Cigarette Smoke Inhibits Human Bronchial Epithelial Cell Repair Processes

Wang, Hangjun; Liu, Xiangde; Umino, Takeshi; Sköld, C. Magnus; Zhu, Yunkui; Kohyama, Tadashi; Spurzem, John R.; Romberger, Debra J.; Rennard, Stephen I.

doi:10.1165/ajrcmb.25.6.4458

Cited by 140 publications

(85 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…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%

“…One potential adverse consequence of energy depletion in the epithelium could be the impairment of cell migration. Cell migration, measured by chemotaxis assays, is fundamental to the process of airway remodeling and wound repair (Wang et al, 2001;Christensen et al, 2004). It is likely that cell migration is dependent on mitochondrial ATP-dependent mechanisms (Phillips et al, 2005;Wu et al, 2005;Campello et al, 2006;Chen et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

Sarafian

Montes

Harui

et al. 2008

Toxicology and Applied Pharmacology

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

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

View full text Add to dashboard Cite

show abstract

“…Components of cigarette smoke inhibit fibroblasts and epithelial cell migration and proliferation in vitro (134)(135)(136), indicating that cigarette smoke itself interferes with normal repair processes in the lung. However, there is currently little information about the roles of proteinases and oxidants in lung repair in COPD.…”

Section: Repair In Copdmentioning

confidence: 99%

Proteinases and Oxidants as Targets in the Treatment of Chronic Obstructive Pulmonary Disease

Owen¹

2005

Proceedings of the American Thoracic Society

View full text Add to dashboard Cite

There is now compelling evidence that proteinases and oxidative stress play pathogenetic roles in the following pathologies in chronic obstructive pulmonary disease: airspace enlargement; chronic inflammation in the airways, lung interstitium, and alveolar space; and mucus hypersecretion in the large airways. Proteinases and oxidants may also contribute to remodeling processes in the small airways. In addition, data are emerging that show interactions between classes of proteinases and between proteinases and oxidants, which amplify lung inflammation and injury in chronic obstructive pulmonary disease. This review discusses the biologic roles of proteinases and oxidants, their roles in the pathogenesis of chronic obstructive pulmonary disease, and their potential as targets for therapy.Keywords: antiinflammatory drugs; antioxidants; oxidative stress; proteinase inhibition; proteinases PROTEINASES AND OXIDANTS IN THE PATHOGENESIS OF COPDThe proteinase-antiproteinase hypothesis for the pathogenesis of chronic obstructive pulmonary disease (COPD) was formulated almost 40 yr ago in response to two key observations. First, genetic deficiency of ␣ 1 -antitrypsin (AAT, the major inhibitor of neutrophil elastase [NE] in the lower respiratory tract) is associated with early onset, severe panlobular emphysema (1). Second, instillation of papain (an enzyme with elastase activity) into rat lungs results in progressive airspace enlargement (2). Since then, other elastolytic proteinases have been shown to cause airspace enlargement when instilled into rodent lungs. Consequently, it was thought that an imbalance between proteinases (especially elastases derived from polymorphonuclear neutrophils [PMNs]) and their inhibitors causes pulmonary emphysema. Although excessive activity of PMN-derived elastases is likely to be important in the panlobular pulmonary emphysema associated with AAT deficiency, this is probably an oversimplification of mechanisms underlying common, "garden variety" COPD in cigarette smokers. Other factors have now been implicated in airspace enlargement in COPD, including other classes of proteinases (matrix metalloproteinases [MMPs] and cysteine proteinases), oxidative stress, and apoptosis of lung structural cells. In addition, COPD is clinically and pathologically a heterogeneous disease and includes chronic inflammation in the airways, lung interstitium, and the alveolar space; mucus hypersecretion; and subepithelial fibrosis in the small airways. There is evidence

show abstract

“…The reduced systemic levels may reflect increased extravasation of circulating fibronectin to sites of local injury and accelerated turnover owing to chronic inflammation [34]. Cigarette smoking, which is the main cause of COPD, may further reduce fibronectin levels by inhibiting local production [35]. However, based on the present study, it is unclear whether the reduced fibronectin to CRP ratio was a cause or an effect of COPD.…”

Section: Discussionmentioning

confidence: 82%

Circulating fibronectin to C-reactive protein ratio and mortality: a biomarker in COPD?

Man¹,

Li²,

Connett³

et al. 2008

Eur Respir J

View full text Add to dashboard Cite

The balance between inflammatory and repair processes is important in maintaining lung homeostasis in chronic obstructive pulmonary disease (COPD). The aim of the present study was to determine whether or not an integrated index of a biomarker involved in inflammation, C-reactive protein (CRP), and another involved in wound repair, fibronectin, may be a good measure to predict clinical outcomes in COPD.Circulating blood levels of CRP and fibronectin were measured in 4,787 individuals with mild-tomoderate COPD who were prospectively followed for .7 yrs after blood collection as part of the Lung Health Study. To assess the balance between repair and inflammation, a simple ratio was calculated by dividing fibronectin levels by CRP levels and a Cox proportional hazards model was used to determine the relationship between this ratio and all-cause and disease-specific causes of mortality.The relationship between the fibronectin to CRP ratio and all-cause mortality was L-shaped. There was an exponential decay in the adjusted hazard function (i.e. the risk of mortality) as the ratio decreased until a value of 148 was reached, beyond which point the hazard function did not change significantly. Similar results were observed for the risk of coronary and cardiovascular mortality.Circulating fibronectin to CRP ratio is significantly associated with all-cause mortality of COPD patients. However, in contrast to other biomarkers, the relationship appears to be L-shaped (and not linear), suggesting a threshold at ,150. While promising, future studies are needed to validate this simple index as a biomarker in COPD.

show abstract

Cigarette Smoke Inhibits Human Bronchial Epithelial Cell Repair Processes

Cited by 140 publications

References 25 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

Proteinases and Oxidants as Targets in the Treatment of Chronic Obstructive Pulmonary Disease

Circulating fibronectin to C-reactive protein ratio and mortality: a biomarker in COPD?

Contact Info

Product

Resources

About