Distal Airways in Mice Exposed to Cigarette Smoke

Adair-Kirk, Tracy L.; Atkinson, Jeffrey J.; Griffin, Gail L.; Watson, Mark A.; Kelley, Diane G.; deMello, Daphne E.; Senior, Robert M.; Betsuyaku, Tomoko

doi:10.1165/rcmb.2007-0295oc

Cited by 69 publications

(26 citation statements)

References 61 publications

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“…CS exposure progressively reduced murine airway CC16 expression which could be due to reduced synthesis of CC16 by Club cells or loss of airway Club cells (24). Club cells have the highest levels of cytochrome P450 in the lung and are the main site of lung detoxification of xenobiotics (25).…”

Section: Discussionmentioning

confidence: 99%

“…Club cells have the highest levels of cytochrome P450 in the lung and are the main site of lung detoxification of xenobiotics (25). Murine Club cells are sensitive to injury following inhalation of naphthalene [a component of CS (26)] or CS itself (24). Polymorphisms in the CC16 locus were weakly linked to COPD in the ECLIPSE cohort and associated with low plasma CC16 levels, but these findings were not replicated in other smaller COPD cohorts having different inclusion criteria (27).…”

Section: Discussionmentioning

confidence: 99%

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Protective role for club cell secretory protein-16 (CC16) in the development of COPD

et al. 2015

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Rationale Club cell secretory protein-16 (CC16) is the major secreted product of airway Club cells, but its role in the pathogenesis of COPD is unclear. We measured CC16 airway expression in humans with and without COPD and CC16 function in a cigarette smoke (CS)-induced COPD mice model. Methods Airway CC16 expression was measured in COPD patients, smokers without COPD, and non-smokers. We exposed wild-type (WT) and CC16-/- mice to CS or air for up to 6 months, and measured airway CC16 expression, pulmonary inflammation, alveolar septal cell apoptosis, airspace enlargement, airway MUC5AC expression, small airway remodeling, and pulmonary function. Results Smokers and COPD patients had reduced airway CC16 immunostaining that decreased with increasing COPD severity. Exposing mice to CS reduced airway CC16 expression. CC16-/- mice had greater CS-induced emphysema, airway remodeling, pulmonary inflammation, alveolar cell apoptosis, airway MUC5AC expression, and more compliant lungs than WT mice. These changes were associated with increased nuclear factor-κB (NFκB) activation in CC16-/- lungs. CS-induced acute pulmonary changes were reversed by adenoviral-mediated over-expression of CC16. Conclusions CC16 protects lungs from CS-induced injury by reducing lung NFκB activation. CS-induced airway CC16 deficiency increases CS-induced pulmonary inflammation and injury and likely contributes to the pathogenesis of COPD.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Protective role for club cell secretory protein-16 (CC16) in the development of COPD

et al. 2015

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“…In addition, Nrf2, an important shear stress-responsive transcription factor regulating redox-sensitive responses, 36 has been shown to significantly increase TXNIP expression. 37 The roles of MondoA:Mlx and Nrf2 as mediators for TXNIP induction by d-flow need further elucidation.…”

Section: Discussionmentioning

confidence: 99%

Thioredoxin Interacting Protein Promotes Endothelial Cell Inflammation in Response to Disturbed Flow by Increasing Leukocyte Adhesion and Repressing Kruppel-Like Factor 2

Wang

Nigro

Fujiwara

et al. 2012

Circulation Research

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Rationale Endothelial cells (EC) at regions exposed to disturbed flow (d-flow) are predisposed to inflammation and the subsequent development of atherosclerosis. We previously showed that thioredoxin interacting protein (TXNIP) was required for tumor necrosis factor (TNF)-mediated expression of vascular cell adhesion molecule (VCAM)-1. Objective We sought to investigate the role of TXNIP in d-flow-induced cell adhesion molecule expression and leukocyte interaction with vessels, and the mechanisms by which TXNIP suppresses athero-protective gene expression. Methods and Results Using en face staining of mouse aorta, we found a dramatic increase of TXNIP in EC at sites exposed to d-flow as compared to steady flow (s-flow). EC-specific TXNIP knockout (ECTXNIP KO) mice showed significant decreases in VCAM-1 and intercellular adhesion molecule-1 (ICAM-1) mRNA expression in the d-flow regions of mouse aorta. Intravital microscopy of mesenteric venules showed that leukocyte rolling time was decreased, while rolling velocity was increased significantly in EC-TXNIP KO mice. In vitro experiments utilizing a cutout flow chamber to generate varying flow patterns showed that increased TXNIP was required for d-flow-induced EC-monocyte adhesion. Furthermore, we found that the expression of Kruppel-like factor 2 (KLF2), a key anti-inflammatory transcription factor in EC, was inhibited by TXNIP. Luciferase and chromatin immunoprecipitation (ChIP) assays showed that TXNIP was present within a repressing complex on the KLF2 promoter. Conclusions These data demonstrate the essential role for TXNIP in mediating EC-leukocyte adhesion under d-flow, as well as define a novel mechanism by which TXNIP acts as a transcriptional corepressor to regulate KLF2-dependent gene expression.

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“…Nrf2 is a transcription factor upregulated in response to oxidative stress and smoke (Adair-Kirk, Atkinson et al 2008; Hubner, Schwartz et al 2009). Hmox is regulated by Nrf2 and is increased in all mice (Figure 4B).…”

Section: Resultsmentioning

confidence: 99%

Effects of side-stream tobacco smoke and smoke extract on glutathione- and oxidative DNA damage repair-deficient mice and blood cells

Yamamoto

Chapman

Schiestl

2013

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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Cigarette smoke causes direct oxidative DNA damage as well as indirect damage through inflammation. Epidemiological studies show a strong relationship between secondhand smoke and cancer; however, the mechanisms of secondhand smoke-induced cancer are not well understood. Animal models with either i) deficient oxidative DNA damage repair, or ii) a decreased capacity to combat oxidative stress may help determine the pathways important in mitigating damage caused by smoke. In this study, we used mice lacking Ogg1 and Myh, both of which are involved in base excision repair by removing oxidatively damaged DNA bases. Gclm-deficient mice, which have decreased levels of glutathione (GSH), were used to look at the role of smoke-induced oxidative damage. Ex vivo experiments show significantly elevated levels of DNA single-strand breaks and chromosomal aberrations in peripheral blood lymphocytes from Ogg1−/−Myh−/− double knockout mice compared to wild type (WT) mice after 24 hours of exposure to cigarette smoke extract (CSE). The average γH2AX foci per cell was significantly elevated 3 hours after exposure to CSE in cells from Ogg1 −/−Myh −/− double knockout mice compared to wildtype mice. In vivo we found that all mice had increased markers of DNA damage after exposure to side-stream tobacco smoke (SSTS). Ogg1−/− Myh−/− and Gclm−/− mice had altered levels of peripheral blood glutathione after SSTS exposure whereas wild type mice did not. This may be due to differential regulation of glutathione synthesis in the lung. We also found that Ogg1−/−Myh−/− mice had a decreased lifespan after oral gavage with benzo[a]pyrene compared to wildtype mice and sham-exposed Ogg1−/−Myh−/− mice. Our results are important in investigating the roles of oxidative stress and oxidative DNA damage repair in cigarette smoke-induced cancers and characterizing the role of genetic polymorphisms in smoke-related disease susceptibility.

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Distal Airways in Mice Exposed to Cigarette Smoke

Cited by 69 publications

References 61 publications

Protective role for club cell secretory protein-16 (CC16) in the development of COPD

Protective role for club cell secretory protein-16 (CC16) in the development of COPD

Thioredoxin Interacting Protein Promotes Endothelial Cell Inflammation in Response to Disturbed Flow by Increasing Leukocyte Adhesion and Repressing Kruppel-Like Factor 2

Effects of side-stream tobacco smoke and smoke extract on glutathione- and oxidative DNA damage repair-deficient mice and blood cells

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