Semi-automated micro-computed tomography lung segmentation and analysis in mouse models.

Computed Tomography (CT) is a standard clinical tool utilized to diagnose known lung pathologies based on established grading methods. However, for preclinical trials and toxicity investigations in animal models, more comprehensive datasets are typically needed to determine discriminative features between experimental treatments, which oftentimes require analysis of multiple images and their associated differential quantification using manual segmentation methods. Furthermore, for manual segmentation of image data, three or more readers is the gold standard of analysis, but this requirement can be time-consuming and inefficient, depending on variability due to reader bias. In previous papers, microCT image manual segmentation was a valuable tool for assessment of lung pathology in several animal models; however, the manual segmentation approach and the commercial software used was typically a major rate-limiting step. To improve the efficiency, the semi-manual segmentation method was streamlined, and a semi-automated segmentation process was developed to produce:•Quantifiable segmentations: using manual and semi-automated analysis methods for assessing experimental injury and toxicity models,•Deterministic results and efficiency through automation in an unbiased and parameter free process, thereby reducing reader variance, user time, and increases throughput in data analysis,•Cost-Effectiveness: portable with low computational resource demand, based on a cross-platform open-source ImageJ program.

Concentration-associated pathology of alkali burn in a mouse model using anterior segment optical coherence tomography with angiography.

Pathological features of alkali concentration-associated burn were studied using non-invasive anterior segment optical coherence tomography (AS-OCT) and OCT angiography (OCTA). Alkali burn was induced in C57BL/6J mice (n = 20) by placing filter paper soaked in 0.1, 0.25, 0.5, and 1 M NaOH for 30s on the right eye (left eye control). Longitudinal imaging was performed with AS-OCT/OCTA and fluorescein angiography over 14 days, after which eyes were enucleated at 7 and 14 days for histology and immunofluorescence. Concentration-associated corneal swelling was maximal at 0.5M, increasing linearly in a concentration-dependent fashion at 0.1, 0.25, and 0.5 M NaOH, to levels of 50%, 100%, and 175% of control, respectively. At 0.1M, corneal swelling and surface erosions were prominent, while at 0.25M, deep tissue damage, limbal neovascularization, and stromal haze were evident at 7 days. At 0.5M and 1M, severe exacerbation of the corneal swelling, angle closure, Descemet's membrane detachment, hyphema, and profuse central neovascularization were noted as early as day 3, which further progressed to inflammation, fibrosis, and opacity by day 7. We conclude that alkali concentration-dependent burn intensity biomarkers can be assessed by non-invasive AS-OCT/OCTA, distinguishing between mild, moderate, and severe ocular injury, with potential relevance toward clinical utilization in human eyes.

Spatial-Temporal Speckle Variance in the En-Face View as a Contrast for Optical Coherence Tomography Angiography (OCTA).

Optical Coherence Tomography (OCT) is an adaptable depth-resolved imaging modality capable of creating a non-invasive 'digital biopsy' of the eye. One of the latest advances in OCT is optical coherence tomography angiography (OCTA), which uses the speckle variance or phase change in the signal to differentiate static tissue from blood flow. Unlike fluorescein angiography (FA), OCTA is contrast free and depth resolved. By combining high-density scan patterns and image processing algorithms, both morphometric and functional data can be extracted into a depth-resolved vascular map of the retina. The algorithm that we explored takes advantage of the temporal-spatial relationship of the speckle variance to improve the contrast of the vessels in the en-face OCT with a single frame. It also does not require the computationally inefficient decorrelation of multiple A-scans to detect vasculature, as used in conventional OCTA analysis. Furthermore, the spatial temporal OCTA (ST-OCTA) methodology tested offers the potential for post hoc analysis to improve the depth-resolved contrast of specific ocular structures, such as blood vessels, with the capability of using only a single frame for efficient screening of large sample volumes, and additional enhancement by processing with choice of frame averaging methods. Applications of this method in pre-clinical studies suggest that the OCTA algorithm and spatial temporal methodology reported here can be employed to investigate microvascularization and blood flow in the retina, and possibly other compartments of the eye.

Optical biosensing of markers of mucosal inflammation.

We report the design and adaptation of iron/iron oxide nanoparticle-based optical nanobiosensors for enzymes or cytokine/chemokines that are established biomarkers of lung diseases. These biomarkers comprise ADAM33, granzyme B, MMP-8, neutrophil elastase, arginase, chemokine (C-C motif) ligand 20 and interleukin-6. The synthesis of nanobiosensors for these seven biomarkers, their calibration with commercially available enzymes and cytokines/chemokines, as well as their validation using bronchoalveolar lavage (BAL) obtained from a mouse model of TLR3-mediated inflammation are discussed here. Exhaled Breath Condensate (EBC) is a minimally invasive approach for sampling airway fluid in the diagnosis and management of various lung diseases in humans (e.g., asthma, COPD and viral infections). We report the proof-of-concept of using human EBC in conjunction with nanobiosensors for diagnosis/monitoring airway inflammation. These findings suggest that, with nanosensor technology, human EBC can be utilized as a liquid biopsy to monitor inflammation/remodeling in lung disease.

Lung metabolome of 1,3-butadiene exposed Collaborative Cross mice reflects metabolic phenotype of human lung cancer.

1,3-Butadiene (BD) exposure is known to cause numerous adverse health effects, including cancer, in animals and humans. BD is metabolized to reactive epoxide intermediates, which are genotoxic, but it is not well know what other effects BD has on cellular metabolism. We examined the effects of exposure to BD on the mouse lung metabolome in the genetically heterogeneous collaborative cross outbred mouse model. Mice were exposed to 3 concentra-tions of BD for 10 days (2, 20, and 200 ppm), and lung tissues were analyzed using high-resolution mass spectrometry-based metabolomics. As compared to controls (0 ppm BD), BD had extensive effects on lung metabolism at all concentrations of exposure, including the lowest concentration of 2 ppm, as reflected by reprogramming of multiple metabolic pathways. Metabolites participating in glycolysis and the tricarboxylic acid cycle were elevated, with 8 out of 10 metabolites demonstrating a 2 to 8-fold increase, including the oncometabolite fumarate. Fatty acid levels, sphingosine, and sphinganine were decreased (2 to 8-fold), and fatty acyl-CoAs were significantly increased (16 to 31-fold), suggesting adjustments in lipid metabolism. Furthermore, metabolites involved in basic amino acid metabolism, steroid hormone metabolism, and nucleic acid metabolism were significantly altered. Overall, these changes mirror the metabolic alterations found in lung cancer cells, suggesting that very low doses of BD induce metabolic adaptations that may prevent or promote adverse health effects such as tumor formation.

Efficacy of Novel Highly Specific Bromodomain-Containing Protein 4 Inhibitors in Innate Inflammation-Driven Airway Remodeling.

NF-κB/RelA triggers innate inflammation by binding to bromodomain-containing protein 4 (BRD4), an atypical histone acetyltransferase (HAT). Although RelA·BRD4 HAT mediates acute neutrophilic inflammation, its role in chronic and functional airway remodeling is not known. We observed that BRD4 is required for Toll-like receptor 3 (TLR3)-mediated mesenchymal transition, a cell-state change that is characteristic of remodeling. We therefore tested two novel highly selective BRD4 inhibitors, ZL0420 and ZL0454, for their effects on chronic airway remodeling produced by repetitive TLR3 agonist challenges, and compared their efficacy with that of two nonselective bromodomain and extraterminal (BET) protein inhibitors, JQ1 and RVX208. We observed that ZL0420 and ZL0454 more potently reduced polyinosinic:polycytidylic acid-induced weight loss and fibrosis as assessed by microcomputed tomography and second harmonic generation microscopy. These measures correlated with the collagen deposition observed in histopathology. Importantly, the ZL inhibitors were more effective than the nonselective BET inhibitors at equivalent doses. The ZL inhibitors had significant effects on lung physiology, reversing TLR3-associated airway hyperresponsiveness and increasing lung compliance in vivo. At the molecular level, ZL inhibitors reduced elaboration of the transforming growth factor-ß-induced growth program, thereby preventing mucosal mesenchymal transition and disrupting BRD4 HAT activity and complex formation with RelA. We also observed that ZL0454 treatment blocked polyinosinic:polycytidylic acid-associated expansion of the α-SMA1+/COL1A+ myofibroblast population and prevented myofibroblast transition in a coculture system. We conclude that 1) BRD4 is a central effector of the mesenchymal transition that results in paracrine activation of myofibroblasts, mechanistically linking innate inflammation to airway hyperresponsiveness and fibrosis, and 2) highly selective BRD4 inhibitors may be effective in reversing the effects of repetitive airway viral infections on innate inflammation-mediated remodeling.

Noninvasive allergic sinus congestion and resolution assessments using microcomputed tomography imaging.

Sinus congestion resultant of allergic rhinosinusitis is associated with development and worsening of asthma and can result in difficulty breathing, headaches, and missed days of school and work. Quantification of sinus congestion is important in the understanding of allergic rhinosinusitis and the development of new drugs for its treatment. Noninvasive microcomputed tomography (micro-CT) was investigated in a guinea pig model of allergic rhinosinusitis to determine its utility to determine accurately the degree of sinus congestion and resolution with anti-inflammatory drug administration. Three-dimensional sinus air-space volume, two-dimensional sinus width, sinus image air-space area, and sinus image sinus perimeter were measured in guinea pigs administered ragweed pollen (RWP), intranasally (i.n.), followed by administration of fluticasone, i.n. To determine their relative accuracy in assessing sinus congestion, the micro-CT image results were compared with the "gold-standard" method of sinus fluid fill-volume (SFFV) measurements. As measured by SFFV method, RWP increased sinus congestion in a RWP concentration-dependent fashion, approaching near-total sinus blockage with concentrations ≥22 µg of RWP. At this level of congestion, fluticasone (25-100 µg) progressively decreased sinus congestion in a concentration-dependent fashion. The noninvasive micro-CT methods were found to accurately determine the amount of sinus congestion and resolution, with patterns of increases and decreases of congestion that were nearly identical to the SFFV method. We conclude that noninvasive micro-CT measurements of allergic sinus congestion can be useful as an investigative tool in the assessment of congestion intensity and the development of new drug therapies for its treatment. NEW & NOTEWORTHY Allergic rhinosinusitis afflicts significant portions of the world population, resulting in loss of work productivity and decreased quality of life. Thus the development of methodological approaches, which incorporate accurate and reproducible noninvasive assessments of sinus congestion, are desirable. Microcomputed tomography of the guinea pig sinuses offers a noninvasive evaluation tool in an animal model of IgE-dependent allergy similar to that in humans, with potential relevance toward development of therapeutics for human sinus diseases.

National estimates of 30-day readmissions among children hospitalized for asthma in the United States.

OBJECTIVE: Previous single-center studies have reported that up to 40% of children hospitalized for asthma will be readmitted. The study objectives are to investigate the prevalence and timing of 30-day readmissions in children hospitalized with asthma, and to identify factors associated with 30-day readmissions. METHODS: Data (n = 12,842) for children aged 6-18 years hospitalized for asthma were obtained from the 2013 Nationwide Readmission Database (NRD). The primary study outcome was time to readmission within 30 days after discharge attributable to any cause. Several predictors associated with the risk of admission were included: patient (age, sex, median household income, insurance type, county location, and pediatric chronic complex condition), admission (type, day, emergency services utilization, length of stay (LOS), and discharge disposition), and hospital (ownership, bed size, and teaching status). Cox's proportional hazards model was used to identify predictors. RESULTS: Of 12,842 asthma-related index hospitalizations, 2.5% were readmitted within 30-days post-discharge. Time to event models identified significantly higher risk of readmission among asthmatic children aged 12-18 years, those who resided in micropolitan counties, those with >4-days LOS during index hospitalization, those who were hospitalized in an urban hospital, who had unfavorable discharge (hazard ratio 2.53, 95% confidence interval 1.33-4.79), and those who were diagnosed with a pediatric complex chronic condition, respectively, than children in respective referent categories. CONCLUSION: A multi-dimensional approach including effective asthma discharge action plans and follow-up processes, home-based asthma education, and neighborhood/community-level efforts to address disparities should be integrated into the routine clinical care of asthma children.

Diagnosis and Management of Asthma in Adults: A Review.

Importance: Asthma affects about 7.5% of the adult population. Evidence-based diagnosis, monitoring, and treatment can improve functioning and quality of life in adult patients with asthma. Observations: Asthma is a heterogeneous clinical syndrome primarily affecting the lower respiratory tract, characterized by episodic or persistent symptoms of wheezing, dyspnea, and cough. The diagnosis of asthma requires these symptoms and demonstration of reversible airway obstruction using spirometry. Identifying clinically important allergen sensitivities is useful. Inhaled short-acting ß2-agonists provide rapid relief of acute symptoms, but maintenance with daily inhaled corticosteroids is the standard of care for persistent asthma. Combination therapy, including inhaled corticosteroids and long-acting ß2-agonists, is effective in patients for whom inhaled corticosteroids alone are insufficient. The use of inhaled long-acting ß2-agonists alone is not appropriate. Other controller approaches include long-acting muscarinic antagonists (eg, tiotropium), and biological agents directed against proteins involved in the pathogenesis of asthma (eg, omalizumab, mepolizumab, reslizumab). Conclusions and Relevance: Asthma is characterized by variable airway obstruction, airway hyperresponsiveness, and airway inflammation. Management of persistent asthma requires avoidance of aggravating environmental factors, use of short-acting ß2-agonists for rapid relief of symptoms, and daily use of inhaled corticosteroids. Other controller medications, such as long-acting bronchodilators and biologics, may be required in moderate and severe asthma. Patients with severe asthma generally benefit from consultation with an asthma specialist for consideration of additional treatment, including injectable biologic agents.

Advanced Collaborative Emissions Study Auxiliary Findings on 2007-Compliant Diesel Engines: A Comparison With Diesel Exhaust Genotoxicity Effects Prior to 2007.

Since its beginning, more than 117 years ago, the compression-ignition engine, or diesel engine, has grown to become a critically important part of industry and transportation. Public concerns over the health effects from diesel emissions have driven the growth of regulatory development, implementation, and technological advances in emission controls. In 2001, the United States Environmental Protection Agency and California Air Resources Board issued new diesel fuel and emission standards for heavy-duty engines. To meet these stringent standards, manufacturers used new emission after-treatment technology, and modified fuel formulations, to bring about reductions in particulate matter and nitrogen oxides within the exhaust. To illustrate the impact of that technological transition, a brief overview of pre-2007 diesel engine exhaust biomarkers of genotoxicity and health-related concerns is provided, to set the context for the results of our research findings, as part of the Advanced Collaborative Emissions Study (ACES), in which the effects of a 2007-compliant diesel engine were examined. In agreement with ACES findings reported in other tissues, we observed a lack of measurable 2007-compliant diesel treatment-associated DNA damage, in lung tissue (comet assay), blood serum (8-hydroxy-2'-deoxyguanosine [8-OHdG] assay), and hippocampus (lipid peroxidation assay), across diesel exhaust exposure levels. A time-dependent assessment of 8-OHdG and lipid peroxidation also suggested no differences in responses across diesel exhaust exposure levels more than 24 months of exposure. These results indicated that the 2007-compliant diesel engine reduced measurable reactive oxygen species-associated tissue derangements and suggested that the 2007 standards-based mitigation approaches were effective.

1,3-Butadiene-induced mitochondrial dysfunction is correlated with mitochondrial CYP2E1 activity in Collaborative Cross mice.

Cytochrome P450 2E1 (CYP2E1) metabolizes low molecular weight hydrophobic compounds, including 1,3-butadiene, which is converted by CYP2E1 to electrophilic epoxide metabolites that covalently modify cellular proteins and DNA. Previous CYP2E1 studies have mainly focused on the enzyme localized in the endoplasmic reticulum (erCYP2E1); however, active CYP2E1 has also been found in mitochondria (mtCYP2E1) and the distribution of CYP2E1 between organelles can influence an individual's response to exposure. Relatively few studies have focused on the contribution of mtCYP2E1 to activation of chemical toxicants. We hypothesized that CYP2E1 bioactivation of 1,3-butadiene within mitochondria adversely affects mitochondrial respiratory complexes I-IV. A population of Collaborative Cross mice was exposed to air (control) or 200ppm 1,3-butadiene. Subcellular fractions (mitochondria, DNA, and microsomes) were collected from frozen livers and CYP2E1 activity was measured in microsomes and mitochondria. Individual activities of mitochondrial respiratory complexes I-IV were measured using in vitro assays and purified mitochondrial fractions. In air- and 1,3-butadiene-exposed mouse samples, mtDNA copy numbers were assessed by RT-PCR, and mtDNA integrity was assessed through a PCR-based assay. No significant changes in mtDNA copy number or integrity were observed; however, there was a decrease in overall activity of mitochondrial respiratory complexes I, II, and IV after 1,3-butadiene exposure. Additionally, higher mtCYP2E1 (but not erCYP2E1) activity was correlated with decreased mitochondrial respiratory complex activity (in complexes I-IV) in the 1,3-butadiene-exposed (not control) animals. Together, these results represent the first in vivo link between mitochondrial CYP2E1 activity and mitochondrial toxicity.

NF-κB Mediates Mesenchymal Transition, Remodeling, and Pulmonary Fibrosis in Response to Chronic Inflammation by Viral RNA Patterns.

Airway remodeling is resultant of a complex multicellular response associated with a progressive decline of pulmonary function in patients with chronic airway disease. Here, repeated infections with respiratory viruses are linked with airway remodeling through largely unknown mechanisms. Although acute activation of the Toll-like receptor (TLR) 3 pathway by extracellular polyinosinic:polycytidylic acid (poly[I:C]) induces innate signaling through the NF-κB transcription factor in normal human small airway epithelial cells, prolonged (repetitive or tonic) poly(I:C) stimulation produces chronic stress fiber formation, mesenchymal transition, and activation of a fibrotic program. Chronic poly(I:C) stimulation enhanced the expression of core mesenchymal regulators Snail family zinc finger 1, zinc finger E-box binding homeobox, mesenchymal intermediate filaments (vimentin), and extracellular matrix proteins (fibronectin-1), and collagen 1A. This mesenchymal transition was prevented by silencing expression of NF-κB/RelA or administration of a small-molecule inhibitor of the IκB kinase, BMS345541. Acute poly(I:C) exposure in vivo induced profound neutrophilic airway inflammation. When administered repetitively, poly(I:C) resulted in enhanced fibrosis observed by lung micro-computed tomography, second harmonic generation microscopy of optically cleared lung tissue, and by immunohistochemistry. Epithelial flattening, expansion of the epithelial mesenchymal trophic unit, and enhanced Snail family zinc finger 1 and fibronectin 1 expression in airway epithelium were also observed. Repetitive poly(I:C)-induced airway remodeling, fibrosis, and epithelial-mesenchymal transition was inhibited by BMS345541 administration. Based on this novel model of viral inflammation-induced remodeling, we conclude that NF-κB is a major controller of epithelial-mesenchymal transition and pulmonary fibrosis, a finding that has potentially important relevance to airway remodeling produced by repetitive viral infections.

The Potential Role of 8-Oxoguanine DNA Glycosylase-Driven DNA Base Excision Repair in Exercise-Induced Asthma.

Asthma is characterized by reversible airway narrowing, shortness of breath, wheezing, coughing, and other symptoms driven by chronic inflammatory processes, commonly triggered by allergens. In 90% of asthmatics, most of these symptoms can also be triggered by intense physical activities and severely exacerbated by environmental factors. This condition is known as exercise-induced asthma (EIA). Current theories explaining EIA pathogenesis involve osmotic and/or thermal alterations in the airways caused by changes in respiratory airflow during exercise. These changes, along with existing airway inflammatory conditions, are associated with increased cellular levels of reactive oxygen species (ROS) affecting important biomolecules including DNA, although the underlying molecular mechanisms have not been completely elucidated. One of the most abundant oxidative DNA lesions is 8-oxoguanine (8-oxoG), which is repaired by 8-oxoguanine DNA glycosylase 1 (OGG1) during the base excision repair (BER) pathway. Whole-genome expression analyses suggest a cellular response to OGG1-BER, involving genes that may have a role in the pathophysiology of EIA leading to mast cell degranulation, airway hyperresponsiveness, and bronchoconstriction. Accordingly, this review discusses a potential new hypothesis in which OGG1-BER-induced gene expression is associated with EIA symptoms.

The Multidisciplinary Translational Team (MTT) Model for Training and Development of Translational Research Investigators.

Multiinstitutional research collaborations now form the most rapid and productive project execution structures in the health sciences. Effective adoption of a multidisciplinary team research approach is widely accepted as one mechanism enabling rapid translation of new discoveries into interventions in human health. Although the impact of successful team-based approaches facilitating innovation has been well-documented, its utility for training a new generation of scientists has not been thoroughly investigated. We describe the characteristics of how multidisciplinary translational teams (MTTs) promote career development of translational research scholars through competency building, interprofessional integration, and team-based mentoring approaches. Exploratory longitudinal and outcome assessments from our experience show that MTT membership had a positive effect on the development of translational research competencies, as determined by a self-report survey of 32 scholars. We also observed that all trainees produced a large number of collaborative publications that appeared to be associated with their CTSA association and participation with MTTs. We conclude that the MTT model provides a unique training environment for translational and team-based learning activities, for investigators at early stages of career development.

Part 3. Assessment of genotoxicity and oxidative damage in rats after chronic exposure to new-technology diesel exhaust in the ACES bioassay.

In 2001, the U.S. Environmental Protection Agency (EPA*) and the California Air Resources Board (CARB) adopted new standards for diesel fuel and emissions from heavy-duty diesel engines. By 2007, diesel engines were required to meet these new standards for particulate matter (PM), with other standards to follow. Through a combination of advanced compression-ignition engine technology, development of exhaust aftertreatment systems, and reformulated fuels, stringent standards were introduced. Before the 2007 standards were put in place by the EPA, human health effects linked to diesel exhaust (DE) exposure had been associated with diesel-fuel solvent and combustion components. In earlier research, diesel engine exhaust components were, in turn, linked to increased mutagenicity in cultures of Salmonella typhimurium and mammalian cells (Tokiwa and Ohnishi 1986). In addition, DE was shown to increase both the incidence of tumors and the induction of 8-hydroxy-deoxyguanosine (8-OHdG) adducts in rodents (Ichinose et al. 1997) and total DNA adducts in rats (Bond et al. 1990). Furthermore, DE is composed of a complex mixture of polycyclic aromatic hydrocarbons (PAHs) and particulates. One such PAH, 3-nitrobenzanthrone (3-NBA), is also found in urban air. 3-NBA has been observed to induce micronucleus formation in the DNA of human hepatoma cells (Lamy et al. 2004). The current study is part of the Advanced Collaborative Emissions Study (ACES), a multidisciplinary program carried out by the Health Effects Institute and the Coordinating Research Council. Its purpose was to determine whether recent improvements in the engineering of heavy-duty diesel engines reduce the toxicity associated with exposure to DE components. To this end, we evaluated potential genotoxicity and induction of oxidative stress in bioassays of serum and tissues from Wistar Han rats chronically exposed--for up to 24 months--to DE from a 2007-compliant diesel engine (new-technology diesel exhaust, or NTDE). Genotoxicity was measured as DNA strand breaks in lung tissue, using an alkaline-modified comet assay. As a correlate of possible DNA damage evaluated in the comet assay, concentrations of the free DNA adduct 8-OHdG were evaluated in serum by a competitive enzyme-linked immunosorbent assay (ELISA). The 8-OHdG fragment found in the serum is a specific biomarker for the repair of oxidative DNA damage. In addition, an assay for thiobarbituric acid reactive substances (TBARS) was used to assess oxidative stress and damage in the form of lipid peroxidation in the hippocampus region of the brains of the DE-exposed animals. These endpoints were evaluated at 1, 3, 12, and 24 months of exposure to DE or to a control atmosphere (filtered air). At the concentrations of DE evaluated, there were no significant effects of exposure in male or female rats after 1, 3, 12, or 24 months in any measure of DNA damage in the comet assay (%DNA in tail, tail length, tail moment, or olive moment). The comparison of exposure groups versus control and the comparison of groups by sex for 1 and 3 months of exposure showed no significant differences in serum 8-OHdG concentrations (P > 0.05). The concentrations of 8-OHdG in all exposure groups at 3 months were higher than those in exposure groups at any other time point (P < 0.05). Looking at the levels of 8-OHdG in serum in the 12-month and 24-month groups, we saw a significant difference from control in the 12-month group at the mid and high levels (P < 0.05), as well as some other scattered changes. Sex differences were noted in the 12-month high-level group (P < 0.05). However, these differences did not follow an exposure-dependent pattern. All other comparisons were not significant (P > 0.05). Hippocampal concentrations of TBARs, measured as malondialdehyde (MDA), showed some small and scattered changes in groups exposed to different levels of DE and at different time points, but we did not consider these to be exposure-related. We concluded that exposure to DE in these rats did not produce any significant increase in oxidative damage to lipids or damage to DNA in the form of strand breaks.

Mechanisms of Heightened Airway Sensitivity and Responses to Inhaled SO2 in Asthmatics.

Sulfur dioxide (SO2) is a problematic inhalable air pollutant in areas of widespread industrialization, not only in the United States but also in countries undergoing rapid industrialization, such as China, and it can be a potential trigger factor for asthma exacerbations. It is known that asthmatics are sensitive to the effects of SO2; however, the basis of this enhanced sensitivity remains incompletely understood. A PubMed search was performed over the course of 2014, encompassing the following terms: asthma, airway inflammation, sulfur dioxide, IL-10, mouse studies, and human studies. This search indicated that biomarkers of SO2 exposure, SO2 effects on airway epithelial cell function, and animal model data are useful in our understanding of the body's response to SO2, as are SO2-associated amplification of allergic inflammation, and potential promotion of neurogenic inflammation due to chemical irritant properties. While definitive answers are still being sought, these areas comprise important foci of consideration regarding asthmatic responses to inhaled SO2. Furthermore, IL-10 deficiency associated with asthma may be another important factor associated with an inability to resolve inflammation and mitigate oxidative stress resulting from SO2 inhalation, supporting the idea that asthmatics are predisposed to SO2 sensitivity, leading to asthma exacerbations and airway dysfunction.

Whole transcriptome analysis reveals an 8-oxoguanine DNA glycosylase-1-driven DNA repair-dependent gene expression linked to essential biological processes.

Reactive oxygen species inflict oxidative modifications on various biological molecules, including DNA. One of the most abundant DNA base lesions, 8-oxo-7,8-dihydroguanine (8-oxoG) is repaired by 8-oxoguanine DNA glycosylase-1 (OGG1) during DNA base excision repair (OGG1-BER). 8-OxoG accumulation in DNA has been associated with various pathological and aging processes, although its role is unclear. The lack of OGG1-BER in Ogg1(-/-) mice resulted in decreased inflammatory responses and increased susceptibility to infections and metabolic disorders. Therefore, we proposed that OGG1 and/or 8-oxoG base may have a role in immune and homeostatic processes. To test our hypothesis, we challenged mouse lungs with OGG1-BER product 8-oxoG base and changes in gene expression were determined by RNA sequencing and data were analyzed by Gene Ontology and statistical tools. RNA-Seq analysis identified 1592 differentially expressed (≥ 3-fold change) transcripts. The upregulated mRNAs were related to biological processes, including homeostatic, immune-system, macrophage activation, regulation of liquid-surface tension, and response to stimulus. These processes were mediated by chemokines, cytokines, gonadotropin-releasing hormone receptor, integrin, and interleukin signaling pathways. Taken together, these findings point to a new paradigm showing that OGG1-BER plays a role in various biological processes that may benefit the host, but when in excess could be implicated in disease and/or aging processes.

Inhaled environmental allergens and toxicants as determinants of the asthma phenotype.

The driving environmental factors behind the development of the asthma phenotype remain incompletely studied and understood. Here, we present an overview of inhaled allergic/atopic and mainly nonallergic/nonatopic or toxicant shapers of the asthma phenotype, which are present in both the indoor and outdoor environment around us. The inhaled allergic/atopic factors include fungus, mold, animal dander, cockroach, dust mites, and pollen; these allergic triggers and shapers of the asthma phenotype are considered in the context of their ability to drive the immunologic IgE response and potentially induce interactions between the innate and adaptive immune responses, with special emphasis on the NADPH-dependent reactive oxygen-species-associated mechanism of pollen-associated allergy induction. The inhaled nonallergic/nonatopic, toxicant factors include gaseous and volatile agents, such as sulfur dioxide, ozone, acrolein, and butadiene, as well as particulate agents, such as rubber tire breakdown particles, and diesel exhaust particles. These toxicants are reviewed in terms of their relevant chemical characteristics and hazard potential, ability to induce airway dysfunction, and potential for driving the asthma phenotype. Special emphasis is placed on their interactive nature with other triggers and drivers, with regard to driving the asthma phenotype. Overall, both allergic and nonallergic environmental factors can interact to acutely exacerbate the asthma phenotype; some may also promote its development over prolonged periods of untreated exposure, or possibly indirectly through effects on the genome. Further therapeutic considerations should be given to these environmental factors when determining the best course of personalized medicine for individuals with asthma.