scholarly journals Autophagy proteins are required for club cell structure and function in airways

2019 ◽  
Vol 317 (2) ◽  
pp. L259-L270 ◽  
Author(s):  
Nicole P. Malvin ◽  
Justin T. Kern ◽  
Ta-Chiang Liu ◽  
Steven L. Brody ◽  
Thaddeus S. Stappenbeck
Keyword(s):  
Epithelial Cells ◽  
Cigarette Smoke ◽  
Host Defense ◽  
Cell Morphology ◽  
Cell Structure ◽  
Smoke Exposure ◽  
Cigarette Smoke Exposure ◽  
Defense Proteins ◽  
Club Cell ◽  
Club Cells

Epithelial cells that line lung airways produce and secrete proteins with important roles in barrier function and host defense. Secretion of airway goblet cells is controlled by autophagy proteins during inflammatory conditions, resulting in accumulation of mucin proteins. We hypothesized that autophagy proteins would also be important in the function of club cells, dominant secretory airway epithelial cells that are dysregulated in chronic lung disease. We found that in the absence of an inflammatory stimulus, mice with club cells deficient for the autophagy protein Atg5 had a markedly diminished expression of secreted host defense proteins secretoglobulin family 1A, member 1 (Scgb1a1) and surfactant proteins A1 and D (Sftpa1 and Sftpd), as well as abnormal club cell morphology. Adult mice with targeted loss of Atg5 also showed diminished levels of host defense proteins in regenerating cells following ablation with naphthalene. A mouse strain with global deficiency of Atg16-like 1 (Atg16l1), an Atg5 binding partner, had a similar loss of host defense proteins and abnormal club cell morphology. Cigarette smoke exposure reduced levels of Scgb1a1 in wild-type mice as expected. Smoke exposure was not required to trigger club cell abnormalities in mice bearing the human ATG16 variant Atg16l1T300A/T300A, which had low Scgb1a1 levels independent of this environmental stress. Evaluation of lung tissues from former smokers with severe chronic obstructive pulmonary disease showed evidence of reduced autophagy and SCGB1A1 expression in club cells. Thus, autophagy proteins are required for the function of club cells, independent of the cellular stress of cigarette smoke, with roles that appear to be distinct from those of other secretory cell types.

scholarly journals In vivo Cigarette Smoke Exposure Decreases CCL20, SLPI, and BD-1 Secretion by Human Primary Nasal Epithelial Cells

2016 ◽  
Vol 6 ◽  
Author(s):  
James Jukosky ◽  
Benoit J. Gosselin ◽  
Leah Foley ◽  
Tenzin Dechen ◽  
Steven Fiering ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Cigarette Smoke ◽  
Smoke Exposure ◽  
Cigarette Smoke Exposure ◽  
Nasal Epithelial Cells

Differential protease, innate immunity, and NF-κB induction profiles during lung inflammation induced by subchronic cigarette smoke exposure in mice

2006 ◽  
Vol 290 (5) ◽  
pp. L931-L945 ◽  
Author(s):  
R. Vlahos ◽  
S. Bozinovski ◽  
J. E. Jones ◽  
J. Powell ◽  
J. Gras ◽  
...  
Keyword(s):  
Plasminogen Activator ◽  
Cigarette Smoke ◽  
Host Defense ◽  
Smoke Exposure ◽  
Tissue Type ◽  
Cigarette Smoke Exposure ◽  
Colony Stimulating Factor ◽  
Mucus Cell ◽  
Type Plasminogen Activator ◽  
Stimulating Factor

Cigarette smoke exposure is a major determinant of adverse lung health, but the molecular processes underlying its effects on inflammation and immunity remain poorly understood. Therefore, we sought to understand whether inflammatory and host defense determinants are affected during subchronic cigarette smoke exposure. Dose-response and time course studies of lungs from Balb/c mice exposed to smoke generated from 3, 6, and 9 cigarettes/day for 4 days showed macrophage- and S100A8-positive neutrophil-rich inflammation in lung tissue and bronchoalveolar lavage (BAL) fluid, matrix metalloproteinase (MMP) and serine protease induction, sustained NF-κB translocation and binding, and mucus cell induction but very small numbers of CD3+CD4+ and CD3+CD8+ lymphocytes. Cigarette smoke had no effect on phospho-Akt but caused a small upregulation of phospho-Erk1/2. Activator protein-1 and phospho-p38 MAPK could not be detected. Quantitative real-time PCR showed upregulation of chemokines (macrophage inflammatory protein-2, monocyte chemoattractant protein-1), inflammatory mediators (TNF-α, IL-1β), leukocyte growth and survival factors [granulocyte-macrophage colony-stimulating factor, colony-stimulating factor (CSF)-1, CSF-1 receptor], transforming growth factor-β, matrix-degrading MMP-9 and MMP-12, and Toll-like receptor (TLR)2, broadly mirroring NF-κB activation. No upregulation was observed for MMP-2, urokinase-type plasminogen activator, tissue-type plasminogen activator, and TLRs 3, 4, and 9. In mouse strain comparisons the rank order of susceptibility was Balb/c > C3H/HeJ > 129SvJ > C57BL6. Partition of responses into BAL macrophages vs. lavaged lung strongly implicated macrophages in the inflammatory responses. Strikingly, except for IL-10 and MMP-12, macrophage and lung gene profiles in Balb/c and C57BL/6 mice were very similar. The response pattern we observed suggests that subchronic cigarette smoke exposure may be useful to understand pathogenic mechanisms triggered by cigarette smoke in the lungs including inflammation and alteration of host defense.

scholarly journals Cigarette smoke dampens antiviral signaling in small airway epithelial cells by disrupting TLR3 cleavage

2018 ◽  
Vol 314 (3) ◽  
pp. L505-L513 ◽  
Author(s):  
Parker F. Duffney ◽  
Claire E. McCarthy ◽  
Aitor Nogales ◽  
Thomas H. Thatcher ◽  
Luis Martinez-Sobrido ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Cigarette Smoke ◽  
Airway Epithelial Cells ◽  
Smoke Exposure ◽  
Small Airway ◽  
Poly I:C ◽  
Cigarette Smoke Exposure ◽  
Airway Epithelial ◽  
Antiviral Responses ◽  
Small Airway Epithelial Cells

Cigarette smokers and people exposed to second-hand smoke are at an increased risk for pulmonary viral infections, and yet the mechanism responsible for this heightened susceptibility is not understood. To understand the effect of cigarette smoke on susceptibility to viral infection, we used an air-liquid interface culture system and exposed primary human small airway epithelial cells (SAEC) to whole cigarette smoke, followed by treatment with the viral mimetic polyinosinic polycytidylic acid (poly I:C) or influenza A virus (IAV). We found that prior smoke exposure strongly inhibited production of proinflammatory (interleukin-6 and interleukin-8) and antiviral [interferon-γ-induced protein 10 (IP-10) and interferons] mediators in SAECs in response to poly I:C and IAV infection. Impaired antiviral responses corresponded to increased infection with IAV. This was associated with a decrease in phosphorylation of the key antiviral transcription factor interferon response factor 3 (IRF3). Here, we found that cigarette smoke exposure inhibited activation of Toll-like receptor 3 (TLR3) by impairing TLR3 cleavage, which was required for downstream phosphorylation of IRF3 and production of IP-10. These results identify a novel mechanism by which cigarette smoke exposure impairs antiviral responses in lung epithelial cells, which may contribute to increased susceptibility to respiratory infections.

Acute cigarette smoke exposure impairs proteasome function in the lung

2012 ◽  
Vol 303 (9) ◽  
pp. L814-L823 ◽  
Author(s):  
Sabine H. van Rijt ◽  
Ilona E. Keller ◽  
Gerrit John ◽  
Kathrin Kohse ◽  
Ali Ö. Yildirim ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Cigarette Smoke ◽  
Ubiquitin Proteasome System ◽  
Smoke Exposure ◽  
Proteasome Activity ◽  
Alveolar Epithelial Cells ◽  
Acute Exposure ◽  
Cellular Damage ◽  
Cigarette Smoke Exposure ◽  
Ubiquitin Proteasome

Cigarette smoke mediates DNA damage, lipid peroxidation, and modification and misfolding of proteins, thereby inducing severe cellular damage. The ubiquitin proteasome system serves as the major disposal system for modified and misfolded proteins and is thus essential for proper cellular function. Its role in cigarette smoke-induced cell damage, however, is largely unknown. We hypothesized that the ubiquitin-proteasome system is involved in the degradation of cigarette smoke-damaged proteins and that cigarette smoke exposure impairs the proteasome itself. Here, we show that treatment of human alveolar epithelial cells with cigarette smoke extract (CSE) induced time- and dose-dependent cell death, a rise in intracellular reactive oxygen species, and increased levels of carbonylated and polyubiquitinated proteins. While high doses of CSE severely impaired all three proteasomal activities, low CSE concentrations significantly inhibited only the trypsin-like activity of the proteasome in alveolar and bronchial epithelial cells. Moreover, acute exposure of mice to cigarette smoke significantly impaired the trypsin-like activity by 25% in the lungs. Reduced proteasome activity was not due to transcriptional regulation of the proteasome. Notably, cigarette smoke exposure induced accumulation of polyubiquitinated proteins in the soluble and insoluble protein fraction of the lung. We show for the first time that acute exposure to cigarette smoke directly impairs proteasome activity in the lungs of mice and in human epithelial cells at low doses without affecting proteasome expression. Our results indicate that defective proteasomal protein quality control may exacerbate the detrimental effects of cigarette smoke in the lung.

Sign in / Sign up

Export Citation Format

Share Document