scholarly journals Macrophages in Lung Injury, Repair, and Fibrosis

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 436 ◽  
Author(s):  
Peiyong Cheng ◽  
Shuangyan Li ◽  
Huaiyong Chen
Keyword(s):  
Lung Injury ◽  
Macrophage Polarization ◽  
Current Data ◽  
Lung Epithelial Cells ◽  
Lung Fibroblasts ◽  
Fibrotic Response ◽  
Injury Repair ◽  
Lung Epithelial ◽  
Activated Macrophage ◽  
Potential Benefits

Fibrosis progression in the lung commonly results in impaired functional gas exchange, respiratory failure, or even death. In addition to the aberrant activation and differentiation of lung fibroblasts, persistent alveolar injury and incomplete repair are the driving factors of lung fibrotic response. Macrophages are activated and polarized in response to lipopolysaccharide- or bleomycin-induced lung injury. The classically activated macrophage (M1) and alternatively activated macrophage (M2) have been extensively investigated in lung injury, repair, and fibrosis. In the present review, we summarized the current data on monocyte-derived macrophages that are recruited to the lung, as well as alveolar resident macrophages and their polarization, pyroptosis, and phagocytosis in acute lung injury (ALI). Additionally, we described how macrophages interact with lung epithelial cells during lung repair. Finally, we emphasized the role of macrophage polarization in the pulmonary fibrotic response, and elucidated the potential benefits of targeting macrophage in alleviating pulmonary fibrosis.

Tannic acid prevents macrophage-induced pro-fibrotic response in lung epithelial cells via suppressing TLR4-mediated macrophage polarization

2019 ◽  
Vol 68 (12) ◽  
pp. 1011-1024 ◽  
Author(s):  
Ayyanar Sivanantham ◽  
Dhamotharan Pattarayan ◽  
Nandhine Rajasekar ◽  
Adithi Kannan ◽  
Lakshmanan Loganathan ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Tannic Acid ◽  
Macrophage Polarization ◽  
Lung Epithelial Cells ◽  
Fibrotic Response ◽  
Lung Epithelial

scholarly journals Regulation of ACE-2 enzyme by hyperoxia in lung epithelial cells by post-translational modification

2021 ◽  
Vol 8 (2) ◽  
pp. 47-52
Author(s):  
Tarek Mohamed ◽  
Amal Abdul-Hafez ◽  
Bruce D Uhal
Keyword(s):  
Lung Injury ◽  
Cell Line ◽  
A549 Cells ◽  
Lung Epithelial Cells ◽  
Lung Fibroblasts ◽  
A549 Cell Line ◽  
Mas Receptor ◽  
Cell Extracts ◽  
Lung Epithelial ◽  
Hyperoxic Lung Injury

Background: Bronchopulmonary Dysplasia (BPD) occurs in premature neonates with respiratory distress who require supplemental oxygen in the first days after birth. BPD involves uniform arrest of alveolar development and variable interstitial cellularity and/or fibroproliferation. Previous studies by our lab showed that the enzyme, angiotensin converting enzyme-2 (ACE-2) and its product Ang1-7 exerting action on the receptor Mas oncogene in what is known as ACE-2/Mas axis is protective to lung cells. We also showed that ACE-2 is expressed in fetal human lung fibroblasts but is significantly decreased by hyperoxic gas lung injury, an effect caused by ACE-2 enzyme shedding mediated by TNF-alpha-converting enzyme (TACE/ADAM17). However, no reports yet exist about the regulation of ACE-2 in the alveolar epithelia in hyperoxic lung injury. Objective: In this study we aim to define the effects of hyperoxic lung injury on the protective ACE-2 enzyme in the human lung alveolar epithelial cell line A549. Design/Methods: Cultured A549 cells were exposed to hyperoxia (95% O2) or normoxia (21% O2) for 3 or 7 days in serum-free nutrient media. Cells were lysed and culture media were collected to test for cellular ACE-2 enzymatic activity and for ACE-2, Mas receptor, TACE/ADAM17, and ubiquitin proteins abundance by immunoblotting. Cells were harvested in Trizol for RNA extraction and ACE-2 qRT-PCR. Whole cell extracts of A549 cell line was used for ACE-2 immunoprecipitation and subsequent ubiquitin immunoblotting. Whole cell extracts of A549 cell line was used for ACE-2 immunoprecipitation and subsequent ubiquitin immunoblotting. Results: Total ubiquitinated proteins were increased by hyperoxia treatment, while ACE-2 and Mas receptor proteins abundance and ACE-2 enzymatic activity were decreased significantly in A549 cells exposed to hyperoxia relative to the normoxia controls. The percent decrease in ACE-2 activity corresponded with increased time of hyperoxic gas exposure. However, in contrast to our data from lung fibroblasts, no significant change was noted in ACE-2 protein released into the media or in ACE-2 mRNA levels by the hyperoxic treatment. Ubiquitin immunoreactive bands were detectable in the ACE-2 immunoprecipitate. Conclusion(s): These data suggest that hyperoxic exposure of the lung epithelial cells decreases the protective enzyme ACE-2 by cell type specific mechanisms independent of shedding by TACE/ADAM17. The data also suggest a regulatory level of ACE-2 downstream of transcription may involve ACE-2 ubiquitination and targeting for degradation.

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.

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

2001 ◽  
Vol 280 (1) ◽  
pp. L30-L38 ◽  
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.

scholarly journals Curcumin augments lung maturation, preventing neonatal lung injury by inhibiting TGF-β signaling

2011 ◽  
Vol 301 (5) ◽  
pp. L721-L730 ◽  
Author(s):  
Reiko Sakurai ◽  
Yishi Li ◽  
John S. Torday ◽  
Virender K. Rehan
Keyword(s):  
Lung Injury ◽  
Intraperitoneal Administration ◽  
Lung Fibroblasts ◽  
Related Protein ◽  
Lung Maturation ◽  
Injury Repair ◽  
Parathyroid Hormone Related Protein ◽  
Neonatal Lung ◽  
Neonatal Lung Injury ◽  
Pthrp Receptor

There is no effective intervention to prevent or treat bronchopulmonary dysplasia (BPD). Curcumin has potent antioxidant and anti-inflammatory properties, and it modulates signaling of peroxisome proliferator-activated receptor-γ (PPARγ), an important molecule in the pathobiology of BPD. However, its role in the prevention of BPD is not known. We determined 1) if curcumin enhances neonatal lung maturation, 2) if curcumin protects against hyperoxia-induced neonatal lung injury, and 3) if this protection is mediated by blocking TGF-β. Embryonic day 19 fetal rat lung fibroblasts were exposed to 21% or 95% O2 for 24 h following 1 h of treatment with curcumin. Curcumin dose dependently accelerated e19 fibroblast differentiation [increased parathyroid hormone-related protein (PTHrP) receptor, PPARγ, and adipocyte differentiation-related protein (ADRP) levels and triolein uptake] and proliferation (increased thymidine incorporation). Pretreatment with curcumin blocked the hyperoxia-induced decrease (PPARγ and ADRP) and increase (α-smooth muscle actin and fibronectin) in markers of lung injury/repair, as well as the activation of TGF-β signaling. In a separate set of experiments, neonatal Sprague-Dawley rat pups were exposed to 21% or 95% O2 for 7 days with or without intraperitoneal administration of curcumin. Analysis for markers of lung injury/repair [PTHrP receptor, PPARγ, ADRP, fibronectin, TGF-β receptor (activin receptor-like kinase 5), and Smad3] and lung morphology (radial alveolar count) demonstrated that curcumin effectively blocks TGF-β activation and hyperoxia-induced lung injury. Therefore, curcumin accelerates lung maturation by stimulating key alveolar epithelial-mesenchymal interactions and prevents hyperoxia-induced neonatal lung injury, possibly by blocking TGF-β activation, suggesting that it is a potential intervention against BPD.

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

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.

Expression and functional implications of CCR2 expression on murine alveolar epithelial cells

2004 ◽  
Vol 286 (1) ◽  
pp. L68-L72 ◽  
Author(s):  
Paul J. Christensen ◽  
Ming Du ◽  
Bethany Moore ◽  
Susan Morris ◽  
Galen B. Toews ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Lung Injury ◽  
Basement Membranes ◽  
Alveolar Epithelial Cells ◽  
Lung Epithelial Cells ◽  
Alveolar Epithelial ◽  
Ccr2 Expression ◽  
Lung Epithelial ◽  
Functional Consequences ◽  
Delayed Closure

Acute lung injury results in damage to the alveolar epithelium, leading to leak of proteins into the alveolar space and impaired gas exchange. Lung function can be restored only if the epithelial layer is restored. The process of reepithelialization requires migration of lung epithelial cells to cover denuded basement membranes. The factors that control the migration of lung epithelial cells are incompletely understood. We examined isolated murine type II alveolar epithelial cells (AECs) for expression of CC chemokine receptor 2 (CCR2) and functional consequences of the binding of the main CCR2 ligand monocyte chemoattractant protein-1 (MCP-1). We found that primary AECs bound MCP-1 and expressed CCR2 mRNA. These cells demonstrated functional consequences of CCR2 expression with migration in response to MCP-1 in chemotaxis/haptotaxis assays. Primary AECs cultured from mice lacking CCR2 did not respond to MCP-1. Monolayers of AECs lacking CCR2 demonstrated delayed closure of mechanical wounds compared with AEC monolayers expressing CCR2. Delayed closure of mechanical wounds of wild-type AECs was also demonstrated in the presence of anti-MCP-1 antibody. These data demonstrate for the first time that AECs express CCR2 and are capable of using this receptor for chemotaxis and healing of wounds. CCR2-MCP-1 interactions may be important in the process of reepithelialization after lung injury.

Positive transcriptional regulatory element located within exon 1 of elastin gene

2006 ◽  
Vol 291 (3) ◽  
pp. L391-L399 ◽  
Author(s):  
Richard A. Pierce ◽  
Carla H. Moore ◽  
Meltem Cevik Arikan
Keyword(s):  
Regulatory Element ◽  
Lung Epithelial Cells ◽  
Lung Fibroblasts ◽  
Regulatory Sequences ◽  
Rat Lung ◽  
Enhancer Activity ◽  
Nuclear Extracts ◽  
Lung Epithelial ◽  
Exon 1 ◽  
Elastin Gene

Elastin gene transcription is cell type specific and developmentally regulated, but the promoter often exhibits relatively weak activity in transient transfections of cells that express elastin at high levels. To search for positive-acting regulatory sequences, we isolated genomic clones spanning the mouse elastin gene and extensive 5′- and 3′-flanking regions. Restriction fragments of potential regulatory regions were ligated 5′ or 3′ relative to the active promoter to test for enhancer activity in transient transfections of fetal rat lung fibroblasts, which express elastin at high levels, and distal lung epithelial cells, which do not express detectable elastin. Fragments of intron 1 did not exhibit significant enhancer activity. Inclusion of the 84-bp exon 1 and adjacent 5′-untranslated region increased activity of the elastin promoter approximately sixfold compared with parental constructs. Transfections with constructs of varying promoter length showed that as little as 40 bp of the 5′ end of exon 1 confers enhanced activity in elastin-expressing rat lung fibroblasts, but these constructs had variable activity in lung epithelial cell lines. This region, localized between the transcription start site and extending into exon 1, binds Sp1 in nuclear extracts from elastin-expressing cells. These studies indicate a role for the 5′ end of the first exon of the elastin gene in regulating strong transcriptional activity in elastogenic cells.

Sign in / Sign up

Export Citation Format

Share Document