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

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

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00629.2020 ◽

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.

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

Biological and Pharmaceutical Bulletin ◽

10.1248/bpb.31.386 ◽

2008 ◽

Vol 31 (3) ◽

pp. 386-390 ◽

Cited By ~ 18

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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Neutrophil transfer of miR-223 to lung epithelial cells dampens acute lung injury in mice

Science Translational Medicine ◽

10.1126/scitranslmed.aah5360 ◽

2017 ◽

Vol 9 (408) ◽

pp. eaah5360 ◽

Cited By ~ 61

Author(s):

Viola Neudecker ◽

Kelley S. Brodsky ◽

Eric T. Clambey ◽

Eric P. Schmidt ◽

Thomas A. Packard ◽

...

Keyword(s):

Acute Lung Injury ◽

Epithelial Cells ◽

Lung Injury ◽

Lung Epithelial Cells ◽

Lung Epithelial

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Attenuation of IgG immune complex‐induced acute lung injury by silencing C5aR in lung epithelial cells

The FASEB Journal ◽

10.1096/fj.09-133694 ◽

2009 ◽

Vol 23 (11) ◽

pp. 3808-3818 ◽

Cited By ~ 31

Author(s):

Lei Sun ◽

Ren-Feng Guo ◽

Hongwei Gao ◽

J. Vidya Sarma ◽

Firas S. Zetoune ◽

...

Keyword(s):

Acute Lung Injury ◽

Epithelial Cells ◽

Lung Injury ◽

Immune Complex ◽

Lung Epithelial Cells ◽

Lung Epithelial

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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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Ionizing radiation enhances matrix metalloproteinase-2 production in human lung epithelial cells

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.2001.280.1.l30 ◽

2001 ◽

Vol 280 (1) ◽

pp. L30-L38 ◽

Cited By ~ 41

Author(s):

Jun Araya ◽

Muneharu Maruyama ◽

Kazuhiko Sassa ◽

Tadashi Fujita ◽

Ryuji Hayashi ◽

...

Keyword(s):

Epithelial Cells ◽

Ionizing Radiation ◽

Basement Membrane ◽

Lung Injury ◽

Human Lung ◽

A549 Cells ◽

Lung Epithelial Cells ◽

Lung Epithelial ◽

Radiation Induced ◽

Human Lung Epithelial Cells

Radiation pneumonitis is a major complication of radiation therapy. However, the detailed cellular mechanisms have not been clearly defined. Based on the recognition that basement membrane disruption occurs in acute lung injury and that matrix metalloproteinase (MMP)-2 can degrade type IV collagen, one of the major components of the basement membrane, we hypothesized that ionizing radiation would modulate MMP-2 production in human lung epithelial cells. To evaluate this, the modulation of MMP-2 with irradiation was investigated in normal human bronchial epithelial cells as well as in A549 cells. We measured the activity of MMP-2 in the conditioned medium with zymography and the MMP-2 mRNA level with RT-PCR. Both of these cells constitutively expressed 72-kDa gelatinolytic activity, corresponding to MMP-2, and exposure to radiation increased this activity. Consistent with the data of zymography, ionizing radiation increased the level of MMP-2 mRNA. This radiation-induced increase in MMP-2 expression was mediated via p53 because the p53 antisense oligonucleotide abolished the increase in MMP-2 activity as well as the accumulation of p53 after irradiation in A549 cells. These results indicate that MMP-2 expression by human lung epithelial cells is involved in radiation-induced lung injury.

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Inhibition of acute lethal pulmonary inflammation by the IDO–AhR pathway

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1615280114 ◽

2017 ◽

Vol 114 (29) ◽

pp. E5881-E5890 ◽

Cited By ~ 16

Author(s):

Soung-Min Lee ◽

Ha Young Park ◽

Young-Sill Suh ◽

Eun Hye Yoon ◽

Juyang Kim ◽

...

Keyword(s):

T Cells ◽

Epithelial Cells ◽

Pulmonary Inflammation ◽

Lung Parenchyma ◽

Lung Epithelial Cells ◽

Dependent Manner ◽

Independent Manner ◽

Hematopoietic Stem ◽

Lung Epithelial ◽

Ifn Γ

The lung is a prototypic organ that was evolved to reduce immunopathology during the immune response to potentially hazardous endogenous and exogenous antigens. In this study, we show that donor CD4+ T cells transiently induced expression of indoleamine 2,3-dioxygenase (IDO) in lung parenchyma in an IFN-γ–dependent manner early after allogeneic hematopoietic stem cell transplantation (HSCT). Abrogation of host IDO expression by deletion of the IDO gene or the IFN-γ gene in donor T cells or by FK506 treatment resulted in acute lethal pulmonary inflammation known as idiopathic pneumonia syndrome (IPS). Interestingly, IL-6 strongly induced IDO expression in an IFN-γ–independent manner when deacetylation of STAT3 was inhibited. Accordingly, a histone deacetylase inhibitor (HDACi) could reduce IPS in the state where IFN-γ expression was suppressed by FK506. Finally, l-kynurenine produced by lung epithelial cells and alveolar macrophages during IPS progression suppresses the inflammatory activities of lung epithelial cells and CD4+ T cells through the aryl hydrocarbon receptor pathway. Taken together, our results reveal that IDO is a critical regulator of acute pulmonary inflammation and that regulation of IDO expression by HDACi may be a therapeutic approach for IPS after HSCT.

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3D printed lung on a chip device with a stretchable nanofibrous membrane for modeling ventilator induced lung injury

10.1101/2021.07.02.450873 ◽

2021 ◽

Author(s):

Sinem Tas ◽

Emil Rehnberg ◽

Deniz A. Bölükbaş ◽

Jason P. Beech ◽

Liora Nasi Kazado ◽

...

Keyword(s):

Cell Death ◽

Epithelial Cells ◽

Lung Injury ◽

Mechanical Stretch ◽

Cell Types ◽

Lung Epithelial Cells ◽

Nanofibrous Membrane ◽

Ventilator Induced Lung Injury ◽

Lung Epithelial ◽

3D Printed

Mechanical ventilation is often required in patients with pulmonary disease to maintain adequate gas exchange. Despite improved knowledge regarding the risks of over ventilating the lung, ventilator induced lung injury (VILI) remains a major clinical problem due to inhomogeneities within the diseased lung itself as well as the need to increase pressure or volume of oxygen to the lung as a life-saving measure. VILI is characterized by increased physical forces exerted within the lung, which results in cell death, inflammation and long-term fibrotic remodeling. Animal models can be used to study VILI, but it is challenging to distinguish the contributions of individual cell types in such a setup. In vitro models, which allow for controlled stretching of specific lung cell types have emerged as a potential option, but these models and the membranes used in them are unable to recapitulate some key features of the lung such as the 3D nanofibrous structure of the alveolar basement membrane while also allowing for cells to be cultured at an air liquid interface (ALI) and undergo increased mechanical stretch that mimics VILI. Here we develop a lung on a chip device with a nanofibrous synthetic membrane to provide ALI conditions and controllable stretching, including injurious stretching mimicking VILI. The lung on a chip device consists of a thin (i.e. ~20 μm) stretchable poly(caprolactone) (PCL) nanofibrous membrane placed between two channels fabricated in polydimethylsiloxane (PDMS) using 3D printed molds. We demonstrate that this lung on a chip device can be used to induce mechanotrauma in lung epithelial cells due to cyclic pathophysiologic stretch (~25%) that mimics clinical VILI. Pathophysiologic stretch induces cell injury and subsequently cell death, which results in loss of the epithelial monolayer, a feature mimicking the early stages of VILI. We also validate the potential of our lung on a chip device to be used to explore cellular pathways known to be altered with mechanical stretch and show that pathophysiologic stretch of lung epithelial cells causes nuclear translocation of the mechanotransducers YAP/TAZ. In conclusion, we show that a breathable lung on a chip device with a nanofibrous membrane can be easily fabricated using 3D printing of the lung on a chip molds and that this model can be used to explore pathomechanisms in mechanically induced lung injury.

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