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author:("allert, Terry")
1.  Radical-Containing Particles Activate Dendritic Cells and Enhance Th17 Inflammation in a Mouse Model of Asthma 
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.
doi:10.1165/rcmb.2011-0001OC
PMCID: PMC3262685  PMID: 21493781
EPFR; dendritic cell; asthma; Th17; neutrophil
2.  Environmentally persistent free radicals induce airway hyperresponsiveness in neonatal rat lungs 
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.
doi:10.1186/1743-8977-8-11
PMCID: PMC3061909  PMID: 21388553
3.  Inchoate CD8+ T Cell Responses in Neonatal Mice Permit Influenza Induced Persistent Pulmonary Dysfunction1 
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.
PMCID: PMC2659373  PMID: 18714021
Rodents; T Cells, Cytotoxic; Viral infection; Inflammation; Lung
4.  Modulation of lung inflammation by vessel dilator in a mouse model of allergic asthma 
Respiratory Research  2009;10(1):66.
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.
doi:10.1186/1465-9921-10-66
PMCID: PMC2716304  PMID: 19615076
5.  Sediment from Hurricane Katrina: Potential to Produce Pulmonary Dysfunction in Mice 
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.
PMCID: PMC2596316  PMID: 19079667
Hurricane Katrina; pulmonary dysfunction; respiratory toxicology

Results 1-5 (5)