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Characterization of a Guinea Pig Model of Toluene Diisocyanate Induced-Occupational Asthma

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Beatti, J. Gregory (1996). Characterization of a Guinea Pig Model of Toluene Diisocyanate Induced-Occupational Asthma Mémoire. Québec, Université du Québec, Institut national de la recherche scientifique, Maîtrise en science expérimentale de la santé, 150 p.

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Résumé

The lungs are the most heavily utilized organs in the body. In a lifetime, the average persan will breath over 300 x 106 L of air, a volume 5000 times greater than the volumetrie intake of food or water (Phalen and Prassard, 1989). In addition to being responsible for the uptake of oxygen to maintain metabolism and the elimination of carbon dioxide produced by cellular metabolic processes, the lungs must defend against countless airborne aggressors including pollutants, allergens, viruses, bacteria and microbes. As a result of the vital role of the lung, pulmonary diseases have an enormous social and economie impact. Ofthese diseases, asthma is certainly the most important. Asthma has been estimated to affect 10-15% of the population of industrialized countries (Sears, 1990) and is known to be the only "preventable" disease for which morbidity and mortality are rising (Page, 1993). A common cause of asthma in industrialized countries is occupational exposure to certain chemicals, ofwhich toluene diisocyanate (TDI) is considered one of the most important. The study ofTDI-induced asthma in guinea pigs represents a very useful model for the investigation of the pathogenesis ofTDI-induced occupational asthma and of asthma in general.

The objective of this research was to characterize the effects of TDI vapor exposure in the guinea pig lung, under the conditions established in our laboratory, through the correlation of inflammatory changes in the respiratory tract, branchial hyperreactivity to agonist challenge, and histopathological and morphometric effects in the bronchiolar epithelium.

In this research guinea pigs were sacrificed for pharmacological, cytological, morphological and morphometric evaluations one, seven and 21 days following 5 days of 4 hour per day inhalation exposure to 3 ppm toluene diisocyanate (TDI).

Bronchoalveolar lavage (BAL) provided evidence of a marked infiltration of leukocytes into the airways following 5 days of exposure to TDI. When compared with concurrent contrais, a greater than four fold increase in total number of cells recovered in bronchoalveolar lavage fluid (BALF) was observed one day after the completion of TDI exposure. Seven days post-exposure the total number of cells recruited into BALF bad decreased to approximately twice the concurrent control values while 21 days after exposure completion approximately equivalent numbers of cells were retrieved in BALF. In addition to marked infiltration of total numbers of leukocytes, BALF results provided evidence of changes in the proportional representation of cell populations recovered from the airways of air and TDI-exposed guinea pigs. Differentiai cell counts were performed to determine the relative numbers of macrophages, eosinophils and neutrophils. When compared with corresponding controls, these counts indicated two, 20 and 50 fold increases in the numbers of macrophages, eosinophils and neutrophils, respectively, one day after exposure completion.

Challenge of standardized, isolated bronchial strips with non-specifie agonists (histamine and acetylcholine) provided marked evidence of branchial hyperreactivity. Responses were most pronounced the day after exposure completion. When expressed in terms of the area under the doseresponse curves constructed from the summed right and left bronchial responses, the responses l day after exposure were approximately 3 to 4 times that observed 7 and 21 days post-exposure. Responses observed 7 and 21 days post-exposure were similar and were approximately two to three times the concurrent control values.

Qualitative microscopie evaluation of all sections obtained from guinea pigs sacrificed 1, 7 and 21 days after exposure completion were performed. When compared with air controls, histopathological changes observed 1 day following exposure completion clearly indicated epithelial damage characterized by epithelial sloughing, replacement of the normal pseudostratified, ciliated columnar epithelium by stratified cuboidal epitheliod cells lacking cilia, clear submucosal inflammation and edema. Seven days after exposure completion, the beginnings of repair were evident and were most obvious by the Jack of epithelial sloughing. While submucosal inflammation was still observed, it was present to a lesser extent than was observed the day following exposure completion. Similarly, the epithelium bad not yet returned to the normal pseudostratified, ciliated columnar appearance. Slides prepared from animais sacrificed 21 days after exposure completion indicated obvious epithelial regeneration and a relatively normal histopathological appearance.

Histomorphometric evaluations of one representative control and one TDI-exposed guinea pig sacrificed 1, 7 and 21 days after exposure completion were used to provide a semi-quantitative evaluation of the ratio of the volume of infiltrating ce lis to the submucosal surface area. The data indicated that 1 day after exposure completion the volume of the submucosa represented by infiltrating cells was approximately 3 times that the control value, while 7 and 21 days later this had decreased to approximately twice and approximately 1.5 times the control value, respectively.

The characterization of the response of the guinea pig Jung to TDI vapors described in this research provides an excellent correlation between inflammatory changes in the respiratory tract, branchial hyperreactivity to agonist challenge, and histopathological and morphometric changes in the bronchiolar epithelium. This research provides a solid foundation on which to continue investigations into the causes ofTDI-induced asthma. This mode! may be used in the future to study the mechanisms of TDI-induced asthma through pharmacological intervention with the goal of abrogating or inhibiting one or more responses observed in these studies.

Type de document: Thèse Mémoire
Directeur de mémoire/thèse: Côté, M.G.
Co-directeurs de mémoire/thèse: Sirois, P.
Mots-clés libres: -
Centre: Centre INRS-Institut Armand Frappier
Date de dépôt: 20 févr. 2019 16:16
Dernière modification: 20 févr. 2019 16:16
URI: http://espace.inrs.ca/id/eprint/7545

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