Cigarette smoke extract induces oxidative stress and apoptosis in human lung fibroblasts

Carnevali, S; Petruzzelli, Stefano; Longoni, Biancamaria; Vanacore, Renato; Barale, Roberto; Cipollini, Monica; Scatena, F.; Paggiaro, Pierluigi; Celi, Alessandro; Giuntini, C.

doi:10.1152/ajplung.00466.2001

Cited by 235 publications

(204 citation statements)

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“…Cigarette smoke (CS) exposure is the main risk factor for COPD (Yoshida & Tuder, 2007). CS contains a high concentration of reactive oxygen species (ROS, 10 17 /puff) and thus plays a major role in promoting oxidative stress in COPD (Church & Pryor, 1985), (Carnevali et al, 2003). Oxidative stress provokes inflammation and participates in the emergence of cell senescence, another major feature of this disease (Barnes, 2017).…”

Section: Introductionmentioning

confidence: 99%

Heme oxygenase‐1 induction attenuates senescence in chronic obstructive pulmonary disease lung fibroblasts by protecting against mitochondria dysfunction

et al. 2018

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Chronic obstructive pulmonary disease (COPD) is associated with lung fibroblast senescence, a process characterized by an irreversible proliferation arrest associated with secretion of inflammatory mediators. ROS production, known to induce senescence, is increased in COPD fibroblasts and mitochondria dysfunction participates in this process. Among the battery of cellular responses against oxidative stress damage, heme oxygenase (HO)‐1 plays a critical role in defending the lung against oxidative stress and inflammation. Therefore, we investigated whether pharmacological induction of HO‐1 by chronic hemin treatment attenuates senescence and improves dysfunctional mitochondria in COPD fibroblasts. Fibroblasts from smoker controls (S‐C) and COPD patients were isolated from lung biopsies. Fibroblasts were long‐term cultured in the presence or absence of hemin, and/or ZnPP or QC‐15 (HO‐1 inhibitors). Lung fibroblasts from smokers and COPD patients displayed in long‐term culture a senescent phenotype, characterized by a reduced replicative capacity, an increased senescence and inflammatory profile. These parameters were significantly higher in senescent COPD fibroblasts which also exhibited decreased mitochondrial activity (respiration, glycolysis, and ATP levels) which led to an increased production of ROS, and mitochondria biogenesis and impaired mitophagy process. Exposure to hemin increased the gene and protein expression level of HO‐1 in fibroblasts and diminished ROS levels, senescence, the inflammatory profile and simultaneously rescued mitochondria dysfunction by restoring mitophagy in COPD cells. The effects of hemin were abolished by a cotreatment with ZnPP or QC‐15. We conclude that HO‐1 attenuates senescence in COPD fibroblasts by protecting, at least in part, against mitochondria dysfunction and restoring mitophagy.

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Section: Introductionmentioning

confidence: 99%

Heme oxygenase‐1 induction attenuates senescence in chronic obstructive pulmonary disease lung fibroblasts by protecting against mitochondria dysfunction

et al. 2018

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“…More recent work has shown that Rtp801, which promotes oxidative stress-induced cell death through activation of NF-κB, is significantly overexpressed in human smokers (6). Oxidants apparently produced in the lung in response to smoking have been implicated with decreased expression of the anti-apoptotic protein, vascular endothelial growth factor (VEGF) (25,26), increased apoptosis (27,28), and lung cell autophagy (29). Curiously, a recent report has ascribed lung protein nitration by peroxynitrite, generated from iNOS-derived NO, exclusively to CS-induced lung injury, and even claimed reversal of such damage through global inhibition of iNOS (23).…”

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confidence: 99%

Ascorbate attenuates pulmonary emphysema by inhibiting tobacco smoke and Rtp801-triggered lung protein modification and proteolysis

Gupta

Ganguly

Rozanas³

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Cigarette smoking causes emphysema, a fatal disease involving extensive structural and functional damage of the lung. Using a guinea pig model and human lung cells, we show that oxidant(s) present in tobacco smoke not only cause direct oxidative damage of lung proteins, contributing to the major share of lung injury, but also activate Rtp801, a key proinflammatory cellular factor involved in tobacco smoke-induced lung damage. Rtp801 triggers nuclear factor κB and consequent inducible NOS (iNOS)-mediated overproduction of NO, which in combination with excess superoxide produced during Rtp801 activation, contribute to increased oxidonitrosative stress and lung protein nitration. However, lung-specific inhibition of iNOS with a iNOS-specific inhibitor, N6-(1-iminoethyl)-L-lysine, dihydrochloride (L-NIL) solely restricts lung protein nitration but fails to prevent or reverse the major tobacco smoke-induced oxidative lung injury. In comparison, the dietary antioxidant, ascorbate or vitamin C, can substantially prevent such damage by inhibiting both tobacco smoke-induced lung protein oxidation as well as activation of pulmonary Rtp801 and consequent iNOS/NO-induced nitration of lung proteins, that otherwise lead to increased proteolysis of such oxidized or nitrated proteins by endogenous lung proteases, resulting in emphysematous lung damage. Vitamin C also restricts the up-regulation of matrix-metalloproteinase-9, the major lung protease involved in the proteolysis of such modified lung proteins during tobacco smoke-induced emphysema. Overall, our findings implicate tobacco-smoke oxidant(s) as the primary etiopathogenic factor behind both the noncellular and cellular damage mechanisms governing emphysematous lung injury and demonstrate the potential of vitamin C to accomplish holistic prevention of such damage.cigarette smoke | emphysema | vitamin C | ascorbate | Rtp801

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“…1 As such, cigarette smoke has been reported to induce many cellular effects, including DNA damage and apoptosis, activate protein kinase C, and inducing of interleukin-8 expression. 9,10 In the present study, we aimed to evaluate the cellular and molecular mechanism(s) by which cigarette smoke alters endothelial function. Specifically, we investigated the effects of cigarette smoke extract (CSE) on the major pathways of arginine and NO metabolism in endothelial cells using a series of complementary approaches.…”

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Adverse Effects of Cigarette Smoke on NO Bioavailability

et al. 2006

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Abstract-Endothelial dysfunction is a hallmark of cardiovascular disease, and the L-arginine:NO pathway plays a critical role in determining endothelial function. Recent studies suggest that smoking, a well-recognized risk factor for vascular disease, may interfere with L-arginine and NO metabolism; however, this remains poorly characterized. Accordingly, we performed a series of complementary in vivo and in vitro studies to elucidate the mechanism by which cigarette smoke adversely affects endothelial function. In current smokers, plasma levels of asymmetrical dimethyl-arginine (ADMA) were 80% higher (Pϭ0.01) than nonsmokers, whereas citrulline (17%; PϽ0.05) and N-hydroxy-L-arginine (34%; PϽ0.05) were significantly lower. Exposure to 10% cigarette smoke extract (CSE) significantly affected endothelial arginine metabolism with reductions in the intracellular content of citrulline (81%), N-hydroxy-L-arginine (57%), and arginine (23%), while increasing ADMA (129%). CSE significantly inhibited (38%) arginine uptake in conjunction with a 34% reduction in expression of the arginine transporter, CAT1. In conjunction with these studies, CSE significantly reduced the activity of eNOS and NO production by endothelial cells, while stimulating the production of reactive oxygen species. In conclusion, cigarette smoke adversely affects the endothelial L-arginine NO synthase pathway, resulting in reducing NO production and elevated oxidative stress. In conjunction, exposure to cigarette smoke increases ADMA concentration, the latter being a risk factor for cardiovascular disease. Key Words: smoking Ⅲ endothelium Ⅲ metabolism A therosclerotic coronary and cerebrovascular disease are leading causes of death and disability in the Western world, and cigarette smoking has been clearly identified as a risk factor for coronary artery disease (reviewed by Ambrose and Barua 1 ). In this context, measures of endothelial function have been associated with cardiovascular outcome, 2 and smoking has been widely associated with reduced endothelial function. 3 The endothelium plays a central role in the modulation of vascular tone, the inhibition of platelet aggregation and vascular smooth muscle proliferation, and a key participation in angiogenesis under appropriate conditions. NO is well recognized as playing a pivotal part in these endothelial properties, being produced by the endothelial isoform of NO from its preferred substrate L-arginine. In this context, provision of sufficient L-arginine is critical for the sustained production of NO supply, 4 mediated in endothelial cells (ECs) principally by the type 1 cationic amino acid transporter (CAT1). Previous studies indicate that deleterious actions of cigarette smoke on endothelial function could be mitigated by supplemental L-arginine; 5 however, to date, the precise basis for this interaction remains unclear. One explanation is that cigarette smoke exerts an inhibitory effect on components of the L-arginine:NO pathway to influence NO production. In addition, potential effects of cigar...

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Cigarette smoke extract induces oxidative stress and apoptosis in human lung fibroblasts

Cited by 235 publications

References 40 publications

Heme oxygenase‐1 induction attenuates senescence in chronic obstructive pulmonary disease lung fibroblasts by protecting against mitochondria dysfunction

Heme oxygenase‐1 induction attenuates senescence in chronic obstructive pulmonary disease lung fibroblasts by protecting against mitochondria dysfunction

Ascorbate attenuates pulmonary emphysema by inhibiting tobacco smoke and Rtp801-triggered lung protein modification and proteolysis

Adverse Effects of Cigarette Smoke on NO Bioavailability

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