Dataset Information

Protein kinase C-? mediates lung injury induced by diesel exhaust particles.

ABSTRACT: Recently, we reported that diesel exhaust particles (DEPs) disrupt tight junctions (TJs) in alveolar epithelial cells (AECs) via an increase in reactive oxygen species (ROS). In this study, we investigated the role of protein kinase C (PKC)-? activation in DEP-induced lung injury. C57/bl6 mice were instilled intratracheally with 50 ?l of saline containing 100 ?g of DEPs or titanium dioxide (TiO2). Twenty-four hours later, bronchoalveolar lavage was performed to assess neutrophil counts and protein concentrations. In addition, in vitro experiments were performed in primary rat and human AECs exposed to DEPs (50 ?g/cm(2)) for 3 hours. Transepithelial electrical conductance was measured, and TJ protein association was analyzed by immunoprecipitation. To determine whether the overexpression of antioxidants prevented DEP-induced lung injury, AECs and mice were infected with adenoviruses containing catalase and manganese superoxide dismutase (MnSOD) plasmids. In vivo, the overexpression of catalase and MnSOD prevented DEP-induced neutrophil recruitment. The inhibition of PKC-? activation also prevented DEP-induced neutrophil recruitment in vivo. In vitro, DEPs activated PKC-? in AECs, but not in alveolar macrophages. Using a specific myristolated PKC-? pseudosubstrate pepetide (PKC-? ps), we showed that PKC-? mediated the DEP-induced dissociation of occludin and zonula occludin-1 (ZO1) in rat and human AECs. In addition, the overexpression of constitutively active PKC-? induced the dissociation of occludin and ZO1 in AECs. DEP-induced TJ disruption occurs via PKC-?. TJ disruption seems to be in part responsible for DEP-induced lung injury.

SUBMITTER: Caraballo JC

PROVIDER: S-EPMC3604088 | biostudies-other | 2013 Mar

REPOSITORIES: biostudies-other

ACCESS DATA

Publications

Protein kinase C-ζ mediates lung injury induced by diesel exhaust particles.

Caraballo Juan C JC Borcherding Jennifer J Thorne Peter S PS Comellas Alejandro P AP

American journal of respiratory cell and molecular biology 20121206 3

Recently, we reported that diesel exhaust particles (DEPs) disrupt tight junctions (TJs) in alveolar epithelial cells (AECs) via an increase in reactive oxygen species (ROS). In this study, we investigated the role of protein kinase C (PKC)-ζ activation in DEP-induced lung injury. C57/bl6 mice were instilled intratracheally with 50 μl of saline containing 100 μg of DEPs or titanium dioxide (TiO2). Twenty-four hours later, bronchoalveolar lavage was performed to assess neutrophil counts and prote ...[more]

PMID: 23221045

Similar Datasets

Project description:The potential effects of combinations of dilute whole diesel exhaust (DE) and ozone (O?), each a common component of ambient airborne pollutant mixtures, on lung function were examined. Healthy young human volunteers were exposed for 2 hr to pollutants while exercising (~50 L/min) intermittently on two consecutive days. Day 1 exposures were either to filtered air, DE (300 ?g/m³), O? (0.300 ppm), or the combination of both pollutants. On Day 2 all exposures were to O? (0.300 ppm), and Day 3 served as a followup observation day. Lung function was assessed by spirometry just prior to, immediately after, and up to 4 hr post-exposure on each exposure day. Functional pulmonary responses to the pollutants were also characterized based on stratification by glutathione S-transferase mu 1 (GSTM1) genotype. On Day 1, exposure to air or DE did not change FEV1 or FVC in the subject population (n?=?15). The co-exposure to O? and DE decreased FEV1 (17.6%) to a greater extent than O? alone (9.9%). To test for synergistic exposure effects, i.e., in a greater than additive fashion, FEV1 changes post individual O? and DE exposures were summed together and compared to the combined DE and O? exposure; the p value was 0.057. On Day 2, subjects who received DE exposure on Day 1 had a larger FEV1 decrement (14.7%) immediately after the O? exposure than the individuals' matched response following a Day 1 air exposure (10.9%). GSTM1 genotype did not affect the magnitude of lung function changes in a significant fashion. These data suggest that altered respiratory responses to the combination of O? and DE exposure can be observed showing a greater than additive manner. In addition, O?-induced lung function decrements are greater with a prior exposure to DE compared to a prior exposure to filtered air. Based on the joint occurrence of these pollutants in the ambient environment, the potential exists for interactions in more than an additive fashion affecting lung physiological processes.

Project description:BackgroundMost studies of the association between diesel exhaust exposure and lung cancer suggest a modest, but consistent, increased risk. However, to our knowledge, no study to date has had quantitative data on historical diesel exposure coupled with adequate sample size to evaluate the exposure-response relationship between diesel exhaust and lung cancer. Our purpose was to evaluate the relationship between quantitative estimates of exposure to diesel exhaust and lung cancer mortality after adjustment for smoking and other potential confounders.MethodsWe conducted a nested case-control study in a cohort of 12?315 workers in eight non-metal mining facilities, which included 198 lung cancer deaths and 562 incidence density-sampled control subjects. For each case subject, we selected up to four control subjects, individually matched on mining facility, sex, race/ethnicity, and birth year (within 5 years), from all workers who were alive before the day the case subject died. We estimated diesel exhaust exposure, represented by respirable elemental carbon (REC), by job and year, for each subject, based on an extensive retrospective exposure assessment at each mining facility. We conducted both categorical and continuous regression analyses adjusted for cigarette smoking and other potential confounding variables (eg, history of employment in high-risk occupations for lung cancer and a history of respiratory disease) to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Analyses were both unlagged and lagged to exclude recent exposure such as that occurring in the 15 years directly before the date of death (case subjects)/reference date (control subjects). All statistical tests were two-sided.ResultsWe observed statistically significant increasing trends in lung cancer risk with increasing cumulative REC and average REC intensity. Cumulative REC, lagged 15 years, yielded a statistically significant positive gradient in lung cancer risk overall (P (trend) = .001); among heavily exposed workers (ie, above the median of the top quartile [REC ? 1005 ?g/m(3)-y]), risk was approximately three times greater (OR = 3.20, 95% CI = 1.33 to 7.69) than that among workers in the lowest quartile of exposure. Among never smokers, odd ratios were 1.0, 1.47 (95% CI = 0.29 to 7.50), and 7.30 (95% CI = 1.46 to 36.57) for workers with 15-year lagged cumulative REC tertiles of less than 8, 8 to less than 304, and 304 ?g/m(3)-y or more, respectively. We also observed an interaction between smoking and 15-year lagged cumulative REC (P (interaction) = .086) such that the effect of each of these exposures was attenuated in the presence of high levels of the other.ConclusionOur findings provide further evidence that diesel exhaust exposure may cause lung cancer in humans and may represent a potential public health burden.

Dataset Information

Protein kinase C-? mediates lung injury induced by diesel exhaust particles.

Publications

Protein kinase C-ζ mediates lung injury induced by diesel exhaust particles.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure