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Medicine Lodge, United States

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. Source


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 Source


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. Source


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. Source


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. Source

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