Background

Exposure to ambient particulate matter (PM) has been associated with adverse cardiovascular effects in epidemiological studies. Current knowledge of independent effects of individual PM characteristics remains limited.

Methods

Using a semi-experimental design we investigated which PM characteristics were consistently associated with blood biomarkers believed to be predictive of the risk of cardiovascular events. We exposed healthy adult volunteers at 5 different locations chosen to provide PM exposure contrasts with reduced correlations among PM characteristics. Each of the 31 volunteers was exposed for 5 h, exercising intermittently, 3–7 times at different sites from March to October 2009. Extensive on-site exposure characterization included measurements of PM mass and number concentration, elemental- (EC) and organic carbon (OC), trace metals, sulfate, nitrate, and PM oxidative potential (OP). Before and 2 h and 18 h after exposure we measured acute vascular blood biomarkers - C-reactive protein, fibrinogen, platelet counts, von Willebrand Factor, and tissue plasminogen activator/plasminogen activator inhibitor-1 complex. We used two-pollutant models to assess which PM characteristics were most consistently associated with the measured biomarkers.

Results and Conclusion

We found OC, nitrate and sulfate to be most consistently associated with different biomarkers of acute cardiovascular risk. Associations with PM mass concentrations and OP were less consistent, whereas other measured components of the air pollution mixture, including PNC, EC, trace metals and NO2, were not associated with the biomarkers after adjusting for other pollutants.

Objective

The construction of a new road tunnel in Sydney, Australia, and concomitant reduction in traffic on a major road presented the opportunity to study the effects of this traffic intervention on respiratory health.

Methods

We made measurements in a cohort of residents in the year before the tunnel opened (2006) and in each of two years afterwards (2007–2008). Cohort members resided in one of four exposure zones, including a control zone. Each year, a respiratory questionnaire was administered (n = 2,978) and a panel sub-cohort (n = 380) performed spirometry once and recorded peak expiratory flow and symptoms twice daily for nine weeks.

Results

There was no consistent evidence of improvement in respiratory health in residents living along the bypassed main road, despite a reduction in traffic from 90,000 to 45,000 vpd. Residents living near tunnel feeder roads reported more upper respiratory symptoms in the survey but not in the panel sub-cohort. Residents living around the tunnel ventilation stack reported more upper and lower respiratory symptoms and had lower spirometric volumes after the tunnel opened. Air pollutant levels measured near the stack did not increase over the study period.

Conclusion

The finding of adverse health effects among residents living around the stack is unexpected and difficult to explain, but might be due to unmeasured pollutants or risk factors or an unrecognized pollutant source nearby. The lack of improvement in respiratory health among people living along the bypassed main road probably reflects a minimal change in exposure due to distance of residence from the road.

ATP released in the early inflammatory processes acts as a danger signal by binding to purinergic receptors expressed on immune cells. A major contribution of the P2Y2 receptor of ATP/UTP to dendritic cell function and Th2 lymphocyte recruitment during asthmatic airway inflammation was previously reported. We investigated here the involvement of P2Y2 receptor in lung inflammation initiated by pneumonia virus of mice infection. We demonstrated that P2Y2−/− mice display a severe increase in morbidity and mortality rate in response to the virus. Lower survival of P2Y2−/− mice was not significantly correlated with excessive inflammation despite the higher level of neutrophil recruiters in their bronchoalveolar fluids. Interestingly, we observed reduced ATP level and lower numbers of dendritic cells, CD4+ T cells and CD8+ T cells in P2Y2−/− compared to P2Y2+/+ infected lungs. Lower level of IL-12 and higher level of IL-6 in bronchoalveolar fluid support an inhibition of Th1 response in P2Y2−/− infected mice. Quantification of DC recruiter expression revealed comparable IP-10 and MIP-3α levels but a reduced BRAK level in P2Y2−/− compared to P2Y2+/+ bronchoalveolar fluids. The increased morbidity and mortality of P2Y2−/− mice could be the consequence of a lower viral clearance leading to a more persistent viral load correlated with the observed higher viral titer. The decreased viral clearance could result from the defective Th1 response to PVM with a lack of DC and T cell infiltration. In conclusion, P2Y2 receptor, previously described as a target in cystic fibrosis therapy and as a mediator of Th2 response in asthma, may also regulate Th1 response protecting mice against lung viral infection.

Tumor-associated eosinophilia has been observed in numerous human cancers and several tumor models in animals, however, the details surrounding this eosinophilia remain largely undefined and anecdotal. We used a B16-F10 melanoma cell injection model to demonstrate that eosinophil infiltration of tumors occurred from the earliest palpable stages with significant accumulations only in the necrotic and capsule regions. Furthermore, the presence of diffuse extracellular matrix staining for eosinophil major basic protein was restricted to the necrotic areas of tumors indicating that eosinophil degranulation was limited to this region. Antibody-mediated depletion of CD4+ T cells and adoptive transfer of eosinophils suggested, respectively, that the accumulation of eosinophils is not associated with Th2-dependent immune responses and that recruitment is a dynamic ongoing process, occurring throughout tumor growth. Ex vivo migration studies have identified what appears to be a novel chemotactic factor(s) released by stressed/dying melanoma cells, suggesting that the accumulation of eosinophils in tumors occurs, in part, through a unique mechanism dependent on a signal(s) released from areas of necrosis. Collectively, these studies demonstrate that the infiltration of tumors by eosinophils is an early and persistent response that is spatial restricted. More importantly, these data also show that the mechanism(s) that elicits this host response occurs independent of immune surveillance, suggesting that eosinophils are part of an early inflammatory reaction at the site of tumorigenesis.

We identified a previously unrecognized component of airborne particulate matter (PM) formed in combustion and thermal processes, namely, environmentally persistent free radicals (EPFRs). The pulmonary health effects of EPFRs are currently unknown. In the present study, we used a model EPFR-containing pollutant-particle system referred to as MCP230. We evaluated the effects of MCP230 on the phenotype and function of bone marrow–derived dendritic cells (BMDCs) in vitro and lung dendritic cells (DCs) in vivo, and the subsequent T-cell response. We also investigated the adjuvant role of MCP230 on airway inflammation in a mouse model of asthma. MCP230 decreased intracellular reduced glutathione (GSH) and the GSH/oxidized glutathione ratio in BMDCs, and up-regulated the expression of costimulatory molecules CD80 and CD86 on DCs. The maturation of DCs was blocked by inhibiting oxidative stress or the uptake of MCP230. BMDCs exposed to MCP230 increased their antigen-specific T-cell proliferation in vitro. In a model of asthma, exposure to MCP230 exacerbated pulmonary inflammation, which was attributed to the increase of neutrophils and macrophages but not eosinophils. This result correlated with an increase in Th17 cells and cytokines, compared with non–MCP230-treated but ovalbumin (OVA)–challenged mice. The percentage of Th2 cells was comparable between OVA and OVA + MCP230 mice. Our data demonstrate that combustion-generated, EPFR-containing PM directly induced the maturation of DCs in an uptake-dependent and oxidative stress–dependent manner. Furthermore, EPFR-containing PM induced a Th17-biased phenotype in lung, accompanied by significant pulmonary neutrophilia. Exposure to EPFR-containing PM may constitute an important and unrecognized risk factor in the exacerbation and development of a severe asthma phenotype in humans.

The need for an efficacious vaccine against Francisella tularensis is a consequence of its low infectious dose and high mortality rate if left untreated. This study sought to characterize a live attenuated subspecies novicida-based vaccine strain (U112ΔiglB) in an established second rodent model of pulmonary tularemia, namely the Fischer 344 rat using two distinct routes of vaccination (intratracheal [i.t.] and oral). Attenuation was verified by comparing replication of U112ΔiglB with wild type parental strain U112 in F344 primary alveolar macrophages. U112ΔiglB exhibited an LD50>107 CFU compared to the wild type (LD50 = 5×106 CFU i.t.). Immunization with 107 CFU U112ΔiglB by i.t. and oral routes induced antigen-specific IFN-γ and potent humoral responses both systemically (IgG2a>IgG1 in serum) and at the site of mucosal vaccination (respiratory/intestinal compartment). Importantly, vaccination with U112ΔiglB by either i.t. or oral routes provided equivalent levels of protection (50% survival) in F344 rats against a subsequent pulmonary challenge with ∼25 LD50 (1.25×104 CFU) of the highly human virulent strain SCHU S4. Collectively, these results provide further evidence on the utility of a mucosal vaccination platform with a defined subsp. novicida U112ΔiglB vaccine strain in conferring protective immunity against pulmonary tularemia.

The activity of the serine protease in the German cockroach allergen is important to the development of allergic disease. The protease-activated receptor (PAR)-2, which is expressed in numerous cell types in lung tissue, is known to mediate the cellular events caused by inhaled serine protease. Alveolar macrophages express PAR-2 and produce considerable amounts of tumor necrosis factor (TNF)-α. We determined whether the serine protease in German cockroach extract (GCE) enhances TNF-α production by alveolar macrophages through the PAR-2 pathway and whether the TNF-α production affects GCE-induced pulmonary inflammation. Effects of GCE on alveolar macrophages and TNF-α production were evaluated using in vitro MH-S and RAW264.6 cells and in vivo GCE-induced asthma models of BALB/c mice. GCE contained a large amount of serine protease. In the MH-S and RAW264.7 cells, GCE activated PAR-2 and thereby produced TNF-α. In the GCE-induced asthma model, intranasal administration of GCE increased airway hyperresponsiveness (AHR), inflammatory cell infiltration, productions of serum immunoglobulin E, interleukin (IL)-5, IL-13 and TNF-α production in alveolar macrophages. Blockade of serine proteases prevented the development of GCE induced allergic pathologies. TNF-α blockade also prevented the development of such asthma-like lesions. Depletion of alveolar macrophages reduced AHR and intracellular TNF-α level in pulmonary cell populations in the GCE-induced asthma model. These results suggest that serine protease from GCE affects asthma through an alveolar macrophage and TNF-α dependent manner, reflecting the close relation of innate and adaptive immune response in allergic asthma model.

Background

In Madagascar, very little is known about the etiology and prevalence of acute respiratory infections (ARIs) in a rural tropical area. Recent data are needed to determine the viral and atypical bacterial etiologies in children with defined clinical manifestations of ARIs.

Methods

During one year, we conducted a prospective study on ARIs in children between 2 to 59 months in the community hospital of Ampasimanjeva, located in the south-east of Madagascar. Respiratory samples were analyzed by multiplex real-time RT-PCR, including 18 viruses and 2 atypical bacteria. The various episodes of ARI were grouped into four clinical manifestations with well-documented diagnosis: “Community Acquired Pneumonia”(CAP, group I), “Other acute lower respiratory infections (Other ALRIs, group II)”, “Upper respiratory tract infections with cough (URTIs with cough, group III)”and “Upper respiratory tract infections without cough (URTIs without cough, group IV)”.

Results

295 children were included in the study between February 2010 and February 2011. Viruses and/or atypical bacteria respiratory pathogens were detected in 74.6% of samples, the rate of co-infection was 27.3%. Human rhinovirus (HRV; 20.5%), metapneumovirus (HMPV A/B, 13.8%), coronaviruses (HCoV, 12.5%), parainfluenza virus (HPIV, 11.8%) and respiratory syncytial virus A and B (RSV A/B, 11.8%) were the most detected. HRV was predominantly single detected (23.8%) in all the clinical groups while HMPV A/B (23.9%) was mainly related to CAP (group I), HPIV (17.3%) to the “Other ALRIs” (group II), RSV A/B (19.5%) predominated in the group “URTIs with cough” (group III) and Adenovirus (HAdV, 17.8%) was mainly detected in the “without cough” (group IV).

Interpretation

This study describes for the first time the etiology of respiratory infections in febrile children under 5 years in a malaria rural area of Madagascar and highlights the role of respiratory viruses in a well clinically defined population of ARIs.

Destruction of toxic chemicals by thermal treatment can be a highly effective method for remediation of sites contaminated with hazardous substances. Of the 977 Superfund source control treatment projects in the United States from 1982 to 2005, 16% used incineration or other thermal treatments (the proportion is similar for 126 projects in the period 2002–2005).1 However, as with other technologies, if thermal treatments are not matched correctly with the site or are improperly operated, harmful by-products can form, requiring further treatment.

The mechanisms that regulate the host immune response induced by human metapneumovirus (hMPV), a newly-recognized member of the Paramyxoviridae family, are largely unknown. Cytokines play an important role in modulating inflammatory responses during viral infections. IL-12p40, a known important mediator in limiting lung inflammation, is induced by hMPV and its production is sustained after the resolution phase of infection suggesting that this cytokine plays a role in the immune response against hMPV. In this work, we demonstrated that in mice deficient in IL-12p40, hMPV infection induced an exacerbated pulmonary inflammatory response and mucus production, altered cytokine response, and decreased lung function. However, hMPV infection in these mice does not have an effect on viral replication. These results identify an important regulatory role of IL-12p40 in hMPV infection.

Background

The nitric oxide (NO) pathway is involved in asthma, and eosinophils participate in the regulation of the NO pool in pulmonary tissues. We investigated associations between single nucleotide polymorphisms (SNPs) of NO synthase genes (NOS) and biological NO-related phenotypes measured in two compartments (exhaled breath condensate and plasma) and blood eosinophil counts.

Methodology

SNPs (N = 121) belonging to NOS1, NOS2 and NOS3 genes were genotyped in 1277 adults from the French Epidemiological study on the Genetics and Environment of Asthma (EGEA). Association analyses were conducted on four quantitative phenotypes: the exhaled fraction of NO (FeNO), plasma and exhaled breath condensate (EBC) nitrite-nitrate levels (NO2–NO3) and blood eosinophils in asthmatics and non-asthmatics separately. Genetic heterogeneity of these phenotypes between asthmatics and non-asthmatics was also investigated.

Principal Findings

In non-asthmatics, after correction for multiple comparisons, we found significant associations of FeNO levels with three SNPs in NOS3 and NOS2 (P≤0.002), and of EBC NO2–NO3 level with NOS2 (P = 0.002). In asthmatics, a single significant association was detected between FeNO levels and one SNP in NOS3 (P = 0.004). Moreover, there was significant heterogeneity of NOS3 SNP effect on FeNO between asthmatics and non-asthmatics (P = 0.0002 to 0.005). No significant association was found between any SNP and NO2–NO3 plasma levels or blood eosinophil counts.

Conclusions

Variants in NO synthase genes influence FeNO and EBC NO2–NO3 levels in adults. These genetic determinants differ according to asthma status. Significant associations were only detected for exhaled phenotypes, highlighting the critical relevance to have access to specific phenotypes measured in relevant biological fluid.

Background and Objectives

Despite India's substantial economic growth in the past two decades, girls in India are discriminated against in access to preventive healthcare including immunizations. Surprisingly, no study has assessed the contribution of gender based within-household discrimination to the overall inequality in immunization status of Indian children. This study therefore has two objectives: to estimate the gender based within-household inequality (GWHI) in immunization status of Indian children and to examine the inter-regional and inter-temporal variations in the GWHI.

Data and Methods

The present study used households with a pair of male-female siblings (aged 1–5 years) from two rounds of National Family Health Survey (NFHS, 1992–93 and 2005–06). The overall inequality in the immunization status (after controlling for age and birth order) of children was decomposed into within-households and between-households components using Mean log deviation to obtain the GWHI component. The analysis was conducted at the all-India level as well as for six specified geographical regions and at two time points (1992–93 and 2005–06). Household fixed-effects models for immunization status of children were also estimated.

Results and Conclusions

Findings from household fixed effects analysis indicated that the immunization scores of girls were significantly lower than that of boys. The inequality decompositions revealed that, at the all-India level, the absolute level of GWHI in immunization status decreased from 0.035 in 1992–93 to 0.023 in 2005–06. However, as a percentage of total inequality, it increased marginally (15.5% to 16.5%). In absolute terms, GWHI decreased in all the regions except in the North-East. But, as a percentage of total inequality it increased in the North-Eastern, Western and Southern regions. The main conclusions are the following: GWHI contributes substantially to the overall inequality in immunization status of Indian children; and though the overall inequality in immunization status declined in all the regions, the changes in GWHI were mixed.

Exposure to airborne particles is associated with increased cardiovascular morbidity and mortality. During the combustion of chlorine-containing hazardous materials and fuels, chlorinated hydrocarbons chemisorb to the surface of transition metal-oxide-containing particles, reduce the metal, and form an organic free radical. These radical-particle systems can survive in the environment for days and are called environmentally persistent free radicals (EPFRs). This study determined whether EPFRs could decrease left ventricular function before and after ischemia and reperfusion (I/R) in vivo. Male Brown Norway rats were dosed (8 mg/kg, i.t.) 24 hr prior to testing with particles containing the EPFR of 1, 2-dichlorobenzene (DCB230). DCB230 treatment decreased systolic and diastolic function. DCB230 also produced pulmonary and cardiac inflammation. After ischemia, systolic, but not diastolic function was significantly decreased in DCB230-treated rats. Ventricular function was not affected by I/R in control rats. There was greater oxidative stress in the heart and increased 8-isoprostane (biomarker of oxidative stress) in the plasma of treated vs control rats after I/R. These data demonstrate for the first time that DCB230 can produce inflammation and significantly decrease cardiac function at baseline and after I/R in vivo. Furthermore, these data suggest that EPFRs may be a risk factor for cardiac toxicity in healthy individuals and individuals with ischemic heart disease. Potential mechanisms involving cytokines/chemokines and/or oxidative stress are discussed.

Respiratory syncytial virus (RSV) causes significant morbidity and mortality in infants worldwide. Severe RSV infections in infants cause bronchiolitis, wheeze, and/or cough and significantly increase the risk of developing asthma. RSV pathogenesis is thought to be due to a Th2-type immune response initiated in response to RSV infection specifically in the infant. Using a neonatal mouse system as an appropriate model for human infants, we sought to determine if local inhibition of IL-4Rα expression during primary RSV infection in the neonate would prevent Th2-skewed responses to secondary RSV infection and improve long-term pulmonary function. To reduce IL-4Rα expression, antisense oligonucleotides (ASO) specific for IL-4Rα were administered intranasally to neonatal mice at the time of primary infection. Mice were initially infected with RSV at one week of age and reinfected at six weeks of age. Administration of IL-4Rα ASO during primary RSV infection in neonatal mice abolished the pulmonary dysfunction normally observed following reinfection in the adult. This ablation of pulmonary dysfunction correlated with a persistent rebalancing of the Th cell compartment with decreased Th2 responses (i.e. reduced goblet cell hyperplasia and Th2 cells and cytokine secretion) and increased Th1 responses (i.e. elevated Th1 cell numbers and type I antibodies and cytokines). Our data support our hypothesis that a reduction in the Th2 immune response during primary infection in neonates prevents Th2-mediated pulmonary pathology initially and upon reinfection; and further suggest that vaccine strategies incorporating IL-4Rα ASO may be of significant benefit to infants.

Respiratory syncytial virus (RSV) infection is the most significant cause of viral death in infants worldwide. The significant morbidity and mortality associated with this disease underscores the urgent need for the development of an RSV vaccine. The development of an RSV vaccine has been hampered by our limited understanding of the human host immune system, which plays a significant role in RSV pathogenesis, susceptibility and vaccine efficacy. As a result, animal models have been developed to better understand the mechanisms by which RSV causes disease. Within the past few years, a revolutionary variation on these animal models has emerged – age at time of initial infection – and early studies in neonatal mice (aged <7 days at time of initial infection) indicate the validity of this model to understand RSV infection in infants. This article reviews available information on current murine and emerging neonatal mouse RSV models.

Background

Increased asthma risk/exacerbation in children and infants is associated with exposure to elevated levels of ultrafine particulate matter (PM). The presence of a newly realized class of pollutants, environmentally persistent free radicals (EPFRs), in PM from combustion sources suggests a potentially unrecognized risk factor for the development and/or exacerbation of asthma.

Methods

Neonatal rats (7-days of age) were exposed to EPFR-containing combustion generated ultrafine particles (CGUFP), non-EPFR containing CGUFP, or air for 20 minutes per day for one week. Pulmonary function was assessed in exposed rats and age matched controls. Lavage fluid was isolated and assayed for cellularity and cytokines and in vivo indicators of oxidative stress. Pulmonary histopathology and characterization of differential protein expression in lung homogenates was also performed.

Results

Neonates exposed to EPFR-containing CGUFP developed significant pulmonary inflammation, and airway hyperreactivity. This correlated with increased levels of oxidative stress in the lungs. Using differential two-dimensional electrophoresis, we identified 16 differentially expressed proteins between control and CGUFP exposed groups. In the rats exposed to EPFR-containing CGUFP; peroxiredoxin-6, cofilin1, and annexin A8 were upregulated.

Conclusions

Exposure of neonates to EPFR-containing CGUFP induced pulmonary oxidative stress and lung dysfunction. This correlated with alterations in the expression of various proteins associated with the response to oxidative stress and the regulation of glucocorticoid receptor translocation in T lymphocytes.

Strong correlations exist between exposure to PM2.5 and adverse pulmonary effects. PM2.5 consists of fine (≤2.5 μm) and ultrafine (≤0.1 μm) particles with ultrafine particles accounting for >70% of the total particles. Environmentally persistent free radicals (EPFRs) have recently been identified in airborne PM2.5. To determine the adverse pulmonary effects of EPFRs associated with exposure to elevated levels of PM2.5, we engineered 2.5 μm surrogate EPFR-particle systems. We demonstrated that EPFRs generated greater oxidative stress in vitro, which was partly responsible for the enhanced cytotoxicity following exposure. In vivo studies using rats exposed to EPFRs containing particles demonstrated minimal adverse pulmonary effects. Additional studies revealed that fine particles failed to reach the alveolar region. Overall, our study implies qualitative differences between the health effects of PM size fractions.

Metal oxide nanoparticles are often used as industrial catalysts and elevated levels of these particles have been clearly demonstrated at sites surrounding factories. To date, limited toxicity data on metal oxide nanoparticles are available. To understand the impact of these airborne pollutants on the respiratory system, airway epithelial (HEp-2) cells were exposed to increasing doses of silicon oxide (SiO2), ferric oxide (Fe2O3) and copper oxide (CuO) nanoparticles, the leading metal oxides found in ambient air surrounding factories. CuO induced the greatest amount of cytotoxicity in a dose dependent manner; while even high doses (400 µg/cm2) of SiO2 and Fe2O3 were non-toxic to HEp-2 cells. Although all metal oxide nanoparticles were able to generate ROS in HEp-2 cells, CuO was better able to overwhelm antioxidant defenses (e.g. catalase and glutathione reductase). A significant increase in the level of 8-isoprostanes and in the ratio of GSSG to total glutathione in cells exposed to CuO suggested that ROS generated by CuO induced oxidative stress in HEp-2 cells. Co-treatment of cells with CuO and the antioxidant resveratrol increased cell viability suggesting that oxidative stress may be the cause of the cytotoxic effect of CuO. These studies demonstrated that there is a high degree of variability in the cytotoxic effects of metal oxides, that this variability is not due to the solubility of the transition metal, and that this variability appears to involve sustained oxidative stress possibly due to redox cycling.

Influenza infection remains a significant cause of pulmonary morbidity and mortality worldwide with the highest hospitalization and mortality rates occurring in infants and elder adults. The mechanisms inducing this considerable morbidity and mortality are largely unknown. To address this question, we established a neonatal mouse model of influenza infection to test the hypothesis that the immaturity of the neonatal immune system is responsible for the severe pulmonary disease observed in infants. Seven-day-old mice were infected with influenza A virus (H1N1) and allowed to mature. As adults, these mice showed enhanced airway hyperreactivity, chronic pulmonary inflammation, and diffuse emphysematous-type lesions in the lungs. The adaptive immune responses of the neonates were much weaker than those of adults. This insufficiency appeared to be in both magnitude and functionality and was most apparent in the CD8+ T cell population. To determine the role of neonatal CD8+ T cells in disease outcome, adult, naive CD8+ T cells were adoptively transferred into neonates prior to infection. Neonatal mice receiving the adult CD8+ T cells had significantly lower pulmonary viral titers and greatly improved pulmonary function as adults (airway resistance similar to SHAM). Additional adoptive transfer studies using adult CD8+ T cells from IFN-γ-deficient mice demonstrated the importance of IFN-γ from CD8+ T cells in controlling the infection and in determining disease outcome. Our data indicate that neonates are more vulnerable to severe infections due to immaturity of their immune system and emphasize the importance of vaccination in infants.

Background

Atrial natriuretic peptide (ANP) and its receptor, NPRA, have been extensively studied in terms of cardiovascular effects. We have found that the ANP-NPRA signaling pathway is also involved in airway allergic inflammation and asthma. ANP, a C-terminal peptide (amino acid 99–126) of pro-atrial natriuretic factor (proANF) and a recombinant peptide, NP73-102 (amino acid 73–102 of proANF) have been reported to induce bronchoprotective effects in a mouse model of allergic asthma. In this report, we evaluated the effects of vessel dilator (VD), another N-terminal natriuretic peptide covering amino acids 31–67 of proANF, on acute lung inflammation in a mouse model of allergic asthma.

Methods

A549 cells were transfected with pVD or the pVAX1 control plasmid and cells were collected 24 hrs after transfection to analyze the effect of VD on inactivation of the extracellular-signal regulated receptor kinase (ERK1/2) through western blot. Luciferase assay, western blot and RT-PCR were also performed to analyze the effect of VD on NPRA expression. For determination of VD's attenuation of lung inflammation, BALB/c mice were sensitized and challenged with ovalbumin and then treated intranasally with chitosan nanoparticles containing pVD. Parameters of airway inflammation, such as airway hyperreactivity, proinflammatory cytokine levels, eosinophil recruitment and lung histopathology were compared with control mice receiving nanoparticles containing pVAX1 control plasmid.

Results

pVD nanoparticles inactivated ERK1/2 and downregulated NPRA expression in vitro, and intranasal treatment with pVD nanoparticles protected mice from airway inflammation.

Conclusion

VD's modulation of airway inflammation may result from its inactivation of ERK1/2 and downregulation of NPRA expression. Chitosan nanoparticles containing pVD may be therapeutically effective in preventing allergic airway inflammation.

Background

Combustion generated particulate matter is deposited in the respiratory tract and pose a hazard to the lungs through their potential to cause oxidative stress and inflammation. We have previously shown that combustion of fuels and chlorinated hydrocarbons produce semiquinone-type radicals that are stabilized on particle surfaces (i.e. environmentally persistent free radicals; EPFRs). Because the composition and properties of actual combustion-generated particles are complex, heterogeneous in origin, and vary from day-to-day, we have chosen to use surrogate particle systems. In particular, we have chosen to use the radical of 2-monochlorophenol (MCP230) as the EPFR because we have previously shown that it forms a EPFR on Cu(II)O surfaces and catalyzes formation of PCDD/F. To understand the physicochemical properties responsible for the adverse pulmonary effects of combustion by-products, we have exposed human bronchial epithelial cells (BEAS-2B) to MCP230 or the CuO/silica substrate. Our general hypothesis was that the EPFR-containing particle would have greater toxicity than the substrate species.

Results

Exposure of BEAS-2B cells to our combustion generated particle systems significantly increased reactive oxygen species (ROS) generation and decreased cellular antioxidants resulting in cell death. Resveratrol treatment reversed the decline in cellular glutathione (GSH), glutathione peroxidase (GPx), and superoxide dismutase (SOD) levels for both types of combustion-generated particle systems.

Conclusion

The enhanced cytotoxicity upon exposure to MCP230 correlated with its ability to generate more cellular oxidative stress and concurrently reduce the antioxidant defenses of the epithelial cells (i.e. reduced GSH, SOD activity, and GPx). The EPFRs in MCP230 also seem to be of greater biological concern due to their ability to induce lipid peroxidation. These results are consistent with the oxidizing nature of the CuO/silica ultrafine particles and the reducing nature and prolonged environmental and biological lifetimes of the EPFRs in MCP230.

On August 29, 2005, Hurricane Katrina made landfall along the Gulf Coast as a Category 3 hurricane. The associated storm surge and heavy rainfall resulted in major flooding throughout the New Orleans area. As the flood waters receded, thick sediment was left covering the ground and coating the interior of homes. This sediment was dispersed into the air and inhaled as dust by returning residents and workers. Our objective in this study was to evaluate the potential pulmonary effects associated with the respirable particulate matter (PM) derived from Hurricane Katrina (HK-PM) in mice. Samples of PM were collected from several locations along the Gulf Coast on September 30 and October 2, 2005 and had a mean aerodynamic diameter ranging from 3-5 μm). Chemical analysis and cytotoxicity assays were performed for all HK-PM samples. A few samples with varying levels of cytotoxicity were chosen for an acute inhalation exposure study. Airborne PM10 levels recorded in the New Orleans area post-Katrina were variable, ranging from 70 μg/m3 in Gentilly to 688 μg/m3 in Lakeview (residential areas). Mice exposed to one of these samples developed significant pulmonary inflammation and airways resistance and hyperresponsiveness to methacholine challenge. These studies demonstrate that dispersion of certain Katrina sediment samples through either natural (e.g., wind) or mechanical (e.g., vehicles) processes promotes airflow obstruction in mice.

Background

Respiratory syncytial virus (RSV) is the most common cause of acute bronchiolitis in infants and the elderly. Furthermore, epidemiological data suggest that RSV infection during infancy is a potent trigger of subsequent wheeze and asthma development. However, the mechanism by which RSV contributes to asthma is complex and remains largely unknown. A recent study indicates that the age of initial RSV infection is a key factor in determining airway response to RSV rechallenge. We hypothesized that severe RSV infection during neonatal development significantly alters lung structure and the pulmonary immune micro-environment; and thus, neonatal RSV infection is crucial in the development of or predisposition to allergic inflammatory diseases such as asthma.

Methods

To investigate this hypothesis the present study was conducted in a neonatal mouse model of RSV-induced pulmonary inflammation and airway dysfunction. Seven-day-old mice were infected with RSV (2 × 105 TCID50/g body weight) and allowed to mature to adulthood. To determine if neonatal RSV infection predisposed adult animals to enhanced pathophysiological responses to allergens, these mice were then sensitized and challenged with ovalbumin. Various endpoints including lung function, histopathology, cytokine production, and cellularity in bronchoalveolar lavage were examined.

Results

RSV infection in neonates alone led to inflammatory airway disease characterized by airway hyperreactivity, peribronchial and perivascular inflammation, and subepithelial fibrosis in adults. If early RSV infection was followed by allergen exposure, this pulmonary phenotype was exacerbated. The initial response to neonatal RSV infection resulted in increased TNF-α levels in bronchoalveolar lavage. Interestingly, increased levels of IL-13 and mucus hyperproduction were observed almost three months after the initial infection with RSV.

Conclusion

Neonatal RSV exposure results in long term pulmonary inflammation and exacerbates allergic airways disease. The early increase in TNF-α in the bronchoalveolar lavage implicates this inflammatory cytokine in orchestrating these events. Finally, the data presented emphasize IL-13 and TNF-α as potential therapeutic targets for treating RSV induced-asthma.

High-temperature, controlled incineration and thermal treatment of contaminated soils, sediments, and wastes at Superfund sites are often preferred methods of remediation of contaminated sites under the Comprehensive Environmental Response, Compensation, and Liability Act of 1980 and related legislation. Although these methods may be executed safely, formation of toxic combustion or reaction by-products is still a cause of concern. Emissions of polycyclic aromatic hydrocarbons (PAHs); chlorinated hydrocarbons (CHCs), including polychlorinated dibenzo-p-dioxins and dibenzofurans; and toxic metals (e.g., chromium VI) have historically been the focus of combustion and health effects research. However, fine particulate matter (PM) and ultrafine PM, which have been documented to be related to cardiovascular disease, pulmonary disease, and cancer, have more recently become the focus of research. Fine PM and ultrafine PM are effective delivery agents for PAHs, CHCs, and toxic metals. In addition, it has recently been realized that brominated hydrocarbons (including brominated/chlorinated dioxins), redox-active metals, and redox-active persistent free radicals are also associated with PM emissions from combustion and thermal processes. In this article, we discuss the origin of each of these classes of pollutants, the nature of their association with combustion-generated PM, and the mechanisms of their known and potential health impacts.

Background

Severe respiratory syncytial virus infection (RSV) during infancy has been shown to be a major risk factor for the development of subsequent wheeze. However, the reasons for this link remain unclear. The objective of this research was to determine the consequences of early exposure to RSV and allergen in the development of subsequent airway hyperreactivity (AHR) using a developmental time point in the mouse that parallels that of the human neonate.

Methods

Weanling mice were sensitized and challenged with ovalbumin (Ova) and/or infected with RSV. Eight days after the last allergen challenge, various pathophysiological endpoints were examined.

Results

AHR in response to methacholine was enhanced only in weanling mice exposed to Ova and subsequently infected with RSV. The increase in AHR appeared to be unrelated to pulmonary RSV titer. Total bronchoalveolar lavage cellularity in these mice increased approximately two-fold relative to Ova alone and was attributable to increases in eosinophil and lymphocyte numbers. Enhanced pulmonary pathologies including persistent mucus production and subepithelial fibrosis were observed. Interestingly, these data correlated with transient increases in TNF-α, IFN-γ, IL-5, and IL-2.

Conclusion

The observed changes in pulmonary structure may provide an explanation for epidemiological data suggesting that early exposure to allergens and RSV have long-term physiological consequences. Furthermore, the data presented here highlight the importance of preventative strategies against RSV infection of atopic individuals during neonatal development.