scholarly journals Sirt1 restrains lung inflammasome activation in a murine model of sepsis

2015 ◽  
Vol 308 (8) ◽  
pp. L847-L853 ◽  
Author(s):  
Rong Gao ◽  
Zhongsen Ma ◽  
Yuxin Hu ◽  
Jiao Chen ◽  
Sreerama Shetty ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Inflammatory Responses ◽  
Cecal Ligation ◽  
High Mobility ◽  
The Elderly ◽  
Organ Injury ◽  
Inflammasome Activation ◽  
Acute Lung Inflammation ◽  
Inflammatory Signaling ◽  
Proinflammatory Mediators

Excessive inflammation is a major cause of organ damage during sepsis. The elderly are highly susceptible to sepsis-induced organ injury. Sirt1 expression is reduced during aging. In the present study, we investigated the role of Sirt1, a histone deacetylase, in controlling inflammatory responses in a murine sepsis model induced by cecal ligation and puncture (CLP). We examined lung inflammatory signaling in inducible Sirt1 knockout (Sirt1−/−) mice and wild-type littermates (Sirt1+/+) after CLP. Our results demonstrated that Sirt1 deficiency led to severe lung inflammatory injury. To further investigate molecular mechanisms of Sirt1 regulation of lung inflammatory responses in sepsis, we conducted a series of experiments to assess lung inflammasome activation after CLP. We detected increased lung inflammatory signaling including NF-κB, signal transducer and activator of transcription 3, and ERK1/2 activation in Sirt1−/− mice after CLP. Furthermore, inflammasome activity was increased in Sirt1−/− mice after CLP, as demonstrated by increased IL-1β and caspase-7 cleavage and activation. Aggravated inflammasome activation in Sirt1−/− mice was associated with the increased production of lung proinflammatory mediators, including ICAM-1 and high-mobility group box 1, and further disruption of tight junctions and adherens junctions, as demonstrated by dramatic reduction of lung claudin-1 and vascular endothelial-cadherin expression, which was associated with the upregulation of matrix metallopeptidase 9 expression. In summary, our results suggest that Sirt1 suppresses acute lung inflammation during sepsis by controlling inflammasome activation pathway.

scholarly journals Deletion of Src family kinase Lyn aggravates endotoxin-induced lung inflammation

2015 ◽  
Vol 309 (11) ◽  
pp. L1376-L1381 ◽  
Author(s):  
Rong Gao ◽  
Zhongsen Ma ◽  
Mengshi Ma ◽  
Jinyan Yu ◽  
Jiao Chen ◽  
...  
Keyword(s):  
Tyrosine Kinases ◽  
Lung Inflammation ◽  
Inflammatory Responses ◽  
Pulmonary Inflammation ◽  
Inflammasome Activation ◽  
Inflammatory Signaling ◽  
Endotoxin Challenge ◽  
Proinflammatory Mediators ◽  
Src Family Tyrosine Kinases ◽  
Inhibitory Signaling

Overwhelming acute inflammation often leads to tissue damage during endotoxemia. In the present study, we investigated the role of Lyn, a member of the Src family tyrosine kinases, in modulating inflammatory responses in a murine model of endotoxemia. We examined lung inflammatory signaling in Lyn knockout (Lyn−/−) mice and wild-type littermates (Lyn+/+) during endotoxemia. Our data indicate that Lyn deletion aggravates endotoxin-induced pulmonary inflammation and proinflammatory signaling. We found increased activation of proinflammatory transcription factor NF-κB in the lung tissues of Lyn−/− mice after endotoxin challenge. Furthermore, during endotoxemia, the lung tissues of Lyn−/− mice showed increased inflammasome activation indicated by augmented caspase-1 and IL-1β cleavage and activation. The aggravated lung inflammatory signaling in Lyn−/− mice was associated with increased production of proinflammatory mediators and elevated matrix metallopeptidase 9 and reduced VE-cadherin levels. Our results suggest that Lyn kinase modulates inhibitory signaling to suppress endotoxin-induced lung inflammation.

scholarly journals Histatin-1 Attenuates LPS-Induced Inflammatory Signaling in RAW264.7 Macrophages

2021 ◽  
Vol 22 (15) ◽  
pp. 7856
Author(s):  
Sang Min Lee ◽  
Kyung-No Son ◽  
Dhara Shah ◽  
Marwan Ali ◽  
Arun Balasubramaniam ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Cytokine Production ◽  
Inflammatory Responses ◽  
Critical Role ◽  
Mapk Signaling ◽  
Response To Treatment ◽  
No Production ◽  
Inflammatory Signaling ◽  
Raw264.7 Macrophages ◽  
Inflammatory Mediator Production

Macrophages play a critical role in the inflammatory response to environmental triggers, such as lipopolysaccharide (LPS). Inflammatory signaling through macrophages and the innate immune system are increasingly recognized as important contributors to multiple acute and chronic disease processes. Nitric oxide (NO) is a free radical that plays an important role in immune and inflammatory responses as an important intercellular messenger. In addition, NO has an important role in inflammatory responses in mucosal environments such as the ocular surface. Histatin peptides are well-established antimicrobial and wound healing agents. These peptides are important in multiple biological systems, playing roles in responses to the environment and immunomodulation. Given the importance of macrophages in responses to environmental triggers and pathogens, we investigated the effect of histatin-1 (Hst1) on LPS-induced inflammatory responses and the underlying molecular mechanisms in RAW264.7 (RAW) macrophages. LPS-induced inflammatory signaling, NO production and cytokine production in macrophages were tested in response to treatment with Hst1. Hst1 application significantly reduced LPS-induced NO production, inflammatory cytokine production, and inflammatory signaling through the JNK and NF-kB pathways in RAW cells. These results demonstrate that Hst1 can inhibit LPS-induced inflammatory mediator production and MAPK signaling pathways in macrophages.

scholarly journals Senkyunolide I Protects against Sepsis-Associated Encephalopathy by Attenuating Sleep Deprivation in a Murine Model of Cecal Ligation and Puncture

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Jian Xie ◽  
Zhen-zhen Zhao ◽  
Peng Li ◽  
Cheng-long Zhu ◽  
Yu Guo ◽  
...  
Keyword(s):  
Sleep Deprivation ◽  
Cognitive Dysfunction ◽  
Murine Model ◽  
Inflammatory Responses ◽  
Cecal Ligation ◽  
Signaling Proteins ◽  
Cecal Ligation And Puncture ◽  
Inflammatory Signaling ◽  
Tnf Α ◽  
Senkyunolide I

Sepsis may lead to sleep deprivation, which will promote the development of neuroinflammation and mediate the progression of sepsis-associated encephalopathy (SAE). Senkyunolide I, an active component derived from an herb medicine, has been shown to provide a sedative effect to improve sleep. However, its role in sepsis is unclear. The present study was performed to investigate whether Senkyunolide I protected against SAE in a murine model of cecal ligation and puncture (CLP). Here, we showed that Senkyunolide I treatment improved the 7-day survival rate and reduced the excessive release of cytokines including TNF-α, IL-6, and IL-1β. A fear conditioning test was performed, and the results showed that Senkyunolide I attenuated CLP-induced cognitive dysfunction. Senkyunolide I treatment also decreased the phosphorylation levels of inflammatory signaling proteins, including p-ERK, p-JNK, p-P38, and p-P65, and the level of inflammatory cytokines, including TNF-α, IL-6, and IL-1β, in the hippocampus homogenate. Sleep deprivation was attenuated by Senkyunolide I administration, as demonstrated by the modification of the BDNF and c-FOS expression. When sleep deprivation was induced manually, the protective effect of Senkyunolide I against inflammatory responses and cognitive dysfunction was reversed. Our data demonstrated that Senkyunolide I could protect against sepsis-associated encephalopathy in a murine model of sepsis via relieving sleep deprivation.

scholarly journals Transcriptomic analysis of equine chorioallantois reveals immune networks and molecular mechanisms involved in nocardioform placentitis

2021 ◽  
Vol 52 (1) ◽  
Author(s):  
Hossam El-Sheikh Ali ◽  
Shavahn C. Loux ◽  
Laura Kennedy ◽  
Kirsten E. Scoggin ◽  
Pouya Dini ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Glucose Transporter ◽  
Inflammasome Activation ◽  
Molecular Pathways ◽  
Toll Like Receptor ◽  
Inflammatory Signaling ◽  
Leukocytic Infiltration ◽  
Apoptosis Pathways ◽  
Placental Inflammation ◽  
First Time

AbstractNocardioform placentitis (NP) continues to result in episodic outbreaks of abortion and preterm birth in mares and remains a poorly understood disease. The objective of this study was to characterize the transcriptome of the chorioallantois (CA) of mares with NP. The CA were collected from mares with confirmed NP based upon histopathology, microbiological culture and PCR for Amycolatopsis spp. Samples were collected from the margin of the NP lesion (NPL, n = 4) and grossly normal region (NPN, n = 4). Additionally, CA samples were collected from normal postpartum mares (Control; CRL, n = 4). Transcriptome analysis identified 2892 differentially expressed genes (DEGs) in NPL vs. CRL and 2450 DEGs in NPL vs. NPN. Functional genomics analysis elucidated that inflammatory signaling, toll-like receptor signaling, inflammasome activation, chemotaxis, and apoptosis pathways are involved in NP. The increased leukocytic infiltration in NPL was associated with the upregulation of matrix metalloproteinase (MMP1, MMP3, and MMP8) and apoptosis-related genes, such as caspases (CASP3 and CASP7), which could explain placental separation associated with NP. Also, NP was associated with downregulation of several placenta-regulatory genes (ABCG2, GCM1, EPAS1, and NR3C1), angiogenesis-related genes (VEGFA, FLT1, KDR, and ANGPT2), and glucose transporter coding genes (GLUT1, GLUT10, and GLUT12), as well as upregulation of hypoxia-related genes (HIF1A and EGLN3), which could elucidate placental insufficiency accompanying NP. In conclusion, our findings revealed for the first time, the key regulators and mechanisms underlying placental inflammation, separation, and insufficiency during NP, which might lead to the development of efficacious therapies or diagnostic aids by targeting the key molecular pathways.

scholarly journals The Protective Effect of Lidocaine on Septic Rats via the Inhibition of High Mobility Group Box 1 Expression and NF-κB Activation

2013 ◽  
Vol 2013 ◽  
pp. 1-9 ◽  
Author(s):  
Huan-Liang Wang ◽  
Yan-Qiu Xing ◽  
Ying-Xue Xu ◽  
Fei Rong ◽  
Wei-Fu Lei ◽  
...  
Keyword(s):  
Protective Effect ◽  
Cecal Ligation ◽  
High Mobility ◽  
Inhibitory Effect ◽  
High Mobility Group ◽  
Organ Injury ◽  
Hmgb1 Level ◽  
Multiple Organs ◽  
Hmgb1 Expression ◽  
Local Anesthetic Drug

Lidocaine, a common local anesthetic drug, has anti-inflammatory effects. It has demonstrated a protective effect in mice from septic peritonitis. However, it is unknown whether lidocaine has effects on high mobility group box 1 (HMGB1), a key mediator of inflammation. In this study, we investigated the effect of lidocaine treatment on serum HMGB1 level and HMGB1 expression in liver, lungs, kidneys, and ileum in septic rats induced by cecal ligation and puncture (CLP). We found that acute organ injury induced by CLP was mitigated by lidocaine treatment and organ function was significantly improved. The data also demonstrated that lidocaine treatment raised the survival of septic rats. Furthermore, lidocaine suppressed the level of serum HMGB1, the expression of HMGB1, and the activation of NF-κB p65 in liver, kidneys, lungs, and ileum. Taken together, these results suggest that lidocaine treatment exerts its protective effection on CLP-induced septic rats. The mechanism was relative to the inhibitory effect of lidocaine on the mRNA expression level of HMGB1 in multiple organs, release of HMGB1 to plasma, and activation of NF-κB.

scholarly journals Mycotoxin Zearalenone Attenuates Innate Immune Responses and Suppresses NLRP3 Inflammasome Activation in LPS-Activated Macrophages

Toxins ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 593
Author(s):  
Po-Yen Lee ◽  
Ching-Chih Liu ◽  
Shu-Chi Wang ◽  
Kai-Yin Chen ◽  
Tzu-Chieh Lin ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Adverse Effects ◽  
Signaling Pathways ◽  
Nlrp3 Inflammasome ◽  
Inflammatory Responses ◽  
Mammalian Species ◽  
Inflammasome Activation ◽  
Amino Terminal ◽  
Proinflammatory Mediators ◽  
Nlrp3 Inflammasome Activation

Zearalenone (ZEA) is a mycotoxin that has several adverse effects on most mammalian species. However, the effects of ZEA on macrophage-mediated innate immunity during infection have not been examined. In the present study, bacterial lipopolysaccharides (LPS) were used to induce the activation of macrophages and evaluate the effects of ZEA on the inflammatory responses and inflammation-associated signaling pathways. The experimental results indicated that ZEA suppressed LPS-activated inflammatory responses by macrophages including attenuating the production of proinflammatory mediators (nitric oxide (NO) and prostaglandin E2 (PGE2)), decreased the secretion of proinflammatory cytokines (tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6), inhibited the activation of c-Jun amino-terminal kinase (JNK), p38 and nuclear factor-κB (NF-κB) signaling pathways, and repressed the nucleotide-binding and oligomerization domain (NOD)-, leucine-rich repeat (LRR)- and pyrin domain-containing protein 3 (NLRP3) inflammasome activation. These results indicated that mycotoxin ZEA attenuates macrophage-mediated innate immunity upon LPS stimulation, suggesting that the intake of mycotoxin ZEA-contaminated food might result in decreasing innate immunity, which has a higher risk of adverse effects during infection.

scholarly journals Beneficial effect of STAT3 decoy oligodeoxynucleotide transfection on organ injury and mortality in mice with cecal ligation and puncture-induced sepsis

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Samar Imbaby ◽  
Naoyuki Matsuda ◽  
Kengo Tomita ◽  
Kohshi Hattori ◽  
Sailesh Palikhe ◽  
...  
Keyword(s):  
Critical Role ◽  
Cecal Ligation ◽  
High Mobility ◽  
Organ Injury ◽  
Cecal Ligation And Puncture ◽  
Signal Transducers ◽  
Significant Survival ◽  
Upstream Kinase ◽  
Stat3 Decoy

Abstract Sepsis is a major clinical challenge with unacceptably high mortality. The signal transducers and activators of transcription (STAT) family of transcription factors is known to activate critical mediators of cytokine responses, and, among this family, STAT3 is implicated to be a key transcription factor in both immunity and inflammatory pathways. We investigated whether in vivo introduction of synthetic double-stranded STAT3 decoy oligodeoxynucleotides (ODNs) can provide benefits for reducing organ injury and mortality in mice with cecal ligation and puncture (CLP)-induced polymicrobial sepsis. We found that STAT3 was rapidly activated in major end-organ tissues following CLP, which was accompanied by activation of the upstream kinase JAK2. Transfection of STAT3 decoy ODNs downregulated pro-inflammatory cytokine/chemokine overproduction in CLP mice. Moreover, STAT3 decoy ODN transfection significantly reduced the increases in tissue mRNAs and proteins of high mobility group box 1 (HMGB1) and strongly suppressed the excessive elevation in serum HMGB1 levels in CLP mice. Finally, STAT3 decoy ODN administration minimized the development of sepsis-driven major end-organ injury and led to a significant survival advantage in mice after CLP. Our results suggest a critical role of STAT3 in the sepsis pathophysiology and the potential usefulness of STAT3 decoy ODNs for sepsis gene therapy.

scholarly journals Targeting NLRP3 Inflammasome Activation in Severe Asthma

2019 ◽  
Vol 8 (10) ◽  
pp. 1615 ◽  
Author(s):  
Efthymia Theofani ◽  
Maria Semitekolou ◽  
Ioannis Morianos ◽  
Konstantinos Samitas ◽  
Georgina Xanthou
Keyword(s):  
Severe Asthma ◽  
Nlrp3 Inflammasome ◽  
Molecular Mechanisms ◽  
Inflammatory Responses ◽  
Pulmonary Inflammation ◽  
Airflow Obstruction ◽  
Inflammasome Activation ◽  
Pyrin Domain ◽  
Nlrp3 Inflammasome Activation ◽  
Reversible Airflow Obstruction

Severe asthma (SA) is a chronic lung disease characterized by recurring symptoms of reversible airflow obstruction, airway hyper-responsiveness (AHR), and inflammation that is resistant to currently employed treatments. The nucleotide-binding oligomerization domain-like Receptor Family Pyrin Domain Containing 3 (NLRP3) inflammasome is an intracellular sensor that detects microbial motifs and endogenous danger signals and represents a key component of innate immune responses in the airways. Assembly of the NLRP3 inflammasome leads to caspase 1-dependent release of the pro-inflammatory cytokines IL-1β and IL-18 as well as pyroptosis. Accumulating evidence proposes that NLRP3 activation is critically involved in asthma pathogenesis. In fact, although NLRP3 facilitates the clearance of pathogens in the airways, persistent NLRP3 activation by inhaled irritants and/or innocuous environmental allergens can lead to overt pulmonary inflammation and exacerbation of asthma manifestations. Notably, administration of NLRP3 inhibitors in asthma models restrains AHR and pulmonary inflammation. Here, we provide an overview of the pathophysiology of SA, present molecular mechanisms underlying aberrant inflammatory responses in the airways, summarize recent studies pertinent to the biology and functions of NLRP3, and discuss the role of NLRP3 in the pathogenesis of asthma. Finally, we contemplate the potential of targeting NLRP3 as a novel therapeutic approach for the management of SA.

scholarly journals The role of adenosine 1a receptor signaling on GFR early after the induction of sepsis

2018 ◽  
Vol 314 (5) ◽  
pp. F788-F797
Author(s):  
Jonathan M. Street ◽  
Erik H. Koritzinsky ◽  
Tiffany R. Bellomo ◽  
Xuzhen Hu ◽  
Peter S. T. Yuen ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Inflammatory Responses ◽  
Cecal Ligation ◽  
Kidney Injury ◽  
Cumulative Effect ◽  
Organ Damage ◽  
Tubuloglomerular Feedback ◽  
Organ Injury ◽  
Sodium Reabsorption ◽  
Wild Type

Sepsis and acute kidney injury (AKI) synergistically increase morbidity and mortality in the ICU. How sepsis reduces glomerular filtration rate (GFR) and causes AKI is poorly understood; one proposed mechanism includes tubuloglomerular feedback (TGF). When sodium reabsorption by the proximal tubules is reduced in normal animals, the macula densa senses increased luminal sodium chloride, and then adenosine-1a receptor (A1aR) signaling triggers tubuloglomerular feedback, reducing GFR through afferent arteriole vasoconstriction. We measured GFR and systemic hemodynamics early during cecal ligation and puncture-induced sepsis in wild-type and A1aR-knockout mice. A miniaturized fluorometer was attached to the back of each mouse and recorded the clearance of FITC-sinistrin via transcutaneous fluorescence to monitor GFR. Clinical organ injury markers and cytokines were measured and hemodynamics monitored using implantable transducer telemetry devices. In wild-type mice, GFR was stable within 1 h after surgery, declined by 43% in the next hour, and then fell to less than 10% of baseline after 2 h and 45 min. In contrast, in A1aR-knockout mice GFR was 37% below baseline immediately after surgery and then gradually declined over 4 h. A1aR-knockout mice had similar organ injury and inflammatory responses, albeit with lower heart rate. We conclude that transcutaneous fluorescence can accurately monitor GFR and detect changes rapidly during sepsis. Tubuloglomerular feedback plays a complex role in sepsis; initially, TGF helps maintain GFR in the 1st hour, and over the subsequent 3 h, TGF causes GFR to plummet. By 18 h, TGF has no cumulative effect on renal or extrarenal organ damage.

scholarly journals Neutrophil gelatinase-associated lipocalin as a potential therapeutic integrator of glycolipid metabolic and inflammatory signaling

2017 ◽  
Vol 4 (8) ◽  
pp. 2381 ◽  
Author(s):  
Junhua Gong ◽  
Rongtao Zhu ◽  
Jianping Gong ◽  
Kun He ◽  
Jiahai Chen
Keyword(s):  
Metabolic Syndrome ◽  
Therapeutic Target ◽  
Molecular Mechanisms ◽  
Inflammatory Responses ◽  
Subclinical Inflammation ◽  
Inflammatory Signaling ◽  
Potential Therapeutic Target ◽  
Alcoholic Fatty Liver ◽  
Neutrophil Gelatinase Associated Lipocalin ◽  
Neutrophil Gelatinase

Metabolic syndrome constitutes a group of metabolic conditions that increase the risk of developing diseases, including cardiovascular disease (CVD), non-alcoholic fatty liver disease (NAFLD), obesity and type 2 diabetes mellitus (T2DM) etc. Subclinical inflammation is a candidate etiological factor in the pathogenesis of metabolic syndrome and in the progression of related diseases. Although studies have revealed that subclinical inflammation was activated by intermediary products of basic metabolic processes, the cellular and molecular mechanisms in this association remain largely uncharacterized. Recently, increasing evidence suggests that neutrophil gelatinase-associated lipocalin (NGAL) not only plays a significant role in the glycolipid metabolism, but also modulates immune and inflammatory responses in macrophages. Taking together the ability of NGAL in metabolic and inflammatory signaling, these data suggest that NGAL may be a potential therapeutic target for metabolic and inflammatory signaling for intervention in human glycolipid metabolic disease. This review focuses on current knowledge of the integrators role of NGAL in both glucose and lipid metabolism and inflammatory signaling and discusses the potential therapeutic target in the treatment of glycolipid metabolic-related disease.

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