MECHANISTIC STUDIES OF BYSSINOSIS USING AN ANIMAL MODEL

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Byssinosis is a respiratory disease seen in cotton textile mill workers. Although characterized clinically for more than a century, both the underlying pathogenesis and etiologic agent(s) remain obscure. This research project is designed to assess pathogenic mechanisms of byssinosis using an animal model. Mechanisms to be evaluated are release of pharmacologic mediators and alterations in the beta-adrenergic system after cotton dust exposure. Experimental evidence suggests both of these may play a role in disease pathogenesis; however, the in vivo challenge studies necessary to confirm these findings are currently lacking. The model will also be used to evaluate lipopolysaccharides (LPS), isolated from the gram-negative bacteria which contaminate cotton dust, as the etiologic agent(s) of byssinosis. An animal model which assesses several mechanisms and correlates these with pulmonary function changes is necessary to discriminate between epi-phenomena and disease-related factors. The advantage of this model is that it closely simulates human dust exposure and disease development. Guinea pigs will be exposed to cotton dust by inhalation for 6 hrs a day, 5 days a week, followed by a two day rest. Exposures will be continued until the animals exhibit a decline in pulmonary function, as measured by whole body plethysmography, when exposed to dust following a two day rest. After this decline in lung function has been demonstrated, animals will be challenged with aqueous cotton dust extract (ACDE), LPS, and, as a control, with microcrystalline cellulose extract (MCE), via intratracheal instillation. Subsequent to in vivo challenge, lungs will be excised and cells teased from tissue. Levels of histamine, thromboxane B2, prostaglandin (PG) F2a, PGE2, and leukotrienes released from this tissue into the supernatant will be determined. The effect on the beta-adrenergic system will be evaluated, in lung cells, by quantitating receptor number and assessing their functional ability by evaluating cyclic AMP production after stimulation with isoproterenol. To assess the role of LPS in the etiology of byssinosis, guinea pigs will be exposed to LPS coupled with an inert carrier (microcrystalline cellulose). After exposures, animals will be challenged with ACDE, LPS, or MCE, as above. Resulting data should determine whether exposure to LPS simulates effects of cotton dust exposure and establish the role of LPS in byssinosis pathogenesis.