scholarly journals Effect of Slit/Robo signaling on regeneration in lung emphysema

2021 ◽  
Author(s):  
Jin-Soo Park ◽  
RyeonJin Cho ◽  
Eun-Young Kang ◽  
Yeon-Mok Oh
Keyword(s):  
Epithelial Cells ◽  
Mouse Model ◽  
Lung Epithelial Cells ◽  
Mouse Lung ◽  
Chronic Obstructive ◽  
Irreversible Damage ◽  
Lung Epithelial ◽  
And Migration ◽  
Proliferation And Migration

AbstractEmphysema, a pathological component of chronic obstructive pulmonary disease, causes irreversible damage to the lung. Previous studies have shown that Slit plays essential roles in cell proliferation, angiogenesis, and organ development. In this study, we evaluated the effect of Slit2 on the proliferation and migration of mouse lung epithelial cells and its role in regeneration in an emphysema lung mouse model. Here, we have shown that Slit2/Robo signaling contributes to the regeneration of lungs damaged by emphysema. Mouse epithelial lung cells treated with Slit2 exhibited increased proliferation and migration in vitro. Our results also showed that Slit2 administration improved alveolar regeneration in the emphysema mouse model in vivo. Furthermore, Slit2/Robo signaling increased the phosphorylation of ERK and Akt, which was mediated by Ras activity. These Slit2-mediated cellular signaling processes may be involved in the proliferation and migration of mouse lung epithelial cells and are also associated with the potential mechanism of lung regeneration. Our findings suggest that Slit2 administration may be beneficial for alveolar regeneration in lungs damaged by emphysema.

scholarly journals Asymmetric dimethylarginine potentiates lung inflammation in a mouse model of allergic asthma

2010 ◽  
Vol 299 (6) ◽  
pp. L816-L825 ◽  
Author(s):  
Elizabeth Klein ◽  
Jason Weigel ◽  
Mary C. Buford ◽  
Andrij Holian ◽  
Sandra M. Wells
Keyword(s):  
Epithelial Cells ◽  
Lung Inflammation ◽  
Lavage Fluid ◽  
Lung Lavage ◽  
Airway Epithelial Cells ◽  
Inos Expression ◽  
Lung Epithelial Cells ◽  
Mouse Lung ◽  
Lung Epithelial

Nitric oxide (NO), formed by nitric oxide synthase (NOS), is an important mediator of lung inflammation in allergic asthma. Asymmetric dimethylarginine (ADMA), a competitive endogenous inhibitor of NOS, is metabolized by the enzyme dimethylarginine dimethylaminohydrolase (DDAH). Elevated ADMA has been shown to affect lung function in mice, and by inhibiting NOS it alters NO and reactive oxygen species production in mouse lung epithelial cells. However, the effects of altered ADMA levels during lung inflammation have not been explored. A model of allergen-induced airway inflammation was utilized in combination with the modulation of endogenous circulating ADMA levels in mice. Airway inflammation was assessed by quantifying inflammatory cell infiltrates in lung lavage and by histology. Lung DDAH expression was assessed by quantitative PCR and immunohistochemistry. Nitrite levels were determined in lung lavage fluid as a measure of NO production. iNOS expression was determined by immunohistochemistry, immunofluorescence, Western blot, and quantitative PCR. NF-κB binding activity was assessed by a transcription factor binding assay. Allergen-induced lung inflammation was potentiated in mice with elevated circulating ADMA and was reduced in mice overexpressing DDAH. Elevated ADMA reduced nitrite levels in lung lavage fluid in both allergen-challenged and control animals. ADMA increased iNOS expression in airway epithelial cells in vivo following allergen challenge and in vitro in stimulated mouse lung epithelial cells. ADMA also increased NF-κB binding activity in airway epithelial cells in vitro. These data support that ADMA may play a role in inflammatory airway diseases such as asthma through modulation of iNOS expression in lung epithelial cells.

Bleomycin initiates apoptosis of lung epithelial cells by ROS but not by Fas/FasL pathway

2006 ◽  
Vol 290 (4) ◽  
pp. L790-L796 ◽  
Author(s):  
Shulamit B. Wallach-Dayan ◽  
Gabriel Izbicki ◽  
Pazit Y. Cohen ◽  
Regina Gerstl-Golan ◽  
Alan Fine ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Epithelial Cells ◽  
Lung Epithelial Cells ◽  
Mouse Lung ◽  
Caspase 8 ◽  
Caspase 9 ◽  
Lung Epithelial ◽  
Induced Apoptosis

Epithelial cells are considered to be a main target of bleomycin-induced lung injury, which leads to fibrosis in vivo. We studied the characteristics of in vitro bleomycin-induced apoptosis in a mouse lung epithelial (MLE) cell line. Bleomycin caused an increase of reactive oxygen species (ROS) resulting in oxidative stress, mitochondrial leakage, and apoptosis. These were associated with elevated caspase-8 and resultant caspase-9 activity and with upregulation of Fas expression. Glutathione and inhibitors of caspase-8 or caspase-9, but not of FasL, inhibited these effects, suggesting their dependence on ROS, caspase-8 and -9, in a Fas/FasL-independent pathway. However, postbleomycin-exposed MLE cells were more sensitive to Fas-mediated apoptosis. These results demonstrate that the initial bleomycin-induced oxidative stress causes a direct apoptotic effect in lung epithelial cells involving a regulatory role of caspase-8 on caspase-9. Fas represents an amplification mechanism, and not a direct trigger of bleomycin-induced epithelial cell apoptosis.

scholarly journals SARS-CoV-2 Infection-Induced Promoter Hypomethylation as an Epigenetic Modulator of Heat Shock Protein A1L (HSPA1L) Gene

2021 ◽  
Vol 12 ◽  
Author(s):  
Jibran Sualeh Muhammad ◽  
Narjes Saheb Sharif-Askari ◽  
Zheng-Guo Cui ◽  
Mawieh Hamad ◽  
Rabih Halwani
Keyword(s):  
Epithelial Cells ◽  
Mrna Expression ◽  
Candidate Genes ◽  
Epigenetic Regulation ◽  
Dna Methyltransferases ◽  
Lung Epithelial Cells ◽  
Potential Candidate ◽  
Blood Samples ◽  
Lung Epithelial

Numerous researches have focused on the genetic variations affecting SARS-CoV-2 infection, whereas the epigenetic effects are inadequately described. In this report, for the first time, we have identified potential candidate genes that might be regulated via SARS-CoV-2 induced DNA methylation changes in COVID-19 infection. At first, in silico transcriptomic data of COVID-19 lung autopsies were used to identify the top differentially expressed genes containing CpG Islands in their promoter region. Similar gene regulations were also observed in an in vitro model of SARS-CoV-2 infected lung epithelial cells (NHBE and A549). SARS-CoV-2 infection significantly decreased the levels of DNA methyltransferases (DNMT1, DNMT3A, and DNMT3B) in lung epithelial cells. Out of 14 candidate genes identified, the expression of 12 genes was upregulated suggesting promoter hypomethylation, while only two genes were downregulated suggesting promoter hypermethylation in COVID-19. Among those 12 upregulated genes, only HSPA1L and ULBP2 were found to be upregulated in AZA-treated lung epithelial cells and immune cells, suggesting their epigenetic regulation. To confirm the hypomethylation of these two genes during SARS-CoV-2 infection, their promoter methylation and mRNA expression levels were determined in the genomic DNA/RNA obtained from whole blood samples of asymptomatic, severe COVID-19 patients and equally matched healthy controls. The methylation level of HSPA1L was significantly decreased and the mRNA expression was increased in both asymptomatic and severe COVID-19 blood samples suggesting its epigenetic regulation by SARS-CoV-2 infection. Functionally, HSPA1L is known to facilitate host viral replication and has been proposed as a potential target for antiviral prophylaxis and treatment.

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