◽

Cited By ~ 28

Author(s):

Paola Patrignani ◽

Concetta Di Febbo ◽

Stefania Tacconelli ◽

Valeria Moretta ◽

Giovanna Baccante ◽

...

Keyword(s):

Urinary Excretion ◽

Intima Media Thickness ◽

Selective Inhibition ◽

Toll Like Receptor ◽

Wild Type ◽

Toll Like Receptor 4 ◽

The Common ◽

Common Carotid Arteries ◽

Recent Demonstration

The recent demonstration that platelets express a functional toll-like receptor 4 (TLR4) prompted us to explore the influence of TLR4 polymorphisms (Asp299Gly alone or in combination with Thr399Ile) on thromboxane A2 (TXA2) biosynthesis in vivo. In 17 subjects with TLR4 polymorphisms versus 17 wild type (untreated with aspirin, matched for age, sex, and cardiovascular risk factors), intima-media thickness in the common carotid arteries was significantly lower. Average urinary excretion of 11-dehydro-TXB2, an index of systemic biosynthesis of TX, was significantly reduced by 65%. The urinary excretion of 2,3-dinor-6-keto-prostaglandin F1α, an index of systemic biosynthesis of prostacyclin, was marginally depressed but the prostacyclin/TXA2 biosynthesis ratio was significantly higher than in wild type. Selective inhibition of cyclooxygenase 2-dependent prostacyclin (by rofecoxib or etoricoxib) was associated with increased urinary excretion of 11-dehydro-TXB2 in carriers of TLR4 polymorphisms, but not in wild-type, suggesting a restrainable effect of prostacyclin on platelet function in vivo in this setting. Reduced TXA2 biosynthesis may contribute to the protective cardiovascular phenotype of TLR4 polymorphisms.

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Neutrophil Extracellular Traps Are Pathogenic in Ventilator-Induced Lung Injury and Partially Dependent on TLR4

BioMed Research International ◽

10.1155/2017/8272504 ◽

2017 ◽

Vol 2017 ◽

pp. 1-13 ◽

Cited By ~ 9

Author(s):

Haosi Li ◽

Pinhua Pan ◽

Xiaoli Su ◽

Shuai Liu ◽

Lemeng Zhang ◽

...

Keyword(s):

Lung Injury ◽

Neutrophil Extracellular Traps ◽

Toll Like Receptor ◽

Wild Type ◽

Toll Like Receptor 4 ◽

Mechanically Ventilated ◽

Extracellular Traps ◽

Ventilator Induced Lung Injury ◽

Dnase Treatment

The pathogenesis of ventilator-induced lung injury (VILI) is associated with neutrophils. Neutrophils release neutrophil extracellular traps (NETs), which are composed of DNA and granular proteins. However, the role of NETs in VILI remains incompletely understood. Normal saline and deoxyribonuclease (DNase) were used to study the role of NETs in VILI. To further determine the role of Toll-like receptor 4 (TLR4) in NETosis, we evaluated the lung injury and NET formation in TLR4 knockout mice and wild-type mice that were mechanically ventilated. Some measures of lung injury and the NETs markers were significantly increased in the VILI group. DNase treatment markedly reduced NETs markers and lung injury. After high-tidal mechanical ventilation, the NETs markers in the TLR4 KO mice were significantly lower than in the WT mice. These data suggest that NETs are generated in VILI and pathogenic in a mouse model of VILI, and their formation is partially dependent on TLR4.

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Toll-like Receptor 4-Myeloid Differentiation Factor 88 Signaling Contributes to Ventilator-induced Lung Injury in Mice

Anesthesiology ◽

10.1097/aln.0b013e3181e89ab2 ◽

2010 ◽

Vol 113 (3) ◽

pp. 619-629 ◽

Cited By ~ 15

Author(s):

Huihua Li ◽

Xiaoli Su ◽

Xuebin Yan ◽

Karla Wasserloos ◽

Wei Chao ◽

...

Keyword(s):

Lung Injury ◽

Myeloid Differentiation ◽

Toll Like Receptor ◽

Wild Type ◽

Toll Like Receptor 4 ◽

Ventilator Induced Lung Injury ◽

Differentiation Factor ◽

Extracellular Signal ◽

Myd88 Signaling ◽

Myeloid Differentiation Factor

Background The mechanisms of ventilator-induced lung injury, an iatrogenic inflammatory condition induced by mechanical ventilation, are not completely understood. Toll-like receptor 4 (TLR4) signaling via the adaptor protein myeloid differentiation factor 88 (MyD88) is proinflammatory and plays a critical role in host immune response to invading pathogen and noninfectious tissue injury. The role of TLR4-MyD88 signaling in ventilator-induced lung injury remains incompletely understood. Methods Mice were ventilated with low or high tidal volume (HTV), 7 or 20 ml/kg, after tracheotomy for 4 h. Control mice were tracheotomized without ventilation. Lung injury was assessed by: alveolar capillary permeability to Evans blue albumin, wet/dry ratio, bronchoalveolar lavage analysis for cell counts, total proteins and cytokines, results of histopathological examination of the lung, and plasma cytokine levels. Results Wild-type mice subjected to HTV had increased pulmonary permeability, inflammatory cell infiltration/lung edema, and interleukin-6/macrophage-inflammatory protein-2 in the lavage compared with control mice. In HTV, levels of inhibitor of kappaB alpha decreased, whereas phosphorylated extracellular signal-regulated kinases increased. TLR4 mutant and MyD88 mice showed markedly attenuated response to HTV, including less lung inflammation, pulmonary edema, cell number, protein content, and the cytokines in the lavage. Furthermore, compared with wild-type mice, both TLR4 mutant and MyD88 mice had significantly higher levels of inhibitor of kappaB alpha and reduced extracellular signal-regulated kinase phosphorylation after HTV. Conclusions TLR4-MyD88 signaling plays an important role in the development of ventilator-induced lung injury in mice, possibly through mechanisms involving nuclear factor-kappaB and mitogen-activated protein kinase pathways.

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Chelidonine Attenuates Sepsis-Induced Acute Lung Injury via Suppressing Toll-like Receptor 4/Myeloid Differentiation Factor 88/Nuclear Factor-॔B Signaling Pathway in Newborn Mice

Current Topics in Nutraceutical Research ◽

10.37290/ctnr2641-452x.19:120-126 ◽

2020 ◽

Vol 19 (1) ◽

pp. 120-126

Author(s):

Ayinuerguli Adili ◽

Adilijiang Kari ◽

Chuanlong Song ◽

Abulaiti Abuduhaer

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Nuclear Factor Kappa B ◽

Myeloid Differentiation ◽

Nuclear Factor ◽

Toll Like Receptor ◽

Toll Like Receptor 4 ◽

Inflammatory Infiltration ◽

Newborn Mice ◽

Myeloid Differentiation Factor

We have examined the mechanism underlying amelioration of sepsis-induced acute lung injury by chelidonine in newborn mice. To this end, a sepsis model was established using cecal ligation and puncture in newborn mice. The sepsis-induced acute lung injury was associated with an increased inflammatory infiltration and pulmonary congestion, as well as abnormal alveolar morphology. The lung injury-associated increased tumor necrosis factor-α and interleukin-1β in bronchoalveolar lavage fluid and lung, the markers of inflammatory infiltration and pulmonary congestion, diminished by chelidonine treatment. Chelidonine administration also downregulated protein levels of toll-like receptor 4, myeloid differentiation factor 88, phosphorylated nuclear factor-kappa B, and nuclear factor-kappa B that are elevated in response to sepsis. In conclusion, chelidonine provides a potential therapeutic strategy for newborn mice with acute lung injury.

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Juglone Attenuates Sepsis-Induced Acute Lung Injury via Suppression of the TLR4/Nf-κb Pathway

Current Topics in Nutraceutical Research ◽

10.37290/ctnr2641-452x.18:201-206 ◽

2020 ◽

Vol 18 (2) ◽

pp. 201-206

Author(s):

Qiu Nan ◽

Xu Xinmei ◽

He Yingying ◽

Fan Chengfen

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Nuclear Factor Kappa B ◽

Cecal Ligation ◽

Myeloperoxidase Activity ◽

Nuclear Factor ◽

Cecal Ligation And Puncture ◽

Toll Like Receptor ◽

Toll Like Receptor 4 ◽

Nuclear Factor Kappa

Sepsis, with high mortality, induces deleterious organ dysfunction and acute lung injury. Natural compounds show protective effect against sepsis-induced acute lung injury. Juglone, a natural naphthoquinone, demonstrates pharmacological actions as a pro-apoptotic substrate in tumor treatment and anti-inflammation substrate in organ injury. In this study, the influence of juglone on sepsis-induced acute lung injury was investigated. First, a septic mice model was established via cecal ligation and puncture, and then verified via histopathological analysis of lung tissues, the wet/dry mass ratio and myeloperoxidase activity was determined. Cecal ligation and puncture could induce acute lung injury in septic mice, as demonstrated by alveolar damage and increase of wet/dry mass ratio and myeloperoxidase activity. However, intragastric administration juglone attenuated cecal ligation and puncture-induced acute lung injury. Secondly, cecal ligation and puncture-induced increase of inflammatory cells in bronchoalveolar lavage fluid was also alleviated by the administration of juglone. Similarly, the protective effect of juglone against cecal ligation and puncture-induced acute lung injury was accompanied by a reduction of pro-inflammatory factor secretion in bronchoalveolar lavage fluid and lung tissues. Cecal ligation and puncture could activate toll-like receptor 4/nuclear factor-kappa B signaling pathway, and administration of juglone suppressed toll-like receptor 4/nuclear factor-kappa B activation. In conclusion, juglone attenuated cecal ligation and puncture-induced lung damage and inflammatory response through inactivation of toll-like receptor 4/nuclear factor-kappa B, suggesting a potential therapeutic strategy in the treatment of sepsis-induced acute lung injury.

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Myocarditis-associated necrotizing coronary vasculitis: incidence, cause, and outcome

European Heart Journal ◽

10.1093/eurheartj/ehaa973 ◽

2020 ◽

Author(s):

Andrea Frustaci ◽

Maria Alfarano ◽

Romina Verardo ◽

Chiara Agrati ◽

Rita Casetti ◽

...

Keyword(s):

Hospital Mortality ◽

Hypereosinophilic Syndrome ◽

Left Ventricular ◽

Response To Therapy ◽

Left Ventricular Ejection ◽

Toll Like Receptor ◽

Toll Like Receptor 4 ◽

Ventricular Ejection Fraction ◽

Immune Mediated ◽

Coronary Vasculitis

Abstract Aims Necrotizing coronary vasculitis (NCV) is a rare entity usually associated to myocarditis which incidence, cause, and response to therapy is unreported. Methods and results Among 1916 patients with biopsy-proven myocarditis, 30 had NCV. Endomyocardial samples were retrospectively investigated with immunohistochemistry for toll-like receptor 4 (TLR4) and real-time polymerase chain reaction (PCR) for viral genomes. Serum samples were processed for anti-heart autoantibodies (Abs), IL-1β, IL-6, IL-8, tumour necrosis factor (TNF)-α. Identification of an immunologic pathway (including virus-negativity, TLR4-, and Ab-positivity) was followed by immunosuppression. Myocarditis-NCV cohort was followed for 6 months with 2D-echo and/or cardiac magnetic resonance and compared with 60 Myocarditis patients and 30 controls. Increase in left ventricular ejection fraction ≥10% was classified as response to therapy. Control endomyocardial biopsy followed the end of treatment. Twenty-six Myocarditis-NCV patients presented with heart failure; four with electrical instability. Cause of Myocarditis-NCV included infectious agents (10%) and immune-mediated causes (chest trauma 3%; drug hypersensitivity 7%; hypereosinophilic syndrome 3%; primary autoimmune diseases 33%, idiopathic 44%). Abs were positive in immune-mediated Myocarditis-NCV and virus-negative Myocarditis; Myocarditis-NCV patients with Ab+ presented autoreactivity in vessel walls. Toll-like receptor 4 was overexpressed in immune-mediated forms and poorly detectable in viral. Interleukin-1β was significantly higher in Myocarditis-NCV than Myocarditis, the former presenting 24% in-hospital mortality compared with 1.5% of Myocarditis cohort. Immunosuppression induced improvement of cardiac function in 88% of Myocarditis-NCV and 86% of virus-negative Myocarditis patients. Conclusion Necrotizing coronary vasculitis is histologically detectable in 1.5% of Myocarditis. Necrotizing coronary vasculitis includes viral and immune-mediated causes. Intra-hospital mortality is 24%. The immunologic pathway is associated with beneficial response to immunosuppression.

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Toll-like Receptor 4 Signaling in Ventilator-induced Diaphragm Atrophy

Anesthesiology ◽

10.1097/aln.0b013e3182608cc0 ◽

2012 ◽

Vol 117 (2) ◽

pp. 329-338 ◽

Cited By ~ 34

Author(s):

Willem-Jan M. Schellekens ◽

Hieronymus W. H. van Hees ◽

Michiel Vaneker ◽

Marianne Linkels ◽

P. N. Richard Dekhuijzen ◽

...

Keyword(s):

Mechanical Ventilation ◽

Caspase 3 ◽

Toll Like Receptor ◽

Wild Type ◽

Toll Like Receptor 4 ◽

Ubiquitin Proteasome Pathway ◽

Ubiquitin Proteasome ◽

Proteasome Pathway ◽

Diaphragm Atrophy ◽

Deficient Mice

Background Mechanical ventilation induces diaphragm muscle atrophy, which plays a key role in difficult weaning from mechanical ventilation. The signaling pathways involved in ventilator-induced diaphragm atrophy are poorly understood. The current study investigated the role of Toll-like receptor 4 signaling in the development of ventilator-induced diaphragm atrophy. Methods Unventilated animals were selected for control: wild-type (n = 6) and Toll-like receptor 4 deficient mice (n = 6). Mechanical ventilation (8 h): wild-type (n = 8) and Toll-like receptor 4 deficient (n = 7) mice.Myosin heavy chain content, proinflammatory cytokines, proteolytic activity of the ubiquitin-proteasome pathway, caspase-3 activity, and autophagy were measured in the diaphragm. Results Mechanical ventilation reduced myosin content by approximately 50% in diaphragms of wild-type mice (P less than 0.05). In contrast, ventilation of Toll-like receptor 4 deficient mice did not significantly affect diaphragm myosin content. Likewise, mechanical ventilation significantly increased interleukin-6 and keratinocyte-derived chemokine in the diaphragm of wild-type mice, but not in ventilated Toll-like receptor 4 deficient mice. Mechanical ventilation increased diaphragmatic muscle atrophy factor box transcription in both wild-type and Toll-like receptor 4 deficient mice. Other components of the ubiquitin-proteasome pathway and caspase-3 activity were not affected by ventilation of either wild-type mice or Toll-like receptor 4 deficient mice. Mechanical ventilation induced autophagy in diaphragms of ventilated wild-type mice, but not Toll-like receptor 4 deficient mice. Conclusion Toll-like receptor 4 signaling plays an important role in the development of ventilator-induced diaphragm atrophy, most likely through increased expression of cytokines and activation of lysosomal autophagy.

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Salidroside Protects Against Influenza A Virus-Induced Acute Lung Injury in Mice

Dose-Response ◽

10.1177/15593258211011335 ◽

2021 ◽

Vol 19 (2) ◽

pp. 155932582110113

Author(s):

Rufeng Lu ◽

Yueguo Wu ◽

Honggang Guo ◽

Zhuoyi Zhang ◽

Yuzhou He

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Influenza A Virus ◽

Influenza A ◽

H1n1 Virus ◽

Antiviral Agents ◽

Toll Like Receptor ◽

Virus Infections ◽

Toll Like Receptor 4 ◽

Inflammatory Cytokine Production

Influenza A virus infections can cause acute lung injury (ALI) in humans; thus, the identification of potent antiviral agents is urgently required. Herein, the effects of salidroside on influenza A virus-induced ALI were investigated in a murine model. BALB/c mice were intranasally inoculated with H1N1 virus and treated with salidroside. The results of this study show that salidroside treatment (30 and 60 mg/kg) significantly attenuated the H1N1 virus-induced histological alterations in the lung and inhibited inflammatory cytokine production. Salidroside also decreased the wet/dry ratio, viral titers, and Toll-like receptor 4 expression in the lungs. Therefore, salidroside may represent a potential therapeutic reagent for the treatment of influenza A virus-induced ALI.

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Bilobalide Ameliorates Sepsis Induced Acute Lung Injury by Inactivating Toll-Like Receptor 4/Myeloid Differentiation Factor 88/Nuclear Factor-Kappa B Pathway

Current Topics in Nutraceutical Research ◽

10.37290/ctnr2641-452x.19:277-282 ◽

2020 ◽

Vol 19 (3) ◽

pp. 277-282

Author(s):

Tian Liu ◽

Siyi Jiang ◽

Shengwei Jia ◽

Fuxiang Fan

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Nuclear Factor Kappa B ◽

Cecal Ligation ◽

Myeloid Differentiation ◽

Nuclear Factor ◽

Cecal Ligation And Puncture ◽

Toll Like Receptor ◽

Toll Like Receptor 4 ◽

Myeloid Differentiation Factor

Acute lung injury refers to the injury of alveolar epithelial cells and pulmonary capillary endothelial cells caused by noncardiac factors. To better combat the disease, there is an urgent need to develop more effective drugs. Sepsis is a syndrome of systemic inflammation caused by infection, and the molecular mechanism by which sepsis induces acute lung injury has not been clearly determined. Bilobalide is a unique component of Ginkgo biloba. Although it has multiple biological functions, its role in sepsis induced acute lung injury needs further study. In this study, we found that bilobalide alleviated cecal ligation and puncture induced acute lung injury. Additionally, bilobalide regulated cecal ligation and puncture induced lung injury through toll-like receptor 4/myeloid differentiation factor 88/nuclear factor-kappa B pathway. We therefore conclude that bilobalide may be a potential drug for the treatment of sepsis induced acute lung injury.

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