Inhalation toxicity profiles of particulate matter: a comparison between brake wear with other sources of emission.

Objective: There is substantial evidence that exposure to airborne particulate matter (PM) from road traffic is associated with adverse health outcomes. Although it is often assumed to be caused by vehicle exhaust emissions such as soot, other components may also contribute to detrimental effects. The toxicity of fine PM (PM2.5; <2.5 µm mass median aerodynamic diameter) released from brake pads was compared to PM from other sources. Materials and methods: PM2.5 of different types of brake pads (low-metallic, semi-metallic, NAO and ECE-NAO hybrid), tires and road pavement, poultry as well as the combustion of diesel fuel and wood (modern and old-fashioned stove technologies) were collected as suspensions in water. These were subsequently aerosolized for inhalation exposures. Female BALB/cOlaHsd mice were exposed for 1.5, 3, or 6 hours by nose-only inhalation up to 9 mg/m3. Results: Neither cytotoxicity nor oxidative stress was observed after exposure to any of the re-aerosolized PM2.5 samples. Though, at similar PM mass concentrations the potency to induce inflammatory responses was strongly dependent on the emission source. Exposure to most examined PM2.5 sources provoked inflammation including those derived from the poultry farm, wear emissions of the NAO and ECE-NAO hybrid brake pads as well as diesel and wood combustion, as indicated by neutrophil chemoattractant, KC and MIP-2 and lung neutrophil influx. Discussion and conclusions: Our study revealed considerable variability in the toxic potency of brake wear particles. Understanding of sources that are most harmful to health can provide valuable information for risk management strategies and could help decision-makers to develop more targeted air pollution regulation.

Investigation of the effects of short-term inhalation of carbon nanoparticles on brains and lungs of c57bl/6j and p47(phox-/-) mice.

Recent studies indicate that the brain is a target for toxic carbonaceous nanoparticles present in ambient air. It has been proposed that the neurotoxic effects of such particles are driven by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase mediated generation of reactive oxygen species (ROS) in activated microglia. In the present study, we have evaluated the effects of short term (4h) nose-only inhalation exposure to carbon NP (CNP) in the brains and lungs of C57BL/6J mice and in p47(phox-/-) mice that lack a functional NADPH oxidase. It was shown that the lungs of the p47(phox-/-) mice are less responsive to CNP inhalation than lungs of the corresponding C57BL/6J control animals. Lung tissue mRNA expression of the oxidative stress/DNA damage response genes 8-oxoguanine glycosylase (OGG1) and apurinic/apyrimidinic endonuclease 1 (APE1) were induced by CNP exposure in C57BL/6J but not in the p47(phox-/-) mice. In contrast, the expression of these genes, as well as Tumor Necrosis Factor-α (TNFα), Cyclooxygenase-2 (COX-2) and Heme Oxygenase-1 (HO-1) was not altered in the olfactory bulb, cerebellum or remaining brain tissue part of either mouse background. This indicates that neuroinflammation was not induced by this exposure. CNP inhalation for 4h or for 4h on three consecutive days also did not affect brain tissue protein expression of interleukin (IL)-1ß, while a clear significant difference in constitutive expression level of this pro-inflammatory cytokine was found between C57BL/6J and p47(phox-/-) mice. In conclusion, short-term inhalation exposure to pure carbon nanoparticles can trigger mild p47(phox) dependent oxidative stress responses in the lungs of mice whereas in their brains at the same exposure levels signs of oxidative stress and inflammation remain absent. The possible role of p47(phox) in the neuro-inflammatory effects of nanoparticles in vivo remains to be clarified.

Factor XII activation is essential to sustain the procoagulant effects of particulate matter.

BACKGROUND: Particulate matter (PM) is a key component of ambient air pollution and has been associated with an increased risk of thrombotic events and mortality. The underlying mechanisms remain unclear. OBJECTIVES: To study the mechanisms of PM-driven procoagulant activity in human plasma and to investigate mainly, the coagulation driven by ultrafine particles (UFPs; < 0.1 µm) in genetically modified mice. METHODS: Thrombin generation in response to PM of different sizes was assessed in normal human platelet-poor plasma, as well as in plasmas deficient in the intrinsic pathway proteases factors XII (FXII) or XI (FXI). In addition, UFPs were intratracheally instilled in wild-type (WT) and FXII-deficient (FXII(-/-) ) mice and plasma thrombin generation was analyzed in plasma from treated mice at 4 and 20 h post-exposure. RESULTS: In normal human plasma, thrombin generation was enhanced in the presence of PM, whereas PM-driven thrombin formation was completely abolished in FXII- and FXI-deficient plasma. UFPs induced a transient increase in tissue factor (TF)-driven thrombin formation at 4 h post-instillation in WT mice compared with saline instillation. Intratracheal instillation of UFPs resulted in a procoagulant response in WT mice plasma at 20 h, whereas it was entirely suppressed in FXII(-/-) mice. CONCLUSIONS: Overall, the data suggest that PM promotes its early procoagulant actions mostly through the TF-driven extrinsic pathway of coagulation, whereas PM-driven long lasting thrombogenic effects are predominantly mediated via formation of activated FXII. Hence, FXII-driven thrombin formation may be relevant to an enhanced thrombotic susceptibility upon chronic exposure to PM in humans.

Inflammation and tissue damage in mouse lung by single and repeated dosing of urban air coarse and fine particles collected from six European cities.

The authors have previously demonstrated heterogeneities in the inflammatory activities of urban air fine (PM(2.5-0.2)) and coarse (PM(10-2.5)) particulate samples collected from six European cities with contrasting air pollution situations. The same samples (10 mg/kg) were intratracheally instilled to healthy C57BL/6J mice either once or repeatedly on days 1, 3, and 6 of the study week. The lungs were lavaged 24 h after the single dose or after the last repeated dosing. In both size ranges, repeated dosing of particles increased the total cell number in bronchoalveolar lavage fluid (BALF) more than the respective single dose, whereas cytokine concentrations were lower after repeated dosing. The lactate dehydrogenase (LDH) responses increased up to 2-fold after repeated dosing of PM(2.5-0.2) samples and up to 6-fold after repeated dosing of PM(10-2.5) samples. PM(10-2.5) samples evoked a more extensive interstitial inflammation in the mouse lungs. The constituents with major contributions to the inflammatory responses were oxidized organic compounds and transition metals in PM(2.5-0.2) samples, Cu and soil minerals in PM(10-2.5) samples, and Zn in both size ranges. In contrast, poor biomass and coal combustion were associated with elevated levels of polycyclic aromatic hydrocarbons (PAHs) and a consistent inhibitory effect on the inflammatory activity of PM(2.5-0.2) samples. In conclusion, repeated intratracheal instillation of both fine and coarse particulate samples evoked enhanced pulmonary inflammation and cytotoxicity compared to single-dose administration. The sources and constituents of urban air particles responsible for these effects appear to be similar to those encountered in the authors' previous single-dose study.

Signal transduction pathways involved in particulate matter induced relaxation in rat aorta--spontaneous hypertensive versus Wistar Kyoto rats.

UNLABELLED: Previously we reported that in vivo exposure to ambient particulate matter (PM) induces vasodilatation in rat aorta. The purpose of the current study was to investigate the intracellular messengers involved in PM-elicited vasodilatation in aortas from spontaneous hypertensive (SHR) and normotensive (WKY) rats. METHODS: The contribution of three different intracellular pathways, i.e. (1) the NO-cGMP pathway, (2) prostanoids signaling and (3) endothelial hyperpolarisation factors were evaluated by using specific inhibitors (NS2028, Diclofenac and high K-concentration/17-ODYA, respectively). Using antagonists of capsaicin- or histamine receptors we tested potential interactions of PM with these receptors. Particle suspensions (EHC-93), particle filtrates (particle-free) and Cu(2+)- or Zn(2+)-containing solutions were used to obtain cumulative dose-response curves of relaxation in normal and endothelium-denuded rings. RESULTS: Our present data confirm that PM and its soluble components elicit an endothelium-independent vasodilatation in rat aorta rings. The response is mainly linked to the activation of soluble guanylate cyclase (sGC), since its inhibition by NS2028 almost abolished relaxation. Indeed PM suspensions stimulated cGMP production in purified isolated sGC. Neither the receptor nor their signaling pathways played a significant role in the direct relaxation by PM or metals. Vasodilatation responses were significantly higher in SHR than WKY control rats. CONCLUSION: Our data demonstrate that PM elicits a dose-dependent vasodilatation via activation of sGC in vascular smooth muscles. PM components, including soluble transition metals play a major role in this response. The stronger effect in SHR rats is in accordance with the observation that acute effects of PM are mainly seen in patients with underlying cardiovascular diseases.