This proposal is part of a continued effort to examine the role of inflammatory cells and mediators in the airway injury produced by inhalation of environmental and occupational agents. The proposed experiments will focus on the mechanisms by which inhaled endotoxin causes airway dysfunction and on the role of inhaled endotoxin in the airway disease produced by exposure to organic dusts. The first series of studies will examine the role of endogenous mediators in the airway injury produced by inhaled endotoxin. Animals will be challenged with inhaled or intravenous tumor necrosis factor (TNF) and interleukin-1, two cytokines known to be released in response to endotoxin, to determine whether they mimic the airway obstruction and edema observed in guinea pigs exposed to inhaled endotoxin. Additional experiments will examine whether passive immunization with purified antibodies to these cytokines inhibits the airway effects of inhaled endotoxin. In similar experiments, I will examine whether platelet activating factor (PAF) and tachykinis, endogenous mediators known to participate in other models of airway obstruction and edema, are involved in the airway effects of inhaled endotoxin. Polymorphonuclear leukocytes have been shown to play a role in other models of airway obstruction. Since both of these blood elements are activated by endotoxin, their role in the effects of inhaled endotoxin will also be examined. Although several studies have demonstrated that inhaled endotoxin can mimic some of the airway effects of inhaled organic dusts and that significant quantities are present in the respirable fraction of these dusts, there is considerable debate whether endotoxin, and not some other bioactive agent also present, is the etiologic agent. To examine this issue, the proposed studies will focus on the role of endotoxin in the acute airway injury observed in guinea pigs after cotton dust inhalation. To directly examine the role of endotoxin, this proposal will fist study the effects of treatment with specific antibodies or antagonists to endotoxin in animals exposed to inhaled endotoxin. These studies will establish that the antagonists and immunization procedures reported to be effective in models of septic shock and inflammation prevent the effects of inhaled endotoxin. The next series of experiments will determine whether these anti-endotoxin treatments inhibit the airway effects of inhaled cotton dust. Additional experiments will be performed to determine if the same mediators are involved in the responses to both cotton dust and endotoxin. These studies should establish which, if any, of the airway effects of cotton dust are caused by endotoxin. The final group of studies will examine in vitro the role of inflammatory mediators and cytokines in the airway effects of inhaled endotoxin and organic dusts. Thee experiments will examine whether TNF, interleukin-1, are PAF are released by airway explants cultured in the presence of absence of endotoxin. In summary, the proposed experiments will help to provide a clearer understanding of the role of endotoxin in the airway diseases produced by inhaled organic dusts.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
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Respiratory and Applied Physiology Study Section (RAP)
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New York University
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New York
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Hur, T; Squibb, K; Cosma, G et al. (1999) Induction of metallothionein and heme oxygenase in rats after inhalation of endotoxin. J Toxicol Environ Health A 56:183-203
Su, W Y; Gordon, T (1997) In vivo exposure to ozone produces an increase in a 72-kDa heat shock protein in guinea pigs. J Appl Physiol 83:707-11
Su, W Y; Gordon, T (1996) Alterations in surfactant protein A after acute exposure to ozone. J Appl Physiol 80:1560-7
Gordon, T; Nadziejko, C; Plant, M et al. (1996) One-month exposure to inhaled endotoxin produces a dose-dependent increase in stored mucosubstances in rat intrapulmonary airways. Exp Lung Res 22:509-23
Gordon, T; Harkema, J R (1995) Mucous cell metaplasia in the airways of rats exposed to machining fluids. Fundam Appl Toxicol 28:274-82
Gordon, T; Harkema, J R (1995) Cotton dust produces an increase in intraepithelial mucosubstances in rat airways. Am J Respir Crit Care Med 151:1981-8
Gordon, T; Harkema, J R (1994) Effect of inhaled endotoxin on intraepithelial mucosubstances in F344 rat nasal and tracheobronchial airways. Am J Respir Cell Mol Biol 10:177-83
Gordon, T; Weideman, P A; Gunnison, A F (1993) Increased pulmonary response to inhaled endotoxin in lactating rats. Am Rev Respir Dis 147:1100-4
Qu, Q S; Chen, L C; Gordon, T et al. (1993) Alteration of pulmonary macrophage intracellular pH regulation by sulfuric acid aerosol exposures. Toxicol Appl Pharmacol 121:138-43
Gordon, T (1992) Dose-dependent pulmonary effects of inhaled endotoxin in guinea pigs. Environ Res 59:416-26

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