Cristina E. Mapp

Time course of the increase in airway responsiveness associated with late asthmatic reactions to toluene diisocyanate in sensitized subjects.

To understand better the mechanism of the increase in airway responsiveness associated with late asthmatic reactions, we determined the time course of toluene diisocyanate (TDI) effect on airway responsiveness in six sensitized subjects who exhibited a late asthmatic response after TDI exposure (0.018 +/- 0.005 ppm, 30 min) in the laboratory. Airway responsiveness was assessed before TDI exposure and then at 8 hr, 1 day, 1 wk, and 1 mo after TDI exposure. To assess responsiveness we determined the provocative dose of methacholine causing a decrease in FEV1 of 20% (PD20FEV1). The methacholine PD20 decreased from 0.50 mg geometric standard error of the mean (GSEM = 1.54) to 0.06 mg (GSEM = 1.55) (p less than 0.001) at 8 hr after exposure to TDI, was still decreased to 0.15 mg (GSEM = 1.93) (p less than 0.05) at 1 day, returned to 0.26 mg (GSEM = 1.91) (p greater than 0.05) at 1 wk, and returned to 0.43 mg (GSEM = 1.71) at 1 mo, indicating that full recovery occurred within 1 to 4 wk. These results demonstrate that TDI-induced late asthmatic response is associated with a reversible increase in airway responsiveness to methacholine and suggest that the TDI effect is linked to an acute inflammatory response in the airways.

Agents, old and new, causing occupational asthma.

Asthma is common among adults of working age and affects 5–10% of the population worldwide. Occupational asthma has become a common work related respiratory disorder in the industrialised world.1 Blanc and Toren have shown that 9% of cases of adult asthma—including principally new onset asthma and, much more rarely, reactivation of pre-existing asthma—are attributable to occupational factors.2 Studies that have used information collected during military service suggest that occupational factors explain 25% of apparently new cases.3 From a practical point of view, addressing past and present occupational factors should be a priority in the assessment of adult onset asthma. In most cases, occupational exposures induce new onset asthma in a healthy subject, or workplace exposures may reactivate asthma in individuals who have been asymptomatic for years, or may aggravate pre-existing asthma. In each case, identifying which of these possibilities is true (that is, work related exposures as asthma inducers or asthma triggers) is relevant for the management of the disease, including prevention of additional cases, treatment, disability evaluation, and compensation.nnTo date, more than 250 agents capable of causing occupational asthma have been reported.4 5Substances that induce occupational asthma are classified as either high molecular weight allergens (>u20095u2009kDa)—usually protein derived allergens—or as low molecular weight compounds. It has been hypothesised that low molecular weight chemicals could act as haptens and combine with a body protein to form a complete antigen.nnSince 1989, the SWORD (surveillance of work related and occupational respiratory disease) project has provided a consistent and reliable estimate of the incidence and pattern of occupational respiratory diseases in the UK.1 Occupational asthma continues to be the most reported respiratory disease, although its incidence is lower than in previous years, with an estimated 822 cases (27% of total cases).1 Reporting from previous …

Increase in numbers of CD8 positive lymphocytes and eosinophils in peripheral blood of subjects with late asthmatic reactions induced by toluene diisocyanate.

Occupational asthma induced by toluene diisocyanate (TDI) shares several features with allergic asthma, but the mechanism of action of TDI is poorly understood. Ten sensitised subjects, previously shown to develop a dual or late asthmatic reaction after inhaling TDI were examined. In each subject, forced expiratory volume in one second (FEV1) was measured and venous blood was taken before, and 30 minutes and eight, 24, 48, and 72 hours after exposure to TDI (0.005-0.015 ppm for 10-30 minutes). Filtered air was used as a control. Differential leucocyte counts were determined and phenotypic analysis was performed by immunofluorescence on mononuclear cells using monoclonal antibodies (anti-CD3, anti-CD4, anti-CD8, and anti-HLA-DR). Five subjects developed a dual asthmatic reaction and five had a late reaction. Percentage of CD8 positive lymphocytes increased significantly eight hours after exposure to TDI (from 27 +/- 3 (SEM) % to 42.1 +/- 5%) in the subjects with an isolated late reaction. A delayed significant further increase in suppressor/cytotoxic T lymphocytes was seen in seven of the 10 subjects 48 hours after active exposure (from 27 +/- 2% to 42 +/- 4.8%), irrespective of the type of asthmatic reaction developed after exposure to TDI. Eosinophil percentage increased from 2.5% +/- 1.0 to 6.4% +/- 1.2 24 hours after exposure to TDI and the increase was sustained for up to 48 hours (4.7 +/- 1.1%). No significant variations of FEV1 or cell percentages were seen in the controls. In conclusion, the events triggered by exposure to TDI in sensitised subjects included changes in lung function and systemic effects which lasted longer than bonchoconstriction and concerned suppressor/cytotoxic lymphocytes and eosinophils. These results suggest that TDI induced late asthmatic reactions may be associated with an immunological response to TDI or to its products.

Mechanisms of occupational asthma.

Background The pathogenesis and the pathologic alterations of occupational asthma are similar to those of nonoccupational asthma. Occupational asthma may therefore represent a useful model of human asthma to investigate mechanisms and pathophysiology of asthma in general. In an occupational setting the cause and onset of asthma may be easily identified, and the natural history may be examined in follow-up studies. The mechanisms involved in occupational asthma include genetic predisposition, immunologically mediated responses, as well as nonspecific airway inflammation. In particular, high molecular weight (eg, grain dust, flour) and some low molecular weight sensitizers (eg, acid anhydrides and platinum halide salts) have been shown to induce occupational asthma through an immunoglobulin E (IgE)-dependent mechanism, while cell-dependent immunologic mechanisms are likely to be more relevant for occupational asthma induced by other low molecular weight sensitizers (eg, toluene diisocyanate and plicatic acid contained in western red cedar). The pathology of the airway mucosa of occupational asthma is remarkably similar to the pathology of nonoccupational asthma, ie, characterized by infiltration and accumulation of eosinophils, mast cells, and activated lymphocytes along with subepithelial fibrosis. In this article, the most relevant mechanisms are discussed with particular reference to the similarities and discrepancies between occupational and nonoccupational asthma.

Prednisone inhibits late asthmatic reactions and airway inflammation induced by toluene diisocyanate in sensitized subjects.

To determine the importance of airway inflammation for late asthmatic reactions induced by toluene diisocyanate (TDI), we investigated whether prednisone prevented them [corrected] by modifying the associated airway inflammatory reaction. We measured FEV1 before and at regular intervals after exposure to TDI and performed bronchoalveolar lavage at 8 hours after TDI in two groups of subjects with previously documented late asthmatic reactions, in one group, after no treatment, and in the other group, after treatment with prednisone (50 mg/day for 4 days). After no treatment, each subject developed a late asthmatic reaction, an increase in airway responsiveness, polymorphonuclear leukocytosis, and increased albumin in bronchoalveolar lavage. By contrast, after treatment with prednisone, no subject developed a late asthmatic reaction or an increase in airway responsiveness, and the number of leukocytes and the concentration of albumin were normal in bronchoalveolar lavage. These results suggest that late asthmatic reactions induced by TDI may be caused by airway inflammation and that prednisone may block them [corrected] by inhibiting the inflammatory reaction of the airway induced by TDI in sensitized subjects.

Prostacyclin activates tachykinin release from capsaicin‐sensitive afferents in guinea‐pig bronchi through a ruthenium red‐sensitive pathway

1 We have investigated the ability of prostacyclin (PGI2) to contract guinea‐pig isolated bronchi and the possible involvement of capsaicin‐sensitive primary afferents in the response to PGI2. 2 PGI2 (0.1–100 μm) produced concentration‐dependent contractions of the guinea‐pig isolated bronchi. In vitro capsaicin desensitization (10 μm for 30 min followed by washing) significantly reduced the PGI2‐induced contraction at all concentrations tested. A capsaicin‐resistant component of contraction (40–60% of the overall response) was also evident. 3 Ruthenium red (3 μm), an inorganic dye which acts as a selective functional antagonist of capsaicin, significantly decreased PGI2‐induced contractions, without affecting the response to substance P, neurokinin A or acetylcholine. 4 MEN 10, 207, (Tyr5, d‐Trp6,8,9, Arg10)‐neurokinin A (4–10) (3 μm), a selective antagonist of NK2‐tachykinin receptors, significantly decreased PGI2‐induced contractions and neurokinin A‐induced contractions, without affecting the response to acetylcholine. 5 The effect of ruthenium red and MEN 10,207 on the one hand, and that of ruthenium red and capsaicin on the other was non additive. 6 These results indicate that PGI2‐induced contraction of the guinea‐pig isolated bronchi involves two distinct mechanisms, one of which involves transmitter (tachykinins) release from peripheral endings of capsaicin‐sensitive primary afferents. In as much as PGI2‐activation of primary afferents is sensitive to ruthenium red, we suggest that PGI2 shares a common mechanism of tachykinin release with that activated by capsaicin.

The effects of toluene diisocyanate and of capsaicin on human bronchial smooth muscle in vitro

Toluene diisocyanate contracts guinea-pig bronchial smooth muscle through a mechanism involving capsaicin-sensitive sensory nerves. In the present study, we investigated the effects of toluene diisocyanate, capsaicin and tachykinins on isolated human bronchi. In 44 rings, toluene diisocyanate (0.3 mM) produced a relaxation which averaged 16.9 +/- 1.1%, in ten rings it produced a shortening that was 15.1 +/- 3.3% and in ten preparations it gave no response. A second administration of toluene diisocyanate (0.3 mM) always produced a relaxation (n = 13, 18.1 +/- 3.9%). Capsaicin (0.03 mM) produced shortening in 15 (35 +/- 6.6%) and relaxation in 11 preparations (41 +/- 6.8%), whereas a second administration caused shortening in nine (25.1 +/- 6.1%) and relaxation in 16 rings (36.4 +/- 4.9%). When toluene diisocyanate was given after two consecutive capsaicin administrations, we observed shortening in two rings (10.0 +/- 3.6%), relaxation in ten rings (15.9 +/- 3.6%), and no response in four preparations. To test the role of NK1 and NK2 receptors in these conflicting responses, we performed concentration-response curves to different tachykinins. Substance P, neurokinin A and neurokinin A-(4-10), a specific NK2 receptor agonist, gave a concentration-dependent shortening, with neurokinin A being the most effective and neurokinin A-(4-10) the least. The specific NK1 receptor agonist, [Sar9, Met(O2)11]substance P, produced both shortening and relaxation. We conclude that toluene diisocyanate and capsaicin may produce both shortening and relaxation in isolated human bronchi through NK1 receptors.

Evidence that toluene diisocyanate activates the efferent function of capsaicin-sensitive primary afferents

Isocyanates are an important cause of occupational asthma. The mechanism of isocyanate-induced asthma is still unknown. To determine whether toluene diisocyanate stimulates the efferent function of peripheral endings of capsaicin-sensitive sensory nerves, we investigated the effect of toluene diisocyanate in the rat isolated urinary bladder, a preparation in which the action of capsaicin has been well characterized. Toluene diisocyanate (0.03-3 mM) produced a concentration-dependent contraction of the bladder strips. Its maximal effect was about 50% of the response to capsaicin (1 microM). Previous exposure of the strips to capsaicin followed by washing out produced complete unresponsiveness, both to the first exposure to toluene diisocyanate and to a second exposure of capsaicin. Further, the response to both toluene diisocyanate and capsaicin was completely prevented by extrinsic bladder denervation, achieved by bilateral removal of pelvic ganglia (72 h before). Repeated exposure of the rat bladder to toluene diisocyanate reduced the capsaicin-evoked release of calcitonin gene-related peptide-like immunoreactivity (CGRP-LI), taken as biochemical marker of activation of these sensory nerves. These experiments provide the first evidence that toluene diisocyanate activates directly or indirectly the efferent function of capsaicin-sensitive primary sensory nerves.

Bronchial smooth muscle responses evoked by toluene diisocyanate are inhibited by ruthenium red and by indomethacin

We have investigated the ability of ruthenium red, an inorganic dye with Ca2+ entry-blocking properties and a selective antagonist of capsaicin, and of indomethacin, a cyclooxygenase inhibitor, to inhibit bronchial smooth muscle responses evoked by toluene diisocyanate in guinea pigs. Previous exposure of isolated guinea pig bronchi to ruthenium red significantly decreased the response produced by toluene diisocyanate. Further, the response to toluene diisocyanate was significantly decreased by pretreatment with indomethacin. These findings provide evidence that toluene diisocyanate-induced contractions of guinea pig bronchi are produced indirectly by generation of a prostanoid that activates capsaicin-sensitive afferents via a ruthenium red-sensitive mechanism.

Venous blood platelets decrease during allergen‐induced asthmatic reactions

To determine whether circulating platelets alter during asthmatic reactions induced by allergens, we studied nine subjects previously shown to develop an early or dual asthmatic reaction after inhalation challenge with extracts of house dust mite or grass pollen. In each subject, FEV1, circulating platelets and leucocytes were measured before, 15, 30 and 60 min, and 2, 4, 6 and 8 hr after inhalation of allergen and diluent control administered in a single‐blind, randomized fashion. The same procedure was repeated in six of the nine subjects after bronchoconstriction induced by methacholine. Each subject developed an early asthmatic reaction after allergen inhalation challenge, which was followed by a late asthmatic reaction in six subjects and by an equivocal late asthmatic reaction in two of them (fall in FEV1 of 15 and 17% respectively). Compared with the control day, circulating platelets significantly decreased during the allergen‐induced early asthmatic reaction (P < 0·025, at 30 min). Platelet counts returned to baseline values within 4 hr and remained steady thereafter both in subjects who did and did not develop a late asthmatic reaction. No changes in platelet counts occurred after bronchoconstriction induced by methacholine. Diurnal increase of leucocyte numbers occurred after challenge with both allergen and diluent control. These results suggest that platelets may be involved in the pathogenesis of allergen‐induced asthmatic reactions.