IRF7-Associated Immunophenotypes Have Dichotomous Responses to Virus/Allergen Coexposure and OM-85-Induced Reprogramming

High risk for virus-induced asthma exacerbations in children is associated with an IRF7lo immunophenotype, but the underlying mechanisms are unclear. Here, we applied a Systems Biology approach to an animal model comprising rat strains manifesting high (BN) versus low susceptibility (PVG) to experimental asthma, induced by virus/allergen coexposure, to elucidate the mechanism(s)-of-action of the high-risk asthma immunophenotype. We also investigated potential risk mitigation via pretreatment with the immune training agent OM-85. Virus/allergen coexposure in low-risk PVG rats resulted in rapid and transient airways inflammation alongside IRF7 gene network formation. In contrast, responses in high-risk BN rats were characterized by severe airways eosinophilia and exaggerated proinflammatory responses that failed to resolve, and complete absence of IRF7 gene networks. OM-85 had more profound effects in high-risk BN rats, inducing immune-related gene expression changes in lung at baseline and reducing exaggerated airway inflammatory responses to virus/allergen coexposure. In low-risk PVG rats, OM-85 boosted IRF7 gene networks in the lung but did not alter baseline gene expression or cellular influx. Distinct IRF7-associated asthma risk immunophenotypes have dichotomous responses to virus/allergen coexposure and respond differentially to OM-85 pretreatment. Extrapolating to humans, our findings suggest that the beneficial effects OM-85 pretreatment may preferentially target those in high-risk subgroups

Optical coherence tomography-based contact indentation for diaphragm mechanics in a mouse model of transforming growth factor alpha induced lung disease

Funding provided by the National Health and Medical Research Council (NHMRC) of Australia (1027218). P.N. and K.W. are supported by NHMRC Fellowships (1045824, 1090888). P.W. was supported by the William and Marlene Schrader Postgraduate Scholarship, The University of Western Australia, and C.A. by an NHMRC Preterm Infants CRE top-up scholarship.This study tested the utility of optical coherence tomography (OCT)-based indentation to assess mechanical properties of respiratory tissues in disease. Using OCT-based indentation, the elastic modulus of mouse diaphragm was measured from changes in diaphragm thickness in response to an applied force provided by an indenter. We used a transgenic mouse model of chronic lung disease induced by the overexpression of transforming growth factor-alpha (TGF-α), established by the presence of pleural and peribronchial fibrosis and impaired lung mechanics determined by the forced oscillation technique and plethysmography. Diaphragm elastic modulus assessed by OCT-based indentation was reduced by TGF-α at both left and right lateral locations (p < 0.05). Diaphragm elastic modulus at left and right lateral locations were correlated within mice (r = 0.67, p < 0.01) suggesting that measurements were representative of tissue beyond the indenter field. Co-localised images of diaphragm after TGF-α overexpression revealed a layered fibrotic appearance. Maximum diaphragm force in conventional organ bath studies was also reduced by TGF-α overexpression (p < 0.01). Results show that OCT-based indentation provided clear delineation of diseased diaphragm, and together with organ bath assessment, provides new evidence suggesting that TGF-α overexpression produces impairment in diaphragm function and, therefore, an increase in the work of breathing in chronic lung disease.Publisher PDFPeer reviewe

Four Regional Marine Biodiversity Studies: Approaches and Contributions to Ecosystem-Based Management

We compare objectives and approaches of four regional studies of marine biodiversity: Gulf of Maine Area Census of Marine Life, Baltic Sea History of Marine Animal Populations, Great Barrier Reef Seabed Biodiversity Project, and Gulf of Mexico Biodiversity Project. Each program was designed as an "ecosystem" scale but was created independently and executed differently. Each lasted 8 to 10 years, including several years to refine program objectives, raise funding, and develop research networks. All resulted in improved baseline data and in new, or revised, data systems. Each contributed to the creation or evolution of interdisciplinary teams, and to regional, national, or international science-management linkages. To date, there have been differing extents of delivery and use of scientific information to and by management, with greatest integration by the program designed around specific management questions. We evaluate each research program's relative emphasis on three principal elements of biodiversity organization: composition, structure, and function. This approach is used to analyze existing ecosystem-wide biodiversity knowledge and to assess what is known and where gaps exist. In all four of these systems and studies, there is a relative paucity of investigation on functional elements of biodiversity, when compared with compositional and structural elements. This is symptomatic of the current state of the science. Substantial investment in understanding one or more biodiversity element(s) will allow issues to be addressed in a timely and more integrative fashion. Evaluating research needs and possible approaches across specific elements of biodiversity organization can facilitate planning of future studies and lead to more effective communication between scientists, managers, and stakeholders. Building a general approach that captures how various studies have focused on different biodiversity elements can also contribute to meta-analyses of worldwide experience in scientific research to support ecosystem-based management

Metabolic and ventilatory physiology of the Barrow Island golden bandicoot (Isoodon auratus barrowensis) and the northern brown bandicoot (Isoodon macrourus)

Metabolic and ventilatory parameters were measured for the smallest and largest Isoodon bandicoots; the arid-adapted Barrow Island golden bandicoot (Isoodon auratus barrowensis) and the tropical northern brown bandicoot (Isoodon macrourus). I. a. barrowensis has a number of physiological characteristics that aid its tolerance of high Ta and survival in a hot and dry climate, including a low and labile body temperature, a very low basal metabolic rate, low total evaporative water loss, and an effective panting mechanism. I. macrourus generally has an “average” physiology for a bandicoot despite its size, although a number of its physiological characteristics aid survival in (sub)tropical conditions. These include a low body temperature, low total evaporative water loss and minute ventilation at high ambient temperatures, and an average thermal conductance. These data support the theory that phylogeny is a more important predictor of bandicoot physiology than habitat/distribution

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

No role for neutrophil elastase in influenza-induced cellular recruitment, cytokine production or airway hyperresponsiveness in mice

Previous studies have suggested that in vitro modulation of neutrophil chemokines and Inflammatory cytokines by neutrophil elastase (NE) does not translate to the in vivo setting We aimed to test the role of NE in the recruitment of neutrophils,cytokine production and lung function responses to respiratory viral infection To address this, we Inoculated neutrophil elastase(NE(-/-)) deficient and wild-type (WT) 129Sv mice with 50 mu L of 10(4 5) pfu Influenza A/Mem71 (H3N1) or a control preparation. Mice were subjected to methacholine (MCh) challenge at 3-4 days post-infection during the peak of cellular inflammation Inflammation, protein content and cytokines (TNF-alpha and MIP-2) were assessed in bronchoalveolar lavage fluid Influenza-infected mice had a heightened responsiveness to MCh, increased cellular inflammation, increased protein leak and altered cytokine production, none of which were influenced by the absence of NE These data demonstrate that NE does not modulate neutrophil recruitment, cytokine production, epithelial permeability or responsiveness to bronchoconstricting agents during acute influenza infection in mice. (C) 2010 Elsevier B V All rights reserve

Comment on "Regional particle size dependent deposition of inhaled aerosols in rats and mice" by Kuehl et al.

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Serum vitamin D levels.

<p>Serum 25(OH)D levels of adult female BALB/c mice were measured using ELISA. Serum samples were from four different groups and collected at week 1 [Control (n = 5), Flu (n = 5), HDM (n = 5), and Flu + HDM (n = 5)], 4 [Control (n = 5), Flu (n = 5), HDM (n = 5), and Flu + HDM (n = 5)], and 7 [Control (n = 10), Flu (n = 10), HDM (n = 10), and Flu + HDM (n = 10)]. Data are presented as mean±SD. Two-way ANOVA plus Holm-Sidak multiple comparison test was used to determine the statistical significance.</p