Physiological and inflammatory responses in an anthropomorphically relevant model of acute diesel exhaust particle exposure are sex and dose-dependent

Context: Diesel exhaust particles (DEP) are an important contributor to suspended particulate matter (PM) in urban areas. While epidemiological evidence exists for a sex-influenced dose-response relationship between acute PM exposure and respiratory health, similar data are lacking for DEP. Further, experimental evidence showing deleterious effects on respiratory health due to acute DEP exposure is sparse.

Objective: To establish and characterize a mouse model of acute DEP exposure, comparing male and female mice and assessing the kinetics of the elemental carbon content of alveolar macrophages (AMs) to relate our model to human exposure.

Materials and Methods: Adult BALB/c mice were intranasally inoculated with 0 (control), 10, 30 or 100 µg DEP in saline. Bronchoalveolar lavage cellular inflammation and cytokine levels were assessed 3, 6, 12, 24, 48 and 168 hours post exposure. Elemental carbon uptake by AMs was additionally assessed at 336 and 672 hours post DEP exposure. Thoracic gas volume and lung mechanics were measured 6 and 24 hours post exposure. Results: DEP resulted in dose-dependent cellular inflammation and cytokine production in both sexes. Males and females responded differently with females having more severe and prolonged neutrophilia, monocyte chemoattractant protein-1 and developing greater abnormalities in lung function. The sexual dimorphism in response was not related to the capacity of AMs to phagocytise DEP.

Conclusions: Our mouse model of acute diesel exhaust particle exposure shows a dose dependency and sexual dimorphism in response. Quantification of elemental carbon in AMs allows for comparison of the results of our study with human studies.     

Differential proinflammatory responses induced by diesel exhaust particles with contrasting PAH and metal content

Exposure to diesel engine exhaust particles (DEPs), representing a complex and variable mixture of components, has been linked with cellular production and release of several types of mediators related to pulmonary inflammation. A key challenge is to identify the specific components, which may be responsible for these effects. The aim of this study was to compare the proinflammatory potential of two DEP‐samples with contrasting contents of polycyclic aromatic hydrocarbons (PAHs) and metals. The DEP‐samples were compared with respect to their ability to induce cytotoxicity, expression and release of proinflammatory mediators (IL‐6, IL‐8), activation of mitogen‐activated protein kinases (MAPKs) and expression of CYP1A1 and heme oxygenase‐1 (HO‐1) in human bronchial epithelial (BEAS‐2B) cells. In addition, dithiothreitol and ascorbic acid assays were performed in order to examine the oxidative potential of the PM samples. The DEP‐sample with the highest PAH and lowest metal content was more potent with respect to cytotoxicity and expression and release of proinflammatory mediators, CYP1A1 and HO‐1 expression and MAPK activation, than the DEP‐sample with lower PAH and higher metal content. The DEP‐sample with the highest PAH and lowest metal content also possessed a greater oxidative potential. The present results indicate that the content of organic components may be determinant for the proinflammatory effects of DEP. The findings underscore the importance of considering the chemical composition of particulate matter‐emissions, when evaluating the potential health impact and implementation of air pollution regulations. © 2013 Wiley Periodicals, Inc. Environ Toxicol 30: 188–196, 2015.     

Airway inflammatory responses to diesel exhaust in allergic rhinitics

Abstract

Context: Proximity to traffic, particularly to diesel-powered vehicles, has been associated with inducing and enhancing allergies. To investigate the basis for this association, we performed controlled exposures of allergic rhinitics to diesel exhaust (DE) at a dose known to be pro-inflammatory in healthy individuals.

Objective: We hypothesized that diesel-exhaust exposure would augment lower airway inflammation in allergic rhinitics.

Materials and methods: Fourteen allergic rhinitics were exposed in a double-blinded, randomized trial to DE (100?μg/m³ PM₁₀) and filtered air for 2?h on separate occasions. Bronchoscopy with endobronchial mucosal biopsies and airway lavage was performed 18?h post-exposure, and inflammatory markers were assessed.

Results: No evidence of neutrophilic airway inflammation was observed post-diesel, however, a small increase in myeloperoxidase was found in bronchoalveolar lavage (p?=?0.032). We found no increases in allergic inflammatory cells. Reduced mast cell immunoreactivity for tryptase was observed in the epithelium (p?=?0.013) parallel to a small decrease in bronchial wash stem cell factor (p?=?0.033).

Discussion and conclusion: DE, at a dose previously shown to cause neutrophilic inflammation in healthy individuals, induced no neutrophilic inflammation in the lower airways of allergic rhinitics, consistent with previous reports in asthmatics. Although there was no increase in allergic inflammatory cell numbers, the reduction in tryptase in the epithelium may indicate mast cell degranulation. However, this occurred in the absence of allergic symptoms. These data do not provide a simplistic explanation of the sensitivity in rhinitics to traffic-related air pollution. The role of mast cells requires further investigation.     

Obese mice are resistant to eosinophilic airway inflammation induced by diesel exhaust particles

Particulate matter can exacerbate respiratory diseases such as asthma. Diesel exhaust particles are the substantial portion of ambient particulate matter with a <2.5 µm diameter in urban areas. Epidemiological data indicate increased respiratory health effects of particulate matter in obese individuals; however, the association between obesity and diesel exhaust particle‐induced airway inflammation remains unclear. We aimed to investigate the differences in susceptibility to airway inflammation induced by exposure to diesel exhaust particles between obese mice (db/db) and lean mice (db/+m). Female db/db and db/+m mice were intratracheally administered diesel exhaust particles or vehicle every 2 weeks for a total of seven times. The cellular profile of bronchoalveolar lavage fluid and histological changes in the lungs were assessed and the lungs and serum were analyzed for the generation of cytokines, chemokines and soluble intercellular adhesion molecule 1. Diesel exhaust particle exposure‐induced eosinophilic infiltration in db/+m mice accompanied by T‐helper 2 cytokine, chemokine and soluble intercellular adhesion molecule 1 expression in the lungs. In contrast, it induced mild neutrophilic airway inflammation accompanied by elevated cytokines and chemokines in db/db mice. The lungs of db/db mice exhibited decreased expression of eosinophil activators/chemoattractants such as interleukin‐5, interleukin‐13 and eotaxin compared with those of db/+m mice. In addition, serum eotaxin and monocyte chemotactic protein‐1 levels were significantly higher in db/db mice than in db/+m mice. In conclusion, obesity can affect susceptibility to diesel exhaust particle‐induced airway inflammation, which is possibly due to differences in local and systemic inflammatory responses between lean and obese individuals. Copyright © 2013 John Wiley & Sons, Ltd.     

The acute toxic effects of particulate matter in mouse lung are related to size and season of collection

The toxicity of size-fractionated particulate matter (PM10 and PM2.5) collected in Milano during two different seasons (summer and winter) has been evaluated in vivo. The focus is on time related (3 h, 24 h and 1 week) lung response following a single intratracheal aerosolization in BALB/c mice. The bronchoalveolar lavage fluid (BALf) and the lung parenchyma were screened for different markers of inflammation and cytotoxicity. Histology and immunohistochemistry were performed on excised fixed lungs to assess the effects produced by the different PM fractions. All the analyzed inflammatory markers (PMNs percentage, TNF-α, Hsp70 in the BALf, HO-1 in lung parenchyma), increased after summer PM10 administration; on the contrary winter PM10 and PM2.5 specifically increased the amount of the Cyp1B1, a protein putatively involved in the induction of pro-carcinogenic effect. Moreover, we detected an intensification of LDH activity in the BALf after the administration of winter PM10 and PM2.5, potentially related to an in progress necrotic process while after summer PM10 and PM2.5 administration, the initiation of the caspase cascade suggested a cytotoxic effect sustained by apoptosis. Our results evidenced the toxicity mechanisms elicited by size fractionated PM samples, collected in winter and summer seasons, which differs for dimensions, chemical and microbiological composition. PM10 has been indicated to elicit above all a pro-inflammatory response, linked to its specific biological components, while PM2.5 is supposed to be more harmful due to its smaller dimension and the ability to distribute into the lung alveolar districts. We hypothesized that adverse health effects observed after a single dose of winter PM2.5 is at least partly caused by specific winter PM components, i.e. PAH and transitional metals.     

Heterozygosity in the glutathione synthesis gene Gclm increases sensitivity to diesel exhaust particulate induced lung inflammation in mice

Context: Inhalation of ambient fine particulate matter (PM_2.5) is associated with adverse respiratory and cardiovascular effects. A major fraction of PM_2.5 in urban settings is diesel exhaust particulate (DEP), and DEP-induced lung inflammation is likely a critical event mediating many of its adverse health effects. Oxidative stress has been proposed to be an important factor in PM_2.5-induced lung inflammation, and the balance between pro- and antioxidants is an important regulator of this inflammation. An important intracellular antioxidant is the tripeptide thiol glutathione (GSH). Glutamate cysteine ligase (GCL) carries out the first step in GSH synthesis. In humans, relatively common genetic polymorphisms in both the catalytic (Gclc) and modifier (Gclm) subunits of GCL have been associated with increased risk for lung and cardiovascular diseases.

Objective: This study was aimed to determine the effects of Gclm expression on lung inflammation following DEP exposure in mice.

Materials and methods: We exposed Gclm wild type, heterozygous, and null mice to DEP via intranasal instillation and assessed lung inflammation as determined by neutrophils and inflammatory cytokines in lung lavage, inflammatory cytokine mRNA levels in lung tissue, as well as total lung GSH, Gclc, and Gclm protein levels.

Results: The Gclm heterozygosity was associated with a significant increase in DEP-induced lung inflammation when compared to that of wild type mice.

Discussion and conclusion: This finding indicates that GSH synthesis can mediate DEP-induced lung inflammation and suggests that polymorphisms in Gclm may be an important factor in determining adverse health outcomes in humans following inhalation of PM_2.5.     

Enhancement of antigen-induced eosinophilic inflammation in the airways of mast-cell deficient mice by diesel exhaust particles

The present study was conducted to clarify the involvement of mast cells in the exacerbating effect of diesel exhaust particles (DEP) toward allergic airway inflammation and airway hyperresponsiveness (AHR). Airway inflammation by the infiltration of cosinophils with goblet cell proliferation and AHR, as well as by the production of antigen-specific IgG1 and IgE, in plasma were examined using mast cell-deficient mice (W/W^v) and normal mice (W/W⁺). Both groups of mice received ovalbumin (OVA) or OVA+DEP intratracheally. The eosinophilic airway inflammation and goblet cell proliferation promoted by OVA were significantly greater in W/W⁺ than in W/W^v. A similar result was observed in AHR, but was not significant among both groups of mice. DEP enhanced OVA induced-allergic airway inflammation, goblet cell proliferation, and development of AHR in W/W^v, but not in W/W⁺. DEP decreased production of antigen-specific IgG1 and IgE in both groups of mice. Mast cells were observed in the submucosal layer of the main bronchus in W/W^v. The number of mast cells was significantly decreased by OVA treatment. The results indicate that mast cells are not necessary to enhance airway damage and development of AHR in W/W^v by DEP. However, mast cells may be required for the OVA-induced cosinophilic inflammation, airway damage with goblet cell proliferation, and AHR in W/W⁺.     

Contrasting actions of diesel exhaust particles on the pulmonary and cardiovascular systems and the effects of thymoquinone

BACKGROUND AND PURPOSE: Acute exposure to particulate air pollution has been linked to acute cardiopulmonary events, but the underlying mechanisms are uncertain. EXPERIMENTAL APPROACH We investigated the acute (at 4 and 18 h) effects of diesel exhaust particles (DEP) on cardiopulmonary parameters in mice and the protective effect of thymoquinone, a constituent of Nigella sativa. Mice were given, intratracheally, either saline (control) or DEP (30 μg·per mouse). KEY RESULTS At 18 h (but not 4 h) after giving DEP, there was lung inflammation and loss of lung function. At both 4 and 18 h, DEP caused systemic inflammation characterized by leucocytosis, increased IL-6 concentrations and reduced systolic blood pressure (SBP). Superoxide dismutase (SOD) activity was decreased only at 18 h. DEP reduced platelet numbers and aggravated in vivo thrombosis in pial arterioles. In vitro, addition of DEP (0.1-1 μg·mL(-1)) to untreated blood-induced platelet aggregation. Pretreatment of mice with thymoquinone prevented DEP-induced decrease of SBP and leucocytosis, increased IL-6 concentration and decreased plasma SOD activity. Thymoquinone also prevented the decrease in platelet numbers and the prothrombotic events but not platelet aggregation in vitro. CONCLUSIONS AND IMPLICATIONS: At 4 h after DEP exposure, the cardiovascular changes did not appear to result from pulmonary inflammation but possibly from the entry of DEP and/or their associated components into blood. However, at 18 h, DEP induced significant changes in pulmonary and cardiovascular functions along with lung inflammation. Pretreatment with thymoquinone prevented DEP-induced cardiovascular changes.     

Pulmonary exposure to diesel exhaust particles induces airway inflammation and cytokine expression in NC/Nga mice

Although several studies have reported that diesel exhaust particles (DEP) affect cardiorespiratory health in animals and humans, the effect of DEP on animal models with spontaneous allergic disorders has been far less intensively studied. The Nc/Nga mouse is known to be a typical animal model for human atopic dermatitis (AD). In the present study, we investigated the effects of repeated pulmonary exposure to DEP on airway inflammation and cytokine expression in NC/Nga mice. The animals were randomized into two experimental groups that received vehicle or DEP by intratracheal instillation weekly for six weeks. Cellular profiles of bronchoalveolar lavage (BAL) fluid and expressions of cytokines and chemokines in both the BAL fluid and lung tissues were evaluated 24 h after the last instillation. The DEP challenge produced an increase in the numbers of total cells, neutrophils, and mononuclear cells in BAL fluid as compared to the vehicle challenge (P<0.01). DEP exposure significantly induced the lung expressions of interleukin (IL)-4, keratinocyte chemoattractant (KC), and macrophage inflammatory protein (MIP)-1 when compared to the vehicle challenge. These results indicate that intratracheal exposure to DEP induces the recruitment of inflammatory cells, at least partially, through the local expression of IL-4 and chemokines in NC/Nga mice.     

Suppression of cell-mediated immune responses to listeria infection by repeated exposure to diesel exhaust particles in brown Norway rats.

Diesel exhaust particles (DEP) have been shown to alter pulmonary immune responses to bacterial infection. Exposure of rats to 100 mg/m(3) DEP for 4 h was found to aggravate Listeria monocytogenes(Listeria) infection at 3 days postinfection, but the bacteria were largely cleared at 7 days postinfection due to the development of a strong T cell-mediated immunity. In the present study, we examined the effects of repeated DEP exposure at lower doses on pulmonary responses to bacterial infection. Brown Norway rats were exposed to DEP by inhalation at 20.62 +/- 1.31 mg/m 3 for 4 h/day for 5 days, followed by intratracheal inoculation with 100,000 Listeria at 2 h after the last DEP exposure. DEP-exposed rats showed a significant increase in lung bacterial load at both 3 and 7 days postinfection. The repeated DEP exposure was shown to suppress both the innate, orchestrated by alveolar macrophages (AM), and T cell-mediated responses to Listeria. DEP inhibited AM production of interleukin- (IL-) 1beta, tumor necrosis factor- (TNF-) alpha, and IL-12 but enhanced Listeria-induced AM production of IL-10, which has been shown to prolong the survival of intracellular pathogens such as Listeria. DEP exposure also suppressed the development of bacteria-specific lymphocytes from lung-draining lymph nodes, as indicated by the decreased numbers of T lymphocytes and their CD4(+) and CD8(+) subsets. Furthermore, the DEP exposure markedly inhibited the Listeria-induced lymphocyte secretion of IL-2 at day 7, IL-10 at days 3 and 7, and interferon- (IFN-) gamma at days 3 to 10 postinfection when compared to air-exposed controls. These results show a sustained pattern of downregulation of T cell-mediated immune responses by repeated low-dose DEP exposure, which is different from the results of a single high-dose exposure where the acute effect of DEP aggravated bacteria infection but triggered a strong T cell-mediated immunity.     

Glutathione (GSH) and the GSH synthesis gene Gclm modulate plasma redox and vascular responses to acute diesel exhaust inhalation in mice

Abstract

Context: Inhalation of fine particulate matter (PM_2.5) is associated with acute pulmonary inflammation and impairments in cardiovascular function. In many regions, PM_2.5 is largely derived from diesel exhaust (DE), and these pathophysiological effects may be due in part to oxidative stress resulting from DE inhalation. The antioxidant glutathione (GSH) is important in limiting oxidative stress-induced vascular dysfunction. The rate-limiting enzyme in GSH synthesis is glutamate cysteine ligase and polymorphisms in its catalytic and modifier subunits (GCLC and GCLM) have been shown to influence vascular function and risk of myocardial infarction in humans.

Objective: We hypothesized that compromised de novo synthesis of GSH in Gclm^?/+ mice would result in increased sensitivity to DE-induced lung inflammation and vascular effects.

Materials and methods: WT and Gclm^?/+ mice were exposed to DE via inhalation (300?μg/m³) for 6?h. Neutrophil influx into the lungs, plasma GSH redox potential, vascular reactivity of aortic rings and aortic nitric oxide (NO?) were measured.

Results: DE inhalation resulted in mild bronchoalveolar neutrophil influx in both genotypes. DE-induced effects on plasma GSH oxidation and acetylcholine (ACh)-relaxation of aortic rings were only observed in Gclm^?/+ mice. Contrary to our hypothesis, DE exposure enhanced ACh-induced relaxation of aortic rings in Gclm^?/+ mice.

Discussion and conclusion: These data support the hypothesis that genetic determinants of antioxidant capacity influence the biological effects of acute inhalation of DE. However, the acute effects of DE on the vasculature may be dependent on the location and types of vessels involved. Polymorphisms in GSH synthesis genes are common in humans and further investigations into these potential gene-environment interactions are warranted.     

Effects of subchronic exposure to low‐dose volatile organic compounds on lung inflammation in mice

Inflammatory lung diseases are characterized by chronic inflammation and oxidant/antioxidant imbalance. Exposure to some kinds of volatile organic compounds (VOCs) leads to lung inflammation, oxidative stress, and immune modulation. However, it is suspected that sub‐chronic exposure to low‐dose VOCs mixture induces or aggravates lung inflammation. To clarify the effect of this exposure on lung inflammatory responses, 40 male Kunming mice were exposed in four similar static chambers, 0 (control) and three different doses of VOCs mixture (groups 1–3). The concentrations of VOCs mixture were as follows: formaldehyde, benzene, toluene, and xylene 0.10 + 0.11 + 0.20 + 0.20 mg/m³, 0.50 + 0.55 + 1.00 + 1.00 mg/m³, 1.00 + 1.10 + 2.00 + 2.00 mg/m³, respectively, which corresponded to 1, 5, and 10 times of indoor air quality standard in China. After 90 consecutive days of exposure (2 h/day), oxidative stress markers in lung, cellular infiltration and cytokines, chemokine, neurotrophin in bronchoalveolar lavage fluid (BALF), and immunoglobulin (Ig) in serum were examined. VOCs exposure could increase significantly reactive oxygen species (ROS) in lung, the levels of interleukin‐8 (IL‐8), IL‐4, eotaxin, nerve growth factor (NGF), and various types of leukocytes in BALF, IgE concentration in serum. In contrast, GSH to GSSG ratio and interferon‐gamma were significantly decreased following the VOCs exposure. These results indicate that the VOCs mixture‐induced inflammatory response is at least partly caused by release of the ROS and mediators from the activated eosinophils, neutrophils, alveolar macrophages and epithelial cells. © 2013 Wiley Periodicals, Inc. Environ Toxicol 29: 1089–1097, 2014.     

Pulmonary and cardiovascular effects of traffic-related particulate matter: 4-week exposure of rats to roadside and diesel engine exhaust particles

Traffic-related particulate matter (PM) may play an important role in the development of adverse health effects, as documented extensively in acute toxicity studies. However, rather little is known about the impacts of prolonged exposure to PM. We hypothesized that long-term exposure to PM from traffic adversely affects the pulmonary and cardiovascular system through exacerbation of an inflammatory response. To examine this hypothesis, Fisher F344 rats, with a mild pulmonary inflammation at the onset of exposure, were exposed for 4 weeks, 5 days/week for 6?h a day to: (a) diluted diesel engine exhaust (PM_DEE), or: (b) near roadside PM (PM_2.5). Ultrafine particulates, which are largely present in diesel soot, may enter the systemic circulation and directly or indirectly trigger cardiovascular effects. Hence, we assessed the effects of traffic-related PM on pulmonary inflammation and activity of procoagulants, vascular function in arteries, and cytokine levels in the heart 24?h after termination of the exposures. No major adverse health effects of prolonged exposure to traffic-related PM were detected. However, some systemic effects due to PM_DEE exposure occurred including decreased numbers of white blood cells and reduced von Willebrand factor protein in the circulation. In addition, lung tissue factor activity is reduced in conjunction with reduced lung tissue thrombin generation. To what extent these alterations contribute to thrombotic effects and vascular diseases remains to be established. In conclusion, prolonged exposure to traffic-related PM in healthy animals may not be detrimental due to various biological adaptive response mechanisms.     

接触柴油机废气的火车司乘人员心脑血管疾病死亡情况的队列研究

目的：通过回顾性队列研究分析柴油机废气职业接触者在心脑血管疾病上与一般人口比较是否存在死亡超量。方法：回顾性队列研究。结果：全体队列成员粗死亡率226．35／10万人年．低于外对照。死因前三位为恶性肿瘤，脑血管病，心血管病。以检修工人为主的暴露组脑血管病的RR=2．251．无统计学意义。其SMR=2．257，95％CI为0．90～4．65。该组心血管病死亡的SMR=1．268．95％CI为0．34～3．25。结论：以检修工人为主的暴露组在全死因和脑血管病上很可能存在死亡超量，心血管病死亡是否超量不能确定。     

Protein corona formation in bronchoalveolar fluid enhances diesel exhaust nanoparticle uptake and pro-inflammatory responses in macrophages

In biological fluids nanoparticles bind a range of molecules, particularly proteins, on their surface. The resulting protein corona influences biological activity and fate of nanoparticle in vivo. Corona composition is often determined by the biological milieu encountered at the entry portal into the body, and, can therefore, depend on the route of exposure to the nanoparticle. For environmental nanoparticles where exposure is by inhalation, this will be lung lining fluid.

This study examined plasma and bronchoalveolar fluid (BALF) protein binding to engineered and environmental nanoparticles. We hypothesized that protein corona on nanoparticles would influence nanoparticle uptake and subsequent pro-inflammatory biological response in macrophages.

All nanoparticles bound plasma and BALF proteins, but the profile of bound proteins varied between nanoparticles. Focusing on diesel exhaust nanoparticles (DENP), we identified proteins bound from plasma to include fibrinogen, and those bound from BALF to include albumin and surfactant proteins A and D. The presence on DENP of a plasma-derived corona or one of purified fibrinogen failed to evoke an inflammatory response in macrophages. However, coronae formed in BALF increased DENP uptake into macrophages two fold, and increased nanoparticulate carbon black (NanoCB) uptake fivefold. Furthermore, a BALF-derived corona increased IL-8 release from macrophages in response to DENP from 1720?±?850?pg/mL to 5560?±?1380?pg/mL (p?=?0.014). These results demonstrate that the unique protein corona formed on nanoparticles plays an important role in determining biological reactivity and fate of nanoparticle in vivo. Importantly, these findings have implications for the mechanism of detrimental properties of environmental nanoparticles since the principle route of exposure to such particles is via the lung.     

Effects of diesel exhaust particles on cytokine production by splenocytes stimulated with lipopolysaccharide

It was previously shown that pulmonary exposure of mice to diesel exhaust particles (DEP) enhances inflammatory conditions induced by allergens or bacterial endotoxin (lipopolysaccharide: LPS) via enhanced local expression of cytokines. However, resolution of the underlying mechanisms, in which DEP exaggerate inflammation, remains uncompleted. Investigation of the actions of DEP on mouse-derived mononuclear cells may provide a clue to the mechanisms, because mononuclear cells produce and release several types of cytokines. The present study elucidated the effects of DEP on mononuclear cell reactions stimulated with LPS in vitro. ICR mouse-derived mononuclear cells, isolated from splenocytes, one of the secondary lymphoid tissues, were co-cultured with LPS (1 microg ml(-1)) and DEP (1, 10 or 100 microg ml(-1)). The protein levels of interferon (IFN)-gamma, interleukin (IL)-2, IL-10, and IL-13 in the culture supernatants were measured 72 h after the co-culture. LPS significantly increased the protein levels of IFN-gamma, IL-2 and IL-10. In the presence of LPS, DEP decreased the protein levels in a concentration-dependent manner with an overall trend, whereas DEP (1, 10 microg ml(-1)) moderately elevated the IL-13 level. These results suggest that DEP suppress cytokine production from mononuclear cells stimulated with LPS and provide a possible hint for DEP facilitation on inflammatory conditions, especially related to Th2 response, in vivo.     

Neurotrophin mediation of allergic airways responses to inhaled diesel particles in mice.

Neurotrophins, including nerve growth factor (NGF), partially mediate many features of allergic airways disease including airway hyperresponsiveness. Diesel exhaust particulates (DEP) associated with the combustion of diesel fuel exacerbate many of these allergic airways responses in humans. We tested the hypothesis that DEP-induced enhancement of allergic airways disease in a murine model is dependent on normal function of the low affinity pan-neurotrophin receptor p75(NTR), or tyrosine kinase A (trkA), the primary receptor for NGF. Ovalbumin (OVA)-sensitized and nonallergic BALB/c mice were intranasally instilled with anti-p75(NTR), anti-trkA, or vehicle, 1 h before OVA aerosol challenge, and then exposed nose-only to the particulate matter fraction that was less than 2.5 microns in aerodynamic diameter fraction of Standard Reference Material 2975 DEP (2.0 mg/m(3)) or filtered air for 5 h. One day later, DEP-exposed OVA-allergic mice had significantly greater increases in ventilatory responses to methacholine (Mch), but not increased lung resistance, suggesting that the airflow changes may have originated in the nasal passages. DEP-exposed OVA-allergic mice also had increased lung IL-4 levels relative to all other groups. The instillation of anti-p75(NTR) or anti-trkA completely reversed the DEP-induced increases in ventilatory responses and lung IL-4 protein to levels similar to control mice. OVA-allergic DEP-exposed mice treated with anti-p75(NTR) had significantly less lung resistance in response to Mch relative to OVA-allergic DEP-exposed mice treated with anti-trkA. The results of this study demonstrate that the enhancement of allergic airways responses by DEP exposure is partly dependent on neurotrophins in mice. In addition, neurotrophins that bind p75(NTR), but not trkA, may mediate pulmonary central airways and tissue resistance responses to allergen and DEP exposure.     

Exposure of brown Norway rats to diesel exhaust particles prior to ovalbumin (OVA) sensitization elicits IgE adjuvant activity but attenuates OVA-induced airway inflammation.

Exposure to diesel exhaust particles (DEP) during the sensitization process has been shown to increase antigen-specific IgE production and aggravate allergic airway inflammation in human and animal models. In this study, we evaluated the effect of short-term DEP exposure on ovalbumin (OVA)-mediated responses using a post-sensitization model. Brown Norway rats were first exposed to filtered air or DEP (20.6 +/- 2.7 mg/m3) for 4 h/day for five consecutive days. One day after the final air or DEP exposure (day 1), rats were sensitized with aerosolized OVA (40.5 +/- 6.3 mg/m3), and then again on days 8 and 15, challenged with OVA on day 29, and sacrificed on days 9 or 30, 24 h after the second OVA exposure or the final OVA challenge, respectively. Control animals received aerosolized saline instead of OVA. DEP were shown to elicit an adjuvant effect on the production of antigen-specific IgE and IgG on day 30. At both time points, no significant airway inflammatory responses and lung injury were found for DEP exposure alone. However, the OVA-induced inflammatory cell infiltration, acellular lactate dehydrogenase activity and albumin content in bronchoalveolar lavage (BAL) fluid, and numbers of T cells and their CD4+ and CD8+ subsets in lung-draining lymph nodes were markedly reduced by DEP on day 30 compared with the air-plus-OVA exposure group. The OVA-induced nitric oxide (NO) in the BAL fluid and production of NO, interleukin (IL)-10, and IL-12 by alveolar macrophages (AM) were also significantly lowered by DEP on day 30 as well as day 9. DEP or OVA alone decreased intracellular glutathione (GSH) in AM and lymphocytes on days 9 and 30. The combined DEP and OVA exposure resulted in further depletion of GSH in both cell types. These results show that short-term DEP exposure prior to sensitization had a delayed effect on enhancement of the sensitization in terms of allergen-specific IgE and IgG production, but caused an attenuation of the allergen-induced airway inflammatory responses.