Effect of diesel exhaust on the host response to respiratory viral infection: involvement of toll-like receptor 3

Adverse effects resulting from exposure to air pollutants have become an increasing problem worldwide. Particularly levels of air pollutants have been associated with increases in the susceptibility and response to many respiratory diseases. Of the numerous air pollutants, diesel exhaust (DE) has become a major concern since it can account for a significant amount of the pollutants generated by motor vehicles in many areas. Previous results in our laboratory have demonstrated that prior exposure of respiratory epithelial cells to DE enhances the susceptibility to influenza infections. In this work, these results were confirmed and expanded upon both in vitro and in vivo. The effects of DE on the expression and signaling of toll-like receptor 3 (TLR3), which has previously shown to be needed for a complete innate immune response to influenza infections as well as other respiratory viral infections, were examined as well as mechanistic aspects involved in the observed effects. Increased expression and signaling of TLR3 was observed in respiratory epithelial cells exposed to DE prior to infection with influenza, resulting in an enhancement of the influenza-induced inflammatory and interferon (IFN) responses. A positive-feedback loop involving type I IFNs and DE-induced effects on epithelial cell tight junctional complexes played a role in the observed effects. In vivo exposure of mice to DE enhanced the susceptibility to influenza infections and decreased expression of surfactant proteins A and D, which are an important part of the innate immune defense against influenza and other respiratory viruses. Together, these results demonstrate that exposure to an oxidant air pollutant, such as diesel exhaust, can enhance the susceptibility and response to respiratory viral infection and elucidate potential mechanisms behind some of these effects

Localization of Type I Interferon Receptor Limits Interferon-Induced TLR3 in Epithelial Cells

Previous studies have shown that influenza infections increase Toll-like receptor 3 (TLR3) expression and that type I interferons (IFNs) may play a role in this response. This study aimed to expand on the role of type I IFNs in the influenza-induced upregulation of TLR3 and determine whether and how the localization of the IFN-α/β receptor (IFNAR) in respiratory epithelial cells could modify IFN-induced responses. Using differentiated primary human airway epithelial cells this study demonstrates that soluble mediators secreted in response to influenza infection upregulate TLR3 expression in naive cells. This response was associated with an upregulation of type I IFNs and stimulation with type I, but not type II, IFNs enhanced TLR3 expression. Interestingly, although influenza infection results in IFN-β release both toward the apical and basolateral sides of the epithelium, TLR3 expression is only enhanced in cells stimulated with IFN-β from the basolateral side. Immunohistochemical analysis demonstrates that IFNAR expression is limited to the basolateral side of differentiated human airway epithelial cells. However, non- or poorly differentiated epithelial cells express IFNAR more toward the apical side. These data demonstrate that restricted expression of the IFNAR in the differentiated airway epithelium presents a potential mechanism of regulating type I IFN-induced TLR3 expression

Determinants of host susceptibility to murine respiratory syncytial virus (RSV) disease identify a role for the innate immunity scavenger receptor MARCO gene in human infants

AbstractBackgroundRespiratory syncytial virus (RSV) is the global leading cause of lower respiratory tract infection in infants. Nearly 30% of all infected infants develop severe disease including bronchiolitis, but susceptibility mechanisms remain unclear.MethodsWe infected a panel of 30 inbred strains of mice with RSV and measured changes in lung disease parameters 1 and 5days post-infection and they were used in genome-wide association (GWA) studies to identify quantitative trait loci (QTL) and susceptibility gene candidates.FindingsGWA identified QTLs for RSV disease phenotypes, and the innate immunity scavenger receptor Marco was a candidate susceptibility gene; targeted deletion of Marco worsened murine RSV disease. We characterized a human MARCO promoter SNP that caused loss of gene expression, increased in vitro cellular response to RSV infection, and associated with increased risk of disease severity in two independent populations of children infected with RSV.InterpretationTranslational integration of a genetic animal model and in vitro human studies identified a role for MARCO in human RSV disease severity. Because no RSV vaccines are approved for clinical use, genetic studies have implications for diagnosing individuals who are at risk for severe RSV disease, and disease prevention strategies (e.g. RSV antibodies)

Ambient air pollution and allergic diseases in children

The prevalence of allergic diseases has increased worldwide, a phenomenon that can be largely attributed to environmental effects. Among environmental factors, air pollution due to traffic is thought to be a major threat to childhood health. Residing near busy roadways is associated with increased asthma hospitalization, decreased lung function, and increased prevalence and severity of wheezing and allergic rhinitis. Recently, prospective cohort studies using more accurate measurements of individual exposure to air pollution have been conducted and have provided definitive evidence of the impact of air pollution on allergic diseases. Particulate matter and ground-level ozone are the most frequent air pollutants that cause harmful effects, and the mechanisms underlying these effects may be related to oxidative stress. The reactive oxidative species produced in response to air pollutants can overwhelm the redox system and damage the cell wall, lipids, proteins, and DNA, leading to airway inflammation and hyper-reactivity. Pollutants may also cause harmful effects via epigenetic mechanisms, which control the expression of genes without changing the DNA sequence itself. These mechanisms are likely to be a target for the prevention of allergies. Further studies are necessary to identify children at risk and understand how these mechanisms regulate gene-environment interactions. This review provides an update of the current understanding on the impact of air pollution on allergic diseases in children and facilitates the integration of issues regarding air pollution and allergies into pediatric practices, with the goal of improving pediatric health

Aldose reductase deficiency in mice protects from ragweed pollen extract (RWE)-induced allergic asthma

<p>Abstract</p> <p>Background</p> <p>Childhood hospitalization related to asthma remains at historically high levels, and its incidence is on the rise world-wide. Previously, we have demonstrated that aldose reductase (AR), a regulatory enzyme of polyol pathway, is a major mediator of allergen-induced asthma pathogenesis in mouse models. Here, using AR null (AR^-/-) mice we have investigated the effect of AR deficiency on the pathogenesis of ragweed pollen extract (RWE)-induced allergic asthma in mice and also examined the efficacy of enteral administration of highly specific AR inhibitor, fidarestat.</p> <p>Methods</p> <p>The wild type (WT) and AR^-/-mice were sensitized and challenged with RWE to induce allergic asthma. AR inhibitor, fidarestat was administered orally. Airway hyper-responsiveness was measured in unrestrained animals using whole body plethysmography. Mucin levels and Th2 cytokine in broncho-alveolar lavage (BAL) were determined using mouse anti-Muc5A/C ELISA kit and multiplex cytokine array, respectively. Eosinophils infiltration and goblet cells were assessed by H&E and periodic acid Schiff (PAS)-staining of formalin-fixed, paraffin-embedded lung sections. T regulatory cells were assessed in spleen derived CD4⁺CD25⁺T cells population.</p> <p>Results</p> <p>Deficiency of AR in mice led to significantly decreased PENH, a marker of airway hyper-responsiveness, metaplasia of airway epithelial cells and mucus hyper-secretion following RWE-challenge. This was accompanied by a dramatic decrease in infiltration of eosinophils into sub-epithelium of lung as well as in BAL and release of Th2 cytokines in response to RWE-challenge of AR^-/-mice. Further, enteral administration of fidarestat significantly prevented eosinophils infiltration, airway hyper-responsiveness and also markedly increased population of T regulatory (CD4⁺CD25⁺FoxP3⁺) cells as compared to RWE-sensitized and challenged mice not treated with fidarestat.</p> <p>Conclusion</p> <p>Our results using AR^-/-mice strongly suggest the role of AR in allergic asthma pathogenesis and effectiveness of oral administration of AR inhibitor in RWE-induced asthma in mice supports the use of AR inhibitors in the treatment of allergic asthma.</p

Induction of Heme Oxygenase-1, Biliverdin Reductase and H-Ferritin in Lung Macrophage in Smokers with Primary Spontaneous Pneumothorax: Role of HIF-1α

Few data concern the pathophysiology of primary spontaneous pneumothorax (PSP), which is associated with alveolar hypoxia/reoxygenation. This study tested the hypothesis that PSP is associated with oxidative stress in lung macrophages. We analysed expression of the oxidative stress marker 4-HNE; the antioxidant and anti-inflammatory proteins heme oxygenase-1 (HO-1), biliverdin reductase (BVR) and heavy chain of ferritin (H-ferritin); and the transcription factors controlling their expression Nrf2 and HIF-1alpha, in lung samples from smoker and nonsmoker patients with PSP (PSP-S and PSP-NS), cigarette smoke being a risk factor of recurrence of the disease.mRNA was assessed by RT-PCR and proteins by western blot, immunohistochemistry and confocal laser analysis. 4-HNE, HO-1, BVR and H-ferritin were increased in macrophages from PSP-S as compared to PSP-NS and controls (C). HO-1 increase was associated with increased expression of HIF-1alpha mRNA and protein in alveolar macrophages in PSP-S patients, whereas Nrf2 was not modified. To understand the regulation of HO-1, BVR and H-ferritin, THP-1 macrophages were exposed to conditions mimicking conditions in C, PSP-S and PSP-NS patients: cigarette smoke condensate (CS) or air exposure followed or not by hypoxia/reoxygenation. Silencing RNA experiments confirmed that HIF-1alpha nuclear translocation was responsible for HO-1, BVR and H-ferritin induction mediated by CS and hypoxia/reoxygenation.PSP in smokers is associated with lung macrophage oxidative stress. The response to this condition involves HIF-1alpha-mediated induction of HO-1, BVR and H-ferritin

Indoor Air Quality (IAQ) in Naturally-ventilated Primary Schools in the UK:Occupant-Related Factors

Indoor Air Quality (IAQ) is affected by Context, Occupant and Building (COB) related factors. This paper evaluates IAQ as a function of occupant-related factors including occupants' Adaptive Behaviours (ABs), occupancy patterns, occupant's CO2 generation rates and occupancy density. This study observed occupant-related factors of 805 children in 29 naturally-ventilated (NV) classrooms in UK primary schools during Non-Heating and Heating seasons. Occupant-related factors affecting IAQ include occupants' adaptive behaviours, occupancy patterns, occupants' CO2 generation rate and occupancy densities. Results of this study suggest that a classroom with high potentials for natural ventilation does not necessarily provide adequate IAQ, however, occupants’ good practice of ABs is also required. Average occupancy densities to have CO2 levels of 1000 ± 50 ppm are suggested to be 2.3 ± 0.05m2/p and 7.6 ± 0.25 m3/p. These values correspond to the classroom area of 62.1 ± 1.35 m2 and volume of 205.2 ± 6.75 m3 with a height of 3.3 m. Mean CO2 level is maintained below 900 ppm when all occupant-related factors are in the favour of IAQ, however, it exceeds 1300 ppm when none of the occupant-related factors are in favour of IAQ. It is shown that 17% of CO2 variations are explained by open area (m2), 14% by occupants' generation rates (cm3/s) and 11% by occupancy density (m3/p). IAQ is mostly affected by occupants’ adaptive behaviours than other occupant-related factors in naturally-ventilated classrooms

Ventilation rates in naturally ventilated primary schools in the UK; Contextual, Occupant and Building-related (COB) factors

Indoor Air Quality (IAQ) in classrooms is assessed by CO2 levels and Ventilation Rates (VRs). Factors affecting VRs fall into Contextual, Occupant and Building (COB) related factors. This study investigates how VRs are affected by COB factors in 29 naturally-ventilated classrooms in the UK during Non-Heating and Heating seasons. Building-related factors classify classrooms with high or low potentials for natural ventilation, with 45% of classrooms having high potentials. Contextual factors including season, operative temperature (Top), outdoor temperature (Tout), ‘Top-Tout’ and air density can limit or increase VRs. Occupant-related factors classify occupant's good or poor practice of environmental adaptive behaviours. ‘Open area’ as a reflection of all COB factors is strongly correlated with ventilation rates. Results show that 12% and 19% of variations in ventilation rates are explained by open areas during non-heating and heating seasons, respectively. Findings highlight that to have VR of 8 ± 1.28 l/s.p during non-heating seasons and VR of 8 ± 1.07 l/s.p during heating seasons, average open areas of 3.8 m2 and 2 m2 are required, respectively. This difference can mostly be explained by temperature difference between inside and outside. Results show COB factors need to be considered holistically to maintain adequate VRs. Classrooms in which all COB factors are met provide average VR of 11 l/s.p and classrooms in which none of COB factors are met provide average VR is 3.1 l/s.p. This study highlights that 40% of classrooms according to EN 13779 and 80% of classrooms according to ASHRAE Standard fail to provide adequate VRs

Inhibition of Aldose Reductase Prevents Experimental Allergic Airway Inflammation in Mice

The bronchial asthma, a clinical complication of persistent inflammation of the airway and subsequent airway hyper-responsiveness, is a leading cause of morbidity and mortality in critically ill patients. Several studies have shown that oxidative stress plays a key role in initiation as well as amplification of inflammation in airways. However, still there are no good anti-oxidant strategies available for therapeutic intervention in asthma pathogenesis. Most recent studies suggest that polyol pathway enzyme, aldose reductase (AR), contributes to the pathogenesis of oxidative stress-induced inflammation by affecting the NF-kappaB-dependent expression of cytokines and chemokines and therefore inhibitors of AR could be anti-inflammatory. Since inhibitors of AR have already gone through phase-III clinical studies for diabetic complications and found to be safe, our hypothesis is that AR inhibitors could be novel therapeutic drugs for the prevention and treatment of asthma. Hence, we investigated the efficacy of AR inhibition in the prevention of allergic responses to a common natural airborne allergen, ragweed pollen that leads to airway inflammation and hyper-responsiveness in a murine model of asthma.Primary Human Small Airway Epithelial Cells (SAEC) were used to investigate the in vitro effects of AR inhibition on ragweed pollen extract (RWE)-induced cytotoxic and inflammatory signals. Our results indicate that inhibition of AR prevents RWE -induced apoptotic cell death as measured by annexin-v staining, increase in the activation of NF-kappaB and expression of inflammatory markers such as inducible nitric oxide synthase (iNOS), cycloxygenase (COX)-2, Prostaglandin (PG) E(2), IL-6 and IL-8. Further, BALB/c mice were sensitized with endotoxin-free RWE in the absence and presence of AR inhibitor and followed by evaluation of perivascular and peribronchial inflammation, mucin production, eosinophils infiltration and airway hyperresponsiveness. Our results indicate that inhibition of AR prevents airway inflammation and production of inflammatory cytokines, accumulation of eosinophils in airways and sub-epithelial regions, mucin production in the bronchoalveolar lavage fluid and airway hyperresponsiveness in mice.These results suggest that airway inflammation due to allergic response to RWE, which subsequently activates oxidative stress-induced expression of inflammatory cytokines via NF-kappaB-dependent mechanism, could be prevented by AR inhibitors. Therefore, inhibition of AR could have clinical implications, especially for the treatment of airway inflammation, a major cause of asthma pathogenesis