lignans and plicatic-acid

Topics: Allergens; Anhydrides; Animals; Asthma; Disease Models, Animal; Dogs; Guinea Pigs; Haplorhini; Humans; Isocyanates; Lignans; Mice; Naphthols; Occupational Diseases; Platinum Compounds; Rabbits; Rats; Respiratory Hypersensitivity

Topics: Asthma; Biomechanical Phenomena; Bronchial Provocation Tests; Bronchial Spasm; Bronchitis; Byssinosis; Cyanates; Dust; Edible Grain; Forecasting; Humans; Hypersensitivity; Insecticides; Lignans; Naphthols; Occupational Diseases; Organophosphorus Compounds; Prognosis; Reflex; Respiratory Function Tests; Respiratory Hypersensitivity; Serology; Skin Tests; Smoking; Terminology as Topic

Specific challenge tests with a suspected allergen in the workplace are standard to confirm the diagnosis of asthma. Facilities for sophisticated exposure tests are available only in a few institutions. A pilot study was carried out that used a novel approach for an occupational dust challenge test with a rotahaler.. Nine consecutive patients were enrolled in this study. Six of these proved to have asthma to red cedar by challenge tests with plicatic acid. They were challenged with a maximum dosage of 80 mg of red cedar dust and spruce dust (control) with a rotahaler on separate days in a single blinded manner. A positive reaction was defined as a fall in the forced expiratory volume in one second (FEV1) or the peak expiratory flow (PEF) after a challenge test of > or = 20% below the baseline value.. Three of the six patients who reacted to plicatic acid also had a positive response to red cedar dust delivered through a rotahaler. All three patients with a negative response to challenge with plicatic acid also showed a negative response to red cedar dust.. This pilot study showed that a positive challenge test with a rotahaler to deliver red cedar dust was specific in the diagnosis of red cedar asthma but a negative response could not rule out the diagnosis. The rotahaler has merits of being easy to operate, safe, inexpensive, and readily available. The usefulness of this method and its reproducibility have to be examined in a series of patients.

Topics: Adult; Asthma; Bronchial Provocation Tests; Dust; Forced Expiratory Volume; Humans; Lignans; Male; Middle Aged; Naphthols; Nebulizers and Vaporizers; Occupational Diseases; Peak Expiratory Flow Rate; Pilot Projects; Wood

Topics: Adult; Asthma; Biomarkers; Bronchial Provocation Tests; Gene Expression; Humans; Lignans; Male; Middle Aged; Naphthols; Northwestern United States; Occupational Diseases; Thuja

Topics: Allergens; Asthma, Occupational; Bronchial Hyperreactivity; Dermatitis, Allergic Contact; Humans; Lignans; Naphthols; Pollen; Thuja

Topics: Adiponectin; Adult; Antigens, Plant; Asthma; Body Mass Index; Bronchial Provocation Tests; Dust; Eosinophilia; Forced Expiratory Volume; Humans; Lignans; Male; Methacholine Chloride; Middle Aged; Naphthols; Occupational Diseases; Occupational Exposure; Sputum; Thuja; Young Adult

Topics: Adult; Asthma, Occupational; Basophil Degranulation Test; Bronchial Provocation Tests; Cells, Cultured; Cough; Disease Progression; Dyspnea; Humans; Lignans; Male; Naphthols; Occupational Exposure; Thuja; Young Adult

The first total synthesis of (-)-plicatic acid has been achieved by a concise and enantioselective route. In this synthesis, a conceptually new strategy featuring an asymmetric epoxidation-intramolecular epoxy-ring-opening Friedel-Crafts reaction sequence was developed for the stereoselective construction of the 2,7'-cyclolignane skeleton bearing contiguous quaternary-quaternary-tertiary stereocenters. The implementation of this strategy was enabled by the development of a modified protocol for the Seebach epoxidation with TADOOH, which affords an unprecedented, highly enantioselective and diastereoselective epoxidation with a range of alpha-carbonyl-beta-substituted acrylates 3.

Topics: Alkenes; Epoxy Compounds; Lignans; Naphthols; Stereoisomerism; Substrate Specificity

Western red cedar (Thuja plicata) heartwood contains abundant amounts of structurally complex plicatic acid-derived lignans that help confer protective properties and longevity to this tissue type. Although the lignan biochemical entry point is dirigent protein-mediated, the formation of heartwood and its associated lignans in some species remains poorly understood due to technical difficulties of working with the former. To begin to address such questions, this study therefore focused on the anatomical localization of dirigent protein and 18s rRNA (control) gene transcripts within recalcitrant woody tissues, including heartwood. This in situ mRNA hybridization approach enabled detection of dirigent protein transcripts in cork cambia, vascular cambia and ray parenchyma cells of the sapwood, but not the heartwood under the conditions employed. By contrast, the hybridization of the 18s rRNA (control) transcript resulted in its detection in all tissue types, including radial parenchyma cells of apparently preformed heartwood. Application of in situ hybridization to such recalcitrant tissues thus demonstrates the utility of this technique in identifying specific cell types involved in heartwood formation, as well as the relationship of dirigent protein localization to that of heartwood metabolite generation.

Topics: Gene Expression Regulation, Plant; Lignans; Molecular Structure; Naphthols; Plant Proteins; Protein Transport; RNA, Ribosomal, 18S; Thuja; Wood

Occupational asthma due to western red cedar is associated with histamine release from basophils and mast cells on exposure to plicatic acid (PA), but the mechanisms underlying this response remain unclear. Specific kinase inhibitors were used to study the role of tyrosine and serine/threonine kinases in PA-induced histamine release from human basophils. Pretreatment with the tyrosine kinase inhibitor methyl 2,5-dihydroxy-cinnamate (MDHC) attenuated histamine release from basophils triggered by anti-IgE (29.8% inhibition; n = 15; P < 0.01) or grass pollen (48% inhibition; n = 6; P < 0.01). Inhibition was concentration-dependent and could be reversed by washing the cells in buffer, while the inactive stereoisomer of MDHC did not affect histamine release. In contrast, the protein kinase C inhibitor staurosporine did not affect histamine release by either anti-IgE or grass pollen. Pretreatment with MDHC partially inhibited PA-induced histamine release from basophils of 6/9 patients with red cedar asthma (25.4% vs 33.8%; P = NS). Staurosporine gave a similar level of inhibition of PA-induced histamine release (25.3% vs 33.8%; P = NS). Thus, signal transduction of the human basophil Fc epsilon RI appears to depend upon tyrosine kinase activation, but not on protein kinase C (serine/threonine kinase) activation. The lack of specific effect on plicatic acid-induced histamine release in basophils obtained from patients with occupational asthma due to western red cedar suggests that tyrosine kinases are not as important in this disease as in atopic asthma, and is consistent with the view that histamine release in red cedar asthma is largely IgE-independent.

Topics: Allergens; Antibodies, Anti-Idiotypic; Asthma; Basophils; Cinnamates; Environmental Exposure; Enzyme Activation; Enzyme Inhibitors; Histamine; Histamine Antagonists; Humans; Hypersensitivity; Lignans; Naphthols; Poaceae; Pollen; Protein-Tyrosine Kinases; Trees

T cells are known to play a major role in the pathogenesis of atopic allergic asthma, but it is less clear whether they are involved in occupational asthma caused by low molecular weight chemicals such as plicatic acid.. We sought to determine whether peripheral blood T cells from patients with western red cedar asthma (WRCA) recognize plicatic acid (PA) conjugated to human serum albumin (HSA) as judged by proliferation or cytokine production and to analyze the response to PA inhalation with flow cytometry.. Significant proliferative responses to PA-HSA were observed in eight of 33 patients with WRCA, none of 10 exposed nonasthmatic cedar workers, and one of 18 nonasthmatic control subjects. Two of 25 patients with WRCA also showed proliferative responses to unconjugated PA. All the WRCA responders were either currently exposed to cedar or had ceased exposure within the preceding 2 years. None of the four patients receiving oral steroids responded, but inhaled steroids did not seem to influence responsiveness. No correlations were found between the maximum stimulation response and any of the current FEV1 values, the current PC20 methacholine values, or the magnitude of the late asthmatic response to PA. Peripheral blood T-cell subset proportions and their degree of activation were similar in patients with WRCA and exposed control subjects. There was no change in T-cell phenotypes or their activation markers after PA inhalation challenge. In vitro, PA-HSA stimulation did not affect subset ratios but led to release of small amounts of IL-5 and IFN-gamma, with no detectable increase in IL-4.. PA-HSA-specific T lymphocytes seem to be present in small numbers in the peripheral blood of patients with WRCA and may respond to antigenic exposure by producing IFN-gamma and IL-5. However, the proportion of responding cells would appear to be lower than in comparable studies of atopic asthma.

Topics: Adult; Allergens; Asthma; Cells, Cultured; Humans; Lignans; Lymphocyte Activation; Middle Aged; Naphthols; Occupational Diseases; Plants; Serum Albumin; T-Lymphocytes

The purpose of the present investigation was to study bronchial responsiveness and pulmonary function in Swedish sawmill workers, who are not exposed to plicatic acid, the sensitizer in red wood cedar asthma. Bronchial responsiveness, transfer factor, spirometry, and precipitating antibodies in serum against sawmill fungi were measured in 164 workers at five sawmills. The results from workers inside the sawing area (sawyers, n=59), in the trimming department (trimmers, n=66), and from other workers in the sawmill (sawyer-referents, n=39) were compared. Sawyers had higher bronchial responsiveness than referents. In 55% of the sawyers FEV1 decreased by 20% or more within the highest dose of methacholine compared with 31% of sawyer-referents and 41% of trimmers (p<0.01, sawyers/referents). Sawyers decreased 74% more in FEV1 per milligram of inhaled methacholine compared with referents (geometric means, p<0.01). The transfer test in never-smokers was 13% lower in sawyers than in trimmers (p<0.01) and 8% lower compared with sawyer-referents (nonsignificant p<0.1). Presence of precipitating antibodies was not associated with changes in pulmonary function. Some agents in the sawing area of sawmills appear to increase bronchial responsiveness and decrease diffusion capacity.

Topics: Adult; Allergens; Antibodies, Fungal; Bronchial Hyperreactivity; Bronchial Provocation Tests; Bronchoconstrictor Agents; Dust; Forced Expiratory Volume; Fungi; Humans; Lignans; Lung; Male; Maximal Expiratory Flow Rate; Maximal Midexpiratory Flow Rate; Methacholine Chloride; Middle Aged; Naphthols; Occupational Diseases; Pulmonary Diffusing Capacity; Smoking; Spirometry; Spores; Sweden; Trees; Vital Capacity

Occupational asthma due to Western red cedar is the most common form of occupational asthma in the Pacific Northwest and affects 4-13.5% of the exposed population. It has been shown to be caused by plicatic acid, a low molecular weight compound present uniquely in the wood. The mechanism of asthma induced by plicatic acid is not known, as specific IgG antibodies were found only in about 20% of patients. Sera from patients with red cedar asthma failed to passively sensitize human lung fragments of human basophils. Basophils from patients with this disease released histamine when challenged directly with plicatic acid in a specific manner. Immunologic mechanisms other than Type I hypersensitivity reaction are likely to be involved.

Topics: Allergens; Animals; Antibodies, Anti-Idiotypic; Asthma; Dust; Humans; Immunoglobulin E; Lignans; Naphthols; Occupational Diseases; Trees; Wood

Western red cedar asthma is the most common form of occupational asthma in the Pacific Northwest. Plicatic acid (PA) is the chemical component of Western red cedar that causes asthma. The role of immunologic processes involved in the PA-induced asthmatic reaction has not been established. To characterize the mechanisms of PA-induced asthmatic reaction, guinea pigs were sensitized to PA through biweekly injection of PA-ovalbumin conjugate with aluminum hydroxide as an adjuvant for a period of 6 months. Specific IgG1 antibodies to PA were detected in the blood 3 months after sensitization of animals. The level of specific IgG1 antibodies to ovalbumin after 6 months was about two times the level of specific IgG1 to PA. At 6 months, tracheal tissue from PA-ovalbumin-sensitized guinea pigs contracted after exposure to either PA or ovalbumin in vitro. The degree of contraction induced by PA was two to three times less than the contraction induced by ovalbumin. PA caused histamine, prostaglandin D2, and leukotriene D4 release from both lung mast cells and blood basophils. The amount of histamine and eicosanoids released by PA was also two to three times less than the amount of mediators released by ovalbumin. When the trachea of normal guinea pigs was passively sensitized with serum from PA-ovalbumin-sensitized guinea pigs, it contracted in response to PA or ovalbumin in an organ bath. When the serum of PA-ovalbumin-sensitized guinea pigs was depleted of immunoglobulins and then used for passive sensitization of normal trachea, no contraction was observed when challenged with PA, suggesting that IgG1 antibodies mediate the tracheal reaction to PA.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Allergens; Animals; Asthma; Disease Models, Animal; Guinea Pigs; Immunization; Immunoglobulin G; In Vitro Techniques; Leukotriene D4; Lignans; Lung; Male; Muscle Contraction; Muscle, Smooth; Naphthols; Prostaglandin D2; Time Factors; Trachea; Trees

Occupational asthma caused by western red cedar (Thuja plicata) is a common problem in sawmill industries. The objective of this study was to examine the cellular and immunologic mechanisms of western red cedar asthma (WRCA) more closely.. Bronchial biopsy specimens, bronchoalveolar lavage (BAL) mast cells and peripheral blood basophils from patients with WRCA, patients with atopic asthma, and nonatopic control subjects were challenged in vitro with plicatic acid (PA), PA-human serum albumin conjugate (PA-HSA), grass pollen, or calcium ionophore.. PA (100 micrograms/ml) released histamine from the basophils of 9 of 11 patients with WRCA, 1 of 7 patients with atopic asthma, and 2 of 7 normal subjects. PA triggered histamine release from 10 of 11 bronchial biopsy specimens and 8 of 8 BAL samples from patients with WRCA. Interestingly, PA released histamine from BAL cells and bronchial biopsy specimens from 3 of 7 normal subjects but in none of the patients with atopic asthma. PA-HSA-induced histamine release from basophils and biopsy specimens was confined to patients with WRCA. PA-specific IgE was not detectable in serum from most patients with WRCA, and their serum did not transfer PA sensitivity to human lung fragments or lactate-stripped basophils. After pretreatment with anti-IgE in the absence of calcium, basophils from 14 subjects with WRCA still responded to PA (mean 64% to 67% of pretreatment response), whereas responses to grass pollen or anti-IgE were abolished.. This study confirms that PA releases histamine from bronchial mast cells of most patients with WRCA but not from those of patients with atopic asthma. The PA response of some normal subjects suggests that PA may have both specific and nonspecific actions on mast cells and basophils, whereas the serologic studies indicate histamine release in WRCA cannot simply be attributed to PA-specific IgE.

Topics: Adult; Allergens; Analysis of Variance; Asthma; Basophils; Bronchi; Bronchial Provocation Tests; Bronchoalveolar Lavage Fluid; Female; Humans; Immunoglobulin E; Lignans; Male; Naphthols; Occupational Diseases; Wood

Peak expiratory flow rates (PEF) are often used to confirm the diagnosis of occupational asthma. The records are usually analysed qualitatively, and this may lead to interobserver disagreement. In this study the diagnostic value of a qualitative assessment of change in PEF was compared with objective measures of change in PEF and the results of a specific inhalation challenge test with plicatic acid.. Twenty five patients with possible red cedar asthma recorded PEF six times a day for three weeks at work and for two weeks away from work and underwent a challenge test with plicatic acid at the end of the recording period. Patients were considered to have cedar asthma if the FEV1 after inhalation of plicatic acid was 15% or more below that on the control day. PEF was plotted against time and assessed qualitatively by three physicians. The graph was considered positive for cedar asthma if two of the three physicians agreed that PEF was lower at work than away from work. The 95% confidence interval for variation in PEF between periods at work and away from work was also obtained from 15 asthmatic patients without occupational asthma. Differences in PEF between periods at work and away from work were considered positive for occupational asthma in the patients exposed to cedar when they were outside the 95% confidence interval for variations in PEF in the 15 patients whose asthma was nonoccupational.. Of the 25 men studied, 15 had a positive response to plicatic acid. The qualitative PEF analysis had a sensitivity of 87% and a specificity of 90% in confirming red cedar asthma as diagnosed by the specific challenge test. Among the objective methods tested, only the difference in mean PEF between the maximum PEF at weekends and the minimum PEF on working days had a sensitivity (93%) greater than that of the qualitative method and a similar specificity.. The qualitative assessment of PEF is a good diagnostic test for cedar asthma. Only one objective method of PEF analysis proved to be slightly more sensitive than the qualitative method and similar in specificity.

Topics: Asthma; Bronchial Provocation Tests; Humans; Lignans; Lung; Male; Naphthols; Occupational Diseases; Peak Expiratory Flow Rate; Predictive Value of Tests; Wood

Occupational asthma due to Western Red Cedar (WRCA) is attributed to sensitization to plicatic acid (PA), but does not appear to be dependent on PA-specific IgE antibodies. Exposure to PA induces histamine release in vivo and in vitro, so if IgE is not important, other mechanisms of histamine release must presumably operate in WRCA. To explore the possible role of histamine-releasing factors in WRCA, peripheral blood mononuclear cells were obtained and cultured with PA, PA-albumin conjugate plicatic acid-human serum albumin (PA-HSA), grass pollen or Concanavalin A using a standard histamine releasing factor (HRF) generation protocol. Supernatants were dialysed to remove endogenous histamine and then assayed for histamine releasing activity using human basophils as targets and a Con A-induced bulk supernatant as an internal HRF standard. In contrast to some previous reports, spontaneous HRF release from the peripheral blood mononuclear cells (PBMC) of WRCA patients (n=9) and atopic asthmatic subjects (n=5) was not elevated compared with the non-asthmatic controls (n=11; five atopic and six non-atopic). Both PA and PA-HSA induced the production of small amounts of HRF by PBMC of WRCA patients, but a similar degree of HRF generation was also observed in PBMC from the atopic asthmatic, atopic nonasthmatic, and non-atopic subjects. In contrast, grass pollen induced the production of HRF by PBMC from the subjects with positive skin tests to grass pollen but not by PBMC of non-atopic subjects, confirming that our methods and assay were capable of detecting antigen-specific HRF production. Since neither PA nor PA-HSA induced significantly elevated HRF production from PBMC of WRCA patients, it seems unlikely that PA-induced HRFs play a substantial role in the pathogenesis of WRCA.

Topics: Adult; Allergens; Antibody Specificity; Asthma; Basophil Degranulation Test; Biological Factors; Bronchial Provocation Tests; Concanavalin A; Dust; Female; Histamine Release; Humans; Hypersensitivity, Immediate; Immunoglobulin E; Leukocytes, Mononuclear; Lignans; Male; Middle Aged; Naphthols; Occupational Diseases; Plant Lectins; Poaceae; Pollen; Serum Albumin; Trees; Wood

It is unknown whether factors such as the nature of the agent, gender, age, atopy, smoking habits, continuous or noncontinuous exposure, and pattern of asthmatic reaction can influence the rate of development of symptoms in subjects with occupational asthma. We compared several clinical and functional parameters among three groups of subjects with occupational asthma caused by Western red cedar (group 1, n = 433), isocyanates (group 2, n = 107), and high molecular weight agents acting through an IgE-mediated mechanism (group 3, n = 121). Survival analysis showed that the three curves relating years of exposure before onset of symptoms to the proportion of subjects without symptoms were significantly different in two respects: (1) almost 40% of subjects in groups 1 and 2 as compared with 20% of subjects in group 3 became symptomatic within 1 year of exposure; (2) after 5 years of exposure, the rate of sensitization was slower for subjects in groups 2 and 3 as compared with those in group 1. Having a nonimmediate reaction at the time of specific inhalation challenges, being continuously exposed and being younger slightly increased the risk at each time point on the curve of developing symptoms in subjects with occupational asthma. These data suggest that the natural history for onset of occupational asthma is different depending on the sensitizing agent. Factors such as age, type of exposure, and pattern of reaction on exposure to the agent also modulate the rate of development of this condition.

Topics: Adult; Allergens; Asthma; Cyanates; Female; Forced Expiratory Volume; Humans; Hypersensitivity; Hypersensitivity, Immediate; Lignans; Male; Middle Aged; Molecular Weight; Naphthols; Occupational Diseases; Smoking

After an average follow-up of 6.5 yr (range 1 to 13), 48 of 48 patients with cedar asthma, who were still working in the same industry, were re-examined. In all of them, the diagnosis of cedar asthma had been confirmed with a specific challenge inhalation test with plicatic acid. We graded the severity of asthma symptoms and the requirement for antiasthma medications at the time of diagnosis and at the time of follow-up visit. Spirometry and measurement of airway responsiveness to methacholine (PC20 methacholine) were also done on both visits. The increase or decrease in asthma symptoms, medications requirement, FEV1 and PC20 methacholine between the follow-up and the diagnostic visit were used to determine the outcome of the patients. Using these parameters, 10.4% of patients improved, 62.5% remained stable, 37.5% deteriorated, and none recovered. Among the characteristics of the patients observed at the time of diagnosis, the age of the patient, the atopic status, smoking habit, and the presence of specific IgE to plicatic acid were not useful in predicting the eventual outcome. Reduction of exposure by transfer to a less dusty job and the use of an airstream helmet did not prevent deterioration of asthma. Only the use of the twin-cartridge respirator was associated with a favorable outcome. We conclude that among cedar asthmatics who remained exposed to cedar dust for an average of 6.5 yr, over one-third showed marked deterioration of their asthma symptoms. There is also no way to predict who will deteriorate. A decrease in the amount of exposure to cedar dust does not prevent deterioration of asthma. This suggests that the ideal management of cedar asthma is removal from exposure.

Topics: Allergens; Asthma; British Columbia; Bronchial Provocation Tests; Female; Follow-Up Studies; Forced Expiratory Volume; Humans; Lignans; Male; Methacholine Chloride; Methacholine Compounds; Naphthols; Occupational Diseases; Palliative Care; Remission Induction; Surveys and Questionnaires; Vital Capacity; Wood

The diagnosis of red cedar asthma is usually confirmed by a specific challenge with plicatic acid, the compound responsible for the disease. We performed this study to determine the sensitivity and specificity of two other diagnostic tests, prolonged recording expiratory flow rate (PEFR) and measurement of bronchial responsiveness (provocative dose of methacholine causing a 20% fall in FEV1 [PC20 methacholine]). Twenty-three patients with suspected cedar asthma participated in the study. The patients recorded PEFR during 2 weeks away from work and 3 weeks at work. PC20 was measured both at the end of the nonworking and working period. An obvious decrease in PEFR in 2 of 3 working weeks, when PEFRs of weekends or holidays were compared (by visual inspection of the PEFR recording), and a decrease in PC20 by more than a twofold dilution, when the patient returned to work, were considered as positive tests for cedar asthma. Plicatic acid challenge test was performed at the end of the study; 14 patients reacted, whereas nine patients did not. With the results of the plicatic acid challenge test as the gold standard, the sensitivity and specificity of PEFR recordings were 86% and 89%; changes in PC20, 62% and 78%; and 93% and 45% for a positive clinical history. The combination of PEFR and clinical history revealed a 100% sensitivity with a 45% specificity. Combination of PEFR and PC20 did not improve the diagnostic accuracy.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Allergens; Asthma; Bronchial Provocation Tests; False Positive Reactions; Forced Expiratory Volume; Humans; Lignans; Methacholine Chloride; Methacholine Compounds; Naphthols; Occupational Diseases; Peak Expiratory Flow Rate; Time Factors; Trees

Bronchoalveolar lavage (BAL) was performed before and 10 minutes after inhalation challenge with plicatic acid in five patients with red cedar asthma. There was a significant release of histamine and leukotriene E4 into the BAL fluid in all the patients after challenge. Inhalation challenge with methacholine in six patients with nonoccupational asthma and inhalation challenge with plicatic acid in two subjects without asthma did not result in the release of mediators in the BAL fluid. These studies provide direct evidence that plicatic acid-induced bronchoconstriction was accompanied by increased levels of histamine and leukotriene E4 release, whereas a nonimmunologic induction of bronchoconstriction did not induce such local mediator release. BAL may provide a useful means of studying the pathogenesis of occupational asthma caused by exposure to low-molecular-weight compounds.

Topics: Adolescent; Adult; Allergens; Asthma; Bronchi; Bronchial Provocation Tests; Bronchoalveolar Lavage Fluid; Histamine Release; Humans; Leukotrienes; Lignans; Middle Aged; Naphthols; Occupational Diseases; Trees

Although late bronchospastic reactions after exposure to antigenic and sensitizing agents usually significantly alter bronchial responsiveness to histamine or methacholine, presumably by causing bronchial inflammation, isolated immediate bronchospastic reactions do not induce such changes. We studied three subjects who demonstrated different patterns of reaction. The first individual was diagnosed as having occupational asthma to red cedar. This was confirmed by specific inhalation challenges that resulted in late bronchospastic reaction. No significant changes in the provocative concentration of histamine causing a 20% fall in FEV1 (PC20) were found 1 day after this reaction. Two weeks later, serial assessments (five and six, respectively) of PC20 histamine were recorded on control days and up to 48 hours after exposure to plicatic acid, which caused a late bronchospastic reaction with a maximum fall of 37% in FEV1. No significant changes in PC20 were found; the maximum variations on control days were 0.36 to 0.74 mg/ml, and on active days, from 0.37 to 0.59 mg/ml. By contrast, two other subjects, who demonstrated isolated immediate reactions after exposure to diphenylmethane diisocyanate, had significant changes in PC20 histamine and methacholine, in one subject from 3.1 mg/ml to 0.6 mg/ml 8 hours after exposure, and in the other subject, from 61.0 to 7.4 mg/ml 7 hours after exposure, with recovery during the next few days. These examples demonstrate that the pattern of nonspecific bronchial responsiveness after immediate and late bronchospastic reactions can be different from what has previously been described. Immediate bronchospastic reactions may lead to bronchial hyperresponsiveness, whereas late asthmatic reactions do not always induce changes in bronchial responsiveness.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Asthma; Bronchial Provocation Tests; Bronchial Spasm; Cyanates; Forced Expiratory Volume; Histamine; Humans; Hypersensitivity, Delayed; Hypersensitivity, Immediate; Isocyanates; Lignans; Male; Methacholine Chloride; Methacholine Compounds; Middle Aged; Naphthols; Occupational Diseases

Occupational exposure to cedar and pine woods and pine resin (colophony) can cause asthma and chronic lung disease. Prior studies suggest that plicatic and abietic acids are responsible for the asthmatic reactions that occur in cedar-wood and colophony workers; however, the etiologic mechanism(s) of the chronic lung disease is unknown. To determine if plicatic acid from cedar wood and abietic acid from pine resin could directly damage lung cells, we exposed monolayers of rat type II and human A549 alveolar epithelial cells, intact rat lungs, and rat tracheal explants to solutions of plicatic and abietic acids. As indices of injury, we measured lysis of alveolar epithelial cells with a 51Cr technique, quantitative desquamation of epithelial cells from tracheal explants, and histologic alterations in tracheal explants and intact lungs. Plicatic and abietic acids both caused dose- and time-dependent lysis of alveolar epithelial cells. Instillation of plicatic and abietic acids into rat lungs produced bronchial epithelial sloughing. Abietic acid also caused destruction of the alveolar epithelium. The addition of either acid to rat tracheal explants caused epithelial desquamation that was dose- and time-dependent. Our results suggest that plicatic acid, a unique constituent of cedar wood, and abietic acid, the major constituent in pine resin, can produce lytic damage to alveolar, tracheal, and bronchial epithelial cells. We hypothesize that repeated occupational exposure to these substances might promote the chronic lung damage observed in some cedar- and pine-wood workers and in electronic workers exposed to colophony.

Topics: Abietanes; Bronchi; Diterpenes; Epithelial Cells; Humans; Kinetics; Lignans; Lung Diseases; Naphthols; Occupational Diseases; Phenanthrenes; Pulmonary Alveoli; Trachea

Two hundred twenty-seven workers in a western red cedar sawmill underwent methacholine bronchoprovocation testing at least 2 times during 3 surveys over a 2-yr period. At the first survey, workers completed a respiratory and occupational questionnaire, performed spirometry, gave serum for measurement of plicatic acid-specific IgE antibodies by radioallergosorbent testing, and had skin prick tests to detect atopy. Bronchial hyperresponsiveness was present initially in 18% of the workers. Approximately 15% of those with initially no hyperresponsiveness developed hyperresponsiveness during the follow-up period; 15% of those with initial hyperresponsiveness also lost it during follow-up. Development of hyperresponsiveness tended to coincide with a decrease in level of pulmonary function, whereas loss of hyperresponsiveness was associated with improvement in pulmonary function. Workers with either persistent bronchial hyperresponsiveness or with varying responsiveness had a higher prevalence of plicatic acid IgE antibodies and lower levels of initial pulmonary function than did workers with persistent nonresponsiveness. Workers with persistent hyperresponsiveness had higher initial estimated total airborne dust exposure than did other workers. Age, duration of sawmill employment, atopy, race, and cigarette smoking did not influence the occurrence of hyperresponsiveness. Levels of plicatic-acid-specific IgE antibodies did not change substantially over the 2 yr. These results indicate that immunologic sensitivity to plicatic acid and change in airway caliber are associated with the occurrence of bronchial hyperresponsiveness in cedar workers.

Topics: Allergens; Asthma; British Columbia; Bronchial Diseases; Bronchial Provocation Tests; Humans; Hypersensitivity, Immediate; Lignans; Longitudinal Studies; Male; Methacholine Chloride; Methacholine Compounds; Naphthols; Occupational Diseases; Wood

In order to investigate the relationship between the pattern of response (immediate, late and dual) to specific bronchial challenge test with plicatic acid or red cedar extract and the clinical features of asthma, 332 patients with asthma induced by western red cedar dust were examined at the time of diagnosis. Specific challenge test induced in thirty-one patients (9.3%) an isolated immediate reaction, in 144 patients (43.4%) an isolated late reaction and in 157 patients (47.3%) a dual reaction. Patients with a dual reaction had a longer period of exposure to red cedar dust between the onset of the respiratory symptoms and the time of the definitive diagnosis, a lower FEF 25-75% and a greater degree of non-specific bronchial hyperresponsiveness compared to patients with isolated immediate or isolated late reactions; the difference in bronchial hyperresponsiveness to methacholine among the three groups persisted when the values were adjusted for the different baseline value of FEV1. There was no difference in the prevalence of specific serum IgE antibodies to plicatic acid-human serum albumin conjugate among the three groups of patients with different type of response to red cedar. Except for the greater degree of non-specific bronchial hyperresponsiveness, patients with isolated late reactions were not different from those with isolated immediate reactions in other clinical findings. These findings indicate that a dual reaction in patients with occupational asthma due to simple chemical agents is indicative of a greater severity of disease at diagnosis. The pathogenetic mechanism of various types of asthmatic reaction is unknown and it is likely to be different between isolated immediate and isolated late reactions.

Topics: Adult; Allergens; Asthma; Bronchial Provocation Tests; Humans; Immunoglobulin E; Lignans; Methacholine Chloride; Methacholine Compounds; Middle Aged; Naphthols; Occupational Diseases; Respiratory Function Tests; Skin Tests; Time Factors; Wood

Plasma histamine levels were measured by radio-enzymatic technique in seven patients following 10 challenges: five methacholine challenge tests, four antigen inhalation challenge tests, and one oral aspirin challenge test. Baseline plasma histamine was the same in all patients except in the aspirin-challenged patient, who had a higher baseline histamine level. There was no statistical change in the level of histamine throughout the test in either the methacholine-challenged or the antigen-challenged patients, whereas there was a marked increase in histamine levels in the aspirin challenged patient. A possible explanation is that methacholine and antigen are inhaled and therefore have primarily local effects on the lung, whereas oral aspirin has a systemic effect with consequently systemic changes in histamine which are detectable as changes in plasma level.

Topics: Adult; Antigens; Aspirin; Asthma; Female; Histamine; Humans; Hypersensitivity, Immediate; Lignans; Male; Methacholine Chloride; Methacholine Compounds; Middle Aged; Naphthols; Respiratory Function Tests; Triticum

We describe a rabbit model for the study of the immunogenicity and allergenicity of plicatic acid (PA), the small molecular weight compound in western red cedar responsible for occupational asthma in exposed workers. Specific anti-PA IgE as well as IgG antibodies could be raised, depending on the method of immunization. The sensitized rabbits reacted to antigenic challenge with PA-protein conjugates intravenously, with increases in respiratory frequency and pulmonary resistance. This animal model may be used for the further elucidation of the mechanism of occupational asthma induced by small molecular weight chemical compounds.

Topics: Animals; Antibody Formation; Asthma; Disease Models, Animal; Immunoglobulin E; Immunoglobulin G; Lignans; Naphthols; Rabbits; Respiratory Hypersensitivity

A total of 232 patients with red cedar asthma diagnosed by inhalation provocation tests were observed an average of 4 years after the initial diagnosis. The status during the follow-up examination was as follows: 96 patients continued to work with red cedar, and 136 left the industry and had no further exposure to red cedar in their jobs or hobbies. Of the 136 patients who left the industry, only 55 (40.4%) recovered completely, whereas the remaining 81 (59.6%) continued to experience attacks of asthma of varying severity. The initial pulmonary function tests were significantly higher among the asymptomatic group compared to the symptomatic group (FEV1 99.3 +/- 2.7% versus 90.5 +/- 2.2% predicted, respectively). Methacholine PC20 during the initial examination was higher among the asymptomatic group than in the symptomatic group (1.46 +/- 3.96 mg/ml versus 0.77 +/- 4.52 mg/ml, respectively). These findings indicate that the patients in the asymptomatic group were diagnosed at an earlier stage of the disease. This observation was confirmed by the significantly shorter duration of symptoms before diagnosis among the asymptomatic patients compared to the symptomatic patients (1.6 +/- 1.9 versus 2.6 +/- 4.3 years). Race, smoking status, immediate skin reactivity, and presence of plicatic acid-specific IgE antibodies did not influence the outcome of these patients. Of the 96 patients who continued to work with red cedar, 47 were exposed daily, whereas 41 were exposed intermittently.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Asthma; Bronchi; Bronchial Provocation Tests; Female; Follow-Up Studies; Humans; Lignans; Male; Middle Aged; Naphthols; Occupational Diseases; Respiratory Function Tests

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.

Topics: Adult; Asthma; Biopsy; Bronchi; Bronchial Provocation Tests; Female; Humans; Lignans; Male; Naphthols; Pollen; Therapeutic Irrigation; Trees

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.

Topics: Adult; Antibody Specificity; Asthma; Bronchi; Dust; Humans; Immunoglobulin E; Lignans; Male; Methacholine Compounds; Naphthols; Occupational Diseases; Radioallergosorbent Test; Respiratory Function Tests

A worker developed symptoms of work-related asthma a few weeks after starting to work in a sawmill where eastern white cedar (Thuja occidentalis) was transformed into shingles. The diagnosis of occupational asthma was confirmed by monitoring of peak expiratory flow rates and bronchial responsiveness to histamine off work and at work, and specific inhalation challenges in the laboratory that demonstrated an isolated late asthmatic reaction after exposure for 4 hours to the wood dust. Specific inhalation challenges with western red cedar (thuja plicata) for 2 hours and plicatic acid (PA) for 7 minutes also caused an isolated late asthmatic reaction. Elevated specific IgE levels to PA were present. Antiserum was produced in rabbits that were immunized with PA conjugated to human serum albumin. With this antiserum in inhibition experiments, cross-reactivity between western red cedar and eastern white cedar, both belonging to the family of arborvitae, was found. It is estimated that eastern white cedar contains approximately half the amount of PA present in western red cedar.

Topics: Adult; Allergens; Asthma; Bronchial Provocation Tests; Female; Forced Expiratory Volume; Humans; Lignans; Naphthols; Occupational Diseases; Radioallergosorbent Test

To investigate the optimal lavage technique to study the airway response in patients with asthma, differential volume lavage was carried out in 22 normal subjects and 18 patients with red cedar asthma. Ten ml of fluid was instilled into a main-stem bronchus followed by 5, 10, 20, 50 and 100 ml into different segmental bronchi. Small volume lavage (less than 20 ml) in a main stem bronchus or a segmental bronchus recovered more epithelial cells and neutrophils while a lavage volume of 20-100 ml in a segmental bronchus recovered more lymphocytes, alveolar macrophages, albumin, IgG and alpha 1-antitrypsin. In patients with asthma, a higher proportion of epithelial cells was observed in the 20 ml segmental bronchus lavage 24 to 48 hours after bronchial challenge with plicatic acid, the chemical compound responsible for red cedar asthma. There was an increase in eosinophils and IgG with all volume lavages, but the changes were most marked in the 10 ml main bronchus lavage and the 10 and 20 ml segmental bronchus lavage. The results show the importance of using a systematic lavage protocol to characterize the cellular and protein changes in the airways of patients with asthma. A single volume lavage in one site may not encompass all the changes observed.

Topics: Adolescent; Adult; Asthma; Bronchi; Bronchial Provocation Tests; Cell Count; Humans; Lignans; Middle Aged; Naphthols; Proteins; Therapeutic Irrigation

The lignans nordihydroguaiaretic acid (NDGA), heminordihydroguaiaretic acid (HNDGA) and norisoguaiacin were found to inhibit formyltetrahydrofolate synthetase (formate:tetrahydrofolate ligase (ADP-forming), EC 6.3.4.3) and carboxylesterase (carboxylic-ester hydrolase, EC 3.1.1.1) activity from a wide variety of sources. In all cases, NDGA was the most effective inhibitor. Synthetase activity was reduced by half at NDGA concentrations between 0.11 and 0.24 mM. Esterase activity consisted of NDGA-sensitive and NDGA-resistant forms. The sensitive class was half-inhibited by 2-4 microM NDGA. Irreversible inhibition of formyltetrahydrofolate synthetase by NDGA was observed both at low protein concentration (less than 0.2 mg/ml) and at high protein concentration where precipitation of protein was observed. Inhibition of formyltetrahydrofolate synthetase by NDGA arises from a decrease in Vmax and increase in Km for all substrates. In contrast, NDGA affects only the Vmax parameter of the esterase activity. It is suggested that the broad range of enzymes inhibited by NDGA may be a consequence of the amphipathic character of the molecule and the flexibility to accommodate to a variety of binding sites. It is also suggested that the previously reported ability of NDGA to inhibit phagocytosis may be due to the compound's ability to inhibit carboxylesterases.

Topics: Animals; Antineoplastic Agents; Carboxylic Ester Hydrolases; Catechols; Cattle; Cells, Cultured; Cytoplasm; Formate-Tetrahydrofolate Ligase; Guinea Pigs; Humans; Kinetics; Ligases; Lignans; Macromolecular Substances; Masoprocol; Mice; Microsomes; Naphthols; Plant Extracts; Protein Binding; Rats

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.

Topics: Adult; Asthma; Bronchial Provocation Tests; Forced Expiratory Volume; Humans; Immunoglobulin E; Lignans; Methacholine Chloride; Methacholine Compounds; Middle Aged; Naphthols; Radioallergosorbent Test; Time Factors

Topics: Adult; Asthma; British Columbia; Bronchi; Dust; Follow-Up Studies; Histamine Release; Humans; Lignans; Middle Aged; Naphthols; Occupational Diseases; Time Factors; Wood

The presence of specific IgE antibodies in the serum of patients with occupational asthma resulting from exposure to western red cedar (RCA) was studied by a radioallergosorbent test (RAST). The antigen matrix used in the RAST was either a conjugate of Sepharose particles with antigens in a crude cedar extract or with plicatic acid, the major haptenic component of cedar antigens. Of eighteen patients with clinical RCA and positive reaction to antigenic bronchoprovocation, eight were found to have abnormal RAST values. By appropriate absorption experiments, the serum RAST activity was shown to represent cedar antigen-specific IgE antibodies. No significant RAST activity was detected in the serum specimens from sixteen control subjects or from ten patients with negative bronchoprovocation-reaction to antigenic challenge. These results suggest that IgE antibody-mediated allergic reaction may be an important pathogenetic factor in RCA.

Topics: Allergens; Asthma; Bronchial Provocation Tests; Epitopes; Humans; Immunoglobulin E; Lignans; Naphthols; Occupational Diseases; Poaceae; Pollen; Radioallergosorbent Test; Wood

In an earlier study, we presented evidence that plicatic acid (PA) activated C in normal human serum (NHS) by an immunoglobulin-independent mechanism that did not involve factor B of the alternative pathway and that required Ca++ for initiation. The present paper further verifies that PA acts through the classical pathway. In PA-treated NHS, titers of C1, C4, C3, and C5 decreased after incubation at 37 degrees C, but in C2-deficient serum, only the titers of C1 and C4 were decreased after identical PA treatment. Activation of purified precursor C1 did not occur when it was incubated with PA at concentrations that would have produced C1 consumption in serum. Thus, PA added to serum initiates activation of the classical pathway, but is incapable of activating C1 directly. PA added to a mixture of native C4 and activated C1s did not alter the kinetics or the extent of C4 inactivation by the C1s. However, when mixtures of C4, C1s, and C1-In were incubated with PA, the ability of the inhibitor to inactivate the C1s was markedly reduced. These data indicate that the mechanism by which PA activates C in serum may involve interference with the normal regulatory mechanism that controls C1 activity.

Topics: Angioedema; Animals; Complement Activating Enzymes; Complement Activation; Complement C1 Inactivator Proteins; Complement C1s; Complement C2; Complement C4; Complement Pathway, Classical; Guinea Pigs; Humans; Lignans; Naphthols; Rabbits

Plicatic acid, a low-molecular-weight compound responsible for western red cedar (Thuja plicata) asthma was tested for its ability to activate complement and to generate chemotactic activity from pooled normal human serum (NHS). Dose-dependent complement consumption was found as determined by hemolytic assay (CH50). Activation of complement by plicatic acid was also confirmed by the demonstration of conversion of C3 to C3b on immunoelectrophoresis. This activation was completely prevented by pretreating the serum with either edetate (EDTA) or ethylene glycol tetraacetic acid (EGTA), suggesting that complement was activated via the classical pathway. No conversion of factor B was seen in any of the samples. Leukocyte chemotactic activity was also generated when serum was incubated with plicatic acid. The consumption of C3 and CH50 was unimpaired in two samples of serum from patients with severe, untreated hypogammaglobulinemia and thus appears to be immunoglobulin independent. These observations suggest that plicatic acid could activate complement in vivo, thereby inducing an inflammatory response in the airways and contributing to the higher prevalence of industrial chronic bronchitis in exposed subjects. The pathogenetic role of complement activation in red cedar asthma has yet to elucidated.

Topics: Animals; Asthma; Carboxylic Acids; Chemotaxis, Leukocyte; Complement Activation; Complement C3; Edetic Acid; Egtazic Acid; Humans; Immunoelectrophoresis; Lignans; Naphthols; Rabbits; Sheep; Trees; Zymosan