scholarly journals Lung emphysema and impaired macrophage elastase clearance in mucolipin 3 deficient mice

2022 ◽  
Vol 13 (1) ◽  
Author(s):  
Barbara Spix ◽  
Elisabeth S. Butz ◽  
Cheng-Chang Chen ◽  
Anna Scotto Rosato ◽  
Rachel Tang ◽  
...  
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Lung Injury ◽  
Pulmonary Disease ◽  
Alveolar Macrophages ◽  
Chronic Obstructive ◽  
Endosomal Trafficking ◽  
Obstructive Pulmonary Disease ◽  
Lung Emphysema ◽  
Common Causes ◽  
Deficient Mice

AbstractLung emphysema and chronic bronchitis are the two most common causes of chronic obstructive pulmonary disease. Excess macrophage elastase MMP-12, which is predominantly secreted from alveolar macrophages, is known to mediate the development of lung injury and emphysema. Here, we discovered the endolysosomal cation channel mucolipin 3 (TRPML3) as a regulator of MMP-12 reuptake from broncho-alveolar fluid, driving in two independently generated Trpml3−/− mouse models enlarged lung injury, which is further exacerbated after elastase or tobacco smoke treatment. Mechanistically, using a Trpml3IRES-Cre/eR26-τGFP reporter mouse model, transcriptomics, and endolysosomal patch-clamp experiments, we show that in the lung TRPML3 is almost exclusively expressed in alveolar macrophages, where its loss leads to defects in early endosomal trafficking and endocytosis of MMP-12. Our findings suggest that TRPML3 represents a key regulator of MMP-12 clearance by alveolar macrophages and may serve as therapeutic target for emphysema and chronic obstructive pulmonary disease.

scholarly journals Bioinformatic Analysis of ABCA1 Gene Expression in Smoking and Chronic Obstructive Pulmonary Disease

Membranes ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 674
Author(s):  
Stanislav Kotlyarov ◽  
Anna Kotlyarova
Keyword(s):  
Gene Expression ◽  
Chronic Obstructive Pulmonary Disease ◽  
Pulmonary Disease ◽  
Alveolar Macrophages ◽  
Plasma Membranes ◽  
Bioinformatic Analysis ◽  
Transport Processes ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Abca1 Gene

Smoking is a key modifiable risk factor for developing the chronic obstructive pulmonary disease (COPD). When smoking, many processes, including the reverse transport of cholesterol mediated by the ATP binding cassette transporter A1 (ABCA1) protein are disrupted in the lungs. Changes in the cholesterol content in the lipid rafts of plasma membranes can modulate the function of transmembrane proteins localized in them. It is believed that this mechanism participates in increasing the inflammation in COPD. Methods: Bioinformatic analysis of datasets from Gene Expression Omnibus (GEO) was carried out. Gene expression data from datasets of alveolar macrophages and the epithelium of the respiratory tract in smokers and COPD patients compared with non-smokers were used for the analysis. To evaluate differentially expressed genes, bioinformatic analysis was performed in comparison groups using the limma package in R (v. 4.0.2), and the GEO2R and Phantasus tools (v. 1.11.0). Results: The conducted bioinformatic analysis showed changes in the expression of the ABCA1 gene associated with smoking. In the alveolar macrophages of smokers, the expression levels of ABCA1 were lower than in non-smokers. At the same time, in most of the airway epithelial datasets, gene expression did not show any difference between the groups of smokers and non-smokers. In addition, it was shown that the expression of ABCA1 in the epithelial cells of the trachea and large bronchi is higher than in small bronchi. Conclusions: The conducted bioinformatic analysis showed that smoking can influence the expression of the ABCA1 gene, thereby modulating lipid transport processes in macrophages, which are part of the mechanisms of inflammation development.

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