3. Bronchial Hyperreactivity: Mechanisms and Physiologic Evaluation Airway Inflammation during Late Asthmatic Reactions Induced by Toluene Dllsocyanate':? LEONARDO M. FABBRI, PIERO MAESTRELLI, MARINA SAETTA, and CRISTINA E. MAPP Introduction Sensitized subjects may develop symptoms of asthma after exposure to isocyanates in their place of work (1, 2). After challenges with isocyanates in the laboratory, sensitized subjects may develop immediate, late, and dual asthmatic reactions (3). Dual and late asthmatic reactions are more frequent than early asthmatic reactions after challenge with isoeyanates (4), and like allergen-induced dual and late asthmatic reactions, they probably have more relevance to the natural history of asthma than the immediate asthmatic reactions do. In fact, late asthmatic reactions are usually more severe, last longer, respond to steroids but not to bronchodilators, are more resistant to therapy, and subjects sensitized to toluene diisocyanate (TDI) who develop a dual or late asthmatic reaction continue to have asthma upon cessation of exposure (5). The mechanism ofthe late asthmatic reaction is unknown. We speculated that toluene diisocyanate (TDI) might induce late asthmatic reactions and increasebronchial responsiveness by causing an acute inflammatory reaction in the airways. Bronchial Responsiveness and Late Asthmatic Reactions To test this hypothesis, we first investigated the relationship between late asthmatic reaction and increased bronchial responsiveness induced by TD!. To determine whether the increase in bronchial responsiveness was specifically linked to the late asthmatic reaction induced by isocyanates, or if it was caused by a nonspecific effect of isocyanates, westudied four groups of subjects with different types of response to the exposure to TDI (immediate, late, dual, and no responses) and a group of asthmatic subjects with hyperreactive airways but not exposed occupationally to isocyanates (6). TDI caused no effect on airway caliber and bronchial responsiveness in subjects with hyperreactive airways but not sensitized to TDI, suggesting that the effect of isocyanates on the airways is specific. By contrast, bronchial responsiveness increased in sensitized subjects who developed a late or dual asthmatic reaction, suggesting that the same mechanism might be responsible for both late asthmatic reactions and increased bronchial responsiveness. Such a mechanism was not involved in early asthmatic reactions (6). Then weexamined the time-course of the increase in bronchial responsiveness associated with late asthmatic reactions to TDI (7). We found that the increase in bronchial
SUMMARY To determine the importance of airway inflammation for the development of late asthmatic reactions, we examined sensitized subjects during late asthmatic reactions induced by exposure to toluene diisocyanate (TOI) in the laboratory. Late asthmatic reactions are associated with a transient increase of bronchial responsiveness and, at the same time, with an increase of neutrophils followed by eosinophils, and of LTB4 and albumin in bronchoalveolar lavage fluid. Late asthmatic reactions, increased bronchial responsiveness, and increase of neutrophils, eosinophils, LTB4 , and albumin concentration In bronchoalveolar lavage induced by exposure to TOI are all prevented by pretreatment with prednisone but not with the nonsteroidal anti-inflammatory agent indomethacin. Aerosolized steroids (beclomethasone and desamethasone isonicotinate) completely inhibit late asthmatic reactions induced by TOI, whereas theophylline has a partial, and verapamil, ketotifen, and cromolyn have no protective effect. These results suggest that late asthmatic reactions induced by TOI may be caused by airway inflammation, and that anti-inflammatory steroids should be recomAM REV RE5PIR DI5 1991; 143:537-538 mended in the prophylaxis of TOI asthma.
responsivenesswas still present 24 h after TDI, and then reversed by 1 to 4 wk, i.e., with a time-course similar to the time-course of the increase in bronchial responsiveness induced by other inflammatory stimuli (7). These results suggested to us that the TDI effect may be linked to an acute inflammatory response in the airways.
that steroids inhibit the late reaction and the increase in responsiveness, and, at the same time, prevent the migration of neutrophils and eosinophils and the extravasation of albumin in bronchoalveolar lavage fluid, suggesting that the effect of steroids on the asthmatic reaction is associated with their anti-inflammatory properties (13).
Bronchoalveolar Lavage during Late Asthmatic Reactions Induced by TOI We then investigated whether TDI-induced late asthmatic reactions were associated with airway inflammation and which inflammatory cells were involved. To do that, we obtained bronchoalveolar lavage from sensitized and control subjects after exposure to TDI, and we observed that (1) late, but not early, asthmatic reactions induced by TDI are associated with a marked influx of neutrophils followed by a slight influx of eosinophils in the airways, (2) bronchial responsiveness to methacholine increases after neutrophil migration into the air spaces, and (3) the inflammatory effect as wellas the bronchoconstrictor effect is specific for sensitized subjects but is absent in control subjects. Interestingly, the concentration of albumin also is increased at the time when leukocytes are increased, suggesting that microvascular leakage and edema formation occur (8). Several studies have established a link between airway inflammation and bronchial hyperresponsiveness, but the role of polymorphonuclear leukocyte infiltration during bronchial hyperresponsiveness is still debated (9-12). To answer this question, we studied whether treatment with steroids could inhibit not only thelate reactions and the associated increase in responsivenessbut also the inflammatory reaction in the airways. We observed
Pathology of TOI Asthma The pathology of occupational asthma has not been described in detail. We recently reported the case of a car painter who died at work after exposure to isocyanates (14). In general, the pathologic features we observed are no different from those of status asthmaticus seen in nonoccupational asthma (15). Lungs wereoverinflated, airwayswereplugged with mucus containing abundant exudate, airwayepithelium was extensivelydesquamated, and the mucosa and the lamina propria were edematous and markedly infiltrated with eosinophils. This single observation suggested to us that airway inflammation is an important feature also in fatal asthma of occupational origin. Characteristically, the basement membrane was thickened, and the smooth muscle was hypertrophic and disarrayed. In1 From the Interuniversity Center on "Cellular and Molecular Mechanisms of Lung Injury," Universities of Brescia, Ferrara, Genova, Milano, Padova, and Parma, Italy. 2 Supported in part by Grants Nos. 87.00215.04, 87.00266.56, and 87.01476.04 from the Italian National Research Council, by a grant from the European Community for Coal and Steel, and by a Special Grant from Regione Veneto. 3 Presented at the International Symposium on Airway Hyperreactivity, Sendai, October 26-28, 1988.
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terestingly, lung parenchyma was also involved, with focal areas of atelectasis and of alveolar wall destruction, lesions also present in the early stages of emphysema in smokers (16, 17). Effect of Antiasthma Drugs on Late Asthmatic Reactions Induced by TOI We studied the effect of several antiasthma drugs, and we observed that both oral (13, 18) and topical steroids (19-21) prevent both TDI-induced late asthmatic reactions and the associated increase in bronchial responsiveness, further supporting the hypothesis that an acute inflammatory process in the airways may be involved in the late, asthmatic reaction and in the increased bronchial responsiveness. Slow-release theophylline partially inhibits both the early and the late asthmatic reactions but not the increase in bronchial responsiveness, whereas atropine (22), cromolyn (19), verapamil (19), and ketotifen (23), have no protective effect. At variance with the results obtained with steroids, the nonsteroidal anti-inflammatory agent indomethacin does not inhibit the late reaction and the associated increase in bronchial responsiveness (24). Because steroids prevent inflammation by inhibiting the release of arachidonic acid from membrane phospholipids, and thus preventing the generation of both cyclooxygenase and lipooxygenase metabolites of arachidonic acid (25), whereas indomethacin inhibits the generation of prostaglandins via inhibition of cyclooxygenase (26), isocyanates may cause the development of an acute inflammatory reaction in the airwaysin which lipooxygenase, but not cyclooxygenase, metabolites of arachidonic acid may be involved. Interestingly the concentration of LTB4 in bronchoalveolar fluid is increased during late asthmatic reactions induced by TDI (27), and such increase is prevented by steroids, suggesting that LTB4 might be one of the chemotactic factors attracting leukocytes and/or one of the mediators released by leukocytescontributing to the development of the late asthmatic reactions. Although late asthmatic reactions, increase in bronchial responsiveness, and airway inflammation are all inhibited by steroids, the bronchial hyperresponsiveness already present in most of the subjects before exposure to TDI is not associated with leukocytosis in bronchoalveolar lavage and is not modified by steroids (19-21). Thus, we speculated that this long-lasting component of bronchial hyperresponsiveness is probably caused by mechanisms different from airway inflammation. Interestingly, in some subjects with late asthmatic reactions, bronchial responsiveness
FABBRI, MAESTRELLI, SAETTA, AND MAPP
becomes normal away from exposure to TDI, and increases only after exposure to TDI at the time when the airways are inflamed (28). In these subjects bronchial hyperresponsiveness may be caused entirely by airway inflammation. In conclusion all these studies taken together support the hypothesis that the late asthmatic reaction induced by TDI is dependent on airway inflammation and that polymorphonuclear leukocytes are required for hyperresponsiveness to occur. Although one of the inflammatory mediators (i.e., LTB4 ) has been measured during late asthmatic reactions induced by TDI, the mechanisms of accumulation of neutrophils and eosinophils in the air spaces and their precise role in the pathophysiology of late reaction remain to be established. References 1. Fabbri LM, Salvaggio JE, eds. Occupational asthma. Folia Allergol Immunol Clin 1985;32:1-65. 2. Chan-Yeung M. Occupational asthma update. Chest 1988; 93:407-11. 3. Pepys J, Hutchroft BJ. Bronchial provocation tests in etiologic diagnosis and analysis of asthma. Am Rev Respir Dis 1975; 112:829-59. 4. Mapp CE, Boschetto P, Dal Vecchio L, Maestrelli P, Fabbri LM. Occupational asthma due to isocyanate. Eur Respir J 1988; 1:273-9. 5. O'Byrne PM, Dolovich J, Hargreave FE. Late asthmatic responses. Am Rev Respir Dis 1987; 136:740-51. 6. Mapp CE, Di Giacomo R, Broseghini C, et al. Late, but not early, asthmatic reactions induced by toluene diisocyanate (TDI) are associated with increased airway responsiveness. Eur J Respir Dis 1986; 68:276-84. 7. Mapp CE, Polato R, Maestrelli P, Hendrick DJ, Fabbri LM. Time course of the increase in airway responsiveness associated with late asthmatic reactions to toluene diisocyanate in sensitized subjects. J Allergy Clin Immunol 1985; 75:568-72. 8. Fabbri LM, Boschetto P, Zocca E, et al. Bronchoalveolar neutrophilia during late asthmatic reactions induced by toluene diisocyanate (TDI). Am Rev Respir Dis 1987; 136:36-42. 9. O'Byrne PM, Walters EH, Gold BD, et al. Neutrophil depletion inhibits airway hyperresponsiveness induced by ozone exposure. Am Rev Respir Dis 1984; 130:214-9. 10. Murphy KR, Wilson MC, Irvin CG, et al. The requirement for polymorphonuclear leukocytes in the late asthmatic response and heightened airways reactivity in an animal model. Am Rev Respir Dis 1986; 134:62-8. 11. Kay AB, Wadlaw AJ, Moqbel R, etal.Leukocytes and the asthma process. In Kay AB, ed. Allergy and inflammation. London: Academic Press, 1987; 203-23. 12. Boschetto P, Mapp C, Fabbri LM. Neutrophils and asthma. Eur Respir J 1988; 2(Suppl 6):456s-8s. 13. Boschetto P, Fabbri LM, Zocca E, et al. Pred-
nisone inhibits late asthmatic reactions and airway inflammation induced by toluene diisocyanate in sensitized subjects. J Allergy Clin Immunol 1987; 80:261-7. 14. Fabbri LM, Danieli D, Crescioli S, et al. Fatal asthma in a toluene diisocyanate sensitized subject. Am Rev Respir Dis 1988; 137:1494-8. 15. Hogg JC. The pathology of asthma. In: Weiss SB, Barsan GC, Segal MS, Stein M, eds. Bronchial asthma. Boston: Little, Brown, 1985; 209-17. 16. Saetta M, Shiner RJ, Angus GE, et al. Destructive index: a measurement of lung parenchymal destruction in smokers. Am Rev Respir Dis 1985; 131:764-8. 17. Saetta M, Ghezzo H, Kim WD, et al. Loss of alveolar attachments in smokers. A morphometric correlate of lung function impairment. Am Rev Respir Dis 1985; 132:894-900. 18. Fabbri LM, Chiesura-Corona P, Dal Vecchio L, et al. Prednisone inhibits the late asthmatic reaction and the associated increase in bronchial responsivenessinduced by toluene-diisocyanatein sensitized subjects. Am Rev Respir Dis 1985; 132: 1010-4. 19. Mapp CE, Boschetto P, Dal Vecchio L, et al. Protectiveeffect of antiasthmatic drugs on late asthmatic reaction and increased responsiveness induced by toluene-diisocyanate in sensitized subjects. Am Rev Respir Dis 1987; 136:1403-7. 20. De Marzo N, Fabbri LM, Crescioli S, Plebani M, Testi R, Mapp CEo Dose dependent inhibitory effect of inhaled beclomethasone on late asthmatic reactions and increased airway responsiveness to methacholine induced by toluene diisocyanate in sensitized subjects. Pulmon Pharmacol 1988; 1: 15-20. 21. Tossin L, Leproux GB, De Marzo N, Crescioli S, Mapp CE, Fabbri LM. Dosauxison inhibits late asthmatic reactions induced by toluene diisocyanate in sensitized subjects. Ann Allergy 1989;63:292-6. 22. Paggiaro PL, Bacci E, Talini D, et al. Atropine does not inhibit late asthmatic responses induced by toluene diisocyanate in sensitizedsubjects. Am Rev Respir Dis 1987; 136:1237-41. 23. Tossin L, De Marzo N, Crescioli S, Mapp CE, Fabbri LM. Ketotifen does not inhibit asthmatic reactions induced by toluene diisocyanate in sensitized subjects. Clin Exp Allergy 1989; 18:177-82. 24. Fabbri LM, Di Giacomo R, Dal Vecchio L, et al. Prednisone, indomethacin and airway responsivenessin toluene diisocyanate sensitized subjects. Bull Eur Physiopathol Respir 1985; 21:421-6. 25. Hong S, Levine L. Inhibition of arachidonic acid release from cells as the biochemical action of antiinflammatory steroids. Proc Nat! Acad Sci USA 1976; 73:1730-4. 26. Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nature 1971; 231:232-5. 27. Zocca E, Boschetto P, Mapp CE, et al. Leukotriene B4 and late asthmatic reactions induced by toluene diisocyanate. J Appl Physiol 1990; 68:1576-80. 28. Mapp CE, Dal Vecchio L, Boschetto P, De Marzo N, Fabbri LM. Toluenediisocianate-induced asthma without airway hyperresponsiveness. Eur J Respir Dis 1986; 68:89-95.
SUMMARY To determine the importance of airway inflammation for the development of late asthmatic reactions, we examined sensitized subjects during late asthmatic reactions induced by exposure to toluene diisocyanate (TOI) in the laboratory. Late asthmatic reactions are associated with a transient increase of bronchial responsiveness and, at the same time, with an increase of neutrophils followed by eosinophils, and of LTB4 and albumin in bronchoalveolar lavage fluid. Late asthmatic reactions, increased bronchial responsiveness, and increase of neutrophils, eosinophils, LTB4 , and albumin concentration In bronchoalveolar lavage induced by exposure to TOI are all prevented by pretreatment with prednisone but not with the nonsteroidal anti-inflammatory agent indomethacin. Aerosolized steroids (beclomethasone and desamethasone isonicotinate) completely inhibit late asthmatic reactions induced by TOI, whereas theophylline has a partial, and verapamil, ketotifen, and cromolyn have no protective effect. These results suggest that late asthmatic reactions induced by TOI may be caused by airway inflammation, and that anti-inflammatory steroids should be recomAM REV RE5PIR DI5 1991; 143:537-538 mended in the prophylaxis of TOI asthma.
responsivenesswas still present 24 h after TDI, and then reversed by 1 to 4 wk, i.e., with a time-course similar to the time-course of the increase in bronchial responsiveness induced by other inflammatory stimuli (7). These results suggested to us that the TDI effect may be linked to an acute inflammatory response in the airways.
that steroids inhibit the late reaction and the increase in responsiveness, and, at the same time, prevent the migration of neutrophils and eosinophils and the extravasation of albumin in bronchoalveolar lavage fluid, suggesting that the effect of steroids on the asthmatic reaction is associated with their anti-inflammatory properties (13).
Bronchoalveolar Lavage during Late Asthmatic Reactions Induced by TOI We then investigated whether TDI-induced late asthmatic reactions were associated with airway inflammation and which inflammatory cells were involved. To do that, we obtained bronchoalveolar lavage from sensitized and control subjects after exposure to TDI, and we observed that (1) late, but not early, asthmatic reactions induced by TDI are associated with a marked influx of neutrophils followed by a slight influx of eosinophils in the airways, (2) bronchial responsiveness to methacholine increases after neutrophil migration into the air spaces, and (3) the inflammatory effect as wellas the bronchoconstrictor effect is specific for sensitized subjects but is absent in control subjects. Interestingly, the concentration of albumin also is increased at the time when leukocytes are increased, suggesting that microvascular leakage and edema formation occur (8). Several studies have established a link between airway inflammation and bronchial hyperresponsiveness, but the role of polymorphonuclear leukocyte infiltration during bronchial hyperresponsiveness is still debated (9-12). To answer this question, we studied whether treatment with steroids could inhibit not only thelate reactions and the associated increase in responsivenessbut also the inflammatory reaction in the airways. We observed
Pathology of TOI Asthma The pathology of occupational asthma has not been described in detail. We recently reported the case of a car painter who died at work after exposure to isocyanates (14). In general, the pathologic features we observed are no different from those of status asthmaticus seen in nonoccupational asthma (15). Lungs wereoverinflated, airwayswereplugged with mucus containing abundant exudate, airwayepithelium was extensivelydesquamated, and the mucosa and the lamina propria were edematous and markedly infiltrated with eosinophils. This single observation suggested to us that airway inflammation is an important feature also in fatal asthma of occupational origin. Characteristically, the basement membrane was thickened, and the smooth muscle was hypertrophic and disarrayed. In1 From the Interuniversity Center on "Cellular and Molecular Mechanisms of Lung Injury," Universities of Brescia, Ferrara, Genova, Milano, Padova, and Parma, Italy. 2 Supported in part by Grants Nos. 87.00215.04, 87.00266.56, and 87.01476.04 from the Italian National Research Council, by a grant from the European Community for Coal and Steel, and by a Special Grant from Regione Veneto. 3 Presented at the International Symposium on Airway Hyperreactivity, Sendai, October 26-28, 1988.
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terestingly, lung parenchyma was also involved, with focal areas of atelectasis and of alveolar wall destruction, lesions also present in the early stages of emphysema in smokers (16, 17). Effect of Antiasthma Drugs on Late Asthmatic Reactions Induced by TOI We studied the effect of several antiasthma drugs, and we observed that both oral (13, 18) and topical steroids (19-21) prevent both TDI-induced late asthmatic reactions and the associated increase in bronchial responsiveness, further supporting the hypothesis that an acute inflammatory process in the airways may be involved in the late, asthmatic reaction and in the increased bronchial responsiveness. Slow-release theophylline partially inhibits both the early and the late asthmatic reactions but not the increase in bronchial responsiveness, whereas atropine (22), cromolyn (19), verapamil (19), and ketotifen (23), have no protective effect. At variance with the results obtained with steroids, the nonsteroidal anti-inflammatory agent indomethacin does not inhibit the late reaction and the associated increase in bronchial responsiveness (24). Because steroids prevent inflammation by inhibiting the release of arachidonic acid from membrane phospholipids, and thus preventing the generation of both cyclooxygenase and lipooxygenase metabolites of arachidonic acid (25), whereas indomethacin inhibits the generation of prostaglandins via inhibition of cyclooxygenase (26), isocyanates may cause the development of an acute inflammatory reaction in the airwaysin which lipooxygenase, but not cyclooxygenase, metabolites of arachidonic acid may be involved. Interestingly the concentration of LTB4 in bronchoalveolar fluid is increased during late asthmatic reactions induced by TDI (27), and such increase is prevented by steroids, suggesting that LTB4 might be one of the chemotactic factors attracting leukocytes and/or one of the mediators released by leukocytescontributing to the development of the late asthmatic reactions. Although late asthmatic reactions, increase in bronchial responsiveness, and airway inflammation are all inhibited by steroids, the bronchial hyperresponsiveness already present in most of the subjects before exposure to TDI is not associated with leukocytosis in bronchoalveolar lavage and is not modified by steroids (19-21). Thus, we speculated that this long-lasting component of bronchial hyperresponsiveness is probably caused by mechanisms different from airway inflammation. Interestingly, in some subjects with late asthmatic reactions, bronchial responsiveness
FABBRI, MAESTRELLI, SAETTA, AND MAPP
becomes normal away from exposure to TDI, and increases only after exposure to TDI at the time when the airways are inflamed (28). In these subjects bronchial hyperresponsiveness may be caused entirely by airway inflammation. In conclusion all these studies taken together support the hypothesis that the late asthmatic reaction induced by TDI is dependent on airway inflammation and that polymorphonuclear leukocytes are required for hyperresponsiveness to occur. Although one of the inflammatory mediators (i.e., LTB4 ) has been measured during late asthmatic reactions induced by TDI, the mechanisms of accumulation of neutrophils and eosinophils in the air spaces and their precise role in the pathophysiology of late reaction remain to be established. References 1. Fabbri LM, Salvaggio JE, eds. Occupational asthma. Folia Allergol Immunol Clin 1985;32:1-65. 2. Chan-Yeung M. Occupational asthma update. Chest 1988; 93:407-11. 3. Pepys J, Hutchroft BJ. Bronchial provocation tests in etiologic diagnosis and analysis of asthma. Am Rev Respir Dis 1975; 112:829-59. 4. Mapp CE, Boschetto P, Dal Vecchio L, Maestrelli P, Fabbri LM. Occupational asthma due to isocyanate. Eur Respir J 1988; 1:273-9. 5. O'Byrne PM, Dolovich J, Hargreave FE. Late asthmatic responses. Am Rev Respir Dis 1987; 136:740-51. 6. Mapp CE, Di Giacomo R, Broseghini C, et al. Late, but not early, asthmatic reactions induced by toluene diisocyanate (TDI) are associated with increased airway responsiveness. Eur J Respir Dis 1986; 68:276-84. 7. Mapp CE, Polato R, Maestrelli P, Hendrick DJ, Fabbri LM. Time course of the increase in airway responsiveness associated with late asthmatic reactions to toluene diisocyanate in sensitized subjects. J Allergy Clin Immunol 1985; 75:568-72. 8. Fabbri LM, Boschetto P, Zocca E, et al. Bronchoalveolar neutrophilia during late asthmatic reactions induced by toluene diisocyanate (TDI). Am Rev Respir Dis 1987; 136:36-42. 9. O'Byrne PM, Walters EH, Gold BD, et al. Neutrophil depletion inhibits airway hyperresponsiveness induced by ozone exposure. Am Rev Respir Dis 1984; 130:214-9. 10. Murphy KR, Wilson MC, Irvin CG, et al. The requirement for polymorphonuclear leukocytes in the late asthmatic response and heightened airways reactivity in an animal model. Am Rev Respir Dis 1986; 134:62-8. 11. Kay AB, Wadlaw AJ, Moqbel R, etal.Leukocytes and the asthma process. In Kay AB, ed. Allergy and inflammation. London: Academic Press, 1987; 203-23. 12. Boschetto P, Mapp C, Fabbri LM. Neutrophils and asthma. Eur Respir J 1988; 2(Suppl 6):456s-8s. 13. Boschetto P, Fabbri LM, Zocca E, et al. Pred-
nisone inhibits late asthmatic reactions and airway inflammation induced by toluene diisocyanate in sensitized subjects. J Allergy Clin Immunol 1987; 80:261-7. 14. Fabbri LM, Danieli D, Crescioli S, et al. Fatal asthma in a toluene diisocyanate sensitized subject. Am Rev Respir Dis 1988; 137:1494-8. 15. Hogg JC. The pathology of asthma. In: Weiss SB, Barsan GC, Segal MS, Stein M, eds. Bronchial asthma. Boston: Little, Brown, 1985; 209-17. 16. Saetta M, Shiner RJ, Angus GE, et al. Destructive index: a measurement of lung parenchymal destruction in smokers. Am Rev Respir Dis 1985; 131:764-8. 17. Saetta M, Ghezzo H, Kim WD, et al. Loss of alveolar attachments in smokers. A morphometric correlate of lung function impairment. Am Rev Respir Dis 1985; 132:894-900. 18. Fabbri LM, Chiesura-Corona P, Dal Vecchio L, et al. Prednisone inhibits the late asthmatic reaction and the associated increase in bronchial responsivenessinduced by toluene-diisocyanatein sensitized subjects. Am Rev Respir Dis 1985; 132: 1010-4. 19. Mapp CE, Boschetto P, Dal Vecchio L, et al. Protectiveeffect of antiasthmatic drugs on late asthmatic reaction and increased responsiveness induced by toluene-diisocyanate in sensitized subjects. Am Rev Respir Dis 1987; 136:1403-7. 20. De Marzo N, Fabbri LM, Crescioli S, Plebani M, Testi R, Mapp CEo Dose dependent inhibitory effect of inhaled beclomethasone on late asthmatic reactions and increased airway responsiveness to methacholine induced by toluene diisocyanate in sensitized subjects. Pulmon Pharmacol 1988; 1: 15-20. 21. Tossin L, Leproux GB, De Marzo N, Crescioli S, Mapp CE, Fabbri LM. Dosauxison inhibits late asthmatic reactions induced by toluene diisocyanate in sensitized subjects. Ann Allergy 1989;63:292-6. 22. Paggiaro PL, Bacci E, Talini D, et al. Atropine does not inhibit late asthmatic responses induced by toluene diisocyanate in sensitizedsubjects. Am Rev Respir Dis 1987; 136:1237-41. 23. Tossin L, De Marzo N, Crescioli S, Mapp CE, Fabbri LM. Ketotifen does not inhibit asthmatic reactions induced by toluene diisocyanate in sensitized subjects. Clin Exp Allergy 1989; 18:177-82. 24. Fabbri LM, Di Giacomo R, Dal Vecchio L, et al. Prednisone, indomethacin and airway responsivenessin toluene diisocyanate sensitized subjects. Bull Eur Physiopathol Respir 1985; 21:421-6. 25. Hong S, Levine L. Inhibition of arachidonic acid release from cells as the biochemical action of antiinflammatory steroids. Proc Nat! Acad Sci USA 1976; 73:1730-4. 26. Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nature 1971; 231:232-5. 27. Zocca E, Boschetto P, Mapp CE, et al. Leukotriene B4 and late asthmatic reactions induced by toluene diisocyanate. J Appl Physiol 1990; 68:1576-80. 28. Mapp CE, Dal Vecchio L, Boschetto P, De Marzo N, Fabbri LM. Toluenediisocianate-induced asthma without airway hyperresponsiveness. Eur J Respir Dis 1986; 68:89-95.
