Center for Environmental Medicine

Anderson, United States

Center for Environmental Medicine

Anderson, United States
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Noah T.L.,Center for Environmental Medicine | Zhou H.,Center for Environmental Medicine | Horvath K.,Center for Environmental Medicine | Horvath K.,University of North Carolina at Chapel Hill | And 2 more authors.
Environmental Health Perspectives | Year: 2011

Background: Epidemiologic evidence links tobacco smoke and increased risk for infuenza in humans, but the specifc host defense pathways involved are unclear. oB je c t iv e: We developed a model to examine influenza-induced innate immune responses in humans and test the hypothesis that exposure to cigarette smoke alters nasal infammatory and antiviral responses to live attenuated infuenza virus (LAIV). Methods: Tis was an observational cohort study comparing nasal mucosal responses to LAIV among young adult active smokers (n = 17), nonsmokers exposed to secondhand smoke (SHS; n = 20), and unexposed controls (n = 23). Virus RNA and infammatory factors were measured in nasal lavage fuids (NLF) serially after LAIV inoculation. For key end points, peak and total (area under curve) responses were compared among groups. re su l t s: Compared with controls, NLF interleukin-6 (IL-6) responses to LAIV (peak and total) were suppressed in smokers. Virus RNA in NLF cells was signifcantly increased in smokers, as were interferon-inducible protein 10:virus ratios. Responses in SHS-exposed subjects were generally intermediate between controls and smokers. We observed signifcant associations between urine cotinine and NLF IL-6 responses (negative correlation) or virus RNA in NLF cells (positive correlation) for all subjects combined. co n c l u sio n s: Nasal inoculation with LAIV results in measurable inflammatory and antiviral responses in human volunteers, thus providing a model for investigating environmental efects on infuenza infections in humans. Exposure to cigarette smoke was associated with suppression of specifc nasal infammatory and antiviral responses, as well as increased virus quantity, after nasal inoculation with LAIV. Tese data suggest mechanisms for increased susceptibility to infuenza infection among persons exposed to tobacco smoke.


PubMed | University of Michigan, University of Nebraska Medical Center, Research Service, University of California at Los Angeles and 8 more.
Type: | Journal: Journal of translational medicine | Year: 2015

Subpopulations and Intermediate Outcomes in COPD Study (SPIROMICS) is a multi-center longitudinal, observational study to identify novel phenotypes and biomarkers of chronic obstructive pulmonary disease (COPD). In a subset of 300 subjects enrolled at six clinical centers, we are performing flow cytometric analyses of leukocytes from induced sputum, bronchoalveolar lavage (BAL) and peripheral blood. To minimize several sources of variability, we use a just-in-time design that permits immediate staining without pre-fixation of samples, followed by centralized analysis on a single instrument.The Immunophenotyping Core prepares 12-color antibody panels, which are shipped to the six Clinical Centers shortly before study visits. Sputum induction occurs at least two weeks before a bronchoscopy visit, at which time peripheral blood and bronchoalveolar lavage are collected. Immunostaining is performed at each clinical site on the day that the samples are collected. Samples are fixed and express shipped to the Immunophenotyping Core for data acquisition on a single modified LSR II flow cytometer. Results are analyzed using FACS Diva and FloJo software and cross-checked by Core scientists who are blinded to subject data.Thus far, a total of 152 sputum samples and 117 samples of blood and BAL have been returned to the Immunophenotyping Core. Initial quality checks indicate useable data from 126 sputum samples (83%), 106 blood samples (91%) and 91 BAL samples (78%). In all three sample types, we are able to identify and characterize the activation state or subset of multiple leukocyte cell populations (including CD4+ and CD8+ T cells, B cells, monocytes, macrophages, neutrophils and eosinophils), thereby demonstrating the validity of the antibody panel.Our study design, which relies on bi-directional communication between clinical centers and the Core according to a pre-specified protocol, appears to reduce several sources of variability often seen in flow cytometric studies involving multiple clinical sites. Because leukocytes contribute to lung pathology in COPD, these analyses will help achieve SPIROMICS aims of identifying subgroups of patients with specific COPD phenotypes. Future analyses will correlate cell-surface markers on a given cell type with smoking history, spirometry, airway measurements, and other parameters.This study was registered with ClinicalTrials.gov as NCT01969344 .


PubMed | Gilead Sciences, Center for Environmental Medicine, Parion science Incorporated and University of North Carolina at Chapel Hill
Type: Journal Article | Journal: Journal of applied physiology (Bethesda, Md. : 1985) | Year: 2015

Inhalation of hypertonic saline (HS) acutely enhances mucociliary clearance (MC) in both health and disease. In patients with cystic fibrosis (CF), repeated use of HS causes a sustained improvement in MC as well as clinical benefit. The pharmacodynamic duration of activity on MC may be an important determinant of its therapeutic potential in other airways diseases. Before moving toward testing the clinical benefits of HS for non-CF indications, we sought to assess the duration of pharmacodynamic effects of HS in healthy subjects by performing radiotracer clearance studies at baseline, 30-min post-HS administration, and 4-h post-HS administration. Indeed, acceleration of MC was observed when measured 30 min after HS inhalation. This acceleration was most pronounced in the first 30 min after inhaling the radiotracer in the central lung region (mean Ave30Clr = 15.5 vs. 8.6% for 30-min post-HS treatment vs. mean baseline, respectively, P < 0.005), suggesting that acute HS effects were greatest in the larger bronchial airways. In contrast, when MC was measured 4 h after HS administration, all indices of central lung region MC were slower than at baseline: Ave30Clr = 5.9% vs. 8.6% (P = 0.10); Ave90Clr = 12.4% vs. 16.8% (P < 0.05); clearance through 3 h = 29.4 vs. 43.7% (P < 0.002); and clearance through 6 h = 39.4 vs. 50.2% (P < 0.02). This apparent slowing of MC in healthy subjects 4-h post-HS administration may reflect depletion of airway mucus following acute HS administration.


Wu W.,Xinxiang Medical University | Wu W.,Center for Environmental Medicine | Wages P.A.,University of North Carolina at Chapel Hill | Devlin R.B.,National Health and Environmental Effects Research Laboratory | And 3 more authors.
Environmental Health Perspectives | Year: 2015

Background: Human exposure to ozone (O3) results in pulmonary function decrements and airway infammation. Te mechanisms underlying these adverse effects remain unclear. Epidermal growth factor receptor (EGFR) plays an important role in the pathogenesis of lung infammation. oBjective: We examined the role of EGFR activation in O3-induced expression of the chemokine interleukin 8 (IL-8) in human bronchial epithelial cells (HBEC). Methods: We detected phosphorylated EGFR using immunoblotting. EGFR dimeriza tion was examined through cross-linking reaction and immunoblotting, and levels of IL-8 protein were measured using ELISA. results: Exposure to O3 (0.25–1.0 ppm) induced rapid and marked increase in EGFR phosphorylation at the autophosphorylation site Y1068 and the transphosphorylation site Y845, implicating the involvement of Src kinase. Further investigation showed that O3 stimulation induced phosphorylation of Src at Y416, indicative of Src activation. Pharmacological inhibition of Src kinase activity abrogated O3-induced EGFR phosphorylation at tyrosines 1068 and 845. Moreover, pretreatment of BEAS-2B cells with inhibitor of either EGFR or Src kinase activities signifcantly blocked O3-induced IL-8 expression. conclusion: O3 exposure increased IL-8 expression through Src-mediated EGFR transactivation in HBEC. © 2015(publisher name). All rights Reserved


Noah T.L.,Campus Box | Noah T.L.,Center for Environmental Medicine | Zhou H.,Center for Environmental Medicine | Zhou H.,University of North Carolina at Chapel Hill | And 2 more authors.
Current Opinion in Allergy and Clinical Immunology | Year: 2012

Purpose of review: The purpose of this review is to highlight recent data regarding the impact of exposure to tobacco smoke on influenza virus infection. This is timely because of the continuing pattern for influenza to cause epidemics and pandemics. Recent findings: Experimental animal studies suggest tobacco smoke increases severity of respiratory disease with influenza. The interaction is complex and dependent on dose and chronicity of both virus and smoke exposure. Smoke-induced oxidant stress and suppression of innate immunity are mechanistic factors leading to worse disease. Experiments using human respiratory cells show that tobacco smoke increases viral replication through mechanisms including suppression of antiviral pathways and altered cytokine patterns in cell types with central roles in mucosal innate immunity, such as epithelium, dendritic cells, and natural killer cells. Studies also suggest a role for antioxidant strategies in reducing risk. Human volunteer studies using live attenuated influenza virus as a model appear to corroborate many of these findings. Summary: Exposure to tobacco smoke remains extremely prevalent worldwide. Although avoidance of exposure is a primary goal, it is important to understand the mechanisms underlying increased infection risk with tobacco smoke and other pollutant exposures, so that novel preventive or treatment strategies can be developed. © 2012 Wolters Kluwer Health.


Auerbach A.,Center for Environmental Medicine | Hernandez M.L.,Center for Environmental Medicine | Hernandez M.L.,University of North Carolina at Chapel Hill
Current Opinion in Allergy and Clinical Immunology | Year: 2012

PURPOSE OF REVIEW: Asthma is an inflammatory respiratory condition with significantly associated morbidity and mortality that is increasing in prevalence. Air pollution is an important factor in both the development of asthma and in asthma exacerbations. Oxidative stress as a result of exposure to air pollution and underlying genetic polymorphisms that may play a role in susceptibility to this oxidative stress are the subject of current investigation. This article reviews the data regarding the effects of air pollution on the innate immune response and potential clinical and treatment implications of how genetic polymorphisms affect this response. RECENT FINDINGS: Recent investigation reveals how pollutant-induced oxidative stress impacts airway inflammatory responses. Work by our study group demonstrates that asthmatic patients have an exaggerated inflammatory response to air pollution-induced oxidative stress. New trials investigating antioxidants as potential therapeutic interventions may target this specific issue. SUMMARY: Air pollution plays a critical role in asthma and may affect certain patients more than others. Further investigation into the genetic polymorphisms that affect inflammatory responses may help target patient populations at greatest risk for air pollution-induced asthma and may provide new therapeutic options for these patient populations. © 2012 Lippincott Williams & Wilkins, Inc.


Geiser M.,Center for Environmental Medicine | Geiser M.,University of Bern | Lay J.C.,Center for Environmental Medicine | Bennett W.D.,Center for Environmental Medicine | And 6 more authors.
Journal of Innate Immunity | Year: 2013

Elevated inflammation and altered immune responses are features found in atopic asthmatic airways. Recent studies indicate γ-tocopherol (GT) supplementation can suppress airway inflammation in allergic asthma. We studied the effects of in vitro GT supplementation on receptor-mediated phagocytosis and expression of cell surface molecules associated with innate and adaptive immunity on sputum-derived macrophages. Cells from nonsmoking healthy (n = 6) and mild house dust mite-sensitive allergic asthmatics (n = 6) were treated ex vivo with GT (300 μM) or saline (control). Phagocytosis of opsonized zymosan A bioparticles (Saccharomyces cerevisiae) and expression of surface molecules associated with innate and adaptive immunity were assessed using flow cytometry. GT caused significantly decreased (p < 0.05) internalization of attached zymosan bioparticles and decreased (p < 0.05) macrophage expression of CD206, CD36 and CD86 in allergic asthmatics but not in controls. Overall, GT caused downregulation of both innate and adaptive immune response elements, and atopic status appears to be an important factor. Copyright © 2013 S. Karger AG, Basel.


Hernandez M.L.,Center for Environmental Medicine | Herbst M.,Center for Environmental Medicine | Lay J.C.,Center for Environmental Medicine | Alexis N.E.,Center for Environmental Medicine | And 6 more authors.
Journal of Allergy and Clinical Immunology | Year: 2012

Background: Atopic asthmatic patients are reported to be more sensitive to the effects of environmental endotoxin (LPS) than healthy volunteers (HVs). It is unknown whether this sensitivity is due to dysregulated inflammatory responses after LPS exposure in atopic asthmatic patients. Objective: We sought to test the hypothesis that atopic asthmatic patients respond differentially to inhaled LPS challenge compared with HVs. Methods: Thirteen allergic asthmatic (AA) patients and 18 nonallergic nonasthmatic subjects (healthy volunteers [HVs]) underwent an inhalation challenge to 20,000 endotoxin units of Clinical Center Reference Endotoxin (LPS). Induced sputum and peripheral blood were obtained at baseline and 6 hours after inhaled LPS challenge. Sputum and blood samples were assayed for changes in inflammatory cell numbers and cytokine and cell-surface marker levels on monocytes and macrophages. Results: The percentage of neutrophils in sputum (%PMN) in induced sputum similarly and significantly increased in both HVs and AA patients after inhaled LPS challenge. However, the absolute numbers of leukocytes and PMNs recruited to the airways were significantly lower in AA patients compared with those seen in HVs with inhaled LPS challenge. Sputum levels of IL-6 and TNF-α were significantly increased in both cohorts, but levels of IL-1β and IL-18 were only significantly increased in the HV group. Cell-surface expression of Toll-like receptors 4 and 2 were significantly enhanced only in the HV group. Conclusions: The airway inflammatory response to inhaled LPS challenge is blunted in AA patients compared with that seen in HVs and accompanied by reductions in airway neutrophilia and inflammasome-dependent cytokine production. These factors might contribute to increased susceptibility to airway microbial infection or colonization in AA patients. (J Allergy Clin Immunol 2012;130:869-76.) © 2012 American Academy of Allergy, Asthma & Immunology.


Doreswamy V.,University of North Carolina at Chapel Hill | Alexis N.E.,University of North Carolina at Chapel Hill | Zhou H.,Center for Environmental Medicine | Peden D.B.,University of North Carolina at Chapel Hill
Inhalation Toxicology | Year: 2011

Rationale: We have employed nasal challenge with lipopolysaccharide (LPS) followed by nasal lavage (NL) to experimentally induce and examine upper airway inflammation in human volunteers. It is unclear however whether adaptation within individuals occurs following repeated nasal challenge. This was a pilot study to determine if repeated nasal LPS challenge yields attenuation of markers of inflammation (primarily neutrophil response) in the NL fluid of healthy humans. Methods: We employed a 3-day nasal LPS challenge protocol with NL using a "split nose" design. The control and LPS nares received two consecutive day saline (0.9% saline/day) and LPS (2 Âμ g LPS/day) challenges, respectively followed by an LPS (2 Âμ g/day) challenge to each nare on Day 3. NL was performed immediately pre Day 1 challenges and 6-h post nasal LPS challenges on both Days 1 and 3. Markers of inflammation (PMNs/mg, cytokines) were assessed in NL and the inflammatory response to LPS (measured as the difference between pre and post challenge) was evaluated in both nares on Day 3 and compared to Day 1. Results: Significant (p<0.05) blunting of the LPS-induced polymorphonuclear leukocyte (PMN) response was observed in the nare that received repeated LPS challenges as compared to the control nare (67.60±22.39 vs. 157.8±76.04 PMN/mg) and initial LPS challenge on Day 1 (121±32 PMN/mg). Decreased soluble CD14 and significantly decreased interleukin-8 were also found in the repeat LPS-treated nare. In the LPS-treated nare, the blunted PMN response on Day 3 correlated well with the observed PMN response on Day1 (r=0.58, p=0.02). Conclusions: We show attenuation of PMN response to repeated LPS in the nasal airways in healthy humans. Effect of repeat endotoxin exposure prior to allergen delivery on local airway inflammation in both healthy and atopic subjects can be studied. © 2011 Informa Healthcare USA, Inc.


Zeman K.L.,Center for Environmental Medicine | Wu J.,Center for Environmental Medicine | Donaldson S.H.,University of North Carolina at Chapel Hill | Bennett W.D.,Center for Environmental Medicine
Journal of Aerosol Medicine and Pulmonary Drug Delivery | Year: 2013

Background: Quantification of particle deposition in the lung by gamma scintigraphy requires a reference image for location of regions of interest (ROIs) and normalization to lung thickness. In various laboratories, the reference image is made by a transmission scan (57Co or 99mTc) or gas ventilation scan (133Xe or 81Kr). There has not been a direct comparison of measures from the two methods. Methods: We compared 99mTc transmission scans to 133Xe equilibrium ventilation scans as reference images for 38 healthy subjects and 14 cystic fibrosis (CF) patients for their effects on measures of regional particle deposition: the central-to-peripheral ratio of lung counts (C/P); and ROI area versus forced vital capacity. Whole right lung ROI was based on either an isocontour threshold of three times the soft tissue transmission (TT) or a threshold of 20% of peak xenon ventilation counts (XV). We used a central ROI drawn to 50% of height and of width of the whole right lung ROI and placed along the left lung margin and centered vertically. Results: In general, the correlation of normalized C/P (nC/P) between the two methods was strong. However, the value of nC/P was significantly smaller for the XV method than the TT method. Regression equations for the relationship of nC/P between the two methods were, for healthy subjects, y=0.75x + 0.61, R2=0.64 using rectangular ROIs and y=0.76x + 0.45, R2=0.66 using isocontour ROIs; and for CF patients, y=0.94x + 0.46, R2=0.43 and y=0.85x + 0.42, R2=0.41, respectively. Conclusions: (1) A transmission scan with an isocontour outline in combination with a rectangular central region to define the lung borders may be more useful than a ventilation scan. (2) Close correlation of nC/Ps measured by transmission or gas ventilation should allow confident comparison of values determined by the two methods. © Copyright 2013, Mary Ann Liebert, Inc. 2013.

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