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

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.

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A Novel Protective Mechanism for Melatonin Against Acute Lung Injury: Preserving Mitochondrial Dynamic Equilibrium of Lung Epithelial Cells Through SIRT3-Dependent Deacetylation of SOD2

10.21203/rs.3.rs-1179197/v1 ◽

2022 ◽

Author(s):

Li Ning ◽

Xiong Rui ◽

Li Guorui ◽

Fu Tinglv ◽

Li Donghang ◽

...

Keyword(s):

Oxidative Stress ◽

Acute Lung Injury ◽

Epithelial Cells ◽

Lung Injury ◽

Dynamic Equilibrium ◽

Lung Epithelial Cells ◽

Mitochondrial Dynamic ◽

Lung Epithelial

Abstract Mitochondrial dynamic equilibrium of lung epithelial cells is disturbed during sepsis, which contributes to abnormal mitochondrial function and acute lung injury (ALI). Melatonin is one primary hormone secreted by the pineal gland, displaying favorable antioxidative actions in sepsis and cardiopulmonary disease. However, the potential roles and molecular basis of melatonin in lipopolysaccharide (LPS)-treated lung epithelial cells have not been explored and reported. Herein, we investigated whether melatonin could protect against sepsis-induced ALI and lipopolysaccharide (LPS)-treated lung epithelial cells through mitochondrial dynamic equilibrium as well as its possible molecular targets. Wild type and Sirt3 knockout mice were instilled with LPS intratracheally for 12 hours to construct an in vivo ALI model. And A549 lung epithelial cells were used to explore the possible roles of melatonin in vitro by incubating with small interfering RNA (siRNA) against Sirt3. To figure out the involvement of melatonin receptor, si Mtnr1b and luzindole were used in cells and mice. Melatonin pretreatment significantly inhibited pathological injury, inflammatory response, oxidative stress and apoptosis in LPS-treated lung tissues and LPS-treated lung epithelial cells. Meanwhile, melatonin also shifted the dynamic course of mitochondria from fission into fusion in LPS-treated lung epithelial cells in vivo and in vitro. However, SIRT3 inhibition abolished the protective roles of melatonin in ALI. Mechanistically, we found that melatonin increased the activity and expression of SIRT3, which further promoted the deacetylation of SOD2 at K122 and K68. More importantly, melatonin exerted pulmonary protection by activating MTNR1B but not MTNR1A in ALI. Collectively, melatonin could preserve mitochondrial dynamic equilibrium of lung epithelial cells through the deacetylation of SOD2 in a SIRT3-dependent manner, which eventually alleviated LPS-elicited injury, inflammation, oxidative stress, apoptosis. Thus, melatonin may serve as a promising candidate against ALI in the future.

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

Journal of Biomaterials and Tissue Engineering ◽

10.1166/jbt.2021.2691 ◽

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.

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Dynamics of Influenza-induced Lung-Resident Memory T Cells, Anatomically and Functionally Distinct Lung Mesenchymal Populations, and Dampening of Acute Lung Injury by Neutrophil Transfer of Micro-RNA-223 to Lung Epithelial Cells

American Journal of Respiratory Cell and Molecular Biology ◽

10.1165/rcmb.2018-0047ro ◽

2018 ◽

Vol 59 (3) ◽

pp. 397-399

Author(s):

Keith T. Ferguson ◽

Alexandra C. McQuattie-Pimentel ◽

Elizabeth S. Malsin ◽

Peter H. S. Sporn

Keyword(s):

T Cells ◽

Acute Lung Injury ◽

Epithelial Cells ◽

Lung Injury ◽

Memory T Cells ◽

Micro Rna ◽

Lung Epithelial Cells ◽

Lung Epithelial ◽

Resident Memory T Cells

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Lian Hua Qing Wen Capsules, a Potent Epithelial Protector in Acute Lung Injury Model, Block Proapoptotic Communication Between Macrophages, and Alveolar Epithelial Cells

Frontiers in Pharmacology ◽

10.3389/fphar.2020.522729 ◽

2020 ◽

Vol 11 ◽

Author(s):

Qi Li ◽

Qingsen Ran ◽

Lidong Sun ◽

Jie Yin ◽

Ting Luo ◽

...

Keyword(s):

Acute Lung Injury ◽

Epithelial Cells ◽

Lung Injury ◽

Alveolar Epithelial Cells ◽

Alveolar Epithelial ◽

Injury Model ◽

Model Block ◽

Lung Injury Model

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Human mesenchymal stem cell exosomes attenuate inflammation of lung epithelial cells through miR-223 in acute lung injury

10.1183/13993003.congress-2019.pa3860 ◽

2019 ◽

Author(s):

Jie Chen ◽

Pinhua Pan ◽

Min Li ◽

Rongli Lu ◽

Yimin Fang ◽

...

Keyword(s):

Stem Cell ◽

Acute Lung Injury ◽

Epithelial Cells ◽

Mesenchymal Stem Cell ◽

Lung Injury ◽

Human Mesenchymal Stem Cell ◽

Lung Epithelial Cells ◽

Lung Epithelial

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A High Content Screen for Mucin-1-Reducing Compounds Identifies Fostamatinib as a Candidate for Rapid Repurposing for Acute Lung Injury during the COVID-19 pandemic

10.1101/2020.06.30.180380 ◽

2020 ◽

Cited By ~ 1

Author(s):

Maria Alimova ◽

Eriene-Heidi Sidhom ◽

Abhigyan Satyam ◽

Moran Dvela-Levitt ◽

Michelle Melanson ◽

...

Keyword(s):

Acute Lung Injury ◽

Epithelial Cells ◽

Lung Injury ◽

Drug Repurposing ◽

Lung Epithelial Cells ◽

Drug Candidate ◽

Mucin 1 ◽

Standing Up

SummaryDrug repurposing is the only method capable of delivering treatments on the shortened time-scale required for patients afflicted with lung disease arising from SARS-CoV-2 infection. Mucin-1 (MUC1), a membrane-bound molecule expressed on the apical surfaces of most mucosal epithelial cells, is a biochemical marker whose elevated levels predict the development of acute lung injury (ALI) and respiratory distress syndrome (ARDS), and correlate with poor clinical outcomes. In response to the pandemic spread of SARS-CoV-2, we took advantage of a high content screen of 3,713 compounds at different stages of clinical development to identify FDA-approved compounds that reduce MUC1 protein abundance. Our screen identified Fostamatinib (R788), an inhibitor of spleen tyrosine kinase (SYK) approved for the treatment of chronic immune thrombocytopenia, as a repurposing candidate for the treatment of ALI. In vivo, Fostamatinib reduced MUC1 abundance in lung epithelial cells in a mouse model of ALI. In vitro, SYK inhibition by Fostamatinib promoted MUC1 removal from the cell surface. Our work reveals Fostamatinib as a repurposing drug candidate for ALI and provides the rationale for rapidly standing up clinical trials to test Fostamatinib efficacy in patients with COVID-19 lung injury.

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