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1.  Lung Structure and Function with Age in Normal Rats and Rats With Papain Emphysema 
Journal of Clinical Investigation  1973;52(11):2921-2927.
Intrapulmonary deposition of the proteolytic enzyme papain produces a lesion resembling emphysema in experimental animals. The natural history of this lesion has not been well defined. The present study was performed to evaluate changes in lung structure and function with aging in normal rats and rats exposed to an aerosol of papain at 2 mo of age. Groups of control and papain-exposed animals were studied at 4, 8, and 18 mo of age. The parameters of lung function studied were specific airways' conductance (Gaw/TGV), diffusing capacity per unit of alveolar volume (DLco/VA), diffusing capacity (DLco), and functional residual capacity (FRC). Morphometric parameters were the postfixation lung volume (VL) and mean chord length (LM); internal surface area (ISA) and ISA extrapolated to both the mean VL of the corresponding papain group and a VL of 10 ml (ISA10) were calculated.
At 4 mo of age LM and FRC were significantly increased and ISA, DLco/VA, and DLco were significantly reduced in the papain group. At 8 mo of age LM was significantly increased and ISA was significantly decreased in the papain group: physiologic studies were not performed in this group. At 18 mo of age LM was significantly increased and DLco/VA, DLco, and ISA were significantly decreased. Neither progression nor healing of the lesion was observed despite similar lung growth in both groups.
This study demonstrates that a single proteolytic lung injury produces a fixed deficit of lung parenchyma. Progressive lung destruction may require repeated or continuous lung injury.
PMCID: PMC302560  PMID: 4748515
2.  Sodium channel gating in clonal pituitary cells. The inactivation step is not voltage dependent 
The Journal of General Physiology  1989;94(2):213-232.
We have determined the time course of Na channel inactivation in clonal pituitary (GH3) cells by comparing records before and after the enzymatic removal of inactivation. The cells were subjected to whole- cell patch clamp, with papain included in the internal medium. Inactivation was slowly removed over the course of 10 min, making it possible to obtain control records before the enzyme acted. Papain caused a large (4-100x) increase in current magnitude for small depolarizations (near -40 mV), and a much smaller increase for large ones (approximately 1.5x at +40 mV). For technical reasons it was sometimes convenient to study outward INa recorded with no Na+ outside. The instantaneous I-V (IIV) curve in this condition was nonlinear before papain, and more nearly linear afterwards. The gNa-V curve after papain, obtained by dividing the INa-V curve by the IIV curve, was left- shifted by at least 20 mV and steepened. A spontaneous 5-10 mV left shift occurred in the absence of papain. The rate of the inactivation step was found to vary only slightly from -100 mV to +60 mV, based on the following evidence. (a) Before papain, inactivation rate saturated with voltage and was constant from +20 to +60 mV. (b) We activated the channels with a brief pulse, and studied the time course of the current on changing the voltage to a second, usually more negative level (Na+ present internally and externally). The time course of inactivation at each voltage was obtained by comparing control traces with those after inactivation was removed. When the 5-10-mV spontaneous shift was taken into account, inactivation rate changed by less than 10% from -100 to +60 mV. The data are considered in terms of existing models of the Na channel.
PMCID: PMC2228939  PMID: 2551998
3.  Airways obstruction, coal mining, and disability. 
It has recently been suggested that the inhalation of coal in the absence of complicated coal workers' pneumoconiosis (CWP) or smoking can lead to disabling airways obstruction. The cause of such obstruction has been variously attributed to emphysema or bronchitis. The frequency of significant airways obstruction in a group of United States coal miners seeking compensation for occupationally induced pulmonary impairment was therefore determined. In a sample of 611 "Black Lung" claimants there was only one subject who was a non-smoker and who in the absence of other non-occupationally related diseases,--for example, asthma and bronchiectasis--had sufficient airways obstruction to render it difficult for him to carry out hard labour. An alternative explanation for his reduced ventilatory capacity other than coal dust or smoking may be available. If the inhalation of coal dust in the absence of smoking and complicated CWP ever induces sufficient ventilatory impairment to preclude a miner from working, it is indeed rare.
PMCID: PMC1127953  PMID: 8199664
The intravenous injection of crystalline papain into young rabbits results in depletion of cartilage matrix throughout the body, with loss of rigidity and collapse of the ears, provided the enzyme is inactivated by oxidation or sulfhydryl blocking agents prior to administration. Cysteine-activated crystalline papain, when injected intravenously, produces little or no change in cartilage. The changes which occur in cartilage following an injection of inactivated crystalline papain are indistinguishable from those produced by crude papain. Activation of crude papain by cysteine prior to injection results in loss of its capacity to produce in vivo changes in cartilage. The progressive changes which take place in cartilage in vivo also occur in vitro in isolated rabbit ears removed shortly after an injection of crude papain or inactivated crystalline papain. In vitro ear collapse occurs rapidly at 37°C. and does not occur at 4°C. Collapse is enhanced by exposing the cartilage to cysteine and prevented by exposure to iodoacetamide or p-chloromercuribenzoate. The direct action of crystalline papain on plates of normal cartilage, in vitro, results in the same gross and histological changes which were observed in vivo. The direct action is accelerated by cysteine and inhibited by iodoacetamide or p-chloromercuribenzoate. The intravenous injection of iodoacetamide-treated bromelin produces the same in vivo changes in cartilage as papain. Untreated bromelin has no demonstrable effect on cartilage. It is suggested that the reason for the failure of activated papain to enter cartilage, after being injected intravenously, is that it probably reacts with a substrate or substrates in the blood. Oxidized or otherwise inactivated papain, in contrast, is readily taken up by cartilage and there converted to its active form.
PMCID: PMC2136872  PMID: 13575673
5.  Industrial bronchitis. 
For many years there has been much argument whether workers in the dusty trades are prone to chronic bronchitis. In 1966 the Medical Research Council issued a report of a Select Committee which concluded that occupationally induced bronchitis did not play a significant part in the aetiology of airways obstruction in dust-exposed men. Since then epidemiological studies have demonstrated that the prolonged inhalation of dust leads to an increase in prevalence of cough and sputum. Furthermore, new physiological techniques have demonstrated a slight decrement in ventilatory capacity as a result of industrial bronchitis, and which is related to lifetime dust exposure. Unlike bronchitis induced by cigarette smoke, the predominant effect of industrial bronchitis is on large rather than small airways and the condition is not accompanied by emphysema.
PMCID: PMC1008445  PMID: 367424
6.  Small airway hyperreactivity among lifelong non-atopic non-smokers exposed to isocyanates. 
The development of isocyanate asthma is little understood. To gain more knowledge in this area, a group of 20 workers occupationally exposed to isocyanates, five subjects with clinical isocyanate asthma, and a control group of 10 people not exposed to isocyanate were examined with lung function tests and a methacholine provocation test. Forced expiratory volume in one second and tests aimed at detecting small airways obstruction such as volume of trapped gas, closing volume, and wash out volume were made. To detect abnormal airway reactivity, tests were made before and after inhalation of methacholine and of salbutamol. A significant increased reactivity to methacholine in the exposed and asthma groups was seen compared with the control group as measured by volume of trapped gas. The increase was reversed by inhaling salbutamol. In neither group could a statistically significant reaction be shown in the large airways. The study group had increased small airways reactivity of the same magnitude as the group with isocyanate asthma. The subjects in the study group had no clinical symptoms or spirometric abnormalities. The volume of trapped gas in combination with methacholine seems to disclose significantly altered reactivity of the small airways in workers exposed to isocyanate with no subjective symptoms of disease.
PMCID: PMC1007927  PMID: 3689718
7.  Indices of asthma among atopic and non-atopic woodworkers 
Aims: To investigate the relation between wood dust exposure and different indices of asthma among woodworkers and non-exposed subjects.
Methods: A total of 302 woodworkers and 71 non-exposed subjects answered a respiratory health questionnaire, underwent a non-specific bronchial provocation test using the Yan method, and received a skin prick test with 12 common inhalant allergens. Subgroups performed repeated peak flow monitoring and underwent a reversibility test. A total of 347 dust measurements among 234 woodworkers were performed with passive dust monitors.
Results: The overall geometric mean (geometric standard deviation) exposure to inhalable dust was 0.96 (2.02) mg/m3. There was a tendency to increased risk of asthma among atopic woodworkers compared to atopic non-exposed subjects, with ORs between 3.0 (0.8–11.9) (symptomatic BHR) and 1.3 (0.5–4.2) (work related symptoms). In woodworkers, asthma was associated with atopy, with ORs between 7.4 (2.8–19.7) (symptomatic BHR) and 4.2 (2.4–7.7) (asthma symptoms). Asthma was related to dust level, most pronounced for symptomatic BHR among atopics, with OR 22.9 (1.0–523.6) for the highest compared to the lowest dust level. For work related asthma symptoms the association with dust level was seen only for non-atopics.
Conclusions: Wood dust exposure was associated with asthma, despite a low dust level compared to other studies. Atopy was an important effect modifier in the association between asthma and wood dust exposure.
PMCID: PMC1763653  PMID: 15150389
The catabolism of homologous and heterologous 7S gamma globulin fragments obtained by pepsin and papain digestion was studied in rabbits, guinea pigs, and mice. The elimination from the circulation of I* labeled gamma globulin fragments was followed and the urinary excretion of the total and protein-bound I* activity determined. Evidence is presented that the molecular structure responsible for the catabolism of 7S gamma globulin is located in papain fragment III. The elimination of papain fragment III was slow and closely related to the intact gamma globulin, whereas the pepsin fragment and papain fragments I and II were rapidly eliminated and catabolized in all species examined. Prolonged incubation with cysteine altered papain fragment III as shown by a rapid catabolism of a large portion of incubated fragment III within 24 hours after injection. Small amounts of intact RGG and RGG papain fragment III were excreted as protein-bound I* activity in the urine. On the other hand, large amounts of the pepsin fragment and papain fragments I and II of RGG were excreted as protein-bound I* activity in the urine. The possibility of a molecular structure present in papain fragment III, which may be responsible for tubular reabsorption in the kidney, is discussed. The rate of urinary excretion of fragments obtained from RGG was different from that of fragments obtained from gamma globulin of several other species. In general, small amounts of the pepsin fragment and papain fragment III obtained from gamma globulin other than RGG were excreted as protein-bound I* activity. The amounts of fragment I* excreted as protein-bound I* activity depended on the species in which it was injected, as well as the source of the gamma globulin. The rapid catabolism of the pepsin fragment and papain fragments I or II which bear antibody-combining sites suggest that their use for the prophylactic treatment of tetanus and diphtheria in man is limited.
PMCID: PMC2137959  PMID: 14271318
9.  Asthmagenic properties of a newly developed detergent ingredient: sodium iso-nonanoyl oxybenzene sulphonate. 
The suspicion that a newly developed detergent ingredient, sodium iso-nonanoyl oxybenzene sulphonate (SINOS), was inducing asthma among a workforce led to a series of inhalation challenge tests to determine the specificity and dose response characteristics of its asthma provoking properties. Three previously exposed workers, three non-exposed non-asthmatic controls, and three non-exposed asthmatic controls were challenged with SINOS 0.01-100 micrograms and another chemically similar surface active detergent ingredient, linear alkyl benzene sulphonate (LAS) 0.01-100 micrograms. Asthmatic symptoms, late falls in FEV1, and increases in non-specific bronchial responsiveness were seen after the inhalation of SINOS in all three workers, confirming SINOS as a cause of occupational asthma. No changes were seen after the inhalation of SINOS in either group of control subjects nor after LAS in any subject. These findings suggest that SINOS causes asthma through a specific hypersensitivity mechanism unrelated to its surface active properties.
PMCID: PMC1035191  PMID: 2165800
10.  Secondary prevention of allergic symptoms in a dairy farmer by use of a milking robot 
Animal-derived allergens include lipocalins which play an increasing role in occupational respiratory sensitizations. The prevention of sensitization in stock farming is often difficult due to intense exposure, with traditional milking still requiring close animal contact. Complete avoidance of allergen exposure is only possible if stock farming is abandoned. This is, however, often not feasible in small dairy plants because of the resulting loss of income.
Case presentation
In a 37-year-old female farmer daily asthmatic complaints appeared, associated with cow dust-derived allergen exposure by milking with a conventional device. Respiratory symptoms increased during a period of 12 years. Allergic bronchial asthma was diagnosed, caused by sensitization against cow dust-derived allergens, as demonstrated by positive skin prick test and by detection of IgE antibodies. In a separate specific inhalation challenge test using a 10% extract of cow dust-derived allergens a 330% increase of airway resistance was detected. To enable further dairy farming, a milking robot was installed in 1999, i.e., an automatic milking system. The novel milking technique reduced the daily exposure from over 2 hours to approximately 10 min. The clinical course after the installation of the milking robot was favourable, with less frequent allergic and asthmatic symptoms. Furthermore, asthma medication could be reduced. Improvement was noted also in terms of lung-function and decreased total serum IgE.
The case presented and the evidence from the literature indicates that the strategy of exposure minimization to allergens at workplaces can be an effective alternative to total elimination. In farmers with cow dust allergy a milking robot is an appropriate technical measure to minimize allergen-exposure.
PMCID: PMC1173128  PMID: 15972101
11.  Protective effect of drugs on bronchoconstriction induced by sulphur dioxide. 
Thorax  1982;37(9):671-675.
The response to inhaled sulphur dioxide in eight normal, seven atopic, and 22 asthmatic subjects was studied by measuring thoracic gas volume and airway resistance in a whole-body plethysmograph. The fall in specific airway conductance in relation to the concentration of sulphur dioxide inhaled (0-20 ppm) was determined in all three groups. The specific airway conductance fell significantly in the atopic and asthmatic subjects but not in the normal group. In a double-blind study prior inhalation of disodium cromoglycate caused a significant reduction in the response to sulphur dioxide inhalation in atopic and asthmatic subjects. Prior treatment with inhaled ipratropium bromide blocked the response in the atopic subjects, but the effect was variable in the patients with asthma. Previous treatment with inhaled clemastine also reduced the response in patients with asthma, without causing a change in baseline specific conductance. We conclude that non-allergic bronchial hyperreactivity was increased in the atopic and the asthmatic subjects and that mediator release, in addition to a vagal reflex, has a role in such bronchoconstriction.
PMCID: PMC459404  PMID: 6218648
The Journal of General Physiology  1940;23(3):275-288.
1. A study has been made of the properties of a hitherto unreported proteolytic enzyme from the latex of the milkweed, Asclepias speciosa. The new protease has been named asclepain by the authors. 2. The results of chemical, diffusion, and denaturation tests indicate that asclepain is a protein. 3. Like papain, asclepain dots milk and digests most proteins, particularly if they are dissolved in concentrated urea solution. Unlike papain, asclepain did not clot blood. 4. The activation and inhibition phenomena of asclepain resemble those of papain, and seem best explained on the assumption that free sulfhydryl in the enzyme is necessary for proteolytic activity. The sulfhydryl of asclepain appears more labile than that of papain. 5. The measurement of pH-activity curves of asclepain on casein, ovalbumin, hemoglobin, edestin, and ovovitellin showed no definite digestion maxima for most of the undenatured proteins, while in urea solution there were well defined maxima near pH 7.0. Native hemoglobin and ovovitellin were especially undigestible, while native casein was rapidly attacked. 6. Temperature-activity curves were determined for asclepain on hemoglobin, casein, and milk solutions. The optimum temperature was shown to increase with decreasing time of digestion.
PMCID: PMC2237932  PMID: 19873154
13.  Mucus glycoprotein secretion by tracheal explants: effects of pollutants. 
Tracheal slices incubated with radioactive precursors in tissue culture medium secrete labeled mucus glycoproteins into the culture medium. We have used an in vivtro approach, a combined method utilizing exposure to pneumotoxins in vivo coupled with quantitation of mucus secretion rates in vitro, to study the effects of inhaled pollutants on mucus biosynthesis by rat airways. In addition, we have purified the mucus glycoproteins secreted by rat tracheal explants in order to determine putative structural changes that might by the basis for the observed augmented secretion rates after exposure of rats to H2SO4 aerosols in combination with high ambient levels of ozone. After digestion with papain, mucus glycoproteins secreted by tracheal explants may be separated into five fractions by ion-exchange chromatography, with recovery in high yield, on columns of DEAE-cellulose. Each of these five fractions, one neutral and four acidic, migrates as a single unique spot upon cellulose acetate electrophoresis at pH values of 8.6 and 1.2. The neutral fraction, which is labeled with [3H] glucosamine, does not contain radioactivity when Na2 35SO4 is used as the precursor. Acidic fractions I-IV are all labeled with either 3H-glucosamine or Na2 35SO4 as precursor. Acidic fraction II contains sialic acid as the terminal sugar on its oligosaccharide side chains, based upon its chromatographic behavior on columns of wheat-germ agglutinin-Agarose. Treatment of this fraction with neuraminidase shifts its elution position in the gradient to a lower salt concentration, coincident with acidic fraction I. After removal of terminal sialic acid residues with either neuraminidase or low pH treatment, the resultant terminal sugar on the oligosaccharide side chains is fucose. These results are identical with those observed with mucus glycoproteins secreted by cultured human tracheal explants and purified by these same techniques.
PMCID: PMC1568460  PMID: 7408795
14.  Seasonal variation in non-specific bronchial reactivity: a study of wheat workers with a history of wheat associated asthma. 
Thorax  1988;43(2):103-107.
To investigate seasonal variation in non-specific bronchial reactivity in wheat workers, we carried out histamine inhalation tests in 29 workers (28 of them men) from a small farming community with symptoms of wheat associated asthma before, during and after the 1983-4 Australian wheat harvest season. Four were cigarette smokers, and the age range was 12-54 (mean (SD) 30 (10)) years. Twenty eight subjects were atopic (one positive skinprick test result in tests with 10 common antigens), 60% reacting to house dust mite and all to at least one of eight wheat antigens. Baseline spirometry gave normal results (mean FVC1 90% (SD 8%) predicted; FVC 91% (7%) predicted). Bronchial reactivity was tested by the method of Yan et al. The cumulative doses of histamine acid phosphate (up to 3.91 mumol) that caused a fall of 20% from baseline in FEV1 was determined (PD20) and expressed as the geometric mean. In the low exposure season, May 1983, nine subjects had a PD20 (mean 1.2, range 0.3-3.9 mumol). The number rose to 19 in the summer harvest season, December 1983 (mean 0.8, range 0.07-3.9 mumol) and returned to nine in the subsequent winter, July 1984 (mean 1.8, range 0.4-3.9 mumol). The change in the number of subjects with a PD20 was significant (p less than 0.01). Four additional subjects probably had increased bronchial reactivity in the harvest season: in two the post-saline FEV1 was too unstable to give them histamine challenge and in two the challenge was inadvertently discontinued prematurely. Baseline FEV1 and FVC fell by 8% between the first and second studies (p less than 0.001); values were intermediate in the third study (FEV1 3.74, 3.44, and 3.57; FVC 4.66, 4.28, and 4.41 litres respectively). Linear modelling analysis of log PD20, season, FEV1, FVC, age, seasonality of asthma symptoms and skin test data indicated that the harvest season was the only significant determinant of variation in log PD20. It is concluded that in these wheat workers there is a seasonal variation in bronchial reactivity that may reflect a response to allergens associated with grain.
PMCID: PMC1020750  PMID: 3353882
15.  Airway hyperresponsiveness and bronchial mucosal inflammation in T cell peptide‐induced asthmatic reactions in atopic subjects 
Thorax  2007;62(9):750-757.
Subjects with allergic asthma develop isolated late asthmatic reactions after inhalation of allergen‐derived T cell peptides. Animal experiments have shown that airway hyperresponsiveness (AHR) is CD4+ cell‐dependent. It is hypothesised that peptide inhalation produces increases in non‐specific AHR and a T cell‐dominant bronchial mucosal inflammatory response.
Bronchoscopy, with bronchial biopsies and bronchoalveolar lavage (BAL), was performed in 24 subjects with cat allergy 6 h after aerosol inhalation of short overlapping peptides derived from Fel d 1, the major cat allergen. Biopsy specimens and BAL fluid were studied using immunohistochemistry and ELISA.
Twelve of the 24 subjects developed an isolated late asthmatic reaction without a preceding early (mast cell/histamine‐dependent) reaction characteristic of whole allergen inhalation. These responders had significant between‐group differences (responders vs non‐responders) in the changes (peptide vs diluent) in AHR (p = 0.007) and bronchial mucosal CD3+ (p = 0.005), CD4+ (p = 0.006) and thymus‐ and activation‐regulated chemokine (TARC)+ (p = 0.003) but not CD8+ or CD25+ cells or eosinophils, basophils, mast cells and macrophages. The between‐group difference for neutrophils was p = 0.05 but with a non‐significant within‐group value (peptide vs diluent, responders, p = 0.11). In BAL fluid there was a significant between‐group difference in TARC (p = 0.02) but not in histamine, tryptase, basogranulin, C3a or C5a, leukotrienes C4/D4/E4, prostaglandins D2 or F2α.
Direct activation of allergen‐specific airway T cells by peptide inhalation in patients with atopic asthma leads to increased AHR with local increases in CD3+ and CD4+ cells and TARC but no significant changes in eosinophils or basophil/mast cell products. These findings support previous animal experiments which showed a CD4+ dependence for AHR.
PMCID: PMC2117301  PMID: 17389757
16.  Occupational asthma due to chrome and nickel electroplating 
Thorax  1997;52(1):28-32.
BACKGROUND: Exposure to chromium during electroplating is a recognised though poorly characterised cause of occupational asthma. The first series of such patients referred to a specialist occupational lung disease clinic is reported. METHODS: The diagnosis of occupational asthma was made from a history of asthma with rest day improvement and confirmed by specific bronchial provocation testing with potassium dichromate and nickel chloride. RESULTS: Seven workers had been exposed to chrome and nickel fumes from electroplating for eight months to six years before asthma developed. One subject, although exposed for 11 years without symptoms, developed asthma after a single severe exposure during a ventilation failure. This was the only subject who had never smoked. The diagnosis was confirmed by specific bronchial challenges. Two workers had isolated immediate reactions, one a late asthmatic reaction, and four a dual response following exposure to nebulised potassium dichromate at 1-10 mg/ml. Two of the four subjects were also challenged with nebulised nickel chloride at 0.1-10 mg/ml. Two showed isolated late asthmatic reactions, in one at 0.1 mg/ml, where nickel was probably the primary sensitising agent. Four workers carried out two hourly measurements of peak expiratory flow over days at and away from work. All were scored as having occupational asthma using OASYS-2. Breathing zone air monitoring was carried out in 60 workers from four decorative and two hard chrome plating shops from workers with similar jobs to those sensitised. No measurement exceeded the current occupational exposure standard for chromate or nickel, the mean levels of chromate exposure for jobs similar to those of the affected workers were 9-15 micrograms/m3. CONCLUSION: Chrome used in electroplating is a potential cause of occupational asthma. Sensitivity to chrome in electroplaters may occur in situations where exposure levels are likely to be within the current exposure standards. There may be cross reactivity with nickel. Inhalation challenge with nebulised potassium dichromate solution is helpful in making the specific diagnosis where doubt exists. 

PMCID: PMC1758409  PMID: 9039236
17.  Airway inflammation, basement membrane thickening and bronchial hyperresponsiveness in asthma 
Thorax  2002;57(4):309-316.
Background: There are few data in asthma relating airway physiology, inflammation and remodelling and the relative effects of inhaled corticosteroid (ICS) treatment on these parameters. A study of the relationships between spirometric indices, airway inflammation, airway remodelling, and bronchial hyperreactivity (BHR) before and after treatment with high dose inhaled fluticasone propionate (FP 750 µg bd) was performed in a group of patients with relatively mild but symptomatic asthma.
Methods: A double blind, randomised, placebo controlled, parallel group study of inhaled FP was performed in 35 asthmatic patients. Bronchoalveolar lavage (BAL) and airway biopsy studies were carried out at baseline and after 3 and 12 months of treatment. Twenty two normal healthy non-asthmatic subjects acted as controls.
Results: BAL fluid eosinophils, mast cells, and epithelial cells were significantly higher in asthmatic patients than in controls at baseline (p<0.01). Subepithelial reticular basement membrane (rbm) thickness was variable, but overall was increased in asthmatic patients compared with controls (p<0.01). Multiple regression analysis explained 40% of the variability in BHR, 21% related to rbm thickness, 11% to BAL epithelial cells, and 8% to BAL eosinophils. The longitudinal data corroborated the cross sectional model. Forced expiratory volume in 1 second improved after 3 months of treatment with FP with no further improvement at 12 months. PD20 improved throughout the study. BAL inflammatory cells decreased following 3 months of treatment with no further improvement at 12 months (p<0.05 v placebo). Rbm thickness decreased in the FP group, but only after 12 months of treatment (mean change –1.9, 95% CI –3 to –0.7 µm; p<0.01 v baseline, p<0.05 v placebo). A third of the improvement in BHR with FP was associated with early changes in inflammation, but the more progressive and larger improvement was associated with the later improvement in airway remodelling.
Conclusion: Physiology, airway inflammation and remodelling in asthma are interrelated and improve with ICS. Changes are not temporally concordant, with prolonged treatment necessary for maximal benefit in remodelling and PD20. Determining the appropriate dose of inhaled steroids only by reference to symptoms and lung function, as specified in current international guidelines, and even against indices of inflammation may be over simplistic. The results of this study support the need for early and long term intervention with ICS, even in patients with relatively mild asthma.
PMCID: PMC1746305  PMID: 11923548
18.  Relation of the perception of airway obstruction to the severity of asthma 
Thorax  1999;54(1):15-19.
BACKGROUND—Patients with a poor perception of their symptoms of asthma seem to have an increased risk of an asthma attack. The influence of factors such as airway calibre, bronchial hyperresponsiveness, age and sex on the "perceptiveness" of a patient are poorly understood. It is of clinical importance to identify patients who are likely to have a poor perception of their symptoms. We have studied the perception of bronchoconstriction by asthmatic patients during a histamine provocation test and analysed the influence of bronchial obstruction, hyperresponsiveness, sex, and age. We were particularly interested to establish whether there was any difference in perception between subjects with a greater or lesser severity of asthma (expressed as bronchial obstruction, hyperresponsiveness).
METHODS—One hundred and thirty four patients with allergic asthma underwent a histamine provocation test. The FEV1 was measured after each inhalation of histamine. Subjects were asked to rate subjective quantification of the sensation of breathlessness on a visual analogue scale (VAS). The relationship between changes in VAS values and the reduction in FEV1 as a percentage of the baseline value was analysed by determining the linear regression slope (α) between the two parameters and indicates the perception of airway obstruction. Multiple regression analysis was performed to investigate the effect of baseline FEV1, bronchial hyperresponsiveness, sex and age on the "perceptiveness" for bronchoconstriction.
RESULTS—The median value of the slope α (indicating the perception of airway obstruction) was 0.91 (25-75th percentile: 0.48-1.45). Age and sex had no influence on the perception of bronchoconstriction. Both initial bronchial tone (baseline FEV1) and bronchial hyperresponsiveness (PC20) showed a significant correlation with the perception of bronchoconstriction. The regression coefficients for FEV1 and 2log PC20 in the multiple regression model were 0.20 and 0.10.Patients who had a low baseline FEV1 and/or a high bronchial responsiveness to histamine were more likely to show a low perceptiveness for bronchoconstriction during the challenge test.
CONCLUSIONS—Low baseline FEV1 and high bronchial responsiveness are associated with a low degree of "perceptiveness" for bronchoconstriction. This suggests that patients with a more severe degree of asthma either show adaptation of "perceptiveness" for airway obstruction or that low perceptiveness leads to more severe asthma.

PMCID: PMC1745346  PMID: 10343625
19.  A comparative study of chromosome G-banding using trypsin, papain, and pretreatment with emulphogene. 
Journal of Clinical Pathology  1979;32(5):482-487.
G-banding of chromosome metaphase preparations derived from haemic cells of healthy individuals and from patients with acute myeloid leukaemia was performed with the aid of trypsin, papain, and pretreatment of the chromosome spreads with emulphogene before proteolytic digestion. Papain digestion revealed more distinguishable bands than did trypsin digestion. Pretreatment of the chromosome spreads with emulphogene greatly enhanced the number of distinguishable bands for both enzymes. The combination of pretreatment with emulphogene and digestion with papain revealed optimal numbers of bands for individual chromosomes essentially identical with those agreed at the Paris Conference 1971. The use of the emulphogene-papain technique appears also to offer an advantage in the banding of chromosomes from leukaemic cells.
PMCID: PMC1145711  PMID: 288744
20.  Relationship between exposure to domestic allergens and bronchial hyperresponsiveness in non-sensitised, atopic asthmatic subjects 
Thorax  2005;60(1):17-21.
Background: The effect of exposure to allergens not causing sensitisation in atopic asthmatic subjects has not previously been studied. A study was undertaken to assess the degree of asthma severity (measured by spirometry, airway reactivity and exhaled nitric oxide) in atopic asthmatic patients not sensitised to the domestic allergen to which they were exposed.
Methods: Dust samples were collected from the living room carpet and mattress in the homes of 248 subjects and dust mite, cat and dog allergen concentrations were measured. Spirometry, non-specific bronchial reactivity (BR), and exhaled nitric oxide (eNO) were ascertained. Patients' sensitisation status was assessed by skin prick testing.
Results: Adult atopic asthmatics not sensitised to mite but exposed to high levels of mite allergen had significantly more severe BR than subjects not exposed to high levels of mite (PD20, geometric mean (GM) 0.21 mg (95% CI 0.09 to 0.47) v 0.86 mg (95% CI 0.44 to 1.67), mean ratio difference 4.1 (95% CI 1.5 to 11.4), p = 0.008). Subjects not sensitised but exposed to high levels of dog allergen also had significantly more severe BR than subjects not exposed (PD20 GM 0.16 v 0.52 mg, mean ratio difference 3.3 (95% CI 1.2 to 9.2), p = 0.01). The differences in BR between these groups were still significant after adjusting for confounding factors. This effect of greater airway reactivity was not seen in subjects exposed but not sensitised to cat allergens.
Conclusion: Atopic asthmatic subjects who are exposed to high levels of dust mite or dog allergens but not sensitised to these allergens have evidence of increased airway reactivity.
PMCID: PMC1747172  PMID: 15618577
21.  Occupational asthma. 
Occupational asthma is probably much more common than is generally realized. Though many causes have been described, undoubtedly many more are yet to be recognized. One of the diagnostic difficulties lies in the fact that in most forms of this disease a late asthmatic reaction occurs in the evening rather than at work. The pathogenetic mechanisms differ in various forms of occupational asthma. In some, an immunologic mechanism is likely; in others, a "pharmacologic" action of the offending agent is implicated. Asthma due to inhalation of dusts of western red cedar, isocyanates, detergent enzymes and textiles is considered in detail. Periodic examination of workers at risk is of value for early diagnosis and prevention of irrversible airway obstruction.
PMCID: PMC1956851  PMID: 766943
Thymic stromal lymphopoietin (TSLP) is produced by epithelial cells and triggers dendritic cell-mediated Th2-type inflammation. While TSLP is upregulated in epithelium of patients with asthma, the factors that control TSLP production have not been studied extensively. Because mouse models suggest roles for protease(s) in Th2-type immune responses, we hypothesized that proteases from airborne allergens may induce TSLP production in a human airway epithelial cell line, BEAS-2B. TSLP mRNA and protein were induced when BEAS-2B cells were exposed to prototypic proteases, namely trypsin and papain. TSLP induction by trypsin required intact protease activity and also a protease-sensing G protein-coupled receptor, protease-activated receptor (PAR)-2; TSLP induction by papain was partially dependent on PAR-2. In humans, exposure to ubiquitous airborne fungi, such as Alternaria, is implicated in the development and exacerbation of asthma. When BEAS-2B cells or normal human bronchial epithelial cells were exposed to Alternaria extract, TSLP was potently induced. The TSLP-inducing activity of Alternaria was partially blocked by treating the extract with a cysteine protease inhibitor, E64, or by infecting BEAS-2B cells with small interfering RNA for PAR-2. Protease-induced TSLP production by BEAS-2B cells was enhanced synergistically by IL-4 and abolished by IFN-γ. These findings demonstrate that TSLP expression is induced in airway epithelial cells by exposure to allergen-derived proteases and that PAR-2 is involved in the process. By promoting TSLP production in the airways, proteases associated with airborne allergens may facilitate the development and/or exacerbation of Th2-type airway inflammation, particularly in allergic individuals.
PMCID: PMC2706924  PMID: 19561109
Humans; cytokines; allergy; inflammation; lung
23.  Protease Allergens Induce the Expression of IL-25 via Erk and p38 MAPK Pathway 
Journal of Korean Medical Science  2010;25(6):829-834.
Allergic diseases, including asthma, are characterized by T helper type 2 (Th2) cell-mediated inflammations, coupled with tissue infiltration by eosinophils. In this study, we demonstrate that multiple protease allergens, including papain and DerP1, efficiently induce interleukin (IL)-25 and thymic stromal lymphopoietin (TSLP) gene expression, and this phenomenon is dependent on the protease activities of these allergens. The IL-25 cytokine level in bronchial alveolar lavage (BAL) was also profoundly and significantly increased after treatment with papain. Additionally, the levels of Th2 cytokines were significantly increased, as compared to those in the OVA-only treatment group. The various protease allergens triggered the expression of IL-25 and TSLP mRNA in mouse lung epithelial cells (MLE12) and primary mouse lung epithelial cells; these effects were inhibited by the deactivation of the protease activity of papain. The allergen papain activates the ErK and p38 MAP pathways; the inhibition of these pathways, but not the NFκB or PI-3 kinase pathways, impairs the induction of IL-25 and TSLP expression by proteases. In this study, we demonstrate that the protease allergens induce IL-25 and TSLP via the MAP kinase signal pathways, and their protease activities are essential to this pathway.
PMCID: PMC2877219  PMID: 20514301
L-25; Thymic Stromal Lymphopoietin; Protease Allergen; Mitogen-Activated Protein Kinases
24.  Characterisation of phenotypes based on severity of emphysema in chronic obstructive pulmonary disease 
Thorax  2007;62(11):932-937.
Airflow limitation in chronic obstructive pulmonary disease (COPD) is caused by a mixture of small airway disease and emphysema, the relative contributions of which may vary among patients. Phenotypes of COPD classified purely based on severity of emphysema are not well defined and may be different from the classic phenotypes of “pink puffers” and “blue bloaters”.
To characterise clinical phenotypes based on severity of emphysema, 274 subjects with COPD were recruited, excluding those with physician‐diagnosed bronchial asthma. For all subjects a detailed interview of disease history and symptoms, quality of life (QOL) measurement, blood sampling, pulmonary function tests before and after inhalation of salbutamol (0.4 mg) and high‐resolution CT scanning were performed.
Severity of emphysema visually evaluated varied widely even among subjects with the same stage of disease. No significant differences were noted among three groups of subjects classified by severity of emphysema in age, smoking history, chronic bronchitis symptoms, blood eosinophil count, serum IgE level or bronchodilator response. However, subjects with severe emphysema had significantly lower body mass index (BMI) and poorer QOL scores, evaluated using St George's Respiratory Questionnaire (SGRQ), than those with no/mild emphysema (mean (SD) BMI 21.2 (0.5) vs 23.5 (0.3) kg/m2, respectively; SGRQ total score 40 (3) vs 28 (2), respectively; p<0.001 for both). These characteristics held true even if subjects with the same degree of airflow limitation were chosen.
The severity of emphysema varies widely even in patients with the same stage of COPD, and chronic bronchitis symptoms are equally distributed irrespective of emphysema severity. Patients with the phenotype in which emphysema predominates have lower BMI and poorer health‐related QOL.
PMCID: PMC2117136  PMID: 17573447
The Journal of General Physiology  1955;39(2):185-195.
1. Following intravenous administration of testes hyaluronidase in rabbits and dogs, there is a decrease in the level of the non-specific inhibitor of hyaluronidase in serum. 2. If a large amount of hyaluronidase is injected, the inhibitor level is reduced to zero and hyaluronidase may be present in serum for some time after the injection. The hyaluronidase activity of such samples of serum increases when the serum is incubated with papain. 3. Hyaluronidase activity is found in the livers of the injected animals in large amounts and this activity is increased considerably when the homogenate of this tissue is incubated with papain. 4. Intravenous administration of several proteases or venom produces a decrease in the serum inhibitor level. Intravenous administration of streptokinase produces such a decrease in rabbits but not in dogs. 5. There is a correlation between the depletion of the inhibitor from the serum and the occurrence of a slow, persistent depression of blood pressure upon administration of proteolytic enzymes.
PMCID: PMC2147534  PMID: 13271719

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