[When should one suspect reflux disease as the trigger for asthma?].
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Asthma↗
Biomedical subjects
Z Marom
Publications and source records attributed to Z Marom.
[Practical guide for peak expiratory flow monitoring in asthmatic patients].
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Asthma↗
The prognostic application of cytokeratin typing of nonsmall cell lung carcinoma. A retrospective study.
BACKGROUND: In a previous study, the authors used a variety of anticytokeratin monoclonal antibodies to show that a large proportion of lung tumors cytologically diagnosed as squamous cell carcinoma contain cells expressing simple epithelial cytokeratins, suggesting that these tumors have their origin in adenocarcinoma. These findings raised the possibility that cytokeratin (CK) typing might have a diagnostic capacity not attainable by standard histopathology. The aim of the current study was to assess the value of CK typing for this purpose by determining the correlation between the diagnosis of lung tumors based on CK typing and the survival rate of the patients. METHODS: Paraffin embedded tissue sections of 66 nonsmall cell lung carcinoma (NSCLC) specimens were examined. These included 18 adenocarcinomas, 32 squamous cell carcinomas, and 16 undifferentiated carcinomas, all diagnosed surgically and histopathologically, and further classified as either Stage I or II. CK typing was performed using the streptavidin-biotin-peroxidase method, employing the following anti-CK monoclonal antibodies: Ks.B.17 (which reacts with CK 18), A3-3 (which reacts with CK 13), and E5-9 (which reacts with CK 10). RESULTS: Comparison between the 5-year survival rates (5 ysr) of patients with different NSCLC indicated that all types of Stage II tumors had a much poorer prognosis than Stage I tumors. Differences found in the 5 ysr among patients with different types of Stage I tumors were not statistically significant (adenocarcinomas, 33% 5 ysr; squamous cell carcinomas, 59% 5 ysr; undifferentiated carcinomas, 36% 5 ysr; all diagnosed by conventional histopathology). Similarly, no significant differences were noted in 5 ysr between patients with tumors stained positively or negatively with monoclonal antibodies A3-3 or E5-9 (anti-CK 13 and anti-CK 10, respectively). In contrast, highly significant differences (P = 0.002) were found in the 5 ysr between patients with Stage I tumors positively or negatively stained with monoclonal antibody Ks.B.17 (23% vs. 75% 5 ysr, respectively) regardless of the histologic types of tumors. Especially informative was a combination of immunohistochemical and histologic diagnoses, with best survival rates (87% 5 ysr) in Ks.B.17 negative tumors histologically diagnosed as Stage I squamous cell carcinomas and worst survival rates (14% 5 ysr) in Ks.B.17 positive tumors diagnosed as adenocarcinomas. CONCLUSIONS: The current study showed that CK 18 typing of lung tumors can provide a more accurate diagnosis and therefore facilitate the planning of more suitable therapeutic approaches.
Adenocarcinoma↗
Mucin genes are regulated by estrogen and dexamethasone.
This study demonstrates for the first time that mucin gene expression can be significantly up-regulated by steroid hormones. The effects of estrogen, progesterone and dexamethasone on the expression of three mucin genes, MUC1, MUC4 and MUC5c were determined in a human epithelial cell line. This cell line secretes mucin and contains steroid receptors. Steady-state mRNA levels were quantified by slot blot hybridization using radiolabelled oligonucleotide probes. Normally, these genes (originally isolated from airways) are expressed at low constitutive levels. However, steady state levels of MUC4 and MUC5c mRNA were up-regulated at least 3-4 fold by estrogen supplementation, and 1.5-2 fold by dexamethasone. MUC1 mRNA levels were minimally affected. Progesterone supplementation had no effect but was able to interfere with the up-regulation by estrogen. The mechanism of regulation remains to be determined but may be transcriptional. However, steroids have been shown to control gene expression at several different levels.
Cell Line↗
Pharmacologic characterization of wool dust extract in isolated guinea pig trachea.
Wool mill workers develop respiratory symptoms and lung function abnormalities associated with their work in the textile industry. As in other workplaces, which process organic materials, the dust generated in the manufacture of wool has been implicated as a cause of these respiratory problems. Pharmacologic studies of wool dust extract were performed in vitro on guinea pig tracheal (GPT) segments. A wool dust extract (WDE) was prepared from material collected from a mill previously surveyed. When the standardized WDE solution was added to an organ bath in increments of 10, 30, 100, 300, and 1000 microliters it caused a consistent, dose-dependent constriction of GPT. Pretreatment of guinea pig tracheas, prior to WDE challenge, with atropine (10(-6) M), pyrilamine (10(-6) M), indomethacin (10(-6) M), verapamil (10(-6) M), TMBS (10(-6) M), BW755C (10(-6) M) and LY171883 (10(-6) M) was studied in order to evaluate receptor-dependent and -independent characteristics of WDE-induced constriction. WDE-induced bronchoconstriction was partially inhibited by the antihistamine pyrilamine. Atropine and leukotriene inhibitors (LY171883 and BW755C) were not found to have a significant protective effect on WDE-induced constriction. Both TMBS and verapamil (intra- and extracellular calcium blocking agent) suppressed the effect of wool dust extract in the range tested. These findings suggest that in this model, WDE-induced airway constriction is only partly attributable to common mediators of bronchoconstriction (e.g., histamine). The airway effects of WDE may be modulated by calcium channel blocking agents.
Air Pollutants, Occupational↗
Respiratory function in poultry workers and pharmacologic characterization of poultry dust extract.
A group of 343 workers (252 males and 91 females) employed in four poultry farms in Croatia was studied for the prevalence of acute and chronic respiratory symptoms and lung function changes. There were significantly higher prevalences of chronic cough, chronic phlegm, chronic bronchitis, and chest tightness in poultry workers than in control workers. Male poultry workers who were smokers had significantly higher prevalences of chronic cough, chronic phlegm, and chronic bronchitis than poultry workers who were nonsmokers (P<0.01). Poultry workers exposed for more than 10 years had significantly higher symptoms prevalences than those workers with shorter exposures (except among female smokers). There was also a high prevalence in poultry workers of acute symptoms which developed during the work shift. The measured FVC, FEV1, and FEF25 in poultry workers were significantly lower than predicted normal values. Workers exposed for more than 10 years had lower ventilatory capacity tests (expressed as percentage of predicted) than those workers with shorter exposures. Changes in FEV1, FEF50, and FEF25 were less pronounced than FVC. Additionally we showed that a water-soluble poultry dust extract obtained from this workplace caused a dose-related contraction of nonsensitized guinea pig tracheal smooth muscle when studied in vitro. Pharmacologic studies of this response indicate that it may result from the release of multiple endogenous mediators. Our data suggest that work in poultry farms may, for some workers, cause the development of acute and chronic respiratory symptoms and lung function changes.
Adult↗
Detection of a novel macrophage-derived mucus secretagogue (MMS-68) in bronchoalveolar lavage fluid of patients with asthma.
BACKGROUND: We have previously described a novel high-molecular-weight macrophage-derived mucus secretagogue (MMS-68) that causes mucuslike glycoconjugate release from cultured airways, nasal explants, and the Ishikawa adenocarcinoma cell line. We have generated monoclonal antibodies against MMS-68 and have developed an antigen-capture ELISA to measure MMS-68 levels in biologic fluids. Using this ELISA, we have demonstrated elevated levels of MMS-68 in the bronchoalveolar lavage fluid (BALF) of smokers and persons chronic bronchitis, in a patient with asthma and bronchorrhea, and in nasal lavage from patients with allergic rhinitis challenged with histamine and methacholine. We have also demonstrated that both spontaneous and lipopolysaccharide induced MMS-68 production is increased in the culture supernatants of monocytes from patients with steroid-dependent asthmas compared with those from normal control subjects. METHODS: To delineate further a role for MMS-68 in the regulation of mucus secretion in asthma, we measured MMS-68 levels in the BALF of 37 patients with non-steroid-dependent asthma and of 16 control subjects. RESULTS: There were 21 men and 16 women in the asthma group (age range, 17 to 62 years; mean, 33.8 years) and 11 men and five women in the control group (age range, 18 to 42 years; mean, 27.8 years). There were no statistical differences in either total cell count (145.5 x 103 +/- 75.7 cells/mm3 x 10(3) cells/mm3 vs 134 x 103 +/- 65.9 x 10(3) cells/mm3, p < 0.234) or numbers of alveolar macrophages (103.7 x 10(3) +/- 71.7 x 10(3)/mm3 vs 98.7 x 10(3) +/- 65 x 10(3) cells/mm3, p < 0.244) when the asthmatic group was compared with the control group. The MMS-68 level in the asthmatic group was 2.1 +/- 0.25 micrograms MMS-68 per milligram protein compared with 2.09 +/- 0.26 micrograms MMS-68 per milligram protein (p < 0.256) in the control group. CONCLUSIONS: There was no correlation between MMS-68 levels and total protein content, numbers of alveolar macrophages, or the production of other macrophage-derived cytokines including interleukin-1, interleukin-6, or tumor necrosis factor in the asthmatic BALF. Mild asthma, which is clinically not associated with mucus hypersecretion, was not associated with elevated levels of MMS-68. We believe that direct correlation exists between mucus hypersecretion and MMS-68 levels.
Adolescent↗
Regulation of mucin gene expression in secretory epithelial cells.
To gain insight into the regulation of mucin biosynthesis and secretion at a molecular level, we studied the expression of four mucin genes in several secretory cell types. Oligonucleotide probes for MUC1, MUC2, MUC3, and MUC4 were used in Northern blot analysis of total RNA from the cells. It was shown that MUC4 was constitutively expressed in the endometrial cell line (Ishikawa), which we use as a model system for studying airway mucin. Expression was enhanced by secretagogues. Cultured bronchial epithelial cells gave identical results. MUC1, MUC2, and MUC3 were not detected in either cell system. Secretory phase endometrial tissues also expressed only MUC4, but proliferative tissues expressed both MUC4 and MUC1. The data indicate that the mucin genes are differentially expressed in various cells and suggest a possible regulatory role for steroid hormones.
Blotting, Northern↗
In vivo detection of a novel macrophage-derived protein involved in the regulation of nasal mucus-like glycoconjugate secretion.
BACKGROUND: We recently described a novel 68 kd mucus secretagogue (MMS-68) derived from human monocytes, pulmonary macrophages, and a macrophage hybridoma, clone 63. We detected MMS-68 in monocyte culture supernatants from patients with steroid-dependent asthma and in bronchoalveolar lavage fluid from patients with chronic bronchitis by antigen capture ELISA and in normal lung tissue by immunohistochemistry. METHODS: To determine a role for MMS-68 in the regulation of nasal mucus, we labeled human nasal turbinates with tritiated glucosamine and assayed for the ability of the previously purified MMS-68 (stock solution) to induce mucus-like glycoconjugate release (MLGC). We also performed immunohistochemistry stains with an anti-MMS-68 antibody (1-D-10) on frozen sections (n = 5) of nasal turbinates from patients with allergic and nonallergic rhinitis who were undergoing rhinoplasty and measured MMS-68 levels in nasal lavages from patients who were undergoing topical nasal histamine or methacholine challenge. RESULTS: MMS-68 is a potent nasal MLGC secretagogue causing a dose-dependent increase in MLGC release in vitro. Staining revealed a subepithelial distribution for MMS-68. Antigen capture ELISA of nasal lavages demonstrated mean MMS-68 levels from saline control challenge of 0.9 +/- 0.5 micrograms MMS-68 per milligram of protein (n = 5), 8.6 +/- 1.4 micrograms MMS-68 per milligram of protein from histamine challenge and 20.7 +/- 2.3 micrograms MMS-68 per milligram of protein (n = 5) after methacholine challenge. CONCLUSION: Taken together these data suggest that MMS-68 may play a role in the normal regulation of mucus secretion.
Adult↗
Immunological and respiratory changes in animal food processing workers.
A group of 35 men employed in the processing of animal food was studied to assess the relation between respiratory findings and immunological status. The most frequent positive skin prick reactions to occupational allergens were to fish flour (82.9%), followed by carotene (77.1%), corn (65.7%), four-leaf clover (62.9%), sunflower (54.3%), chicken meat (31.4%), soy (28.6%), and yeast (22.7%). Increased total IgE serum levels were found in 14/35 (40.0%) animal food workers compared to 1/39 (2.6%) in a healthy population (p less than 0.01). A significantly higher prevalence of chronic respiratory symptoms was found among the exposed workers compared to control workers. There was however, no significant difference in the prevalence of chronic respiratory symptoms between animal food workers with positive and negative skin tests to house dust or to fish flour or among those with increased or normal IgE (except for dyspnea). The frequency of acute symptoms associated with the work shift was high among the animal food workers but similar by immunological status. There were significant mean across-shift reductions for all ventilatory capacity tests, being particularly pronounced for FEF25. Workers with positive skin tests to fish flour antigen had significantly larger across-shift reductions in FEF25 than workers with negative skin reactions. An aqueous extract of animal food dust caused a dose-related contractile response of isolated guinea pig tracheal muscle in vitro. Our data suggest that, in addition to any immunological response animal food dust may produce in vivo, it probably also causes direct irritant or pharmacological reactions on the airways as suggested by our in vitro data.
Adult↗
Isolation and characterization of a macrophage-derived high molecular weight protein involved in the regulation of mucus-like glycoconjugate secretion.
Pulmonary macrophages release a variety of mediators that are involved in inflammatory processes and probably are involved in respiratory mucus secretion. Conditioned media obtained from activated pulmonary macrophages were found to contain a protein that functioned as a secretagogue for mucus-like glycoconjugate (MLGC) in an in vitro bioassay. A human macrophage-derived hybridoma cell line, HB-63, exhibited the same properties and was very useful in obtaining large amounts of the protein for purification and characterization. With ultrafiltration membranes and gel electrophoresis, the protein isolated from the conditioned media of zymosan- or lipopolysaccharide-treated cells was found to have a molecular weight of approximately 68 kd. The purified protein obtained from hybridoma cells and from pulmonary macrophages exhibited strong biologic activity when it was used to stimulate MLGC secretion, both in human airway explants and in an in vitro human secretory epithelial cancer cell line. The proteins from both sources were found to have similar amino acid compositions. Preliminary results indicate the presence of the 68 kd protein in the bronchoalveolar lavage fluid of a patient with severe chronic bronchitis and mucus hypersecretion. The role of this novel protein in the lungs is, so far, speculative. The 68 kd protein may be a useful tool for studying the biosynthesis and regulation of MLGC secretion and hypersecretion.
Amino Acids↗
Immunological findings in hemp workers.
Immunological status and its relation to respiratory findings were studied in 42 female textile workers occupationally exposed to hemp dust and in 49 female control workers. Skin prick tests with hemp or flax dust extracts from different parts of the mill in hemp workers demonstrated the following frequencies of positive tests to antigens: a mixture of hemp and flax extracts (64%), followed by flax extracts (48%), hemp from combing machines (41%), hemp from carding machines (38%), hemp from spinning and weaving machines (33%), and hemp from softening machines (20%). The prevalence of positive skin tests to hemp or flax allergens in control workers was consistently lower, ranging from 21 to 5%. Increased total serum IgE was recorded in 35.7% of hemp workers compared to only 5.0% of control workers (P < 0.05). Hemp workers with positive skin tests had significantly higher prevalences of chronic respiratory symptoms than those with negative skin tests. There were, however, no differences for acute symptoms between workers with positive and negative skin tests. Across-shift changes and baseline lung function were not different when compared by immunologic status. We showed additionally that a water-soluble extract of hemp dust causes a dose-related contraction of nonsensitized guinea pig tracheal smooth muscle when studied in vitro. Our results suggest that frequent immunologic abnormalities can be documented in hemp workers but, with the exception of chronic respiratory symptoms, in general, these do not correlate with respiratory findings.
Adult↗
In vivo detection of a novel macrophage-derived protein involved in the regulation of mucus-like glycoconjugate secretion.
We previously described a novel 68,000 D macrophage-derived protein (MMS-68) that can stimulate mucus-like glycoconjugate (MLGC) secretion from cultured human airways, respiratory epithelial cells, and the ishikawa adenocarcinoma cell line. To better characterize this mucus secretagogue, we generated monoclonal antibodies against MMS-68 by injecting crushed SDS-PAGE gel slices containing this protein into Balb-C mice followed by fusion with SP2/0, a nonsecreting mouse myeloma cell line. A panel of monoclonal antibodies was produced that identified the 68,000 D MMS by immunoblot analysis and immunoprecipitation. The monoclonal antibodies detected MMS-68 in normal peripheral blood monocytes and pulmonary macrophages by cytofluorographic analysis and in human airways as determined by immunohistochemistry. Utilizing the monoclonal antibodies, an antigen-capture ELISA assay was developed. Statistically significant elevations in levels of MMS-68 were detected in bronchoalveolar lavage fluid (BALF) of chronic bronchitic subjects and cigarette smokers and in monocyte culture supernatants from steroid-dependent asthmatic patients compared to normal control subjects. The 68,000 D MMS is a potent secretagogue and may play an important role in the regulation of mucus secretion, especially in chronic bronchitis and steroid-dependent asthma.
Adult↗
Immunological and respiratory changes in soy bean workers.
Immunological and respiratory findings were studied in a group of 19 male soybean workers. Twenty control workers also participated in the immunological studies. All soybean workers had positive immediate skin reactions to soybean extract, as did 19/20 control workers. Similarly, 18/19 soy workers reacted to soy antigen prepared after separation from oil, but only 3/19 to soy lecithin antigen and 1 to soy oil antigen. A majority of soy workers (13/19) reacted to house dust. Only 3/19 soy workers had increased levels of soy-specific IgE. The prevalence of chronic respiratory symptoms was higher in exposed than in control workers, being significantly different for dyspnea (P less than 0.01). Workers with increased specific serum IgE or positive skin tests to house dust did not have any more symptoms than workers with negative tests. Ventilatory function was significantly worse in soybean workers than expected. Nevertheless, workers with positive skin or serological tests to house dust had across-shift changes similar to those with negative tests. These data suggest that skin and airway responses to soybean components (particularly the non-lipid ones) are very frequent among soybean workers. In the current study specific (soy) and non-specific (house dust) skin tests and immunoglobulins did not allow us to identify the workers at risk of developing symptoms or lung function abnormalities. This suggests that in addition to any atopic mechanisms, the irritant effect of soy dust may play a role in this occupational airway disease.
Adult↗
Mucus secretagogue production by a human macrophage hybridoma.
A pulmonary macrophage-monocyte-derived mucus secretagogue (MMS) oligopeptide has been previously reported to induce mucus secretion in an in vitro model system with human airway explants and secretory epithelial cells. To understand the possible role of macrophages in the regulation of secretion of mucus, our laboratory has used a series of human macrophage hybridomas that were generated by fusing an hypoxanthine guanine phosphoribosyl transferase-deficient promonocytic line, U937, with macrophages obtaining by maturing monocytes in Teflon bags. The cell lines were proven to be true hybridomas by acquisition of donor class I antigens, additional chromosomes, as well as macrophage specific (maximum velocity) not present on the U937 parent line. One clone, clone 63, produced large amounts of an oligopeptide with an approximate molecular weight of 2000, which was identified from culture supernatants by ultrafiltration, chromatography, isoelectric focusing, and Western blot. Processed clone 63 supernatant had biologic activity causing increased secretion of radiolabeled glycoconjugate in both cultured airways and secretory epithelial cells. Immunoblot analysis with a polyclonal rabbit antisera generated against MMS was positive, and Western blot analysis produced a band at approximately 2000 daltons, consistent with the previously described MMS. MMS secretion could be stimulated by zymosan and lipopolysaccharide and inhibited by both cycloheximide and erythromycin. Dexamethasone had a different effect, appearing to stimulate MMS production intracellularly but inhibiting its release once it was synthesized. The availability of cloned hybridomas allows for study of the regulation of mucus secretagogue production as well as purification of molecular species and provides a valuable tool for the study of mucus secretion.
Cell Line↗
Eosinophil cationic protein stimulates and major basic protein inhibits airway mucus secretion.
Possible roles of eosinophil (EO) products in modulating the release of mucus from airway explants were investigated. Cell- and membrane-free lysates from purified human EOs (1 to 20 x 10(5)) caused a dose-dependent release of respiratory glycoconjugates (RGC) from cultured feline tracheal explants. Crude extracts from isolated EO granules also stimulated RGC release, suggesting that a granular protein might be responsible. Three proteins derived from EO granules, EO-derived neurotoxin, EO cationic protein (ECP), and major basic protein (MBP) were separated by sequential sizing and affinity chromatography. ECP (0.025 to 25 micrograms/ml) caused a dose-dependent increase in RGC release from both feline and human airway explants and also stimulated the release of the serous cell-marker, lactoferrin, from human bronchial explants. EO-derived neurotoxin (0.025 to 50 micrograms/ml) failed to affect RGC release, whereas MBP (50 micrograms/ml) significantly inhibited RGC release from feline explants. Thus, ECP stimulates RGC and lactoferrin release from airway explants, whereas MBP inhibits RGC release.
Airway Obstruction↗
Immunological and respiratory findings in swine farmers.
The prevalence of respiratory symptoms and ventilatory capacity abnormalities in relation to immunological status was studied in 32 swine farmers and in 39 controls. A large number of swine farmers reacted to swine confinement building antigens (swine hair, 34%, swine confinement agents, 28%) but also to other extracts such as animal food (78%) and corn flour (37%). Control workers also reacted to these antigens in similar frequencies. Increased serum IgE levels were found in 3 swine farmers (9.4%) and all 3 had positive skin tests to at least one of the swine antigens. Among control workers one (2.6%) had an increased serum IgE level; this worker exhibited a positive skin reaction to swine food antigen. Swine farmers with positive skin reactions had across-shift reductions of FEF50 and FEF25 significantly larger than those with negative skin tests (P less than 0.01). Preshift measured ventilatory capacity data (FEV1, FEF50, FEF25) in swine farmers with positive skin tests were significantly lower (compared to predicted) than in those with negative skin tests. Additionally, we showed that a water-soluble swine confinement building antigen causes a dose-related contraction of nonsensitized guinea pig trachea smooth muscle studied in vitro. Our data indicate significant differences in lung function between swine workers with positive and negative skin tests. We suggest that skin testing may be helpful in identifying workers at risk for developing lung disease.
Adult↗
Functional antagonism between hormone receptor systems: modulation of glycoprotein secretion in secretory epithelial cells.
A physiologic response such as mucin secretion from epithelial cells in vivo may be under the control of several endogenous substances such as acetylcholine, norepinephrine, and vasoactive intestinal peptide (VIP). These substances may simultaneously activate distinct membrane receptors that exist on the same epithelial cells, and this activation may result in reciprocal physiologic responses or functional antagonism. To test whether simultaneous activation of the VIP and muscarinic receptors or of beta-adrenoreceptors and muscarinic receptors affect mucin secretion in a reciprocal manner, we studied some characteristics of the resultant physiologic response in human epithelial cells secreting radiolabeled mucin-like glycoprotein (MLGP). Both basal and methacholine (M.chol)-induced MLGP secretion could be blocked by VIP (1 pM to 1 microM) and by isoproterenol (ISO) (0.1 nM to 10 nM) in a concentration-dependent and reversible manner. In a membrane preparation from the same cells, VIP (1 to 1,000 nM) and ISO (0.1 to 10 microM) stimulated adenylyl cyclase activity in a concentration-dependent and nonadditive manner. In the same membrane preparation, no effect of M.chol was observed on this response to VIP or to ISO. It is proposed that functional antagonism at the cellular level between basal or cholinergic-stimulated mucin secretion and either activated beta-adrenergic or VIP receptors may play a crucial role in modulation of mucin secretion from epithelial cells.
Adenylyl Cyclases↗