scholarly journals Metformin Protects against Radiation-Induced Acute Effects by Limiting Senescence of Bronchial-Epithelial Cells

2021 ◽  
Vol 22 (13) ◽  
pp. 7064
Author(s):  
Christine Hansel ◽  
Samantha Barr ◽  
Alina V. Schemann ◽  
Kirsten Lauber ◽  
Julia Hess ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Lung Tissue ◽  
Cellular Stress ◽  
Lung Epithelial Cells ◽  
Normal Lung Tissue ◽  
Normal Lung ◽  
Metformin Treatment ◽  
Acute Effects ◽  
Lung Epithelial ◽  
Radiation Induced

Radiation-induced damage to normal lung parenchyma remains a dose-limiting factor in thorax-associated radiotherapy (RT). Severe early and late complications with lungs can increase the risk of morbidity in cancer patients after RT. Herein, senescence of lung epithelial cells following RT-induced cellular stress, or more precisely the respective altered secretory profile, the senescence-associated secretory phenotype (SASP), was suggested as a central process for the initiation and progression of pneumonitis and pulmonary fibrosis. We previously reported that abrogation of certain aspects of the secretome of senescent lung cells, in particular, signaling inhibition of the SASP-factor Ccl2/Mcp1 mediated radioprotection especially by limiting endothelial dysfunction. Here, we investigated the therapeutic potential of a combined metformin treatment to protect normal lung tissue from RT-induced senescence and associated lung injury using a preclinical mouse model of radiation-induced pneumopathy. Metformin treatment efficiently limited RT-induced senescence and SASP expression levels, thereby limiting vascular dysfunctions, namely increased vascular permeability associated with increased extravasation of circulating immune and tumor cells early after irradiation (acute effects). Complementary in vitro studies using normal lung epithelial cell lines confirmed the senescence-limiting effect of metformin following RT finally resulting in radioprotection, while fostering RT-induced cellular stress of cultured malignant epithelial cells accounting for radiosensitization. The radioprotective action of metformin for normal lung tissue without simultaneous protection or preferable radiosensitization of tumor tissue might increase tumor control probabilities and survival because higher radiation doses could be used.

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.

Adenovirus-mediated Foxp3 expression in lung epithelial cells ameliorates acute radiation-induced pneumonitis in mice

Gene Therapy ◽  
2016 ◽  
Vol 24 (2) ◽  
pp. 104-112 ◽  
Author(s):  
D Shin ◽  
G Lee ◽  
S Lee ◽  
S Park ◽  
K-H Jung ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Foxp3 Expression ◽  
Acute Radiation ◽  
Lung Epithelial Cells ◽  
Lung Epithelial ◽  
Radiation Induced

scholarly journals Unbiased Selection of Peptide–Peptoid Hybrids Specific for Lung Cancer Compared to Normal Lung Epithelial Cells

2015 ◽  
Vol 10 (12) ◽  
pp. 2891-2899 ◽  
Author(s):  
Jaya M. Matharage ◽  
John D. Minna ◽  
Rolf A. Brekken ◽  
D. Gomika Udugamasooriya
Keyword(s):  
Lung Cancer ◽  
Epithelial Cells ◽  
Lung Epithelial Cells ◽  
Normal Lung ◽  
Lung Epithelial ◽  
Selection Of

scholarly journals Down-Regulation of p23 in Normal Lung Epithelial Cells Reduces Toxicities From Exposure to Benzo[a]pyrene and Cigarette Smoke Condensate via an Aryl Hydrocarbon Receptor-Dependent Mechanism

2018 ◽  
Vol 167 (1) ◽  
pp. 239-248 ◽  
Author(s):  
Jinyun Chen ◽  
Poonam Yakkundi ◽  
William K Chan
Keyword(s):  
Epithelial Cells ◽  
Aryl Hydrocarbon Receptor ◽  
Cigarette Smoke ◽  
Lung Epithelial Cells ◽  
Normal Lung ◽  
Cigarette Smoke Condensate ◽  
Down Regulation ◽  
Protein Levels ◽  
Aryl Hydrocarbon ◽  
Lung Epithelial

Abstract The aryl hydrocarbon receptor (AHR) is a ligand-activated signaling molecule which controls tumor growth and metastasis, T cell differentiation, and liver development. Expression levels of this receptor protein is sensitive to the cellular p23 protein levels in immortalized cancer cell lines. As little as 30% reduction of the p23 cellular content can suppress the AHR function. Here we reported that down-regulation of the p23 protein content in normal, untransformed human bronchial/tracheal epithelial cells to 48% of its content also suppresses the AHR protein levels to 54% of its content. This p23-mediated suppression of AHR is responsible for the suppression of (1) the ligand-dependent induction of the cyp1a1 gene transcription; (2) the benzo[a]pyrene- or cigarette smoke condensate-induced CYP1A1 enzyme activity, and (3) the benzo[a]pyrene and cigarette smoke condensate-mediated production of reactive oxygen species. Reduction of the p23 content does not alter expression of oxidative stress genes and production of PGE2. Down regulation of p23 suppresses the AHR protein levels in two other untransformed cell types, namely human breast MCF-10A and mouse immune regulatory Tr1 cells. Collectively, down-regulation of p23 suppresses the AHR protein levels in normal and untransformed cells and can in principle protect our lung epithelial cells from AHR-dependent oxidative damage caused by exposure to agents from environment and cigarette smoking.

Cigarette Smoking Condensate Disrupts Endoplasmic Reticulum–Golgi Network Homeostasis Through GOLPH3 Expression in Normal Lung Epithelial Cells

2016 ◽  
Vol 18 (9) ◽  
pp. 1877-1885 ◽  
Author(s):  
Kyeong-Nam Yu ◽  
Hyeon-Jeong Kim ◽  
Sanghwa Kim ◽  
Orkhouselenge Dawaadamdin ◽  
Ah-Young Lee ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Epithelial Cells ◽  
Cigarette Smoking ◽  
Lung Epithelial Cells ◽  
Normal Lung ◽  
Lung Epithelial ◽  
Golgi Network

Abstract 28: Extracellular Matrix Coating Enhances Nanoparticle Uptake by Lung Epithelial Cells

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Primana Punnakitikashem ◽  
Priya Ravikumar ◽  
Jinglei Wu ◽  
Kytai Nguyen ◽  
Connie Hsia ◽  
...  
Keyword(s):  
Gene Expression ◽  
Extracellular Matrix ◽  
Epithelial Cells ◽  
Cellular Uptake ◽  
Lung Tissue ◽  
Protein Release ◽  
Lung Epithelial Cells ◽  
Lung Cells ◽  
Significant Difference ◽  
Lung Epithelial

Introduction: Rapid uptake of drug-loaded nanoparticles (NPs) by lung cells is critical for effective pulmonary delivery of therapeutic agents because of the rapid pulmonary clearance mechanisms. We tested the possibility that coating NPs with extracellular matrix (ECM) derived from lung tissue enhances nanoparticles uptake by lung cells. Methods and Results: Fresh adult porcine lung tissue obtained from a local slaughterhouse was decellularized using detergent (sodium dodecyl sulfate) and then enzymatically digested into a soluble solution. The double emulsion method was utilized to fabricate core-shell poly(lactic-co-glycolic) (PLGA) nanoparticles loaded with bovine serum albumin (BSA) for protein release studies, 6-coumarin for cellular uptake studies, or human erythropoietin receptor (hEPOR) cDNA co-expressing green fluorescent protein (GFP) for in vivo gene expression studies. The ECM was coated onto the nanoparticle surface by physical adsorption using the ECM solution (100 μg/ml). There is no significant difference in the diameter, blood compatibility or cell toxicity between coated and uncoated NPs. ECM-coated NPs showed slower protein release rate than uncoated NPs as the ECM coating hindered protein diffusion into the solution. ECM-coated NPs showed significantly higher cellular uptake by human lung epithelial cells than collagen-coated or uncoated NPs. In addition, ECM-coated and uncoated NPs loaded with hEPOR-GFP cDNA were aerosolized and delivered by inhalation into rat lung. Following single inhalation using uncoated NPs, GFP expression in lung tissue progressively increased for up to 21 days. Using the ECM-coated NPs EPOR expression peaked at 14 days, then declined thereafter. Conclusions: Coating NPs with lung-derived ECM markedly enhances NP uptake by lung cells, delays the release of encapsulated protein or DNA, and shortens the duration of peak tissue gene expression compared to uncoated NPs. This NP formulation may be useful where more precise timing of delayed payload release is desired.

scholarly journals Lung Krüppel-like factor (LKLF) is a transcriptional activator of the cytosolic phospholipase A2 α promoter

2005 ◽  
Vol 387 (1) ◽  
pp. 239-246 ◽  
Author(s):  
Marilee J. WICK ◽  
Stacy BLAINE ◽  
Vicki VAN PUTTEN ◽  
Milene SAAVEDRA ◽  
Raphael A. NEMENOFF
Keyword(s):  
Epithelial Cells ◽  
Phospholipase A2 ◽  
Promoter Activity ◽  
Cytosolic Phospholipase A2 ◽  
Dominant Negative ◽  
Lung Epithelial Cells ◽  
Mitogen Activated Protein Kinase ◽  
Normal Lung ◽  
Cytosolic Phospholipase ◽  
Lung Epithelial

Increased expression of cPLA2 (cytosolic phospholipase A2) has been shown to be the cause of tumorigenesis of NSCLC (non-small-cell lung cancer). Our laboratory has previously demonstrated that oncogenic forms of Ras increase transcription of cPLA2 in normal lung epithelial cells and NSCLC lines through activation of the ERK (extracellular-signal-regulated kinase) and JNK (c-Jun N-terminal kinase) MAPK (mitogen-activated protein kinase) family. We have also defined a minimal region of the cPLA2 promoter that is critical for this induction. To identify potential transcription factors that bind to this region and regulate expression, a yeast one-hybrid screen was performed with a rat lung cDNA library. Multiple members of the Krüppel family were identified, with LKLF (lung Krüppel-like factor) being isolated a number of times. Overexpression of LKLF in lung epithelial cells or Drosophila SL-2 cells increased cPLA2 promoter activity. Conversely, expression of a dominant negative form of LKLF inhibited induction of cPLA2 promoter activity by oncogenic Ras in normal lung epithelial cells and NSCLC. By electrophoretic mobility-shift assay analysis, it was found that LKLF bound to a GC-rich region of the cPLA2 promoter located between −37 and −30 upstream from the transcription start site. Expression of siRNA (small interfering RNA) directed against LKLF inhibited basal expression of cPLA2 in lung epithelial cells and blocked induction by H-Ras. In NSCLC, siRNA against LKLF co-operated with siRNA against Sp1 (stimulatory protein 1) to inhibit cPLA2 promoter activity. Finally, recombinant LKLF was a substrate for ERKs. These results indicate that LKLF is an important regulator of cPLA2 expression and participates in the induction of this protein, which is critical for increased eicosanoid production associated with lung tumorigenesis.

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