scholarly journals The Emerging Roles of Tripartite Motif Proteins (TRIMs) in Acute Lung Injury

2021 ◽  
Vol 2021 ◽  
pp. 1-9
Author(s):  
Yingjie Huang ◽  
Yue Xiao ◽  
Xuekang Zhang ◽  
Xuan Huang ◽  
Yong Li
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Critical Role ◽  
Ubiquitin Ligases ◽  
Pharmacological Intervention ◽  
Inflammatory Disorder ◽  
Mesh Terms ◽  
Pubmed Database ◽  
Tripartite Motif ◽  
Trim Proteins

Acute lung injury (ALI) is an inflammatory disorder of the lung that causes high mortality and lacks any pharmacological intervention. Ubiquitination plays a critical role in the pathogenesis of ALI as it regulates the alveolocapillary barrier and the inflammatory response. Tripartite motif (TRIM) proteins are one of the subfamilies of the RING-type E3 ubiquitin ligases, which contains more than 80 distinct members in humans involved in a broad range of biological processes including antivirus innate immunity, development, and tumorigenesis. Recently, some studies have shown that several members of TRIM family proteins play important regulatory roles in inflammation and ALI. Herein, we integrate emerging evidence regarding the roles of TRIMs in ALI. Articles were selected from the searches of PubMed database that had the terms “acute lung injury,” “ubiquitin ligases,” “tripartite motif protein,” “inflammation,” and “ubiquitination” using both MeSH terms and keywords. Better understanding of these mechanisms may ultimately lead to novel therapeutic approaches by targeting TRIMs for ALI treatment.

scholarly journals TRIM32 and Malin in Neurological and Neuromuscular Rare Diseases

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 820
Author(s):  
Lorena Kumarasinghe ◽  
Lu Xiong ◽  
Maria Adelaida Garcia-Gimeno ◽  
Elisa Lazzari ◽  
Pascual Sanz ◽  
...  
Keyword(s):  
Common Ancestor ◽  
Genetic Diseases ◽  
Ubiquitin Ligases ◽  
E3 Ubiquitin Ligases ◽  
Lafora Disease ◽  
C Terminus ◽  
Rare Genetic Diseases ◽  
Tripartite Motif ◽  
Trim Proteins ◽  
Ring E3

Tripartite motif (TRIM) proteins are RING E3 ubiquitin ligases defined by a shared domain structure. Several of them are implicated in rare genetic diseases, and mutations in TRIM32 and TRIM-like malin are associated with Limb-Girdle Muscular Dystrophy R8 and Lafora disease, respectively. These two proteins are evolutionary related, share a common ancestor, and both display NHL repeats at their C-terminus. Here, we revmniew the function of these two related E3 ubiquitin ligases discussing their intrinsic and possible common pathophysiological pathways.

The SIRT1 inhibitor EX-527 suppresses mTOR activation and alleviates acute lung injury in mice with endotoxiemia

2017 ◽  
Vol 23 (8) ◽  
pp. 678-686 ◽  
Author(s):  
Jing Huang ◽  
Rui Tian ◽  
Yongqiang Yang ◽  
Rong Jiang ◽  
Jie Dai ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Translation Initiation Factor ◽  
Negative Regulator ◽  
Sirtuin 1 ◽  
Initiation Factor ◽  
Pharmacological Intervention ◽  
Inhibitory Effects ◽  
Plasminogen Activator Inhibitor 1 ◽  
Sirt1 Inhibitor

It is generally regarded that Sirtuin 1 (SIRT1), a longevity factor in mammals, acts as a negative regulator of inflammation. However, recent studies also found that SIRT1 might be a detrimental factor under certain inflammatory circumstance. In this study, the potential pathophysiological roles and the underlying mechanisms of SIRT1 in a mouse model with endotoxemia-associated acute lung injury were investigated. The results indicated that treatment with the selective SIRT1 inhibitor EX-527 suppressed LPS-induced elevation of TNF-α and IL-6 in plasma. Treatment with EX-527 attenuated LPS-induced histological abnormalities in lung tissue, which was accompanied with decreased myeloperoxidase level and suppressed induction of tissue factor and plasminogen activator inhibitor-1. Treatment with EX-527 also suppressed LPS-induced phosphorylation of eukaryotic translation initiation factor-binding protein 1 (4E-BP1). Co-administration of a mammalian target of rapamycin (mTOR) activator 3-benzyl-5-[(2-nitrophenoxy) methyl]-dihydrofuran-2 (3H)-one (3BDO) abolished the inhibitory effects of EX-527 on 4E-BP1 phosphorylation. Meanwhile, the inhibitory effects of EX-527 on IL-6 induction and the beneficial effects of EX-527 on lung injury were partially reversed by 3BDO. This study suggests that selective inhibition of SIRT1 by EX-527 might alleviate endotoxemia-associated acute lung injury partially via suppression of mTOR, which implies that SIRT1 selective inhibitors might have potential value for the pharmacological intervention of inflammatory lung injury.

scholarly journals Recipient T lymphocytes modulate the severity of antibody-mediated transfusion-related acute lung injury

Blood ◽  
2010 ◽  
Vol 116 (16) ◽  
pp. 3073-3079 ◽  
Author(s):  
Yoke Lin Fung ◽  
Michael Kim ◽  
Arata Tabuchi ◽  
Rukhsana Aslam ◽  
Edwin R. Speck ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
T Lymphocytes ◽  
Lung Injury ◽  
Pulmonary Edema ◽  
Critical Role ◽  
Severe Combined Immunodeficiency ◽  
Lung Damage ◽  
Moderate Hypothermia ◽  
Combined Immunodeficiency ◽  
Histocompatibility Complex

Abstract Transfusion-related acute lung injury (TRALI) is a serious complication of transfusion and has been ranked as one of the leading causes of transfusion-related fatalities. Nonetheless, many details of the immunopathogenesis of TRALI, particularly with respect to recipient factors are unknown. We used a murine model of antibody-mediated TRALI in an attempt to understand the role that recipient lymphocytes might play in TRALI reactions. Intravenous injection of an IgG2a antimurine major histocompatibility complex class I antibody (34-1-2s) into BALB/c mice induced moderate hypothermia and pulmonary granulocyte accumulation but no pulmonary edema nor mortality. In contrast, 34-1-2s injections into mice with severe combined immunodeficiency caused severe hypothermia, severe pulmonary edema, and approximately 40% mortality indicating a critical role for T and B lymphocytes in suppressing TRALI reactions. Adoptive transfer of purified CD8+ T lymphocytes or CD4+ T cells but not CD19+ B cells into the severe combined immunodeficiency mice alleviated the antibody-induced hypothermia, lung damage, and mortality, suggesting that T lymphocytes were responsible for the protective effect. Taken together, these results suggest that recipient T lymphocytes play a significant role in suppressing antibody-mediated TRALI reactions. They identify a potentially new recipient mechanism that controls the severity of TRALI reactions.

scholarly journals Critical Role of Mortalin/GRP75 In Endothelial Cell Dysfunction Associated With Acute Lung Injury

Shock ◽  
2019 ◽  
Vol Publish Ahead of Print ◽  
Author(s):  
Antony Leonard ◽  
Pei Yi Su ◽  
David I. Yule ◽  
Arshad Rahman ◽  
Fabeha Fazal
Keyword(s):  
Acute Lung Injury ◽  
Endothelial Cell ◽  
Lung Injury ◽  
Critical Role ◽  
Endothelial Cell Dysfunction ◽  
Cell Dysfunction

Src protein tyrosine kinase family and acute inflammatory responses

2006 ◽  
Vol 291 (2) ◽  
pp. L129-L141 ◽  
Author(s):  
Daisuke Okutani ◽  
Monika Lodyga ◽  
Bing Han ◽  
Mingyao Liu
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Tyrosine Kinase ◽  
Reperfusion Injury ◽  
Protein Tyrosine Kinase ◽  
Inflammatory Responses ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Critical Role ◽  
Protein Tyrosine

Acute inflammatory responses are one of the major underlying mechanisms for tissue damage of multiple diseases, such as ischemia-reperfusion injury, sepsis, and acute lung injury. By use of cellular and molecular approaches and transgenic animals, Src protein tyrosine kinase (PTK) family members have been identified to be essential for the recruitment and activation of monocytes, macrophages, neutrophils, and other immune cells. Src PTKs also play a critical role in the regulation of vascular permeability and inflammatory responses in tissue cells. Importantly, animal studies have demonstrated that small chemical inhibitors for Src PTKs attenuate tissue injury and improve survival from a variety of pathological conditions related to acute inflammatory responses. Further investigation may lead to the clinical application of these inhibitors as drugs for ischemia-reperfusion injury (such as stroke and myocardial infarction), sepsis, acute lung injury, and multiple organ dysfunction syndrome.

scholarly journals Dimethyl Fumarate Ameliorates Lipopolysaccharide-induced Acute Lung Injury by Inhibiting NLRP3 Inflammasome-mediated Pyroptosis

2021 ◽  
Author(s):  
Huayu Li ◽  
Mengyan Li ◽  
Chao Dong ◽  
Bing Liu
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Nlrp3 Inflammasome ◽  
Therapeutic Potential ◽  
Critical Role ◽  
Specific Effect ◽  
Dimethyl Fumarate ◽  
Related Factor ◽  
Pyrin Domain ◽  
Anti Inflammatory

Abstract Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are clinically severe respiratory disorders, and there are currently no Food and Drug Administration-approved drug therapies. It is established that Dimethyl fumarate (DMF) exhibits anti inflammatory effects, however, the specific effect of DMF on ALI remains largely unknown. The aim of the present study was to investigate whether, and by which mechanism, DMF alleviated lipopolysaccharide (LPS)-induced ALI. We found that intraperitoneal injection of DMF markedly reduced the pulmonary injury, decreased pulmonary edema and pulmonary permeability. Emerging studies suggested that the NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome-mediated pyroptosis played a critical role during ALI. NLRP3 inflammasome-mediated pyroptosis is significantly activated with the cleavage of caspase-1 and GSDMD occurring in the lung of LPS-induced ALI. DMF inhibited the activation of the NLRP3 inflammasome and pyroptosis in both lung of ALI mice and LPS-induced BEAS-2B cells. Mechanistically, DMF enhanced expressions of Nuclear factor erythroid-2-related factor 2 (Nrf2), leading to inactivation of NLRP3 inflammasome and reduction of pyroptosis in both ALI mice and LPS-induced BEAS-2B cells. Conversely, Nrf2 inhibitor reduced the inhibitory effects of DMF on NLRP3 inflammasome and pyroptosis, and consequently blocked the improvement roles of DMF on ALI in mice. This study for the first time demonstrated that DMF could improve LPS-induced ALI via inhibiting NLRP3 inflammasome and pyroptosis, and that these effects were mediated by triggering Nrf2 expression, suggesting a therapeutic potential of DMF as an anti-inflammatory agent for ALI/ARDS treatment.

scholarly journals Blockade of endothelial, but not epithelial, cell expression of PD-L1 following severe shock attenuates the development of indirect acute lung injury in mice

2020 ◽  
Vol 318 (4) ◽  
pp. L801-L812 ◽  
Author(s):  
Shumin Xu ◽  
Qian Yang ◽  
Jianwen Bai ◽  
Tianzhu Tao ◽  
Lunxian Tang ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Critical Role ◽  
Lavage Fluid ◽  
Protein Levels ◽  
Pulmonary Endothelial Cells ◽  
Junction Protein ◽  
Cell Expression ◽  
Intratracheal Delivery

This study sets out to establish the comparative contribution of PD-L1 expression by pulmonary endothelial cells (ECs) and/or epithelial cells (EpiCs) to the development of indirect acute lung injury (iALI) by taking advantage of the observation that treatment with naked siRNA by intratracheal delivery in mice primarily affects lung EpiCs, but not lung ECs, while intravenous delivery of liposomal-encapsulated siRNA largely targets vascular ECs including the lung, but not pulmonary EpiCs. We showed that using a mouse model of iALI [induced by hemorrhagic shock followed by septic challenge (Hem-CLP)], PD-L1 expression on pulmonary ECs or EpiCs was significantly upregulated in the iALI mice at 24 h post–septic insult. After documenting the selective ability of intratracheal versus intravenous delivery of PD-L1 siRNA to inhibit PD-L1 expression on EpiCs versus ECs, respectively, we observed that the iALI-induced elevation of cytokine/chemokine levels (in the bronchoalveolar lavage fluid, lung lysates, or plasma), lung myeloperoxidase and caspase-3 activities could largely only be inhibited by intravenous, but not intratracheal, delivery of PD-L1 siRNA. Moreover, intravenous, but not intratracheal, delivery led to a preservation of normal tissue architecture, lessened pulmonary edema, and reduced neutrophils influx induced by iALI. In addition, in vitro mouse endothelial cell line studies showed that PD-L1 gene knockdown by siRNA or knockout by CRISPR/Cas9-mediated gene manipulation, reduced monolayer permeability, and maintained tight junction protein levels upon recombinant IFN-γ stimulation. Together, these data imply a critical role for pulmonary vascular ECs in mediating PD-1:PD-L1–driven pathological changes resulting from systemic stimuli such as Hem-CLP.

Temporal changes in pulmonary expression of key procoagulant molecules in rabbits with endotoxin-induced acute lung injury: elevated expression levels of protease-activated receptors

2004 ◽  
Vol 92 (11) ◽  
pp. 966-979 ◽  
Author(s):  
Subrina Jesmin ◽  
Naoyuki Matsuda ◽  
Ichiro Sakuma ◽  
Shigeaki Kobayashi ◽  
Fumika Sakuraya ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Inflammatory Responses ◽  
Tissue Injury ◽  
Critical Role ◽  
Control Level ◽  
Temporal Changes ◽  
Expression Levels ◽  
Time Courses ◽  
Pai 1

SummaryRecently a new concept has emerged implicating thrombin signaling as the “bridge” that connects tissue damage to hemostatic and inflammatory responses. In view of this concept, we hypothesized that induction of protease-activated receptor (PAR) expression may play a critical role in endotoxin-induced tissue injury through the cellular actions of thrombin. Thus, in this study, temporal changes in expression of key precoagulant molecules, including PARs, in lungs from rabbits rendered endotoxemic by 100 μg/kg lipopolysaccharide (LPS) were examined with measurements of variables reflecting acute lung injury (ALI). ALI induction by LPS was confirmed by blood gas derangement, lung vascular hyperpermeability, and histopathological changes, and was characterized by the deposition of fibrin in the alveolar spaces, bronchioles and vessels. Plasminogen activator inhibitor-1 (PAI-1) and tissue factor (TF) were highly expressed in lungs after LPS injection. While the peaks in levels of PAI-1 and TF were comparable (12∼13-fold from control), their expression time-courses were different: PAI-1 exhibited a bell-shaped expression pattern and peak at 6 h, whereas TF level reached maximum at 10 h. Of note, LPS induced a rapid and significant increase in levels of PAR-1 compared to control, with a peak level at 1 h (3.3-fold). Although declining thereafter, it remained significantly higher than the control level throughout the study period. Expressions of PAR-2, -3, and -4 were also increased by LPS with different time courses from PAR-1 expression. Immunofluorescence staining for PAR-1 were localized in blood vessels, bronchial epithelium, and alveolar pneumocytes after LPS. These results suggest that the increased expression levels of PARs, in addition to PAI-1 and TF, may, in part, underlie the development of ALI occurring during endotoxemia.

Determination of acute lung injury after repeated platelet transfusions

Blood ◽  
2011 ◽  
Vol 117 (3) ◽  
pp. 1014-1020 ◽  
Author(s):  
Laurence Corash ◽  
Jin Sying Lin ◽  
Claire D. Sherman ◽  
Joseph Eiden
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Critical Role ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Treatment Groups ◽  
Time To Onset ◽  
Substantial Morbidity ◽  
Platelet Transfusions

Abstract Acute lung injury (ALI) during hematopoietic stem cell transplant (HSCT) is associated with substantial morbidity; however, the frequency of ALI in HSCT patients is poorly characterized. Platelets are postulated to play a critical role in the pathogenesis of ALI. Using a transfusion trial of pathogen inactivated platelet components (PC-Test) compared with conventional PC (Reference) populated with HSCT patients, data were reviewed by an adjudication panel to determine the frequency of ALI overall, by treatment groups, and key outcomes: PC exposure, ventilator-free days, and mortality. The diagnosis of ALI was based on American European Consensus Criteria. Of 645 patients who received PC over 28 days, 100 (15.5%) had clinically serious pulmonary adverse events, and 35 (5.4%) met criteria for ALI. Days of platelet support and number of platelet transfusions for patients with ALI were not significantly different from patients without ALI (P > .05). Mortality was greater for patients with ALI (57%) than those without (17%, P < .001) but not significantly different between treatment groups. For patients with ALI, the distributions of time to onset of mechanical ventilation were significantly different (P = .04). Patients supported with Reference PC were more likely to be ventilated sooner than patients receiving Test PC.

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