Regulated in Development and DNA Damage Response 1 Knockdown Alleviates Lipopolysaccharide-Induced Acute Lung Injury

2021 ◽  
Vol 11 (7) ◽  
pp. 1333-1338
Author(s):  
Han Han ◽  
Zhenxi Yu ◽  
Mei Feng
Keyword(s):  
Acute Lung Injury ◽  
Epithelial Cell ◽  
Epithelial Cells ◽  
Lung Injury ◽  
Cell Activity ◽  
Lung Epithelial Cells ◽  
Lung Epithelial Cell ◽  
Inflammatory Factors ◽  
Lung Epithelial ◽  
Damage Response

Regulated in Development and DNA Damage Response 1 (REDD1) knockdown can reduce the endoplasmic reticulum stress response in liver injury. However, its role on lipopolysaccharide (LPS)-induced acute lung injury (ALI) has not been explored. This study aimed to evaluate the effect of REDD1 on lung epithelial cells induced by LPS. Rt-qPCR and Western blot were used to detect REDD1 expression in 16HBE cells induced by LPS. The interfering REDD1 plasmid was constructed, and CCK8 was used to detect the effect of interference with REDD1 on LPS-induced lung epithelial cell activity. The expression of inflammatory factors was detected by ELISA and the apoptotic level was detected by TUNEL staining. String database was used to predict the combination of REDD1 and EP300 in lung epithelial cells, which was verified by CoIP experiment. An overexpressed plasmid of EP300 was constructed to detect the effects of EP300 on inflammatory factors and apoptosis in REDD1 lung epithelial cells. LPS-induced increased REDD1 expression in lung epithelial cells. Interference with REDD1 inhibits LPS-induced lung epithelial cell activity injury and inflammatory factor expression and inhibits LPS-induced lung epithelial cell apoptosis. After interference with REDD1, the expression of EP300 in LPS-induced lung epithelial cells was inhibited, and the overexpression of EP300 was reversed to promote the production of inflammatory factors and apoptosis. In conclusion, these results demonstrate that REDD1 knockdown alleviates LPS-induced acute lung injury.

Lung epithelial cell apoptosis during acute lung injury in infancy

2007 ◽  
Vol 8 (2) ◽  
pp. 132-137 ◽  
Author(s):  
Reinout A. Bem ◽  
Albert P. Bos ◽  
Gustavo Matute-Bello ◽  
Minke van Tuyl ◽  
Job B. M. van Woensel
Keyword(s):  
Acute Lung Injury ◽  
Epithelial Cell ◽  
Lung Injury ◽  
Cell Apoptosis ◽  
Lung Epithelial Cell ◽  
Lung Epithelial ◽  
Epithelial Cell Apoptosis

scholarly journals TNF Family Cytokines Induce Distinct Cell Death Modalities in the A549 Human Lung Epithelial Cell Line when Administered in Combination with Ricin Toxin

Toxins ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 450 ◽  
Author(s):  
Hodges ◽  
Kempen ◽  
McCaig ◽  
Parker ◽  
Mantis ◽  
...  
Keyword(s):  
Cell Death ◽  
Epithelial Cell ◽  
Epithelial Cells ◽  
Human Lung ◽  
Lung Epithelial Cells ◽  
Lung Epithelial Cell ◽  
Distinct Cell ◽  
Tnf Α ◽  
Lung Epithelial ◽  
Human Lung Epithelial Cells

Ricin is a member of the ribosome-inactivating protein (RIP) family of toxins and is classified as a biothreat agent by the Centers for Disease Control and Prevention (CDC). Inhalation, the most potent route of toxicity, triggers an acute respiratory distress-like syndrome that coincides with near complete destruction of the lung epithelium. We previously demonstrated that the TNF-related apoptosis-inducing ligand (TRAIL; CD253) sensitizes human lung epithelial cells to ricin-induced death. Here, we report that ricin/TRAIL-mediated cell death occurs via apoptosis and involves caspases -3, -7, -8, and -9, but not caspase-6. In addition, we show that two other TNF family members, TNF-α and Fas ligand (FasL), also sensitize human lung epithelial cells to ricin-induced death. While ricin/TNF-α- and ricin/FasL-mediated killing of A549 cells was inhibited by the pan-caspase inhibitor, zVAD-fmk, evidence suggests that these pathways were not caspase-dependent apoptosis. We also ruled out necroptosis and pyroptosis. Rather, the combination of ricin plus TNF-α or FasL induced cathepsin-dependent cell death, as evidenced by the use of several pharmacologic inhibitors. We postulate that the effects of zVAD-fmk were due to the molecule’s known off-target effects on cathepsin activity. This work demonstrates that ricin-induced lung epithelial cell killing occurs by distinct cell death pathways dependent on the presence of different sensitizing cytokines, TRAIL, TNF-α, or FasL.

scholarly journals Lung epithelial cell-derived extracellular vesicles activate macrophage-mediated inflammatory responses via ROCK1 pathway

2015 ◽  
Vol 6 (12) ◽  
pp. e2016-e2016 ◽  
Author(s):  
H-G Moon ◽  
Y Cao ◽  
J Yang ◽  
J H Lee ◽  
H S Choi ◽  
...  
Keyword(s):  
Epithelial Cell ◽  
Epithelial Cells ◽  
Extracellular Vesicles ◽  
Caspase 3 ◽  
Inflammatory Responses ◽  
Lung Epithelial Cells ◽  
Lung Epithelial Cell ◽  
Apoptotic Bodies ◽  
Protein Markers ◽  
Lung Epithelial

Abstract Despite decades of research, the pathogenesis of acute respiratory distress syndrome (ARDS) remains poorly understood, thus impeding the development of effective treatment. Diffuse alveolar damage (DAD) and lung epithelial cell death are prominent features of ARDS. Lung epithelial cells are the first line of defense after inhaled stimuli, such as in the case of hyperoxia. We hypothesized that lung epithelial cells release ‘messenger’ or signaling molecules to adjacent or distant macrophages, thereby initiating or propagating inflammatory responses after noxious insult. We found that, after hyperoxia, a large amount of extracellular vesicles (EVs) were generated and released into bronchoalveolar lavage fluid (BALF). These hyperoxia-induced EVs were mainly derived from live lung epithelial cells as the result of hyperoxia-associated endoplasmic reticulum (ER) stress. These EVs were remarkably different from epithelial ‘apoptotic bodies’, as reflected by the significantly smaller size and differentially expressed protein markers. These EVs fall mainly in the size range of the exosomes and smaller microvesicles (MVs) (50–120 nm). The commonly featured protein markers of apoptotic bodies were not found in these EVs. Treating alveolar macrophages with hyperoxia-induced, epithelial cell-derived EVs led to an increased secretion of pro-inflammatory cytokines and macrophage inflammatory protein 2 (MIP-2). Robustly increased macrophage and neutrophil influx was found in the lung tissue of the mice intranasally treated with hyperoxia-induced EVs. It was determined that EV-encapsulated caspase-3 was largely responsible for the alveolar macrophage activation via the ROCK1 pathway. Caspase-3-deficient EVs induced less cytokine/MIP-2 release, reduced cell counts in BALF, less neutrophil infiltration and less inflammation in lung parenchyma, both in vitro and in vivo. Furthermore, the serum circulating EVs were increased and mainly derived from lung epithelial cells after hyperoxia exposure. These circulating EVs also activated systemic macrophages other than the alveolar ones. Collectively, the results show that hyperoxia-induced, lung epithelial cell-derived and caspase-3 enriched EVs activate macrophages and mediate the inflammatory lung responses involved in lung injury.

The fibrinolytic system and the regulation of lung epithelial cell proteolysis, signaling, and cellular viability

2008 ◽  
Vol 295 (6) ◽  
pp. L967-L975 ◽  
Author(s):  
Sreerama Shetty ◽  
Joseph Padijnayayveetil ◽  
Torry Tucker ◽  
Dorota Stankowska ◽  
Steven Idell
Keyword(s):  
Epithelial Cell ◽  
Epithelial Cells ◽  
Plasminogen Activator ◽  
Mrna Stability ◽  
Fibrinolytic System ◽  
Lung Epithelial Cells ◽  
Lung Epithelial Cell ◽  
Plasminogen Activator Inhibitor 1 ◽  
Lung Epithelial ◽  
Pai 1

The urokinase-type plasminogen activator (uPA), its receptor (uPAR), and plasminogen activator inhibitor-1 (PAI-1) are key components of the fibrinolytic system and are expressed by lung epithelial cells. uPA, uPAR, and PAI-1 have been strongly implicated in the pathogenesis of acute lung injury (ALI) and pulmonary fibrosis. Recently, it has become clear that regulation of uPA, uPAR, and PAI-1 occurs at the posttranscriptional level of mRNA stability in lung epithelial cells. uPA further mediates its own expression in these cells as well as that of uPAR and PAI-1 through induction of changes in mRNA stability. In addition, uPA-mediated signaling controls the expression of the tumor suppressor protein p53 in lung epithelial cells at the posttranslational level. p53 has recently been shown to be a trans-acting uPA, uPAR, and PAI-1 mRNA-binding protein that regulates the stability of these mRNAs. It is now clear that signaling initiated by uPA mediates dose-dependent regulation of lung epithelial cell apoptosis and likewise involves changes in p53, uPA, uPAR, and PAI-1 expression. These findings demonstrate that the uPA-uPAR-PAI-1 system of lung epithelial cells mediates a broad repertoire of responses that encompass but extend well beyond traditional fibrinolysis, involve newly recognized interactions with p53 that influence the viability of the lung epithelium, and are thereby implicated in the pathogenesis of ALI and its repair.

scholarly journals NLRP3 deletion protects from hyperoxia-induced acute lung injury

2013 ◽  
Vol 305 (2) ◽  
pp. C182-C189 ◽  
Author(s):  
Jutaro Fukumoto ◽  
Itsuko Fukumoto ◽  
Prasanna Tamarapu Parthasarathy ◽  
Ruan Cox ◽  
Bao Huynh ◽  
...  
Keyword(s):  
Cell Death ◽  
Acute Lung Injury ◽  
Epithelial Cell ◽  
Lung Injury ◽  
Inflammatory Response ◽  
Lung Epithelial Cell ◽  
Inflammasome Activation ◽  
Nlrp3 Gene ◽  
Lung Epithelial ◽  
Epithelial Cell Death

Inspiration of a high concentration of oxygen, a therapy for acute lung injury (ALI), could unexpectedly lead to reactive oxygen species (ROS) production and hyperoxia-induced acute lung injury (HALI). Nucleotide-binding domain and leucine-rich repeat PYD-containing protein 3 (NLRP3) senses the ROS, triggering inflammasome activation and interleukin-1β (IL-1β) production and secretion. However, the role of NLRP3 inflammasome in HALI is unclear. The main aim of this study is to determine the effect of NLRP3 gene deletion on inflammatory response and lung epithelial cell death. Wild-type (WT) and NLRP3−/− mice were exposed to 100% O2 for 48–72 h. Bronchoalveolar lavage fluid and lung tissues were examined for proinflammatory cytokine production and lung inflammation. Hyperoxia-induced lung pathological score was suppressed in NLRP3−/− mice compared with WT mice. Hyperoxia-induced recruitment of inflammatory cells and elevation of IL-1β, TNFα, macrophage inflammatory protein-2, and monocyte chemoattractant protein-1 were attenuated in NLRP3−/− mice. NLRP3 deletion decreased lung epithelial cell death and caspase-3 levels and a suppressed NF-κB levels compared with WT controls. Taken together, this research demonstrates for the first time that NLRP3-deficient mice have suppressed inflammatory response and blunted lung epithelial cell apoptosis to HALI.

Constitutive transgenic alpha-Klotho overexpression enhances resilience to and recovery from murine acute lung injury

2021 ◽  
Author(s):  
Joshuah M Gagan ◽  
Khoa Cao ◽  
Yu-An Zhang ◽  
Jianning Zhang ◽  
Taylor L Davidson ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Epithelial Cells ◽  
Lung Injury ◽  
Cigarette Smoke ◽  
Lung Epithelial Cells ◽  
Lung Damage ◽  
Dna Breaks ◽  
Age Related ◽  
Lung Epithelial

Aims: Normal lungs do not express alpha-Klotho (Klotho) protein but derive cytoprotection from circulating soluble Klotho. It is unclear whether chronic supranormal Klotho levels confer additional benefit. To address this, we tested the age-related effects of Klotho overexpression on acute lung injury (ALI) and recovery. Methods: Transgenic Klotho-overexpressing (Tg-Kl) and wild-type (WT) mice (2 and 6 months old) were exposed to hyperoxia (95% O2; 72 h) then returned to normoxia (21% O2; 24 h) (Hx-R). Control mice were kept in normoxia. Renal and serum Klotho, lung histology, and bronchoalveolar lavage fluid oxidative damage markers were assessed. Effects of hyperoxia were tested in human embryonic kidney cells stably expressing Klotho. A549 lung epithelial cells transfected with Klotho cDNA or vector were exposed to cigarette smoke; lactate dehydrogenase and double-strand DNA breaks were measured. Results: Serum Klotho decreased with age. Hyperoxia suppressed renal Klotho at both ages and serum Klotho at 2-months of age. Tg-Kl mice at both ages and 2-months-old WT mice survived Hx-R; 6-months-old Tg-Kl mice showed lower lung damage than age-matched WT mice. Hyperoxia directly inhibited Klotho expression and release in vitro; Klotho transfection attenuated cigarette smoke-induced cytotoxicity and DNA double-strand breaks in lung epithelial cells. Conclusions: Young animals with chronic high baseline Klotho expression are more resistant to ALI. Chronic constitutive Klotho overexpression in older Tg-Kl animals attenuates hyperoxia-induced lung damage and improves survival and short-term recovery despite an acute reduction in serum Klotho level during injury. We conclude that chronic enhancement of Klotho expression increases resilience to ALI.

scholarly journals Fas Ligand Released by Activated Monocytes Causes Apoptosis of Lung Epithelial Cells in Human Acute Lung Injury Model in Vitro

2008 ◽  
Vol 31 (3) ◽  
pp. 386-390 ◽  
Author(s):  
Mitsuhiko Mizuta ◽  
Hiroo Nakajima ◽  
Naruhiko Mizuta ◽  
Yoshihiro Kitamura ◽  
Yasufumi Nakajima ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Epithelial Cells ◽  
Lung Injury ◽  
Fas Ligand ◽  
Lung Epithelial Cells ◽  
Injury Model ◽  
Lung Epithelial ◽  
Lung Injury Model ◽  
Activated Monocytes
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