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2.
BackgroundDimethylarginine dimethylaminohydrolase 1 (DDAH1) is an enzyme that can degrade asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase (NOS) inhibitor. Emerging evidence suggests that alterations in the ADMA–DDAH1 pathway are involved in environmental pollution induced airway inflammation. However, the role of DDAH1 in protection against cytotoxicity of ambient airborne particulate matter is unclear. MethodsWe examined the influence of DDAH1 expression on oxidative stress and cell apoptosis in human type II alveolar epithelial A549 cells exposed to PM 2.5 (particulate matter with an aerodynamic diameter less than 2.5 μM). ResultsWe found that PM 2.5 exposure for 48 h significantly decreased DDAH1 expression. However, knockdown of DDAH1 prior to PM 2.5 exposure actually attenuated the cytotoxicity of PM 2.5. Cytoprotection in DDAH1 deficient cells was due to increased reactive oxygen species, activation of PI3K–AKT and mitogen-activated protein kinase (MAPK) pathways, subsequent activation of nuclear factor erythroid-2-related factor 2 (Nrf2) and this caused a subsequent reduction in PM 2.5 induced oxidative stress relative to control. DDAH1 depletion also repressed the induction of inducible NOS (iNOS) in PM 2.5-exposed cells and knockdown of iNOS protected cells against PM 2.5 induced cell death. Interestingly, overexpression of DDAH1 also exerted a protective effect against the cytotoxicity of PM 2.5 and this was associated with a reduction in oxidative stress and upregulation of the anti-apoptotic protein Bcl-2. ConclusionsOur data indicate that DDAH1 plays dual roles in protection against cytotoxicity of PM 2.5 exposure, apparently by limiting PM 2.5 induced oxidative stress. General significanceOur findings reveal new insights into the role(s) of the DDAH1/ADMA in pulmonary protection against airborne pollutants. This article is part of a Special Issue entitled Air Pollution, edited by Wenjun Ding, Andrew J. Ghio and Weidong Wu. 相似文献
3.
In this study, we have estimated the number of total mortality (T-mortality), cardiovascular morbidity (CV-mortality), respiratory mortality (R-mortality), hospital admissions due to cardiovascular diseases (HA-CVD), respiratory diseases (HA-RD), chronic obstructive pulmonary diseases (COPD) and acute myocardial infarction (AMI) due to exposure to particulate matter less than 10 µm (PM 10), 2.5 µm (PM 2.5) and sulfur dioxide (SO 2) in western Iran in 2016. The World Health Organization (WHO) method was used to assess the mortality and morbidity among the exposed people. The results showed that about 3.9% CM (95% CI: 2.9–7.8%), 3.9% HA-RD (95% CI: 2.4–7.8%) and 4.4% HA-CVD (95% CI: 3.0–6.8%) for ambient PM 10 and about 7.3% TM (95% CI: 4.2–9.7%), 12.1% CM (95% CI: 3.5–14.6%) and 3.0% RM (95% CI: 0–6.3%) for PM 2.5 are respectively attributed to concentrations exceeding 10 µg/m 3. Furthermore, 3.2% HA-COPD (95% CI: 0–5.04%) and 4.2% AMI (95% CI: 1.6–4.3%) can be attributed to SO 2 concentrations greater than 10 µg/m 3, respectively. To reduce the adverse health effect of PM, health advices provided by health authorities should be given to general population especially vulnerable people such as people with chronic lung and heart pathologies, elderly and children during the dusty days. 相似文献
4.
Nitroalkene derivative of oleic acid (OA-NO 2), due to its ability to mediate revisable Michael addition, has been demonstrated to have various biological properties and become a therapeutic agent in various diseases. Though its antioxidant properties have been reported in different models of acute kidney injury (AKI), the mechanism by which OA-NO 2 attenuates intracellular oxidative stress is not well investigated. Here, we elucidated the anti-oxidative mechanism of OA-NO 2 in an in vitro model of renal ischemia/reperfusion (I/R) injury. Human tubular epithelial cells were subjected to oxygen and glucose deprivation/re-oxygenation (OGD/R) injury. Pretreatment with OA-NO 2 (1.25?μM, 45?min) attenuated OGD/R triggered reactive oxygen species (ROS) generation and subsequent mitochondrial membrane potential disruption. This action was mediated via up-regulating endogenous antioxidant defense components including superoxide dismutase (SOD1), heme oxygenase 1 (HO-1), and γ-glutamyl cysteine ligase modulatory subunits (GCLM). Moreover, subcellular fractionation analyses demonstrated that OA-NO 2 promoted nuclear translocation of nuclear factor-E2- related factor-2 (Nrf2) and Nrf2 siRNA partially abrogated these protective effects. In addition, OA-NO 2 inhibited NADPH oxidase activation and NADPH oxidase 4 (NOX4), NADPH oxidase 2 (NOX2) and p22 phox up-regulation after OGD/R injury, which was not relevant to Nrf2. These results contribute to clarify that the mechanism of OA-NO 2 reno-protection involves both inhibition of NADPH oxidase activity and induction of SOD1, Nrf2-dependent HO-1, and GCLM. 相似文献
6.
Recent studies have shown that andrographolide (AP) has the potential to be developed as a drug for therapy for osteoarthritis (OA). However, the role of AP in attenuating the progression of OA is still unknown. We hypothesized that its therapeutic effect may be associated with its antioxidant potential. In this study, we investigated the therapeutic effect of AP on chondrocytes injured by H 2O 2 and the association with the oxidation-related signaling pathways through the detection of cell proliferation, cell viability, the expression of oxidative stress-specific genes ( Sod1, Cat, and malonaldehyde [ Mda]) and proteins (superoxide dismutase [SOD], catalase [CAT]) after a culture period of 3 and 5 days, respectively. Further exploration of the expression of nuclear factor erythroid 2-related factor 2 ( Nrf2) messenger RNA and protein was also performed. The results showed that 0.625 µg/ml and 2.5 µg/ml of AP decreased oxidative stress injury of chondrocytes by increasing cell proliferation reduced by H 2O 2 and antioxidant enzyme activity, including SOD and CAT. Inflammation factors, such as matrix metallopeptidase 13 (Mmp13), tissue inhibitor of metalloproteinase 1 (Timp1), and interleukin-6 (Il6), were downregulated in the H 2O 2 group with AP, demonstrating a decrease in the progression of OA. Pathway analyses identified that the kelch-like ECH-associated protein 1 (Keap1)–Nrf2–antioxidant response element (Are) pathway is an important mediator in AP therapy on H 2O 2-induced OA. This study indicates that AP exerts protection effects on oxidative stress via activation of the Keap1–Nrf2–Are pathway in chondrocytes injured by H 2O 2, which may be promising for the therapy of OA. 相似文献
8.
BackgroundExposure to PM 2.5 has been associated with increased morbidity and mortality of lung diseases although the underlying mechanisms have not been fully uncovered. Airway inflammation is a critical event in the pathogenesis of lung diseases. This study aimed to examine the role of oxidative stress and epidermal growth factor receptor (EGFR) in PM 2.5-induced pro-inflammatory response in a human bronchial epithelial cell line, BEAS-2B. MethodsBEAS-2B cells were exposed to 0, 20, 50, 100 and 150 μg/ml of PM 2.5. Secretion of pro-inflammatory mediators including interleukin-6 (IL-6), IL-8 and IL-1β was determined using enzyme linked immunosorbent assay. Levels of intracellular reactive oxygen species (ROS) were determined using flow cytometry. Phosphorylation of the EGFR was examined with immunoblotting. ResultsPM 2.5 exposure increased the secretion of IL-6, IL-8, and IL-1β in a concentration-dependent fashion. Moreover, exposure to PM 2.5 elevated intracellular levels of ROS, and phosphorylation of the EGFR (Y1068). Pretreatment of BEAS-2B cells with either an antioxidant or a specific EGFR inhibitor significantly reduced PM 2.5-induced IL-6, IL-8 and IL-1β secretion, implying that both oxidative stress and EGFR activation were involved in PM 2.5-induced pro-inflammatory response. Furthermore, pre-treatment of BEAS-2B cells with an antioxidant significantly blunted PM 2.5-induced EGFR activation, suggesting that oxidative stress was required for PM 2.5-induced EGFR activation. ConclusionPM 2.5 exposure induces pro-inflammatory response in human bronchial epithelial cells through oxidative stress-mediated EGFR activation. 相似文献
9.
AbstractQuantification of PM 2.5 (particulate matter <2.5?µm) bound heavy metals and their potential health risks were carried out around a cement manufacturing company in Ewekoro, Nigeria. The PM 2.5 samples were collected using Environtech gravimetric sampler. A four-staged sequential extraction procedure was used to fractionate PM 2.5 bound chromium (Cr), lead (Pb), aluminum (Al), copper (Cu), and silver (Ag), and further analyzed using inductively coupled plasma mass spectrometry. Chemical speciation results reveal bioavailable levels of Pb (4.05?µg/m 3), Cr (10.75?µg/m 3), Al (16.47?µg/m 3), Cu (4.38E-01?µg/m 3), and Ag (1.22E-02?µg/m 3) in the airborne particulates. Pb and Cr levels exceeded the World Health Organization allowable limit of 0.5 and 2.5E-05?µg/m 3, respectively. The labile phases showed strong indication of the presence of Cr and Cu metal. Excess cancer risks exposure for adults, outdoor workers and children were higher than the acceptable risk target level of 1E-06. Non-carcinogenic health risk estimated using hazard quotients (HQs) and hazard indices (HIs) showed ingestion route within the safe level of HI <1 implying no adverse effect while inhalation route exceeded the safe level for all receptors. Enforcement of pollution control by authorized agencies, and screening of greenbelts as sinks for air pollutants is strongly recommended. 相似文献
10.
Objective: The influence of different exposures to PM 2.5 (particulate matter with an aerodynamic diameter below 2.5?μm) on the concentrations of biomarkers of exposure and oxidative stress should be investigated. For this purpose, urine samples from individuals travelling from Germany to China were collected and analysed. Materials: Robust LC and LC-MS/MS methods were established for the determination of biomarkers including 8-hydroxy-2′-deoxyguanosine, malondialdehyde, F2α-isoprostanes and hydroxylated polycyclic aromatic hydrocarbons. As a pilot study, nine volunteers travelled from Germany (mean daily concentration of PM2.5: 21?μg/m3) to China (mean daily concentration of PM2.5: 108?μg/m3). Urine samples were collected before and after the trip. Results: In samples collected after return to Germany, the median concentrations of oxidative stress biomarkers were observed to be higher than in samples collected before leaving Germany. Decreasing trends were observed in the sequences of samples collected after return in the following weeks. Correlations were found between exposure and oxidative stress biomarkers. Conclusion: Travellers are ideal models for PM pollution-induced acute health effects study. Exposure to PM pollution can cause oxidative stress and damage. 相似文献
11.
Particulate matter (PM) exposure during in utero life may entail adverse health outcomes in later-life. Air pollution's adverse effects are known to alter gene expression profiles, which can be regulated by microRNAs (miRNAs). We investigate the potential influence of air pollution exposure in prenatal life on placental miRNA expression. Within the framework of the ENVIR ONAGE birth cohort, we measured the expression of six candidate miRNAs in placental tissue from 210 mother-newborn pairs by qRT-PCR. Trimester-specific PM 2.5 exposure levels were estimated for each mother's home address using a spatiotemporal model. Multiple regression models were used to study miRNA expression and in utero exposure to PM 2.5 over various time windows during pregnancy. The placental expression of miR-21 (?33.7%, 95% CI: ?53.2 to ?6.2, P = 0.022), miR-146a (?30.9%, 95% CI: ?48.0 to ?8.1, P = 0.012) and miR-222 (?25.4%, 95% CI: ?43.0 to ?2.4, P = 0.034) was inversely associated with PM 2.5 exposure during the 2nd trimester of pregnancy, while placental expression of miR-20a and miR-21 was positively associated with 1st trimester exposure. Tumor suppressor phosphatase and tensin homolog (PTEN) was identified as a common target of the miRNAs significantly associated with PM exposure. Placental PTEN expression was strongly and positively associated (+59.6% per 5 µg/m³ increment, 95% CI: 26.9 to 100.7, P < 0.0001) with 3rd trimester PM 2.5 exposure. Further research is required to establish the role these early miRNA and mRNA expression changes might play in PM-induced health effects. We provide molecular evidence showing that in utero PM 2.5 exposure affects miRNAs expression as well as its downstream target PTEN. 相似文献
12.
Increased oxidative stress and inflammation have an important role in the pathophysiology of chronic kidney disease (CKD). On the other hand, more affordable therapeutic alternatives for treating this disease are urgently needed. Therefore, we compared the therapeutic efficacy of curcumin and mycophenolate mofetil (MMF) in 5/6 nephrectomy (5/6 Nx) model of CKD. Also, we evaluated whether both compounds provide benefit through the preservation of similar antioxidant mechanisms. Four groups of male Wistar were studied over a period of 4 wk. Control sham group ( n=?12), 5/6 Nx ( n?=?12), 5/6 Nx?+?MMF (30?mg/k BW/day, n?=?11) and 5/6 Nx?+?Curcumin (120?mg/k BW/day, n?=?12). Renal function and markers of oxidative stress and inflammation were evaluated. Also Nrf2-Keap1 and renal dopamine, antioxidant pathways were assessed. 5/6 Nx induced an altered renal autoregulation response, proteinuria, and hypertension; these effects were in association with increased oxidative stress, endothelial dysfunction and renal inflammation. The mechanisms associated with these alterations included a reduced nuclear translocation of Nrf2 and hyperphosphorylation of dopamine D1 receptor with a concurrent overactivation of renal NADPH oxidase. Treatments with MMF and curcumin provided equivalent therapeutic efficacy as both prevented functional renal alterations as well as preserved antioxidant capacity and avoided renal inflammatory infiltration. Moreover, both treatments preserved Nrf2-Keap1 and renal dopamine antioxidant pathways. In summary, therapeutic strategies aimed to preserve renal antioxidant pathways can help to retard the progression of CKD. 相似文献
13.
The State of Kuwait oil fires and military operations associated with the 1991 Gulf War resulted in substantially increased levels of airborne particulate matter (PM) in the Kingdom of Saudi Arabia (KSA) during 1991 and 1992. Using quantitative risk assessment methodology, this article estimates the increase in premature deaths in citizens of the KSA associated with the Gulf War–related increase in PM air pollution levels. Meta-analysis of daily time-series studies of non-accidental mortality associated with increased PM 10 levels using two alternative methodologies yielded exposure-response relative risk functions of 2.7% and 3.5% per 50 μ g/m 3 increase in PM 10 concentration. Combining these exposure-response functions with estimates of the magnitude and duration of the increased PM 10 exposure, the size of the exposed population and baseline mortality rates provided an estimate of approximately 1,080 to 1,370 excess non-accidental deaths of Saudi citizens during 1991–1992 associated with the Gulf War–related increase in PM levels. 相似文献
14.
Ambient particulate matter (PM) exposure has been associated with atherosclerosis. However, research on the effect of real-world exposure to ambient PM in regulating visfatin expression in an animal model is very limited. The objective is to investigate whether Beijing ambient PM exposure could accelerate atherosclerosis in ApoE knockout (ApoE −/−) mice by upregulating visfatin expression. Forty male ApoE −/− mice were exposed to untreated ambient air (PM group, n = 20) or filtered air (FA group, n = 20), 24 h/day, 7 days/week, for 2 months. During the exposure, the mass concentrations of PM 2.5 and PM 10 in the two groups were continuously monitored. Moreover, a receptor source apportionment model was applied to apportion sources of PM 2.5. At the end of the exposure, visfatin in plasma and aorta, biomarkers of inflammation, oxidative stress and lipid metabolism in blood samples, and bronchoalveolar lavage fluid (BALF) were determined, and the plaque area of the atherosclerosis lesions was quantified. PM-exposed mice were significantly higher than FA-exposed mice in terms of plasma visfatin, OxLDL, MDA, serum TC, LDL, TNF-α as well as IL-6, TNF-α, OxLDL, and MDA in BALF, while SOD and GSH-Px activities in plasma and BALF were reduced in PM-exposed mice. Pathological analysis of the aorta demonstrated that the plaque area and visfatin protein in the PM group increased significantly compared to the FA group. Our findings indicate that ambient PM exposure could accelerate atherosclerosis, which is related to visfatin upregulation, as well as the activation of inflammation and oxidative stress. 相似文献
15.
IntroductionEvidence based on ecological studies in China suggests that short-term exposure to particulate matter (PM) is associated with cardiovascular mortality. However, there is less evidence of PM-related morbidity for coronary heart disease (CHD) in China. This study aims to investigate the relationship between acute PM exposure and CHD incidence in people aged above 40 in Shanghai. MethodsDaily CHD events during 2005–2012 were identified from outpatient and emergency department visits. Daily average concentrations for particulate matter with aerodynamic diameter less than 10 microns (PM 10) were collected over the 8-year period. Particulate matter with aerodynamic diameter less than 2.5 microns (PM 2.5) were measured from 2009 to 2012. Analyses were performed using quasi-poisson regression models adjusting for confounders, including long-term trend, seasonality, day of the week, public holiday and meteorological factors. The effects were also examined by gender and age group (41–65 years, and >65 years). ResultsThere were 619928 CHD outpatient and emergency department visits. The average concentrations of PM 10 and PM 2.5 were 81.7μg/m 3 and 38.6μg/m 3, respectively. Elevated exposure to PM 10 and PM 2.5 was related with increased risk of CHD outpatients and emergency department visits in a short time course. A 10 μg/m 3 increase in the 2-day PM 10 and PM 2.5 was associated with increase of 0.23% (95% CI: 0.12%, 0.34%) and 0.74% (95% CI: 0.44%, 1.04%) in CHD morbidity, respectively. The associations appeared to be more evident in the male and the elderly. ConclusionShort-term exposure to high levels of PM 10 and PM 2.5 was associated with increased risk of CHD outpatient and emergency department visits. Season, gender and age were effect modifiers of their association. 相似文献
17.
Stroke involves numerous pathophysiological processes and oxidative stress is considered as a main cellular event in its pathogenesis. The nuclear factor erythroid-2-related factor 2 (Nrf2)/antioxidant response element (ARE) pathway plays a key role in inducing phase II detoxifying enzymes and antioxidant proteins and is now considered as a interesting therapeutic target for the treatment of stroke. The objective of this study is to investigate the protective effect of Gualou Guizhi granule (GLGZG) against oxidative stress and explore the protective mechanism of the Nrf2/ARE pathway. In vivo, administration of GLGZG in a rat model of focal cerebral ischemia significantly suppressed oxidative injury by increasing the activity of superoxide dismutase and glutathione level and decreasing reactive oxygen species and malondialdehyde levels. Western blot analysis showed that GLGZG induced nuclear translocation of Nrf2, and combined with real-time PCR results, which indicated that GLGZG up-regulated the Nrf2/ARE pathway. In addition, in cultured PC12 cells, GLGZG protected against H 2O 2 induced oxidative injury and activated the Nrf2/ARE pathway. All the results demonstrated that GLGZG in the management of cerebral ischemia and H 2O 2 induced oxidative injury may be associated with activation of Nrf2/ARE signaling pathway. 相似文献
18.
The free radical generating activity of airborne particulate matter (PM 10) has been proposed as a primary mechanism in biological activity of ambient air pollution. In an effort to determine the impact of the complex mixtures of extractable organic matter (EOM) from airborne particles on oxidative damage to DNA, the level of 8-oxo-2′-deoxyguanosine (8-oxodG), the most prevalent and stable oxidative lesion, was measured in the human metabolically competent cell line Hep G2. Cultured cells were exposed to equivalent EOM concentrations (5–150 μg/ml) and oxidative DNA damage was analyzed using a modified single cell gel electrophoresis (SCGE), which involves the incubation of whole cell DNA with repair specific DNA endonuclease, which cleaves oxidized DNA at the sites of 8-oxodG. EOMs were extracted from PM 10 collected daily (24 h intervals) in three European cities: Prague (Czech Republic, two monitoring sites, Libuš and Smíchov), Košice (Slovak Republic) and Sofia (Bulgaria) during 3-month sampling periods in the winter and summer seasons. No substantial time- and dose-dependent increase of oxidative DNA lesions was detected in EOM-treated cells with the exception of the EOM collected at the monitoring site Košice, summer sampling. In this case, 2 h cell exposure to EOM resulted in a slight but significant increase of oxidative DNA damage at three from total of six concentrations. The mean 8-oxodG values at these concentrations ranged from 15.3 to 26.1 per 10 6 nucleotides with a value 3.5 per 10 6 nucleotides in untreated cells. B[ a]P, the positive control, induced a variable but insignificant increase of oxidative DNA damage in Hep G2 cell (approximately 1.6-fold increase over control value).Based on these data we believe that EOM samples extracted from airborne particle PM 10 play probably only a marginal role in oxidative stress generation and oxidative lesion formation to DNA. However, adsorbed organic compounds can undergo various interactions (additive or synergistic) with other PM components or physical factors (UV-A radiation) and in this way they might enhance/multiply the adverse health effects of air pollution. 相似文献
19.
Fine particulate matters (PM 2.5) are known to pose serious health problems compared to other air pollutants. The current study employed air dispersion modeling system (AERMOD) to simulate the concentration of PM 2.5 from Tema Oil Refinery (TOR) and to assess the non-cancer risk and mortalities of the exposed population. In addition, the effects of local climatic factors on the distribution and concentration of PM 2.5 within the three main seasons (Major Raining Season (MRS), Low Raining Season (LRS) and Dry Season (DS)) were investigated. The AERMOD results showed that both 24-h (38.8 µ g m ?3) and annual (12.6 µ g m ?3) PM 2.5 concentration levels were in exceedance of the international limits. However, a decreasing trend in seasonal PM 2.5 concentrations was observed. Health risk assessment (HRA), indicated by hazard index (HI), revealed that the amount of Al 2O 3 present in the PM 2.5 caused a significant non-carcinogenic health risk to the exposed population (both adults and children) within the Metropolis (HI = 2.4 for adults and HI = 1.5 for children). Additionally, cardiopulmonary disease related mortalities due to PM 2.5 exposure (181 deaths for adults and 24 deaths for children) were found high compared to deaths caused by lung cancer (137 deaths for adults and 16 deaths for children). 相似文献
20.
We have previously reported that airborne particulate matter air pollution
(PM) activates the intrinsic apoptotic pathway in alveolar epithelial cells
through a pathway that requires the mitochondrial generation of reactive
oxygen species (ROS) and the activation of p53. We sought to examine the
source of mitochondrial oxidant production and the molecular links between ROS
generation and the activation of p53 in response to PM exposure. Using a
mitochondrially targeted ratiometric sensor (Ro-GFP) in cells lacking
mitochondrial DNA (ρ 0 cells) and cells stably expressing a
small hairpin RNA directed against the Rieske iron-sulfur protein, we show
that site III of the mitochondrial electron transport chain is primarily
responsible for fine PM (PM 2.5)-induced oxidant production. In
alveolar epithelial cells, the overexpression of SOD1 prevented the
PM 2.5-induced ROS generation from the mitochondria and prevented
cell death. Infection of mice with an adenovirus encoding SOD1 prevented the
PM 2.5-induced death of alveolar epithelial cells and the associated
increase in alveolar-capillary permeability. Treatment with PM 2.5
resulted in the ROS-mediated activation of the oxidant-sensitive kinase ASK1
and its downstream kinase JNK. Murine embryonic fibroblasts from ASK1
knock-out mice, alveolar epithelial cells transfected with dominant negative
constructs against ASK1, and pharmacologic inhibition of JNK with SP600125 (25
μ m) prevented the PM 2.5-induced phosphorylation of
p53 and cell death. We conclude that particulate matter air pollution induces
the generation of ROS primarily from site III of the mitochondrial electron
transport chain and that these ROS activate the intrinsic apoptotic pathway
through ASK1, JNK, and p53.Epidemiologic studies have consistently demonstrated a strong link between
the daily levels of particulate matter air pollution <2.5 μm in diameter
(PM 2.5) 3
and PM <10 μmin diameter (PM 10) and cardiopulmonary morbidity
and mortality
( 1– 3).
In humans, exposure to PM 10 has been associated with an increase in
mortality from ischemic cardiovascular events including stroke and myocardial
infarction, an acceleration in the age-related decline in lung function in
normal adults, impairment in normal lung development in children,
exacerbations of asthma in children and adults, accelerated atherosclerosis in
women, increased rates of lung cancer, and the development of myocardial
ischemia in men with stable coronary artery disease
( 4– 10).
The intracellular generation of reactive oxygen species (ROS) has emerged as a
common mechanism by which particulates might initiate signaling pathways that
end in these diverse pathologic conditions
( 11). We have reported that
the PM-induced generation of ROS requires a functional electron transport
chain, suggesting that PM might induce the inadvertent transfer of electrons
from one or more sites in the electron transport chain to molecular oxygen
( 12).One of the mechanisms by which exposure to PM can contribute to alveolar
epithelial dysfunction, lung injury and inflammation, and lung cancer is by
activating the intrinsic apoptotic pathway to induce cell death
( 11,
12). We have reported that
this process requires the activation of p53; however, the molecular events
linking the generation of ROS by the mitochondrial electron transport chain
with the activation of p53 are not known
( 12). In this paper, we show
that exposure of alveolar epithelial cells to PM 2.5 induces the
generation of ROS from site III of the mitochondrial electron transport chain.
These mitochondrially derived oxidants activate the mitogen-activated
signaling kinase kinase kinase (MAPKKK) apoptosis signaling kinase 1 (ASK1),
which activates the c-Jun N-terminal kinase (JNK) signaling pathway. The
activation of JNK is required for the phosphorylation of p53 and the
subsequent cell death. Inhibition of mitochondrial oxidant production in mouse
lungs prevents PM 2.5-induced cell death and the associated
PM 2.5-induced increase in the permeability of the
alveolar-capillary barrier. 相似文献
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