Endotoxin (or lipopolysaccharide [LPS]) is a potent inflammatory stimulant which is fund in ambient air in occupation settings. Asthma in the workplace is an increasingly significant problem. Asthma is characterize by airway inflammation and increased reactivity to both allergic and non- allergic stimuli. LPS is known to induced airway inflammation in normal subjects and to enhance airway reactivity in asthmatics. Additionally, both alveolar macrophages and mononuclear cells from asthmatics secrete higher amounts of cytokines (IL-1 IL-8, GM-CSF) than those from normal. Thus, it is likely that LPS enhanced allergen-induced inflammation and that allergic asthmatics are more sensitive to the effects of LPS. Preliminary data from our group show that exposure to low levels (250 ng/m3) of LPS at risk for 4 hours enhances both immediate responsiveness to inhaled allergen and allergen-induced eosinophils as observed in induced sputum. In the nasal airways of allergic, a single dose of 1,000 ng of LPS enhances PMN influx associated with allergen challenge. This latter finding also correlates well with baseline IL-8 and ECP levels, suggesting that constitutive airway inflammation enhances response to these stimuli.
The aims of this is to compare the effect of LPS (5,000 ng) on airway inflammation and methacholine response and lung function in normals and asthmatics; the effect of LPS (500 NG) on allergen-induced reactivity and inflammatory cell influx following LPS exposure (5,000 ng) in asthmatics, likely as a result of decreasing baseline inflammation. To examine potential cellular mediation of the effect of LPS in asthma, cytokine secretion of mononuclear cells to LPS of subjects responding to LPS (or those in whom LPS enhance response to allergen) will be compared to those who did not respond. Comparison of in vitro monocyte and in vivo airway responses of asthmatics who are responsive and non-responsive will be compared to baseline sputum and nasal lavage fluid IL-8 and ECP to determine if either in vitro monocyte responses or IL-8 and ECP in readily obtained airway fluids may serve as biomarkers LPS responsiveness and might be used as a marker for a LPS-response phenotype in humans for future mechanistic and intervention studies. Finally, practical data on the effect of LPS in asthmatics (at levels found in typical work settings) and the ability of standard anti-inflammatory therapy to protect asthmatic workers unavoidable exposed to LPS will be obtained.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL062624-03
Application #
6343652
Study Section
Safety and Occupational Health Study Section (SOH)
Program Officer
Noel, Patricia
Project Start
1999-01-01
Project End
2001-12-31
Budget Start
2001-01-01
Budget End
2001-12-31
Support Year
3
Fiscal Year
2001
Total Cost
$246,797
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Pediatrics
Type
Schools of Medicine
DUNS #
078861598
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
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Yeatts, Karin; Svendsen, Erik; Creason, John et al. (2007) Coarse particulate matter (PM2.5-10) affects heart rate variability, blood lipids, and circulating eosinophils in adults with asthma. Environ Health Perspect 115:709-14
Yeatts, Karin; Sly, Peter; Shore, Stephanie et al. (2006) A brief targeted review of susceptibility factors, environmental exposures, asthma incidence, and recommendations for future asthma incidence research. Environ Health Perspect 114:634-40
Alexis, Neil E; Lay, John C; Zeman, Kirby L et al. (2006) In vivo particle uptake by airway macrophages in healthy volunteers. Am J Respir Cell Mol Biol 34:305-13
Alexis, Neil E; Peden, David B (2006) Inflammatory response of the airway to inhaled endotoxin correlates with body mass index in atopic patients with asthma but not in normal volunteers. J Allergy Clin Immunol 117:1185-6
Alexis, Neil E; Lay, John C; Zeman, Kirby et al. (2006) Biological material on inhaled coarse fraction particulate matter activates airway phagocytes in vivo in healthy volunteers. J Allergy Clin Immunol 117:1396-403
Elliott, L; Heederik, D; Marshall, S et al. (2005) Incidence of allergy and allergy symptoms among workers exposed to laboratory animals. Occup Environ Med 62:766-71
Kleeberger, Steven R; Peden, David (2005) Gene-environment interactions in asthma and other respiratory diseases. Annu Rev Med 56:383-400
Alexis, Neil E; Lay, John C; Almond, Martha et al. (2005) Acute LPS inhalation in healthy volunteers induces dendritic cell maturation in vivo. J Allergy Clin Immunol 115:345-50

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