scholarly journals MLN4924 protects against interleukin-17A-induced pulmonary inflammation by disrupting ACT1-mediated signaling

2019 ◽  
Vol 316 (6) ◽  
pp. L1070-L1080 ◽  
Author(s):  
Rui Hao ◽  
Yunduan Song ◽  
Runsheng Li ◽  
Yaxian Wu ◽  
Xinyi Yang ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Proinflammatory Cytokines ◽  
Inflammatory Diseases ◽  
Pulmonary Inflammation ◽  
Tumor Necrosis Factor Receptor ◽  
Inhibitory Effect ◽  
Chronic Obstructive ◽  
Cytokines And Chemokines ◽  
Interleukin 17A

An excessive inflammatory response in terminal airways, alveoli, and the lung interstitium eventually leads to pulmonary hypertension and chronic obstructive pulmonary disease. Proinflammatory cytokine interleukin-17A (IL-17A) has been implicated in the pathogenesis of pulmonary inflammatory diseases. MLN4924, an inhibitor of NEDD8-activating enzyme (NAE), is associated with the treatment of various types of cancers, but its role in the IL-17A-mediated inflammatory response has not been identified. Here, we report that MLN4924 can markedly reduce the expression of proinflammatory cytokines and chemokines such as IL-1β, IL-6, and CXCL-1 and neutrophilia in a mouse model of IL-17A adenovirus-induced pulmonary inflammation. MLN4924 significantly inhibited IL-17A-induced stabilization of mRNA of proinflammatory cytokines and chemokines in vitro. Mechanistically, MLN4924 significantly blocked the activation of MAPK and NF-κB pathways and interfered with the interaction between ACT1 and tumor necrosis factor receptor-associated factor proteins (TRAFs), thereby inhibiting TRAF6 ubiquitination. Taken together, our data uncover a previously uncharacterized inhibitory effect of MLN4924 on the IL-17A-mediated inflammatory response; this phenomenon may facilitate the development of MLN4924 into an effective small-molecule drug for the treatment of pulmonary inflammatory diseases.

scholarly journals Carbon Monoxide Inhibits Tenascin-C Mediated Inflammation via IL-10 Expression in a Septic Mouse Model

2015 ◽  
Vol 2015 ◽  
pp. 1-14 ◽  
Author(s):  
Md. Jamal Uddin ◽  
Chun-shi Li ◽  
Yeonsoo Joe ◽  
Yingqing Chen ◽  
Qinggao Zhang ◽  
...  
Keyword(s):  
Carbon Monoxide ◽  
Proinflammatory Cytokines ◽  
Tissue Injury ◽  
Inflammatory Diseases ◽  
Septic Mouse ◽  
Induced Expression ◽  
Tenascin C ◽  
Co Gas

Tenascin-C (TN-C), an extracellular matrix (ECM) glycoprotein, is specifically induced upon tissue injury and infection and during septic conditions. Carbon monoxide (CO) gas is known to exert various anti-inflammatory effects in various inflammatory diseases. However, the mechanisms underlying the effect of CO on TN-C-mediated inflammation are unknown. In the present study, we found that treatment with LPS significantly enhanced TN-C expression in macrophages. CO gas, or treatment with the CO-donor compound, CORM-2, dramatically reduced LPS-induced expression of TN-C and proinflammatory cytokines while significantly increased the expression of IL-10. Treatment with TN-C siRNA significantly suppressed the effects of LPS on proinflammatory cytokines production. TN-C siRNA did not affect the CORM-2-dependent increase of IL-10 expression. In cells transfected with IL-10 siRNA, CORM-2 had no effect on the LPS-induced expression of TN-C and its downstream cytokines. These data suggest that IL-10 mediates the inhibitory effect of CO on TN-C and the downstream production of proinflammatory cytokines. Additionally, administration of CORM-2 dramatically reduced LPS-induced TN-C and proinflammatory cytokines production while expression of IL-10 was significantly increased. In conclusion, CO regulated IL-10 expression and thus inhibited TN-C-mediated inflammationin vitroandin vivo.

scholarly journals Eosinophil-derived IL-13 promotes emphysema

2019 ◽  
Vol 53 (5) ◽  
pp. 1801291 ◽  
Author(s):  
Alfred D. Doyle ◽  
Manali Mukherjee ◽  
William E. LeSuer ◽  
Tyler B. Bittner ◽  
Saif M. Pasha ◽  
...  
Keyword(s):  
Mouse Model ◽  
Inflammatory Responses ◽  
Pulmonary Inflammation ◽  
Forced Expiratory Volume ◽  
Chronic Obstructive ◽  
Chronic Type ◽  
Obstructive Pulmonary Disease ◽  
Lung Eosinophilia

The inflammatory responses in chronic airway diseases leading to emphysema are not fully defined. We hypothesised that lung eosinophilia contributes to airspace enlargement in a mouse model and to emphysema in patients with chronic obstructive pulmonary disease (COPD).A transgenic mouse model of chronic type 2 pulmonary inflammation (I5/hE2) was used to examine eosinophil-dependent mechanisms leading to airspace enlargement. Human sputum samples were collected for translational studies examining eosinophilia and matrix metalloprotease (MMP)-12 levels in patients with chronic airways disease.Airspace enlargement was identified in I5/hE2 mice and was dependent on eosinophils. Examination of I5/hE2 bronchoalveolar lavage identified elevated MMP-12, a mediator of emphysema. We showed, in vitro, that eosinophil-derived interleukin (IL)-13 promoted alveolar macrophage MMP-12 production. Airspace enlargement in I5/hE2 mice was dependent on MMP-12 and eosinophil-derived IL-4/13. Consistent with this, MMP-12 was elevated in patients with sputum eosinophilia and computed tomography evidence of emphysema, and also negatively correlated with forced expiratory volume in 1 s.A mouse model of chronic type 2 pulmonary inflammation exhibited airspace enlargement dependent on MMP-12 and eosinophil-derived IL-4/13. In chronic airways disease patients, lung eosinophilia was associated with elevated MMP-12 levels, which was a predictor of emphysema. These findings suggest an underappreciated mechanism by which eosinophils contribute to the pathologies associated with asthma and COPD.

scholarly journals PPARγas a Potential Target to Treat Airway Mucus Hypersecretion in Chronic Airway Inflammatory Diseases

PPAR Research ◽  
2012 ◽  
Vol 2012 ◽  
pp. 1-6 ◽  
Author(s):  
Yongchun Shen ◽  
Lei Chen ◽  
Tao Wang ◽  
Fuqiang Wen
Keyword(s):  
Transcription Factor ◽  
Inflammatory Diseases ◽  
Chronic Obstructive ◽  
Peroxisome Proliferator ◽  
Mucus Hypersecretion ◽  
Mucin Production ◽  
Airway Mucus ◽  
Chronic Airway

Airway mucus hypersecretion (AMH) is a key pathophysiological feature of chronic airway inflammatory diseases such as bronchial asthma, cystic fibrosis, and chronic obstructive pulmonary disease. AMH contributes to the pathogenesis of chronic airway inflammatory diseases, and it is associated with reduced lung function and high rates of hospitalization and mortality. It has been suggested that AMH should be a target in the treatment of chronic airway inflammatory diseases. Recent evidence suggests that a key regulator of airway inflammation, hyperresponsiveness, and remodeling is peroxisome proliferator-activated receptor gamma (PPARγ), a ligand-activated transcription factor that regulates adipocyte differentiation and lipid metabolism. PPARγis expressed in structural, immune, and inflammatory cells in the lung. PPARγis involved in mucin production, and PPARγagonists can inhibit mucin synthesis bothin vitroandin vivo. These findings suggest that PPARγis a novel target in the treatment of AMH and that further work on this transcription factor may lead to new therapies for chronic airway inflammatory diseases.

scholarly journals Long noncoding RNA MALAT1 contributes to inflammatory response of microglia following spinal cord injury via the modulation of a miR-199b/IKKβ/NF-κB signaling pathway

2018 ◽  
Vol 315 (1) ◽  
pp. C52-C61 ◽  
Author(s):  
Heng-Jun Zhou ◽  
Li-Qing Wang ◽  
Duan-Bu Wang ◽  
Jian-Bo Yu ◽  
Yu Zhu ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Inflammatory Response ◽  
Signaling Pathway ◽  
Proinflammatory Cytokines ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Tnf Α ◽  
Cord Injury

Long noncoding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) was widely recognized to be implicated in human cancer, vascular diseases, and neurological disorders. This study was to explore the role and underlying mechanism of MALAT1 in acute spinal cord injury (ASCI). ASCI models in adult rats were established and demonstrated by a numerical decrease in BBB scores. Expression profile of MALAT1 and miR-199b following ASCI in rats and in vitro was determined using quantitative real-time PCR. RNA pull-down assays combined with RIP assays were performed to explore the interaction between MALAT1 and miR-199b. In the present study, MALAT1 expression was significantly increased (2.4-fold that of control) in the spinal cord of the rat contusion epicenter accompanied by activation of IKKβ/NF-κB signaling pathway and an increase in the level of proinflammatory cytokines TNF-α and IL-1β. Upon treatment with LPS, MALAT1 expression dramatically increased in the microglia in vitro, but knockdown of MALAT1 attenuated LPS-induced activation of MGs and TNF-α and IL-1β production. Next, we confirmed that LPS-induced MALAT1 activated IKKβ/NF-κB signaling pathway and promoted the production of proinflammatory cytokines TNF-α and IL-1β through downregulating miR-199b. More importantly, MALAT1 knockdown gradually improved the hindlimb locomotor activity of ASCI rats as well as inhibited TNF-α, IL-1β levels, and Iba-1 protein, the marker of activated microglia in injured spinal cords. Our study demonstrated that MALAT1 was dysregulated in ASCI rats and in LPS-activated MGs, and MALAT1 knockdown was expected to attenuate ASCI through repressing inflammatory response of MGs.

scholarly journals Inflammatory Microenvironment and Adipogenic Differentiation in Obesity: The Inhibitory Effect of Theobromine in a Model of Human Obesity In Vitro

2019 ◽  
Vol 2019 ◽  
pp. 1-10 ◽  
Author(s):  
Maria Pia Fuggetta ◽  
Manuela Zonfrillo ◽  
Cristina Villivà ◽  
Enzo Bonmassar ◽  
Giampiero Ravagnan
Keyword(s):  
Adipose Tissue ◽  
Proinflammatory Cytokines ◽  
Adipogenic Differentiation ◽  
Inhibitory Effect ◽  
Low Grade ◽  
Tissue Inflammation ◽  
Inflammatory Microenvironment ◽  
Adipocyte Cell ◽  
Inflammatory State

Objective. Obesity is considered a clinic condition characterized by a state of chronic low-grade inflammation. The role of macrophages and adipocytokines in adipose tissue inflammation is in growing investigation. The physiopathological mechanisms involved in inflammatory state in obesity are not fully understood though the adipocytokines seem to characterize the biochemical link between obesity and inflammation. The aim of this work is to analyze the effect of theobromine, a methylxanthine present in the cocoa, on adipogenesis and on proinflammatory cytokines evaluated in a model of fat tissue inflammation in vitro. Methods. In order to mimic in vitro this inflammatory condition, we investigated the interactions between human-like macrophages U937 and human adipocyte cell lines SGBS. The effect of theobromine on in vitro cell growth, cell cycle, adipogenesis, and cytokines release in the supernatants has been evaluated. Results. Theobromine significantly inhibits the differentiation of preadipocytes in mature adipocytes and reduces the levels of proinflammatory cytokines as MCP-1 and IL-1β in the supernatants obtained by the mature adipocytes and macrophages interaction. Conclusion. Theobromine reduces adipogenesis and proinflammatory cytokines; these data suggest its potential therapeutic effect for treating obesity by control of macrophages infiltration in adipose tissue and inflammation.

LILRB4 deficiency aggravates the development of atherosclerosis and plaque instability by increasing the macrophage inflammatory response via NF-κB signaling

2017 ◽  
Vol 131 (17) ◽  
pp. 2275-2288 ◽  
Author(s):  
Zhou Jiang ◽  
Juan-Juan Qin ◽  
Yaxing Zhang ◽  
Wen-Lin Cheng ◽  
Yan-Xiao Ji ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Inflammatory Diseases ◽  
Chronic Inflammatory Disease ◽  
Plaque Instability ◽  
Atherosclerotic Lesions ◽  
Bone Marrow Derived Cells ◽  
Underlying Mechanisms ◽  
Human And Mouse

Atherosclerosis is a chronic inflammatory disease. Leukocyte immunoglobulin-like receptor B4 (LILRB4) is associated with the pathological processes of various inflammatory diseases. However, the potential function and underlying mechanisms of LILRB4 in atherogenesis remain to be investigated. In the present study, LILRB4 expression was examined in both human and mouse atherosclerotic plaques. The effects and possible mechanisms of LILRB4 in atherogenesis and plaque instability were evaluated in LILRB4-/-ApoE-/- and ApoE-/- mice fed a high-fat diet (HFD). We found that LILRB4 was located primarily in macrophages, and its expression was up-regulated in atherosclerotic lesions from human coronary arteries and mouse aortic roots. LILRB4 deficiency significantly accelerated the development of atherosclerotic lesions and increased the instability of plaques, as evident by the increased infiltration of lipids, decreased amount of collagen components and smooth muscle cells. Moreover, LILRB4 deficiency in bone marrow derived cells promoted the development of atherosclerosis. In vivo and in vitro analyses revealed that the proinflammatory effects of LILRB4 deficiency were mediated by the increased activation of NF-κB signaling due to decreased src homolog 2 domain containing phosphatase (Shp) 1 phosphorylation. In conclusion, the present study indicates that LILRB4 deficiency promotes atherogenesis, at least partly, through reduced Shp1 phosphorylation, which subsequently enhances the NF-κB-mediated inflammatory response. Thus, targetting the ‘LILRB4-Shp1’ axis may be a novel therapeutic approach for atherosclerosis.

Visualization of pulmonary inflammation using noninvasive fluorescence molecular imaging

2008 ◽  
Vol 104 (3) ◽  
pp. 795-802 ◽  
Author(s):  
Jodi Haller ◽  
Damon Hyde ◽  
Nikolaos Deliolanis ◽  
Ruben de Kleine ◽  
Mark Niedre ◽  
...  
Keyword(s):  
Molecular Imaging ◽  
Quantitative Imaging ◽  
Pulmonary Inflammation ◽  
Small Animal ◽  
Mouse Lung ◽  
Chronic Obstructive ◽  
Therapy Assessment ◽  
Fluorescence Molecular Imaging

The ability to visualize molecular processes and cellular regulators of complex pulmonary diseases such as asthma, chronic obstructive pulmonary disease (COPD), or adult respiratory distress syndrome (ARDS), would aid in the diagnosis, differentiation, therapy assessment and in small animal-based drug-discovery processes. Herein we report the application of normalized transillumination and fluorescence molecular tomography (FMT) for the noninvasive quantitative imaging of the mouse lung in vivo. We demonstrate the ability to visualize and quantitate pulmonary response in a murine model of LPS-induced airway inflammation. Twenty-four hours prior to imaging, BALB/c female mice were injected via tail vein with 2 nmol of a cathepsin-sensitive activatable fluorescent probe (excitation: 750 nm; emission: 780 nm) and 2 nmol of accompanying intravascular agent (excitation: 674 nm; emission: 694 nm). Six hours later, the mice were anesthetized with isoflurane and administered intranasal LPS in sterile 0.9% saline in 25 μl aliquots (one per nostril). Fluorescence molecular imaging revealed the in vivo profile of cysteine protease activation and vascular distribution within the lung typifying the inflammatory response to LPS insult. Results were correlated with standard in vitro laboratory tests (Western blot, bronchoalveolar lavage or BAL analysis, immunohistochemistry) and revealed good correlation with the underlying activity. We demonstrated the capacity of fluorescence tomography to noninvasively and longitudinally characterize physiological, cellular, and subcellular processes associated with inflammatory disease burden in the lung. The data presented herein serve to further evince fluorescence molecular imaging as a technology highly appropriate for the biomedical laboratory.

Biliverdin administration protects against endotoxin-induced acute lung injury in rats

2005 ◽  
Vol 289 (6) ◽  
pp. L1131-L1137 ◽  
Author(s):  
Judit K. Sarady-Andrews ◽  
Fang Liu ◽  
David Gallo ◽  
Atsunori Nakao ◽  
Marcus Overhaus ◽  
...  
Keyword(s):  
Lung Injury ◽  
Inflammatory Response ◽  
Pulmonary Inflammation ◽  
Lethal Dose ◽  
Serum Levels ◽  
Mouse Lung ◽  
Heme Oxygenase 1 ◽  
High Morbidity ◽  
Term Survival

Given the high morbidity and mortality rates associated with pulmonary inflammation in sepsis, there is a pressing need for new therapeutic modalities to prevent acute respiratory distress. The enzyme heme oxygenase-1 (HO-1) provides potent cytoprotection against lung injury; however, the mechanism by which it does so is unclear. HO-1 catabolizes heme into biliverdin (BV), which is rapidly converted to bilirubin by BV reductase. We tested the hypothesis that BV administration could substitute for the effects observed with HO-1. Using the well-described rat model of LPS-induced shock, we demonstrate that exposure to BV imparts a potent defense against lethal endotoxemia systemically, as well as in the lungs, and effectively abrogates the inflammatory response. BV administration before a lethal dose of LPS leads to a significant improvement in long-term survival: 87% vs. 20% in sham-treated controls. BV treatment suppressed LPS-induced increases in lung permeability and lung alveolitis and significantly reduced serum levels of the LPS-induced proinflammatory cytokine IL-6. Moreover, bilirubin administered just after LPS also abrogated lung inflammation. BV treatment also augmented expression of the anti-inflammatory cytokine IL-10. Similar effects on production were observed with BV treatment in vitro in mouse lung endothelial cells and RAW 264.7 macrophages treated with LPS. In conclusion, these data demonstrate that BV can modulate the inflammatory response and suppress pathophysiological changes in the lung and may therefore have therapeutic application in inflammatory disease states of the lung.

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