scholarly journals Citrullinated Histone H3 Mediates Sepsis-Induced Lung Injury Through Activating Caspase-1 Dependent Inflammasome Pathway

2021 ◽  
Vol 12 ◽  
Author(s):  
Yuzi Tian ◽  
Patrick Li ◽  
Zhenyu Wu ◽  
Qiufang Deng ◽  
Baihong Pan ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Lung Injury ◽  
Host Response ◽  
Distress Syndrome ◽  
Histone H3 ◽  
Caspase 1 ◽  
Sepsis Model ◽  
Important Mediator ◽  
Life Threatening

Sepsis is a life-threatening organ dysfunction caused by dysregulated host response to infection that often results in acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). An emerging mechanism of sepsis-induced ARDS involves neutrophils/macrophages undergoing cell death, releasing nuclear histones to cause tissue damage that exacerbates pulmonary injury. While published studies focus on unmodified histones, little is known about the role of citrullinated histone H3 (CitH3) in the pathogenesis of sepsis and ALI. In this study, we found that levels of CitH3 were elevated in the patients with sepsis-induced ARDS and correlated to PaO2/FiO2 in septic patients. Systematic administration of CitH3 peptide in mice provoked Caspase-1 activation in the lung tissue and caused ALI. Neutralization of CitH3 with monoclonal antibody improved survival and attenuated ALI in a mouse sepsis model. Furthermore, we demonstrated that CitH3 induces ALI through activating Caspase-1 dependent inflammasome in bone marrow derived macrophages and bone marrow derived dendritic cells. Our study suggests that CitH3 is an important mediator of inflammation and mortality during sepsis-induced ALI.

scholarly journals Leukocyte immunoglobulin-like receptor B4 deficiency exacerbates acute lung injury via NF-κB signaling in bone marrow-derived macrophages

2019 ◽  
Vol 39 (6) ◽  
Author(s):  
Tao Qiu ◽  
Jiangqiao Zhou ◽  
Tianyu Wang ◽  
Zhongbao Chen ◽  
Xiaoxiong Ma ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Lung Injury ◽  
Lung Injury ◽  
Stromal Cells ◽  
Marrow Cell ◽  
Marrow Transplant ◽  
Cell Source ◽  
Transplant Model ◽  
Acute Inflammatory Disease

AbstractAcute lung injury (ALI) is an acute inflammatory disease. Leukocyte immunoglobulin-like receptor B4 (LILRB4) is an immunoreceptor tyrosine-based inhibitory motif (ITIM)-bearing inhibitory receptor that is implicated in various pathological processes. However, the function of LILRB4 in ALI remains largely unknown. The aim of the present study was to explore the role of LILRB4 in ALI. LILRB4 knockout mice (LILRB4 KO) were used to construct a model of ALI. Bone marrow cell transplantation was used to identify the cell source of the LILRB4 deficiency-aggravated inflammatory response in ALI. The effect on ALI was analyzed by pathological and molecular analyses. Our results indicated that LILRB4 KO exacerbated ALI triggered by LPS. Additionally, LILRB4 deficiency can enhance lung inflammation. According to the results of our bone marrow transplant model, LILRB4 regulates the occurrence and development of ALI by bone marrow-derived macrophages (BMDMs) rather than by stromal cells in the lung. The observed inflammation was mainly due to BMDM-induced NF-κB signaling. In conclusion, our study demonstrates that LILRB4 deficiency plays a detrimental role in ALI-associated BMDM activation by prompting the NF-κB signal pathway.

scholarly journals Cordyceps Militaris Alleviates Severity of Murine Acute Lung Injury Through miRNAs-Mediated CXCR2 Inhibition

2015 ◽  
Vol 36 (5) ◽  
pp. 2003-2011 ◽  
Author(s):  
Sheng Liu ◽  
Jian Tang ◽  
Lei Huang ◽  
Qirong Xu ◽  
Xiang Ling ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Distress Syndrome ◽  
Mrna Level ◽  
Cordyceps Militaris ◽  
Microvascular Endothelial Cells ◽  
Mouse Lung ◽  
Therapeutic Effects ◽  
Beneficial Effects

Background/Aims: Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are lethal diseases in humans, and the current treatments have limited therapeutic effects. Cordyceps militaris (CM) is a caterpillar-grown traditional medicinal mushroom, and has been used as a natural invigorant for longevity, endurance, and vitality in China. Recently, purified extracts from CM have been shown to have beneficial effects on various diseases including cancer. Nevertheless, a role of CM in ALI has not been examined previously. Methods: Here, we used a bleomycin-induced ALI model to study the effects of CM on the severity of ALI in mice. The levels of CXCR2, a receptor for Interleukin 8 (IL-8) in pulmonary microvascular endothelial cells, were examined in different experimental groups. The levels of microRNA (miR)-1321 and miR-3188 were also examined in lung samples and in CM. Adeno-associated viruses carrying miR-1321 and miR-3188 were injected into bleomycin-treated mice for evaluation their effects on the severity of ALI. Results: CM treatment significantly alleviated the severity of bleomycin-induced ALI in mice. The increases in lung CXCR2 by bleomycin were significantly reduced by CM at protein level, but not at mRNA level. CM contained high levels of 2 miRNAs (miR-1321 and miR-3188) that target 3'-UTR of CXCR2 mRNA to inhibit its expression. Overexpression of miR-1321 and miR-3188 in mouse lung through AAV-mediated gene therapy mimicked the effects of CM. Conclusion: CM may alleviate severity of murine ALI through miRNAs-mediated CXCR2 inhibition.

scholarly journals Macrophage Uptake of Necrotic Cell DNA Activates the AIM2 Inflammasome to Regulate a Proinflammatory Phenotype in CKD

2018 ◽  
Vol 29 (4) ◽  
pp. 1165-1181 ◽  
Author(s):  
Takanori Komada ◽  
Hyunjae Chung ◽  
Arthur Lau ◽  
Jaye M. Platnich ◽  
Paul L. Beck ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Inflammasome Activation ◽  
Dna Uptake ◽  
Chronic Injury ◽  
Caspase 1 ◽  
Double Stranded Dna ◽  
Molecular Pattern ◽  
Macrophage Uptake

Nonmicrobial inflammation contributes to CKD progression and fibrosis. Absent in melanoma 2 (AIM2) is an inflammasome-forming receptor for double-stranded DNA. AIM2 is expressed in the kidney and activated mainly by macrophages. We investigated the potential pathogenic role of the AIM2 inflammasome in kidney disease. In kidneys from patients with diabetic or nondiabetic CKD, immunofluorescence showed AIM2 expression in glomeruli, tubules, and infiltrating leukocytes. In a mouse model of unilateral ureteral obstruction (UUO), Aim2 deficiency attenuated the renal injury, fibrosis, and inflammation observed in wild-type (WT) littermates. In bone marrow chimera studies, UUO induced substantially more tubular injury and IL-1β cleavage in Aim2−/− or WT mice that received WT bone marrow than in WT mice that received Aim2−/− bone marrow. Intravital microscopy of the kidney in LysM(gfp/gfp) mice 5–6 days after UUO demonstrated the significant recruitment of GFP+ proinflammatory macrophages that crawled along injured tubules, engulfed DNA from necrotic cells, and expressed active caspase-1. DNA uptake occurred in large vacuolar structures within recruited macrophages but not resident CX3CR1+ renal phagocytes. In vitro, macrophages that engulfed necrotic debris showed AIM2-dependent activation of caspase-1 and IL-1β, as well as the formation of AIM2+ ASC specks. ASC specks are a hallmark of inflammasome activation. Cotreatment with DNaseI attenuated the increase in IL-1β levels, confirming that DNA was the principal damage-associated molecular pattern in this process. Therefore, the activation of the AIM2 inflammasome by DNA from necrotic cells drives a proinflammatory phenotype that contributes to chronic injury in the kidney.

Transfusion-Related Acute Lung Injury Secondary to Biologically Active Mediators

2001 ◽  
Vol 125 (4) ◽  
pp. 523-526
Author(s):  
Susan E. Lenahan ◽  
Ronald E. Domen ◽  
Christopher C. Silliman ◽  
Charles P. Kingsley ◽  
Paula J. Romano
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Distress Syndrome ◽  
Biologically Active ◽  
Blood Components ◽  
Hla Antibodies ◽  
Granulocyte Antibodies ◽  
Priming Activity ◽  
Stored Blood

Abstract Transfusion-related acute lung injury is seen following the transfusion of blood components. The reported incidence is approximately 1 in 2000 transfusions. Clinically, it is similar to adult respiratory distress syndrome. The pathophysiology is unclear but has been attributed to HLA antibodies, granulocyte antibodies, and more recently to biologically active mediators in stored blood components. We report a case with laboratory evidence that supports the role of biologically active mediators in the pathogenesis of transfusion-related acute lung injury. To our knowledge, the case reported here is the first to use lipid extractions of patient samples to determine that lipid-priming activity was present at the time transfusion-related acute lung injury was identified clinically.

Acute lung injury in endotoxemic pigs: role of leukotriene B4

1995 ◽  
Vol 78 (3) ◽  
pp. 1121-1131 ◽  
Author(s):  
T. J. VanderMeer ◽  
M. J. Menconi ◽  
B. P. O'Sullivan ◽  
V. A. Larkin ◽  
H. Wang ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Platelet Activating Factor ◽  
Leukotriene B4 ◽  
Important Mediator ◽  
Preliminary Study ◽  
Receptor Upregulation ◽  
To Receive

The role of leukotriene B4 (LTB4) in the pathogenesis of acute lung injury was examined in endotoxemic pigs. In a preliminary study, the activity and specificity of an LTB4-receptor antagonist, LY-306669, were evaluated. In vitro, LY-306669 completely blocked the functional upregulation of phagocyte opsonin receptors induced by LTB4 but had a much smaller effect on opsonin receptor upregulation induced by platelet-activating factor. In pigs treatment with LY-306669 prevented leukopenia induced by injection of authentic LTB4 but had no effect on the hematologic or hemodynamic effects of PAF or U-48816, a thromboxane-A2 mimetic. In a second study, pigs received an intravenous priming dose of lipopolysaccharide (LPS) at time (t) = -18 h and were randomized to receive 1) no further treatment (n = 5), 2) LPS (250 micrograms/kg over 1 h beginning at t = 0 h) and LY-306669 (10 mg/kg bolus and 3 mg.kg-1.h-1 infusion beginning at t = -15 min) (n = 7), or 3) LPS and vehicle (n = 6). Treatment with LY-306669 significantly ameliorated LPS-induced hypoxemia, pulmonary edema, and alveolitis. These data suggest that LTB4 is an important mediator of pulmonary dysfunction and transendothelial migration of neutrophils in LPS-induced acute lung injury.

scholarly journals Critical Role of Prostaglandin E2Overproduction in Impaired Pulmonary Host Response following Bone Marrow Transplantation

2006 ◽  
Vol 177 (8) ◽  
pp. 5499-5508 ◽  
Author(s):  
Megan N. Ballinger ◽  
David M. Aronoff ◽  
Tracy R. McMillan ◽  
Kenneth R. Cooke ◽  
Krystyna Olkiewicz ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Marrow Transplantation ◽  
Host Response ◽  
Critical Role

scholarly journals Anti-IL-6 versus Anti-IL-6R Blocking Antibodies to Treat Acute Ebola Infection in BALB/c Mice: Potential Implications for Treating Cytokine Release Syndrome

2020 ◽  
Author(s):  
Reid Rubsamen ◽  
Scott Burkholz ◽  
Christopher Massey ◽  
Trevor Brasel ◽  
Tom Hodge ◽  
...  
Keyword(s):  
Host Response ◽  
Viral Infections ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
Important Mediator ◽  
Acute Viral Infection ◽  
Clinical Benefits ◽  
Coronavirus Infection ◽  
Blocking Antibodies

ABSTRACTCytokine release syndrome (CRS) is known to be a factor in morbidity and mortality associated with acute viral infections including those caused by filoviruses and coronaviruses. IL-6 has been implicated as a cytokine negatively associated with survival after filovirus and coronavirus infection. However, IL-6 has also been shown to be an important mediator of innate immunity and important for the host response to an acute viral infection. Clinical studies are now being conducted by various researchers to evaluate the possible role of IL-6 blockers to improve outcomes in critically ill patients with CRS. Most of these studies involve the use of anti-IL-6R monoclonal antibodies (α-IL-6R mAbs). We present data showing that direct neutralization of IL-6 with an α-IL-6 mAb in a BALB/c Ebolavirus (EBOV) challenge model produced a statistically significant improvement in outcome compared with controls when administered within the first 24 hours of challenge and repeated every 72 hours. A similar effect was seen in mice treated with the same dose of α-IL-6R mAb when the treatment was delayed 48 hrs post-challenge. These data suggest that direct neutralization of IL-6, early during the course of infection, may provide additional clinical benefits to IL-6 receptor blockade alone during treatment of patients with virus-induced CRS.

scholarly journals Pathophysiological aspects of severe acute pancreatitis-associated lung injury

2005 ◽  
Vol 133 (1-2) ◽  
pp. 76-81 ◽  
Author(s):  
Maja Surbatovic ◽  
Krsta Jovanovic ◽  
Sonja Radakovic ◽  
Nikola Filipovic
Keyword(s):  
Acute Pancreatitis ◽  
Acute Lung Injury ◽  
Mortality Rate ◽  
Lung Injury ◽  
Severe Acute Pancreatitis ◽  
Distress Syndrome ◽  
Severe Form ◽  
Very High ◽  
Intensive Medicine

Acute pancreatitis is an inflammatory process which occurs in severe form in 20% of all patients, out of whom 1596-25% will die. The incidence of severe acute pancreatitis-associated lung injury (APALI) varies from 15% to 55% and its severity varies from mild hypoxemia to acute respiratory distress syndrome (ARDS). Acute lung injury (ALI) and ARDS are the most significant manifestations of extra abdominal dysfunctions in severe acute pancreatitis with mortality rate as high as 60% in the first week of the onset of illness. Different pathophysiological mechanisms of severe acute pancreatitis-associated lung injury have been described. The role of enzymes, adhesion molecules, neutrophils, fibronectin and various inflammatory mediators has been emphasized. Mechanism of the acute lung injury associated with the acute pancreatitis is very complex and has not been clear yet. There is no specific therapeutic procedure and mortality rate is very high. Therefore, further studies are necessary to address this acute and growing problem in intensive medicine.

scholarly journals Angelica Polysaccharide Ameliorates Sepsis-Induced Acute Lung Injury through Inhibiting NLRP3 and NF-κB Signaling Pathways in Mice

2021 ◽  
Vol 2021 ◽  
pp. 1-9
Author(s):  
Yan Zhu ◽  
Taocheng Meng ◽  
Aichen Sun ◽  
Jintao Li ◽  
Jinlai Li
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Signaling Pathways ◽  
Cecal Ligation ◽  
Weight Ratio ◽  
Receptor Protein ◽  
Lung Edema ◽  
Caspase 1 ◽  
Tnf Α

Objective. This study aimed to explore the role of angelica polysaccharide (AP) in sepsis-induced acute lung injury (ALI) and its underlying molecular mechanism. Methods. A sepsis model of cecal ligation and puncture (CLP) in male BALB/C mice was used. Then, 24 h after CLP, histopathological changes in lung tissue, lung wet/dry weight ratio, and inflammatory cell infiltration were analyzed. Next, levels of inflammatory cytokines (tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6, and IL-18), as well as the activity of myeloperoxidase (MPO), malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione (GSH), were measured to assess the role of AP. The protein expression of NF-κB p65, p-NF-κB p65, IκBα, p-IκBα, nucleotide-binding domain- (NOD-) like receptor protein 3 (NLRP3), ASC, and caspase-1 was detected by western blot. In addition, the expression of p-NF-κB p65 and NLRP3 was detected by immunohistochemistry. Results. AP treatment ameliorated CLP-induced lung injury and lung edema, as well as decreased the number of total cells, neutrophils, and macrophages in bronchoalveolar lavage fluid (BALF). AP reduced the levels of TNF-α, IL-1β, IL-6, and IL-18 in BALF, as well as in serum. Moreover, AP decreased MPO activity and MDA content, whereas increased SOD and GSH levels. AP inhibited the expression of p-NF-κB p65, p-IκBα, NLRP3, ASC, and caspase-1, while promoted IκBα expression. Conclusion. This study demonstrated that AP exhibits protective effects against sepsis-induced ALI by inhibiting NLRP3 and NF-κB signaling pathways in mice.

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