Prognosis of occupational asthma induced by isocyanates

Several studies on the prognosis of isocyanate-induced asthma show that a significant proportion of patients continue to experience asthmatic symptoms and nonspecific bronchial hyperresponsiveness after cessation of work, and that further exposure to isocyanates in sensitized subjects leads almost invariably to persistence of respiratory symptoms and of bronchial hyperresponsiveness and the deterioration of airway function. Specific bronchial reactivity to isocyanates may change after cessation of work; however, some subjects continue to be sensitive to TDI several months after cessation of work. The determinants of an unfavourable prognosis for asthma seem to be the same as those for other types of occupational asthma due to low molecular weight compounds (i.e. red cedar asthma): long duration of exposure before the onset of asthma, long duration of symptoms before diagnosis, airway obstruction, and dual airway response after specific challenge tests. Also, single acute exposure to high levels of TDI in the workplace (spills) can result in persistent nonspecific bronchial hyperresponsiveness. Potential mechanisms of persistence of symptoms and of nonspecific bronchial hyperresponsiveness may be chronic inflammation, bronchial smooth muscle alteration, autonomic nervous system disregulation.     

Nonspecific bronchial reactivity in occupational asthma

The provocative concentration (PC₂₀ mg/ml) of methacholine required to produce a fall in the baseline FEV₁ by 20% was determined in 86 patients with occupational asthma due to exposure to western red cedar, California redwood, grain dust, or isocyanates. Fifty-seven patients were assessed at the time of diagnosis when they were symptomatic. Twenty-nine patients were studied after they had been removed from exposure for a period from 2 mo to 4 yr and were asymptomatic. Nine of the 57 patients with symptomatic asthma had repeat methacholine inhalation tests after removal from exposure. The results were compared with 33 normal healthy subjects, 30 patients with nonoccupational asthma, and 17 patients with nonindustrial chronic bronchitis. Patients with symptomatic occupational asthma had marked increase in bronchial reactivity similar to those with nonoccupational asthma. The degree of hyperreactivity decreased after removal from exposure and increased following re-exposure to the offending agents. There was little overlap in the range of PC₂₀ in the asthmatic compared with the nonasthmatic groups. These findings suggest nonspecific bronchial hyperreactivity is likely to be the consequence rather than the predisposing factor in occupational asthma. Methacholine inhalation test is a simple, safe, and useful procedure in the initial assessment of patients suspected to have occupational asthma before institution of time-consuming specific bronchial provocation test.     

Follow-up study of patients with respiratory disease due to toluene diisocyanate (TDI)

The outcome of the respiratory symptoms, pulmonary function tests and bronchial hyperresponsiveness was studied in forty-seven workers with respiratory disease due to toluene diisocyanate (TDI) (twenty-seven asthmatic and twenty non-asthmatic subjects) after about 2 years from the first examination. Eight of twelve asthmatic subjects who left the industry after the first examination complained at the follow-up of dyspnoea and wheezing, but pulmonary function tests were unchanged; bronchial hyperresponsiveness decreased in three, but most were still positive to challenge test with bethanechol at the follow-up. Fifteen subjects who continued their exposure to TDI showed at the follow-up a significant decrease of the spirometric parameters and an increase of the bronchial hyperresponsiveness, and symptoms of chronic bronchitis were more frequent at the second examination. Non-asthmatic subjects, both exposed and non-exposed to TDI at the second examination, showed a significant decrease of the pulmonary function tests but no relevant changes in bronchial hyperresponsiveness. Our data suggest that stopping occupational exposure to TDI frequently did not produce an improvement of the TDI bronchial asthma, and persistence of the occupational exposure causes a more rapid decline in the respiratory function.     

Plicatic acid-specific IgE and nonspecific bronchial hyperresponsiveness in western red-cedar workers

In a cross-sectional survey of 652 workers in a western red-cedar sawmill, we obtained data on symptoms, pulmonary function, immediate skin reactivity to common allergens, nonspecific bronchial responsiveness, total IgE level, and sensitization to plicatic acid conjugated with human serum albumin as measured by RAST. Dust exposure was estimated by personal and area sampling for total dust during a work shift and cumulative exposure by duration of employment. Seven percent of the workers had an elevated RAST, and 20% had nonspecific bronchial hyperresponsiveness. Elevation in RAST was associated with bronchial hyperresponsiveness. Almost half (46%) of the workers with RAST elevation had bronchial hyperresponsiveness compared to 18% in workers with no RAST elevation. The association was unaffected by total IgE level or by limiting the analysis to workers without respiratory symptoms and was most apparent in younger workers. Bronchial hyperresponsiveness was associated with increased prevalence of respiratory symptoms as well as with lower levels of pulmonary function. The likelihood of bronchial hyperresponsiveness increased with increasing age but was unrelated to the dust-exposure concentration. RAST elevation was unrelated to employment duration or dust exposure and was not associated with an increased prevalence of symptoms or lower levels of pulmonary function independent of bronchial hyperresponsiveness. We conclude that plicatic acid-specific IgE and nonspecific bronchial hyperresponsiveness are associated in western red-cedar workers and that this association may reflect a causal connection.     

Significant changes of bronchial responsiveness to methacholine after early asthmatic reaction to toluene diisocyanate (TDI) in a TDI-sensitive asthmatic worker

Current asthma is often diagnostically excluded by the presence of normal bronchial responsiveness. We report on a TDI-induced occupational asthma patient with normal bronchial responsiveness. He had suffered from shortness of breath during and after TDI exposure for several months. His initial methacholine bronchial challenge test showed a negative response. The bronchoprovacation test with TDI showed an isolated immediate bronchoconstriction. The following methacholine bronchial challenge tests revealed that the bronchial hyperresponsiveness developed seven hours after the TDI challenge (methacholine PC20:5.1 mg/ml), progressed up until 24 hours, and returned to normal on the seventh day. This case provides evidence that the response of the airway to TDI may not always be accompanied by bronchial hyperresponsiveness to methacholine. Screening programs utilizing methacholine challenges may not always identify TDI-sensitized asthmatic workers.     

Chemically induced nonspecific bronchial hyperresponsiveness

Conclusion In summary, it is clear that in some instances, inhalant exposure to irritating chemicals can result in nonspecific bronchial hyperresponsiveness. The physiologic mechanisms underlying the induction of nonspecific bronchial hyperresponsiveness in this setting are poorly understood. Although inflammation is the pathologic hallmark of nonspecific bronchial hyperresponsiveness in asthma, it has not been well demonstrated in chemically-induced nonspecific bronchial hyperresponsiveness. This article has highlighted the observation that despite the large number of individuals exposed to respiratory irritants in our society in and away from industrial settings, very few develop obvious nonspecific bronchial hyperresponsiveness. Further study is necessary in this important area.     

Immunologic and nonimmunologic mechanisms in asthma due to western red cedar (Thuja plicata)

Occupational asthma due to western red cedar (Thuja plicata) is the most common form of occupational asthma in British Columbia, occurring in about 5% of the exposed workers. Plicatic acid, uniquely present in western red cedar, was found to be the agent responsible for the asthmatic reactions. Inhalation provocation tests with an extract of western red cedar or plicatic acid induced late asthmatic reactions alone in 44%, dual (immediate and late) reactions in 49%, and immediate reactions alone in 7% of the 185 patients. Of the 75 patients who left the industry and were no longer exposed to the wood, only 50% recovered completely after an average period of 3 yr; the remaining half continued to have recurrent attacks of asthma. Specific IgE antibodies to crude red cedar extract or plicatic acid-human serum albumin conjugate were found in less than 40% of the patients by the RAST, while IgG antibodies were not detected. There was no correlation between the presence and absence of specific IgE antibodies and the type of asthmatic reaction induced during inhalation challenge. IgE antibodies were not found in exposed subjects with no asthmatic reaction on inhalation challenge. There was significant correlation between the degree of nonspecific bronchial hyperreactivity and the degree of bronchial reactivity to plicatic acid during immediate or late asthnatic reactions. The degree of nonspecific bronchial hyperreactivity was increased after late asthmatic reactions induced by plicatic acid. On the other hand, the degree of nonspecific bronchial hyperreactivity was reduced and gradually returned to normal among patients who became asymptomatic after exposure was discontinued. These findings suggest that nonspecific bronchial hyperreactivity plays an important role in the pathogenesis of red cedar asthma. The mechanism of bronchial hyperreactivity induced by red cedar exposure is unknown; an immunologic mechanism may be important. Direct release of histamine from human basophils and mast cells and direct activation of the complement system by plicatic acid are unlikely pathogenetic mechanisms.     

Cellular and protein changes in bronchial lavage fluid after late asthmatic reaction in patients with red cedar asthma

To investigate the sequence of cellular and protein changes after a late asthmatic reaction (LAR), bronchial lavage was carried out in 44 patients with red cedar asthma at different time intervals after bronchial challenge with plicatic acid. The results were compared to five patients with red cedar asthma who became asymptomatic after removal from exposure to red cedar for more than 2 months and 31 healthy subjects without asthma. The LAR was found to be associated with an increase in eosinophils in the lavage fluid, an increase in sloughing of bronchial epithelial cells, and an increase in degenerated cells consisting mainly of degenerated epithelial cells and alveolar macrophages. There was an increase in vascular permeability as reflected by an increase in albumin in the lavage fluid. Although there was a slight but significant increase in neutrophils 48 hours after bronchial challenge, neutrophil infiltration was not a prominent feature earlier. The potential role of loss of epithelial cells to account for an increase in nonspecific bronchial hyperresponsiveness after an LAR was discussed.     

Toluene diisocyanate-induced airway hyperreactivity and pathology in the guinea pig

We assessed the nature and progression of airway mucosal disease and histaminic reactivity in English short-haired guinea pigs at 2, 24, 72, 168, and 504 hours after toluene diisocyanate (TDI) exposure (4 hours of 3 ppm of TDI for 5 consecutive days). To also determine whether TDI-specific, IgE-like antibodies developed in TDI-exposed animals, passive cutaneous anaphylaxis testing was done 28 days after TDI. Bronchial reactivity was determined serially by measuring specific airway conductance as a function of increasing doses of aerosolized histamine in six exposed and three control animals studied intact and unanesthetized. The remaining 10 exposed and 10 control guinea pigs were sacrificed in groups of two at each time point to obtain airway tissue for light microscopic examination. We found that airway hyperreactivity to histamine occurred after TDI in all animals tested. It was maximal 2 hours after the 5-day exposure and remitted by 72 hours. In addition, marked airway obstruction occurred after TDI that persisted for at least 168 hours. There were dramatic signs of airway mucosal damage associated with the bronchial hyperreactivity that included substantial decreases in epithelial cilia, mucin content, and mast cells, as well as squamous metaplasia, numerous mitotic figures, and a prominent polymorphonuclear leukocytic infiltrate. Passive cutaneous anaphylaxis tests in exposed animals were negative. Our results suggest that TDI-induced bronchial hyperreactivity may be related to airway mucosal injury and inflammation.     

Age-dependent relationship between bronchial hyperresponsiveness to methacholine and total serum IgE level in asthmatic children.

BACKGROUND: A relationship between nonspecific bronchial hyperresponsiveness and allergic airway inflammation has been reported in children and in adults with asthma, but the relationship in infants with asthma is still unclear. OBJECTIVE: To evaluate the relationship between bronchial hyperresponsiveness and total serum IgE level throughout childhood. Bronchial reactivity to methacholine from the age of 1 to 16 years was studied by methacholine inhalation challenge using transcutaneous oxygen pressure (tcPO2) monitoring. METHODS: Two hundred one asthmatic children (boys:girls = 132:69; 7.3+/-4.0 years of age, mean +/- SD) were enrolled in this study. The tcPO2 was measured using a tcPO2 monitor. Serial doses of methacholine were doubled until a 10% decrease in tcPO2 from the baseline was reached. The cumulative dose of methacholine at the inflection point of tcPO2 was considered to represent the bronchial reactivity to methacholine. RESULTS: There was no relationship between the cumulative dose of methacholine at the inflection point of tcPO2 and total serum IgE level in the group of children aged 1 to 4 years (P = 0.212), but significant correlations were found in the groups aged 5 to 10 years and 11 to 16 years (P = 0.044 and P = 0.014, respectively). CONCLUSIONS: We conclude that there is an age-dependent relationship between bronchial reactivity to methacholine and the total serum IgE level and that inhaled allergens, which were more common allergens in older children, may have some effects on the degree of bronchial reactivity to methacholine in children with asthma.     

Clinical and immunological evaluation of isocyanate-exposed workers.

Isocyanates are the most significant cause of occupational asthma in our country. To evaluate the prevalence of work-related respiratory symptoms and immunologic sensitization to it, we performed a questionnaire survey, allergy skin test, radioallergosorbent test (RAST) to toluene diisocyanate (TDI)-human serum albumin (HSA) conjugate and methacholine bronchial challenge test on 23 isocyanate-exposed employees and 9 unexposed controls working in a zipper factory. Six employees (26.1%) complained of work-related respiratory symptoms and three symptomatic workers showed significant bronchoconstrictions on TDI-bronchoprovocation test. Three (13%) asymptomatic workers had high specific IgE antibodies to TDI-HSA and none of the TDI-sensitive asthmatic workers had specific IgE antibody. One of the TDI-sensitive asthmatic workers showed a negative result on the initial methacholine bronchial challenge test, but bronchial hyperresponsiveness developed after the TDI challenge. It was suggested that TDI-sensitive asthma was noted in three (13%) of 23 exposed workers and that asymptomatic workers could have high specific IgE antibody. Measurement of the changes in bronchial hyperresponsiveness after the TDI challenge could be helpful to diagnose TDI-sensitive asthma.     

The effect of immunotherapy on nonspecific bronchial hyperresponsiveness in bronchial asthma and allergic rhinitis

Allergen injection therapy may improve nonallergic bronchial hyperresponsiveness, but results at the moment are less than convincing. The present study was conducted to evaluate the effect of immunotherapy on the degree of nonspecific bronchial hyperresponsiveness in patients with allergic bronchial asthma (BA) and/or allergic rhinitis (AR). Methacholine challenge bronchial provocation test, allergic skin test, serum IgE and peripheral blood eosinophil counts were performed before and after 12 months or more of immunotherapy. The improved group, as determined by a shift of at least two doubling concentrations of methacholine, was 75% of AR (n=16), 41.7% of BA (n=24) and 53.8% of BA+ AR (n=13). The geometric mean of the methacholine provocational concentration (PC20) changed from 3.40 to 14.36 mg/ml (P <0.05) in AR, from 0.73 to 1.04 mg/ml in BA (not significant), and from 1.43 to 5.07 mg/ml (P <0.05) in BA+ AR. In conclusion, nonspecific bronchial hyperresponsiveness was improved by immunotherapy in three quarters of the allergic rhinitis cases and in about a half of the allergic bronchial asthma patients, which suggests that immunotherapy might be helpful at preventing the development of bronchial hyperresponsiveness in allergic rhinitis patients, and that it does not improve bronchial hyperresponsiveness in about a half of allergic bronchial asthma patients.     

Nedocromil sodium prevents the release of 15-hydroxyeicosatetraenoic acid from human bronchial epithelial cells exposed to toluene diisocyanate in vitro

The in vivo exposure to an asthmogenic stimulus, toluene diisocyanate (TDI), causes airway epithelial damage associated with inflammation and increased bronchial hyperresponsiveness. The latter mechanisms might partly be mediated by the release of eicosanoids from bronchial epithelial cells. We have previously demonstrated that the in vitro exposure of bronchial epithelial cells to TDI results in the release of immunoreactive 15-hydroxyeicosatetraenoic acid (15-HETE), a product of activation of the 15-lipoxygenase pathway with inflammatory properties. In the present study we show that TDI-induced release of 15-HETE from epithelial cells can be prevented by nedocromil sodium, an anti-asthmatic drug with anti-inflammatory properties. This mode of action of the compound may explain its clinical effectiveness in asthma.     

Sputum eosinophilia: an early marker of bronchial response to occupational agents

Background: False‐negative responses to specific inhalation challenge (SIC) with occupational agents may occur. We explored whether assessing changes in sputum cell counts would help improve the identification of bronchial reactivity to occupational agents during SICs. Methods: The predictive value of the changes in sputum cell counts after a negative FEV₁ response to a first challenge exposure to an occupational agent was determined using the changes in airway calibre observed during repeated challenges as the ‘gold standard’. The study included 68 subjects investigated for work‐related asthma in a tertiary centre. After a control day, the subjects were challenged with the suspected occupational agent(s) for up to 2 h. All subjects who did not show an asthmatic reaction were re‐challenged on the following day. Additional challenges were proposed to those who demonstrated a ≥ 2% increase in sputum eosinophils or an increase in nonspecific bronchial hyperresponsiveness to histamine after the second challenge day. Results: Six of the 35 subjects without changes in FEV₁ on the first challenge developed an asthmatic reaction on subsequent challenges. ROC analysis revealed that a >3% increase in sputum eosinophils at the end of the first challenge day was the most accurate parameter for predicting the development of an asthmatic response on subsequent challenges with a sensitivity of 67% and a specificity of 97%. Conclusions: An increase in sputum eosinophils is an early marker of specific bronchial reactivity to occupational agents, which may help to identify subjects who will develop an asthmatic reaction only after repeated exposure.     

Pathogenesis of late asthmatic reactions induced by exposure to isocyanates

The importance of airways inflammation for the development of bronchial hyperresponsiveness and for exacerbation of asthma was investigated in subjects with occupational asthma. We examined subjects sensitized to isocyanates, a small molecular weight compound that causes occupational asthma. Studies in asthmatic subjects sensitized to toluene diisocyanate (TDI) demonstrated that late, but not early, asthmatic reactions induced by TDI were associated with an acute increase in bronchial responsiveness, and with a marked infiltration of neutrophils and a slight infiltration of eosinophils into the airways, both prevented by steroids. As the late asthmatic reactions and the increase in responsiveness induced by TDI were prevented by steroids, but not by indomethacin, we speculated that cell membrane phospholipid metabolites, which are inhibited by steroids but not by indomethacin, may be involved in TDI induced hyperresponsiveness. The results of these studies suggest that bronchial hyperresponsiveness and exacerbation of asthma may be related to inflammation of the airways and that cell membrane phospholipid metabolites may be involved.     

Comparison of cellular and protein changes in bronchial lavage fluid of symptomatic and asymptomatic patients with red cedar asthma on follow-up examination

Seventeen patients with occupational asthma due to western red cedar had bronchial lavage during follow-up examination after removal from exposure for at least 1 year. Seven patients were asymptomatic while ten continued to have symptoms of asthma requiring treatment. Symptomatic patients had evidence of airway inflammation, as reflected by a significantly higher total cell count, neutrophils and eosinophils, as well as an increase in protein and albumin in their bronchial lavage fluid compared to those without symptoms. Asymptomatic patients had no evidence of airway inflammation in the lavage fluid. There was no correlation between the degree of non-specific bronchial hyperresponsiveness and the number or percentage of inflammatory cells to suggest that cellular infiltration is the sole cause of persistent bronchial hyperresponsiveness.     

Relationship between types of asthmatic reaction,nonspecific bronchial reactivity,and specific IgE antibodies in patients with red cedar asthma

We studied the relationship between specific IgE antibodies, nonspecific bronchial reactivity to methacholine, and the type of asthmatic reaction in patients with red cedar asthma. The level of circulating specific IgE antibodies (expressed as RAST ratios) was not related to the type of asthmatic reaction, the degree of nonspecific bronchial hyperreactivity [expressed by the provocative concentration of methacholine producing a 20% decrease in the forced expiratory volume in 1 sec (PC₂₀)] or the index of reactivity to plicatic acid. On the other hand, methacholine PC₂₀ was found to correlate with the index of reactivity to plicatic acid in the late asthmatic reaction (LAR) and both the immediate and late components of the dual asthmatic reaction (DAR). Development of the LAR is associated with increase in nonspecific bronchial hyperreactivity. Repeated inhalation challenge with plicatic acid in eight patients with LAR resulted in DAR in all. The results suggest that the mechanism responsible for the LAR is associated with an increase in nonspecific bronchial reactivity; furthermore, the immediate component of DAR could also be related to heightened bronchial hyperreactivity.     

Relationship among pulmonary function, bronchial reactivity, and exhaled nitric oxide in a large group of asthmatic patients.

BACKGROUND: Bronchial reactivity and exhaled nitric oxide (eNO) are not often used to monitor control and severity of asthma in clinical practice. OBJECTIVE: To evaluate the relationship among different physiologic measures (pulmonary function, nonspecific bronchial reactivity, and eNO) in asthmatic patients. METHODS: Cross-sectional, hospital-based study conducted in patients with varied asthma severity. RESULTS: A total of 392 patients participated in the study. There was no difference in eNO levels between patients taking inhaled corticosteroids (ICS group) and patients not receiving inhaled corticosteroids (NICS group). However, the percentage of predicted forced expiratory volume in 1 second (FEV1) and the provocative dose of methacholine causing a 20% decrease in FEV1 were significantly lower in the ICS group compared with the NICS group (mean, 83.2%; 95% confidence interval [CI], 80.4%-86.0%; vs mean, 94.1%; 95% CI, 91.1%-97.1%; P = .001; and geometric mean, 0.32 mg; 95% CI, 0.23-0.45 mg; vs geometric mean, 0.58 mg; 95% CI, 0.42-0.81 mg; P = .01; respectively). Patients with more severe bronchial hyperresponsiveness had a lower percentage of predicted FEV1 values (P < .001) and levels of eNO were significantly increased with increasing bronchial hyperresponsiveness (P < .001). There was no relationship between the percentage of predicted FEV1 and eNO. Atopic patients had significantly higher eNO levels than nonatopic patients (geometric mean, 11.21 ppb; 95% CI, 10.07-12.49 ppb; vs geometric mean, 7.76 ppb; 95% CI, 6.11-9.85 ppb; P = .006; respectively). CONCLUSIONS: eNO values are not related to the degree of airway obstruction but are related to airway reactivity and atopic status independent of inhaled corticosteroid use. Higher values of eNO are seen with increased airway reactivity.     

Expression of interleukin (IL)-4 and IL-5 proteins in asthma induced by toluene diisocyanate (TDI)

Background TDI-induced asthma exhibits clinical, functional and morphological similarities with allergen-induced asthma, suggesting that an immunological mechanism is involved in the sensitization to TDL In vitro studies using the technique of cloning lymphocytes demonstrated that a great proportion of T-cell clones derived from bronchial mucosa of subjects with TDI-induced asthma produced IL-5 and interferon-gamma, but not IL-4, upon in vitro stimulation. Objectives To investigate in vivo the role of IL-4 and IL-5 on the inflammatory response of the bronchial mucosa to TDI in sensitized subjects, we performed a quantitative analysis of bronchial biopsies. Methods We obtained bronchial biopsies from six subjects with TDI asthrha 48 h after an asthmatic reaction induced by TDI challenge (challenged group), in six subjects with TDI asthma 1–4 weeks after the last exposure to TDI (chronic group), and in six non-asthmatic controls. The number of eosinophils, mast cells, T-lymphocytes, and IL-4 and IL-5 protein positive cells was determined by immunohistochemistry in the area 100 μn beneath the epithelial basement membrane. Results The characteristic increase of submucosal eosinophils, but not of mast cells and T-lymphocytes, was observed in the subjects with TDI-induced asthma when compared with controls. No differences were detected between the two groups of asthmatics. In the subjects with TDI-induced asthma, cell immunoreactivity for IL-5 was increased when compared with normal controls. There was no difference in the expression of IL-5 protein between challenged and chronic asthmatics. In contrast, the expression of IL-4 protein was increased only in the asthmatic subjects tested after recent exposure to TDI. Conclusions We demonstrated that TDI asthma 48 h after specific bronchial challenge was associated with increased numbers of cells expressing IL-4 and IL-5, whereas chronic TDI asthma was associated with increased expression of IL-5, but not of IL-4. The results suggest that subjects who developed TDI asthma exhibit increased production of IL-5 even in the absence of a recent trigger by the exogenous sensitizer and that production of TH₂-like cytokines in TDI-induced asthma may not always be co-ordinately regulated in vivo.     

Eosinophil infiltration and enhancement of airway reactivity by leukocyte chemotactic factor, formyl-methionyl-leucyl-phenylalanine (fMLP), in guinea pigs.

N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP) is a bacterial-derived chemotactic factor for eosinophils and neutrophils. This study is aimed to examine whether or not eosinophil infiltration induced by intra-airway administration of fMLP causes the damage of the bronchial epithelium and results in airway hyperresponsiveness in normal non-sensitized guinea pigs. In normal guinea pigs fMLP administered by aerosol inhalation or intratracheal injection caused significant infiltration of eosinophils in the tracheal mucosa and enhanced bronchial reactivity to inhaled histamine 6 and 24 hours after exposure. Electron microscopic examination showed damage of the alignment of the epithelial cells in the bronchial mucosa in fMLP-treated guinea pigs. PAF antagonists CV3988 and WEB2086 and a 5-lipoxygenase inhibitor (AA-861) did not prevent fMLP induced eosinophil infiltration, which suggests that fMLP caused eosinophil infiltration mainly by its chemotactic activity, not by the release of platelet activating factor (PAF) or leukotrienes in this experimental condition. These results showed that in normal guinea pigs a bacteria-derived chemoattractant of fMLP could reproduce a sequence of eosinophil infiltration and airway hyperresponsiveness, similar to the inflammatory pathophysiology after antigen challenge in sensitized animals. We concluded that eosinophil infiltration induced by either immunological or non-immunological mechanisms can cause airway damage and airway hyperresponsiveness.