Protective effect of purinergic agonist ATPγS against acute lung injury

2008 ◽  
Vol 294 (2) ◽  
pp. L319-L324 ◽  
Author(s):  
Irina A. Kolosova ◽  
Tamara Mirzapoiazova ◽  
Liliana Moreno-Vinasco ◽  
Saad Sammani ◽  
Joe G. N. Garcia ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Endothelial Cell ◽  
Lung Injury ◽  
Therapeutic Potential ◽  
Purinergic Receptor ◽  
Biological Effects ◽  
Cell Junctions ◽  
High Morbidity ◽  
Protective Effects ◽  
Intratracheal Administration

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are major causes of acute respiratory failure associated with high morbidity and mortality. Although ALI/ARDS pathogenesis is only partly understood, pulmonary endothelium plays a major role by regulating lung fluid balance and pulmonary edema formation. Consequently, endothelium-targeted therapies may have beneficial effects in ALI/ARDS. Recently, attention has been given to the therapeutic potential of purinergic agonists and antagonists for the treatment of cardiovascular and pulmonary diseases. Extracellular purines (adenosine, ADP, and ATP) and pyrimidines (UDP and UTP) are important signaling molecules that mediate diverse biological effects via cell-surface P2Y receptors. We previously described ATP-induced endothelial cell (EC) barrier enhancement via a complex cell signaling and hypothesized endothelial purinoreceptors activation to exert anti-inflammatory barrier-protective effects. To test this hypothesis, we used a murine model of ALI induced by intratracheal administration of endotoxin/lipopolysaccharide (LPS) and cultured pulmonary EC. The nonhydrolyzed ATP analog ATPγS (50–100 μM final blood concentration) attenuated inflammatory response with decreased accumulation of cells (48%, P < 0.01) and proteins (57%, P < 0.01) in bronchoalveolar lavage and reduced neutrophil infiltration and extravasation of Evans blue albumin dye into lung tissue. In cell culture model, ATPγS inhibited junctional permeability induced by LPS. These findings suggest that purinergic receptor stimulation exerts a protective role against ALI by preserving integrity of endothelial cell-cell junctions.

scholarly journals GRP78 is a novel receptor initiating a vascular barrier protective response to oxidized phospholipids

2014 ◽  
Vol 25 (13) ◽  
pp. 2006-2016 ◽  
Author(s):  
Anna A. Birukova ◽  
Patrick A. Singleton ◽  
Grzegorz Gawlak ◽  
Xinyong Tian ◽  
Tamara Mirzapoiazova ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Endothelial Cell ◽  
Lung Injury ◽  
Ischemia Reperfusion ◽  
Cell Junctions ◽  
Endothelial Barrier ◽  
Oxidized Phospholipids ◽  
Vascular Integrity

Vascular integrity and the maintenance of blood vessel continuity are fundamental features of the circulatory system maintained through endothelial cell–cell junctions. Defects in the endothelial barrier become an initiating factor in several pathologies, including ischemia/reperfusion, tumor angiogenesis, pulmonary edema, sepsis, and acute lung injury. Better understanding of mechanisms stimulating endothelial barrier enhancement may provide novel therapeutic strategies. We previously reported that oxidized phospholipids (oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine [OxPAPC]) promote endothelial cell (EC) barrier enhancement both in vitro and in vivo. This study examines the initiating mechanistic events triggered by OxPAPC to increase vascular integrity. Our data demonstrate that OxPAPC directly binds the cell membrane–localized chaperone protein, GRP78, associated with its cofactor, HTJ-1. OxPAPC binding to plasma membrane–localized GRP78 leads to GRP78 trafficking to caveolin-enriched microdomains (CEMs) on the cell surface and consequent activation of sphingosine 1-phosphate receptor 1, Src and Fyn tyrosine kinases, and Rac1 GTPase, processes essential for cytoskeletal reorganization and EC barrier enhancement. Using animal models of acute lung injury with vascular hyperpermeability, we observed that HTJ-1 knockdown blocked OxPAPC protection from interleukin-6 and ventilator-induced lung injury. Our data indicate for the first time an essential role of GRP78 and HTJ-1 in OxPAPC-mediated CEM dynamics and enhancement of vascular integrity.

scholarly journals Ameliorative Effects of Oleuropein on Lipopolysaccharide-induced Acute Lung Injury Model in Rats

2021 ◽  
Author(s):  
NURSEL DİKMEN ◽  
MUSTAFA CELLAT ◽  
MUHAMMED ETYEMEZ ◽  
CAFER TAYER İŞLER ◽  
AHMET UYAR ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Histopathological Examination ◽  
Lavage Fluid ◽  
Protective Effects ◽  
Intratracheal Administration ◽  
Acute Interstitial Pneumonia ◽  
Injury Model ◽  
Common Causes ◽  
Lung Injury Model

Abstract Acute lung injury (ALI) is one of the most common causes of death in diseases with septic shock. Oleuropein, one of the important components of olive leaf, has antioxidant and anti-inflammatory effects. The objective of this study was to investigate the effects of oleuropein on lipopolysaccharide (LPS)-induced ALI in rats. Oleuropein was administered to rats at a dose of 200 mg/kg for 20 days and LPS was given through intratracheal administration to induce ALI. The study was terminated after 12 hours. The results showed that in the group treated with oleuropein; inflammatory cytokines and oxidative stress decreased in serum, bronchoalveolar lavage fluid (BALF), and lung tissue, and there were significant improvements in the picture of acute interstitial pneumonia (AIP) caused by LPS in histopathological examination. Based on the findings of the present study, oleuropein showed protective effects against LPS-induced ALI.

Keratinocyte and hepatocyte growth factors in the lung: roles in lung development, inflammation, and repair

2002 ◽  
Vol 282 (5) ◽  
pp. L924-L940 ◽  
Author(s):  
Lorraine B. Ware ◽  
Michael A. Matthay
Keyword(s):  
Acute Lung Injury ◽  
Growth Factors ◽  
Growth Factor ◽  
Animal Models ◽  
Lung Injury ◽  
Lung Development ◽  
Therapeutic Potential ◽  
Keratinocyte Growth Factor ◽  
Protective Effects ◽  
Hepatocyte Growth

A growing body of evidence indicates that the epithelial-specific growth factors keratinocyte growth factor (KGF), fibroblast growth factor (FGF)-10, and hepatocyte growth factor (HGF) play important roles in lung development, lung inflammation, and repair. The therapeutic potential of these growth factors in lung disease has yet to be fully explored. KGF has been best studied and has impressive protective effects against a wide variety of injurious stimuli when given as a pretreatment in animal models. Whether this protective effect could translate to a treatment effect in humans with acute lung injury needs to be investigated. FGF-10 and HGF may also have therapeutic potential, but more extensive studies in animal models are needed. Because HGF lacks true epithelial specificity, it may have less potential than KGF and FGF-10 as a targeted therapy to facilitate lung epithelial repair. Regardless of their therapeutic potential, studies of the unique roles played by these growth factors in the pathogenesis and the resolution of acute lung injury and other lung diseases will continue to enhance our understanding of the complex pathophysiology of inflammation and repair in the lung.

scholarly journals Ferroptosis, a New Insight Into Acute Lung Injury

2021 ◽  
Vol 12 ◽  
Author(s):  
Xiaofang Yin ◽  
Guisong Zhu ◽  
Qian Wang ◽  
Yuan Dong Fu ◽  
Juan Wang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Lipid Peroxidation ◽  
Acute Lung Injury ◽  
Lung Injury ◽  
Therapeutic Potential ◽  
High Morbidity ◽  
Compelling Evidence ◽  
Pathophysiological Process ◽  
Insight Into

Acute lung injury (ALI), a common and critical illness with high morbidity and mortality, is caused by multiple causes. It has been confirmed that oxidative stress plays an important role in the development of ALI. Ferroptosis, a newly discovered programmed cell death in 2012, is characterized by iron-dependent lipid peroxidation and involved in many diseases. To date, compelling evidence reveals the emerging role of ferroptosis in the pathophysiological process of ALI. Here, we review the role of ferroptosis in the pathogenesis of ALI and its therapeutic potential in ALI.

scholarly journals Methionine Restriction Prevents Lipopolysaccharide-Induced Acute Lung Injury via Modulating CSE/H2S Pathway

Nutrients ◽  
2022 ◽  
Vol 14 (2) ◽  
pp. 322
Author(s):  
Jiaxiang Duan ◽  
Lunli Xiang ◽  
Zhen Yang ◽  
Li Chen ◽  
Jianteng Gu ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Immune Cell ◽  
Therapeutic Potential ◽  
Alveolar Epithelial Cell ◽  
Receptor Protein ◽  
Protective Effects ◽  
Methionine Restriction ◽  
Production Of Hydrogen ◽  
Underlying Mechanisms

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) result in high mortality, whereas effective treatments are limited. Methionine restriction (MR) has been reported to offer various benefits against multiple pathological processes of organ injuries. However, it remains unknown whether MR has any potential therapeutic value for ALI/ARDS. The current study was set to investigate the therapeutic potential of MR on lipopolysaccharide (LPS)-induced ALI and its underlying mechanisms. We found that MR attenuated LPS-induced pulmonary edema, hemorrhage, atelectasis, and alveolar epithelial cell injuries in mice. MR upregulated cystathionine-gamma-lyase (CSE) expression and enhanced the production of hydrogen sulfide (H2S). MR also inhibited the activation of Toll-like receptors 4 (TLR4)/NF-κB/NOD-like receptor protein 3 (NLRP3), then reduced IL-1β, IL-6, and TNF-α release and immune cell infiltration. Moreover, the protective effects of MR on LPS-induced ALI were abrogated by inhibiting CSE, whereas exogenous H2S treatment alone mimicked the protective effects of MR in Cse−/− mice after LPS administration. In conclusion, our findings showed that MR attenuated LPS-induced lung injury through CSE and H2S modulation. This work suggests that developing MR towards clinical use for ALI/ARDS patients may be a valuable strategy.

scholarly journals Mechanosensitive Rap1 activation promotes barrier function of lung vascular endothelium under cyclic stretch

2019 ◽  
Vol 30 (8) ◽  
pp. 959-974 ◽  
Author(s):  
Yunbo Ke ◽  
Pratap Karki ◽  
Chenou Zhang ◽  
Yue Li ◽  
Trang Nguyen ◽  
...  
Keyword(s):  
Mechanical Ventilation ◽  
Endothelial Cell ◽  
Lung Injury ◽  
Tidal Volume ◽  
Small Gtpase ◽  
Cyclic Stretch ◽  
Cell Junctions ◽  
Protective Effects ◽  
Barrier Dysfunction

Mechanical ventilation remains an imperative treatment for the patients with acute respiratory distress syndrome, but can also exacerbate lung injury. We have previously described a key role of RhoA GTPase in high cyclic stretch (CS)–induced endothelial cell (EC) barrier dysfunction. However, cellular mechanotransduction complexes remain to be characterized. This study tested a hypothesis that recovery of a vascular EC barrier after pathologic mechanical stress may be accelerated by cell exposure to physiologic CS levels and involves Rap1-dependent rearrangement of endothelial cell junctions. Using biochemical, molecular, and imaging approaches we found that EC pre- or postconditioning at physiologically relevant low-magnitude CS promotes resealing of cell junctions disrupted by pathologic, high-magnitude CS. Cytoskeletal remodeling induced by low CS was dependent on small GTPase Rap1. Protective effects of EC preconditioning at low CS were abolished by pharmacological or molecular inhibition of Rap1 activity. In vivo, using mice exposed to mechanical ventilation, we found that the protective effect of low tidal volume ventilation against lung injury caused by lipopolysaccharides and ventilation at high tidal volume was suppressed in Rap1 knockout mice. Taken together, our results demonstrate a prominent role of Rap1-mediated signaling mechanisms activated by low CS in acceleration of lung vascular EC barrier restoration.

scholarly journals Serinc2 deficiency causes susceptibility to sepsis-associated acute lung injury

2021 ◽  
Author(s):  
Shuai Mao ◽  
Jian Lv ◽  
Meng Chen ◽  
Ningning Guo ◽  
Yu Fang ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Inflammatory Responses ◽  
Cecal Ligation ◽  
Underlying Mechanism ◽  
Raw264.7 Cells ◽  
Inflammatory Factors ◽  
High Morbidity ◽  
Positive Staining ◽  
Protective Effects

Abstract Background Severe sepsis and its subsequent complications cause high morbidity and mortality rates worldwide. Lung is one of the most vulnerable organs sensitive to sepsis-associated inflammatory storm, and usually develops into acute respiratory distress syndrome (ARDS)/acute lung injury (ALI). The pathogenesis of sepsis-associated ALI is accompanied by coordinated transmembrane signal transduction and subsequent programmed cell death; however, the underlying mechanism remains largely unclear. Results Here we find that the expression of serine incorporator 2 (Serinc2), a protein involved in phosphatidylserine synthesis and membrane incorporation, is upregulated in cecal ligation and puncture (CLP)-induced ALI. Furthermore, serinc2-knockout (KO) mouse line is generated by CRISPR-cas9 approach. Compared with wildtype mice, the Serinc2-KO mice exhibit exacerbated ALI-related pathologies after CLP. The expressions of pro-inflammatory factors, including IL1β, IL6, TNFα, and MCP1, are significantly enhanced by Serinc2 deficiency, concurrent with over-activation of STAT3, p38 and ERK pathways. Conversely, Serinc2 overexpression in RAW264.7 cells significantly suppresses the inflammatory responses induced by lipopolysaccharide (LPS). Serinc2 KO aggravates CLP-induced apoptosis as evidenced by increases in TUNEL-positive staining, Bax expression, and Caspase-3 cleavage and decreases in BCL-2 expression and Akt phosphorylation, whereas these changes are suppressed by Serinc2 overexpression in LPS-treated RAW264.7 cells. Moreover, administration of AKTin, an inhibitor of Akt, abolishes the protective effects of Serinc2 overexpression against inflammation and apoptosis. Conclusions Our findings demonstrate a protective role of Serinc2 in the lung through activating the Akt pathway, and provide novel insight into the pathogenesis of sepsis-induced ALI.

Current Advances in the Biological Activity of Polysaccharides in Dendrobium with Intriguing Therapeutic Potential

2018 ◽  
Vol 25 (14) ◽  
pp. 1663-1681 ◽  
Author(s):  
Chun-Ting Lee ◽  
Heng-Chun Kuo ◽  
Yung-Hsiang Chen ◽  
Ming-Yen Tsai
Keyword(s):  
Biological Activity ◽  
Therapeutic Potential ◽  
Biological Activities ◽  
Biological Effects ◽  
Herbal Medicines ◽  
Research Field ◽  
Protective Effects ◽  
Pharmacological Effects ◽  
The Family ◽  
Anti Tumor Activity

The polysaccharides in many plants are attracting worldwide attention because of their biological activities and medical properties, such as anti-viral, anti-oxidative, antichronic inflammation, anti-hypertensive, immunomodulation, and neuron-protective effects, as well as anti-tumor activity. Denodrobium species, a genus of the family orchidaceae, have been used as herbal medicines for hundreds of years in China due to their pharmacological effects. These effects include nourishing the Yin, supplementing the stomach, increasing body fluids, and clearing heat. Recently, numerous researchers have investigated possible active compounds in Denodrobium species, such as lectins, phenanthrenes, alkaloids, trigonopol A, and polysaccharides. Unlike those of other plants, the biological effects of polysaccharides in Dendrobium are a novel research field. In this review, we focus on these novel findings to give readers an overall picture of the intriguing therapeutic potential of polysaccharides in Dendrobium, especially those of the four commonly-used Denodrobium species: D. huoshanense, D. offininale, D. nobile, and D. chrysotoxum.

scholarly journals Protectin conjugates in tissue regeneration 1 restores lipopolysaccharide-induced pulmonary endothelial glycocalyx loss via ALX/SIRT1/NF-kappa B axis

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Xin-Yang Wang ◽  
Xin-Yu Li ◽  
Cheng-Hua Wu ◽  
Yu Hao ◽  
Pan-Han Fu ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Inflammatory Cytokines ◽  
Tissue Regeneration ◽  
Umbilical Vein ◽  
Endothelial Glycocalyx ◽  
Lipid Mediator ◽  
Protective Effects ◽  
Pulmonary Vascular Permeability

Abstract Background Endothelial glycocalyx loss is integral to increased pulmonary vascular permeability in sepsis-related acute lung injury. Protectin conjugates in tissue regeneration 1 (PCTR1) is a novel macrophage-derived lipid mediator exhibiting potential anti-inflammatory and pro-resolving benefits. Methods PCTR1 was administrated intraperitoneally with 100 ng/mouse after lipopolysaccharide (LPS) challenged. Survival rate and lung function were used to evaluate the protective effects of PCTR1. Lung inflammation response was observed by morphology and inflammatory cytokines level. Endothelial glycocalyx and its related key enzymes were measured by immunofluorescence, ELISA, and Western blot. Afterward, related-pathways inhibitors were used to identify the mechanism of endothelial glycocalyx response to PCTR1 in mice and human umbilical vein endothelial cells (HUVECs) after LPS administration. Results In vivo, we show that PCTR1 protects mice against lipopolysaccharide (LPS)-induced sepsis, as shown by enhanced the survival and pulmonary function, decreased the inflammatory response in lungs and peripheral levels of inflammatory cytokines such as tumor necrosis factor-α, interleukin-6, and interleukin-1β. Moreover, PCTR1 restored lung vascular glycocalyx and reduced serum heparin sulphate (HS), syndecan-1 (SDC-1), and hyaluronic acid (HA) levels. Furthermore, we found that PCTR1 downregulated heparanase (HPA) expression to inhibit glycocalyx degradation and upregulated exostosin-1 (EXT-1) protein expression to promote glycocalyx reconstitution. Besides, we observed that BAY11-7082 blocked glycocalyx loss induced by LPS in vivo and in vitro, and BOC-2 (ALX antagonist) or EX527 (SIRT1 inhibitor) abolished the restoration of HS in response to PCTR1. Conclusion PCTR1 protects endothelial glycocalyx via ALX receptor by regulating SIRT1/NF-κB pathway, suggesting PCTR1 may be a significant therapeutic target for sepsis-related acute lung injury.

Sign in / Sign up

Export Citation Format

Share Document