Cigarette Smoke Inhibits Alveolar Repair: A Mechanism for the Development of Emphysema

Rennard, Stephen I.; Togo, Shinsaku; Holz, Olaf

doi:10.1513/pats.200605-121sf

Cited by 112 publications

(83 citation statements)

References 65 publications

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“…The chemotactic activity of lung epithelial cells, the primary focus of this report, is felt to play an important role in lung remodeling, host protection and lung repair (Rennard et al, 2006;Shahabuddin et al, 2006). In particular, following lung injury from toxins or airborne particulates, wound healing requires a complex multi-step repair process including cell proliferation and migration.…”

Section: Discussionmentioning

confidence: 99%

“…In particular, following lung injury from toxins or airborne particulates, wound healing requires a complex multi-step repair process including cell proliferation and migration. This airway remodeling involves dynamic interactions between epithelial cells, fibroblasts and extracellular matrix proteins and impaired epithelial responses may play a role in chronic pulmonary diseases (Cantral et al, 1995;Wang et al, 2001;Puchelle et al, 2006;Rennard et al, 2006). Chemotaxis also plays a fundamental role in the development and metastasis of non-small cell lung cancer (Phillips et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

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Clarifying CB2 receptor-dependent and independent effects of THC on human lung epithelial cells

Sarafian

Montes

Harui

et al. 2008

Toxicology and Applied Pharmacology

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Marijuana smoking is associated with a number of abnormal findings in the lungs of habitual smokers. Previous studies revealed that Δ 9 -tetrahydrocannabinol (THC) caused mitochondrial injury in primary lung epithelial cells and in the cell line, A549 (Sarafian et al., 2003;Sarafian et al., 2005). The role of cannabinoid receptors in this injury was unclear, as was the potential impact on cell function. In order to investigate these questions, A549 cells were engineered to over-express the type 2 cannabinoid receptor (CB2R) using a self-inactivating lentiviral vector. This transduction resulted in a 60-fold increase in CB2R mRNA relative to cells transduced with a control vector. Transduced cell lines were used to study the effects of THC on chemotactic activity and mitochondrial function. Chemotaxis in response to a 10 % serum gradient was suppressed in a concentration-dependent manner by exposure to THC. CB2R-transduced cells exhibited less intrinsic chemotactic activity (p < 0.05) and were 80-to 100-fold more sensitive to the inhibitory effects of THC. Studies using SR144528, a selective CB2R antagonist, verified that these effects were mediated by the CB2R. Marijuana smoke extract, but not smoke extracts from tobacco or placebo marijuana cigarettes, reproduced these effects (p < 0.05). THC decreased ATP level and mitochondrial membrane potential (Ψ m ) in both control and CB2R-transduced cells. However, these decreases did not play a significant role in chemotaxis inhibition since cyclosporine A, which protected against ATP loss, did not increase cell migration. Moreover, CB2R-transduced cells displayed higher Ψ m than did control cells. Since both Ψ m and chemotaxis are regulated by intracellular signaling, we investigated the effects of THC on the activation of multiple signaling pathways. Serum exposure activated several signaling events of which phosphorylation of IκB-α and JNK were regulated in a CB2R-and THC-dependent manner. We conclude that airway epithelial cells are sensitive to both CB2R-dependent and independent effects mediated by THC.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Clarifying CB2 receptor-dependent and independent effects of THC on human lung epithelial cells

Sarafian

Montes

Harui

et al. 2008

Toxicology and Applied Pharmacology

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“…Such a decrease in basal DNA damage in lymphocytes of patients with breast cancer (lower than in controls) was associated with repair inhibition and possible elimination of highly damaged cells by apoptosis [14]. It is important to point out that an increased apoptosis in COPD patients has been reported, which persists even after smoking cessation [33][34][35]. The reduced repair capacity among cancer patients and their relatives shows that such capacity can be genetically determined [36,37].…”

Section: Discussionmentioning

confidence: 97%

DNA Damage and Oxidative Stress in Patients with Chronic Obstructive Pulmonary Disease

Silva¹,

Rosa²,

Charlier³

et al. 2013

TOBIOMJ

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Abstract:Background: We aimed to assess the level of DNA damage and susceptibility to exogenous mutagens in peripheral blood cells of Chronic Obstructive Pulmonary Disease (COPD) patients and healthy individuals by comet assay. Oxidative stress was also evaluated by means of thiobarbituric acid reactive species (TBARS) in blood plasma.Methods: Case-control study enrolling 51 COPD patients and 51 controls. Peripheral blood was used to perform the alkaline (pH>13) and neutral (pH=8.5) comet assay. For the assessment of susceptibility to exogenous DNA damage, the cells were treated with methylmethane sulfonate (MMS) for 1-hour or 3-hour at 37° C. The percentage of residual DNA damage after 3-h MMS treatment was calculated using the value of 1-h MMS treatment for each subject as 100%. Lipid peroxidation was evaluated by measuring TBARS in blood plasma.Results: DNA damage in patients was significantly higher than in controls as measured by the neutral and alkaline comet assay. Residual DNA damage detected after MMS treatment increased in patients, in contrast to controls, indicating higher susceptibility to alkylation damage and/or repair inhibition. High susceptibility to exogenous DNA damage in COPD patients correlates with high amount of TBARS and low forced vital capacity and expiratory volume. Conclusion:The positive correlation between increased susceptibility to exogenous DNA damage and TBARS levels in COPD patients suggests the possible involvement of oxidative stress in damage induction and/or repair inhibition.

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“…(4) Additionally, CS is the most common cause of emphysema, leading to macrophage and neutrophil influx and obliteration of the alveolar wall. (5) Although millions of people are chronically exposed to CS and the resultant lung injury is clear, relatively little is known about how smoke exposure impacts motility at the axonemal level. The response to cigarette smoke on cilia depends on the system and the context.…”

Section: Introductionmentioning

confidence: 99%

Particulate Matter in Cigarette Smoke Increases Ciliary Axoneme Beating Through Mechanical Stimulation

Navarrette¹,

Sisson²,

Nance

et al. 2012

Journal of Aerosol Medicine and Pulmonary Drug Delivery

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Background: The lung's ability to trap and clear foreign particles via the mucociliary elevator is an important mechanism for protecting the lung against respirable irritants and microorganisms. Although cigarette smoke (CS) exposure and particulate inhalation are known to alter mucociliary clearance, little is known about how CS and nanoparticles (NPs) modify cilia beating at the cytoskeletal infrastructure, or axonemal, level. Methods: We used a cell-free model to introduce cigarette smoke extract (CSE) and NPs with variant size and surface chemistry to isolated axonemes and measured changes in ciliary motility. We hypothesized that CSE would alter cilia beating and that alterations in ciliary beat frequency (CBF) due to particulate matter would be size-and surface chemistry-dependent. Demembranated axonemes were isolated from ciliated bovine tracheas and exposed to adenosine triphosphate (ATP) to initiate motility. CBF was measured in response to 5% CSE, CSE filtrate, and carboxyl-modified (COOH), sulphate (SO 4 )-modified (sulfonated), or PEG-coated polystyrene (PS) latex NPs ranging in size from 40 nm to 500 nm. Results: CSE concentrations as low as 5% resulted in rapid, significant stimulation of CBF ( p < 0.05 vs. baseline control). Filtering CSE through a 0.2-lm filter attenuated this effect. Introduction of sulphate-modified PS beads *300 nm in diameter resulted in a similar increase in CBF above baseline ATP levels. Uncharged, PEG-coated beads had no effect on CBF regardless of size. Similarly, COOH-coated particles less than 200 nm in diameter did not alter ciliary motility. However, COOH-coated PS particles larger than 300 nm increased CBF significantly and increased the number of motile points. Conclusions: These data show that NPs, including those found in CSE, mechanically stimulate axonemes in a size-and surface chemistry-dependent manner. Alterations in ciliary motility due to physicochemical properties of NPs may be important for inhalational lung injury and efficient drug delivery of respirable particles.

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Cigarette Smoke Inhibits Alveolar Repair: A Mechanism for the Development of Emphysema

Cited by 112 publications

References 65 publications

Clarifying CB2 receptor-dependent and independent effects of THC on human lung epithelial cells

Clarifying CB2 receptor-dependent and independent effects of THC on human lung epithelial cells

DNA Damage and Oxidative Stress in Patients with Chronic Obstructive Pulmonary Disease

Particulate Matter in Cigarette Smoke Increases Ciliary Axoneme Beating Through Mechanical Stimulation

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