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 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 Mitochondrial Regulation of Inflammasome Activation in Chronic Obstructive Pulmonary Disease

2015 ◽  
Vol 8 (2) ◽  
pp. 121-128 ◽  
Author(s):  
Chang Min Yoon ◽  
Milang Nam ◽  
Yeon-Mok Oh ◽  
Charles S. Dela Cruz ◽  
Min-Jong Kang
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Pulmonary Disease ◽  
Inflammatory Responses ◽  
Pulmonary Inflammation ◽  
Innate Immune ◽  
Western Society ◽  
Future Research ◽  
Chronic Obstructive ◽  
Inflammasome Activation ◽  
Obstructive Pulmonary Disease

Chronic obstructive pulmonary disease (COPD) is characterized by enhanced chronic airway and lung inflammatory responses to noxious particles or gases. It is a major unmet medical need worldwide, and in Western society is strongly associated with exposure to cigarette smoke (CS). CS-induced inflammation is believed to be a key immune driver in the pathogenesis of COPD. Since the concept of inflammasomes was first introduced nearly a decade ago, these have been increasingly recognized as a central player in innate immune and inflammatory responses. In addition, studies have emerged demonstrating that mitochondrial innate immune signaling plays an important role in CS-induced inflammasome activation, pulmonary inflammation and tissue remodeling responses. Here, recent discoveries about inflammasome activation and mitochondrial biology and their role in COPD pathogenesis are reviewed. In addition, the current limitations of our understanding of this theme and future research directions are discussed.

scholarly journals Modulation of the NLRP3 inflammasome by Sars-CoV-2 Envelope protein

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Mustafa Yalcinkaya ◽  
Wenli Liu ◽  
Mohammad N. Islam ◽  
Andriana G. Kotini ◽  
Galina A. Gusarova ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Inflammatory Responses ◽  
Pulmonary Inflammation ◽  
Protein A ◽  
Lavage Fluid ◽  
Viral Rna ◽  
Poly I:C ◽  
Inflammasome Activation ◽  
E Protein ◽  
Nlrp3 Inflammasome Activation

AbstractDespite the initial success of some drugs and vaccines targeting COVID-19, understanding the mechanism underlying SARS-CoV-2 disease pathogenesis remains crucial for the development of further approaches to treatment. Some patients with severe Covid-19 experience a cytokine storm and display evidence of inflammasome activation leading to increased levels of IL-1β and IL-18; however, other reports have suggested reduced inflammatory responses to Sars-Cov-2. In this study we have examined the effects of the Sars-Cov-2 envelope (E) protein, a virulence factor in coronaviruses, on inflammasome activation and pulmonary inflammation. In cultured macrophages the E protein suppressed inflammasome priming and NLRP3 inflammasome activation. Similarly, in mice transfected with E protein and treated with poly(I:C) to simulate the effects of viral RNA, the E protein, in an NLRP3-dependent fashion, reduced expression of pro-IL-1β, levels of IL-1β and IL-18 in broncho-alveolar lavage fluid, and macrophage infiltration in the lung. To simulate the effects of more advanced infection, macrophages were treated with both LPS and poly(I:C). In this setting the E protein increased NLRP3 inflammasome activation in both murine and human macrophages. Thus, the Sars-Cov-2 E protein may initially suppress the host NLRP3 inflammasome response to viral RNA while potentially increasing NLRP3 inflammasome responses in the later stages of infection. Targeting the Sars-Cov-2 E protein especially in the early stages of infection may represent a novel approach to Covid-19 therapy.

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 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 Obesity and lung inflammation

2010 ◽  
Vol 108 (3) ◽  
pp. 722-728 ◽  
Author(s):  
Peter Mancuso
Keyword(s):  
Adipose Tissue ◽  
Lung Disease ◽  
Inflammatory Responses ◽  
Acute Phase Proteins ◽  
Pulmonary Inflammation ◽  
Therapeutic Interventions ◽  
Low Grade ◽  
Tissue Mass ◽  
Proinflammatory Mediators ◽  
Increased Risk

The prevalence of obesity has increased dramatically worldwide, predisposing individuals to an increased risk of morbidity and mortality due to cardiovascular disease and type 2 diabetes. Less recognized is the fact that obesity may play a significant role in the pathogenesis of pulmonary diseases through mechanisms that may involve proinflammatory mediators produced in adipose tissue that contribute to a low-grade state of systemic inflammation. In animal models, inflammatory responses in the lung have been shown to influence the production of the adipocytokines, leptin and adiponectin, cytokines, acute phase proteins, and other mediators produced by adipose tissue that may participate in immune responses of the lung. An increased adipose tissue mass may also influence susceptibility to pulmonary infections, enhance pulmonary inflammation associated with environmental exposures, and exacerbate airway obstruction in preexisting lung disease. An increased understanding of the mechanisms by which obesity influences pulmonary inflammation may facilitate the development of novel therapeutic interventions for the treatment of lung disease.

scholarly journals Gender Differences in Low-Molecular-Mass-Induced Acute Lung Inflammation in Mice

2021 ◽  
Vol 22 (1) ◽  
pp. 419
Author(s):  
Yifang Xie ◽  
Dehui Xie ◽  
Bin Li ◽  
Hang Zhao
Keyword(s):  
Gender Differences ◽  
Sex Differences ◽  
Molecular Mass ◽  
Lung Inflammation ◽  
Inflammatory Responses ◽  
Pulmonary Inflammation ◽  
Ovarian Hormones ◽  
Male Mice ◽  
Acute Lung Inflammation ◽  
17Β Estradiol

Gender differences in pulmonary inflammation have been well documented. Although low molecular mass hyaluronan (LMMHA) is known to trigger pulmonary lung inflammation, sex differences in susceptibility to LMMHA are still unknown. In this study, we test the hypothesis that mice may display sex-specific differences after LMMHA administration. After LMMHA administration, male mice have higher neutrophil, cytokine, and chemokine counts compared to that of their female counterparts. Additionally, Ovariectomized (OVX) mice show greater LMMHA-induced inflammation compared to that of mice with intact ovaries. Injections of OVX mice with 17β-estradiol can decrease inflammatory responses in the OVX mice. These results show that ovarian hormones regulate LMMHA induced lung inflammation.

scholarly journals DROSHA-Dependent miRNA and AIM2 Inflammasome Activation in Idiopathic Pulmonary Fibrosis

2020 ◽  
Vol 21 (5) ◽  
pp. 1668 ◽  
Author(s):  
Soo Jung Cho ◽  
Mihye Lee ◽  
Heather W. Stout-Delgado ◽  
Jong-Seok Moon
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Lung Inflammation ◽  
Target Gene ◽  
Inflammatory Responses ◽  
Inflammasome Activation ◽  
Ribonuclease Iii ◽  
Double Stranded Dna ◽  
Current Review ◽  
Molecular Patterns

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease. Chronic lung inflammation is linked to the pathogenesis of IPF. DROSHA, a class 2 ribonuclease III enzyme, has an important role in the biogenesis of microRNA (miRNA). The function of miRNAs has been identified in the regulation of the target gene or protein related to inflammatory responses via degradation of mRNA or inhibition of translation. The absent-in-melanoma-2 (AIM2) inflammasome is critical for inflammatory responses against cytosolic double stranded DNA (dsDNA) from pathogen-associated molecular patterns (PAMPs) and self-DNA from danger-associated molecular patterns (DAMPs). The AIM2 inflammasome senses double strand DNA (dsDNA) and interacts with the adaptor apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), which recruits pro-caspase-1 and regulates the maturation and secretion of interleukin (IL)-1β and IL-18. A recent study showed that inflammasome activation contributes to lung inflammation and fibrogenesis during IPF. In the current review, we discuss recent advances in our understanding of the DROSHA–miRNA–AIM2 inflammasome axis in the pathogenesis of IPF.

scholarly journals A potential role of microvesicle-containing miR-223/142 in lung inflammation

Thorax ◽  
2019 ◽  
Vol 74 (9) ◽  
pp. 865-874 ◽  
Author(s):  
Duo Zhang ◽  
Heedoo Lee ◽  
Xiaoyun Wang ◽  
Michael Groot ◽  
Lokesh Sharma ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Lung Inflammation ◽  
Inflammatory Responses ◽  
Intratracheal Instillation ◽  
Lavage Fluid ◽  
Inflammasome Activation ◽  
Nlrp3 Inflammasome Activation ◽  
Membrane Budding

BackgroundUncontrolled lung inflammation is one of the prominent features in the pathogenesis of lung infection- associated acute lung injury (ALI). Microvesicles (MVs) are extracellular nanovesicles that are generated via direct membrane budding.MethodsBronchoalveolar lavage fluid (BALF) samples were collected from mice with or without intratracheal lipopolysaccharide (LPS) instillation. BALF MVs were characterised and MV-containing microRNA (miRNA) profiles were assessed and confirmed. Secretion and function of MV-containing miR-223/142 (MV-miR-223/142) were analysed in vivo.ResultsIn BALF, MVs are mainly derived from macrophages in response to LPS. After intratracheal instillation (i.t.) of LPS or Klebsiella pneumoniae, MV-containing miR-223/142 are dramatically induced in both BALF and serum. Mechanistically, miRNA 3′ end uridylation mediates the packing of miR-223/142 into MVs. To investigate the functional role of MV-miR-223/142, we loaded miR-223/142 mimics into unstimulated MVs and delivered them into the murine lungs via i.t. The miR-223/142 mimics-enriched MVs selectively targeted lung macrophages and suppressed the inflammatory lung responses that were triggered by LPS or K. pneumoniae. Mechanistically, miR-223 and miR-142 synergistically suppress Nlrp3 inflammasome activation in macrophages via inhibition of Nlrp3 and Asc, respectively.ConclusionsIn the pathogenesis of lung macrophage-mediated inflammatory responses, MV-miR-223/142 secretion is robustly enhanced and detectable in BALF and serum. Furthermore, restoration of intracellular miR-223/142 via vesicle-mediated delivery suppresses macrophage activation and lung inflammation via inhibition of Nlrp3 inflammasome activation.

P1-274 Activation of SRC family tyrosine kinases by tau

2004 ◽  
Vol 25 ◽  
pp. S174
Author(s):  
Vandana M. Sharma ◽  
Kiran Bhaskar ◽  
Gloria Lee
Keyword(s):  
Tyrosine Kinases ◽  
Src Family Tyrosine Kinases
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