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PubMed1999

IL-4 and IL-5 mRNA expression in induced sputum of asthmatic subjects: comparison with bronchial wash.

BACKGROUND: The local production of TH2 -type cytokines is thought to orchestrate the ongoing eosinophilic inflammation and contribute to the pathophysiologic features of allergic asthma. Previous studies investigating cytokine expression in asthmatic individuals have used invasive fiberoptic bronchoscopy techniques. To date, there have been no reports of cytokine mRNA expression in induced sputum as a means of quantifying local inflammatory events. OBJECTIVES: We examined whether IL-4, IL-5, and IFN-gamma mRNA expression could be detected in cells from induced sputum in subjects with mild asthma and normal control subjects. In addition, we compared the profile of inflammatory cells and cytokine mRNA in sputum and bronchial wash fluid. METHODS: Cells positive for IL-4, IL-5, and IFN-gamma mRNA were determined by using in situ hybridization on cytospun aliquots of sputum induced by successive inhalations of hypertonic saline. Inflammatory cells were quantified by using immunologic cell surface markers and immunocytochemistry. RESULTS: IL-4 and IL-5 mRNA were detected in the sputum of all asthmatic subjects, and the number of cells expressing these cytokines was significantly higher than that found in control subjects. Colocalization studies showed CD3-positive T cells were the major sources of IL-4 and IL-5 mRNA. CONCLUSIONS: This study demonstrates that induced sputum can be used to detect mRNA for TH2 -type cytokines in bronchial asthma and that the increase in IL-4 and IL-5 mRNA expression is similar to that seen with more invasive techniques. The qualitative differences in inflammatory cell numbers between sputum induction and bronchial wash are consistent with their sampling of different airway compartments.

Adult↗
PubMedDate not supplied

Induced sputum versus gastric lavage for microbiological confirmation of pulmonary tuberculosis in infants and young children: a prospective study.

BACKGROUND: For microbiological confirmation of diagnosis of pulmonary tuberculosis in young children, sequential gastric lavages are recommended; sputum induction has not been regarded as feasible or useful. We aimed to compare the yield of Mycobacterium tuberculosis from repeated induced sputum with that from gastric lavage in young children from an area with a high rate of HIV and tuberculosis. METHODS: We studied 250 children aged 1 month to 5 years who were admitted for suspected pulmonary tuberculosis in Cape Town, South Africa. Sputum induction and gastric lavage were done on three consecutive days according to a standard procedure. Specimens were stained for acid-fast bacilli; each sample was cultured singly for M tuberculosis. FINDINGS: Median age of children was 13 months (IQR 6-24). A positive smear or culture for M tuberculosis was obtained from 62 (25%) children; of these, 58 (94%) were positive by culture, whereas almost half (29 [47%]) were smear positive. Samples from induced sputum and gastric lavage were positive in 54 (87%) and 40 (65%) children, respectively (difference in yield 5.6% [1.4-9.8%], p=0.018). The yield from one sample from induced sputum was similar to that from three gastric lavages (p=1.0). Microbiological yield did not differ between HIV-infected and HIV-uninfected children (p=0.17, odds ratio 0.7 [95% CI 0.3-1.3]). All sputum induction procedures were well tolerated; minor side-effects were increased coughing, epistaxis, vomiting, or wheezing. INTERPRETATION: Sputum induction is safe and useful for microbiological confirmation of tuberculosis in young children. This technique is preferable to gastric lavage for diagnosis of pulmonary tuberculosis in both HIV-infected and HIV-uninfected infants and children.

AIDS-Related Opportunistic Infections↗
PubMedDate not supplied

[Induced sputum in asthma: study of validity and repeatability].

To assess the validity and reproducibility of determining total and differential cell (DC) counts and of eosinophilic cationic protein (EPC) levels in induced sputum. Clinical analysis of validity and reliability of a measurement tool. Twenty-one asthmatics [age: 31(14) years; FEV1: 78(21)% of reference value; PC20FEV1: 0.02(1.1)mg/ml] and 10 healthy subjects [age: 30(3) years, FEV1: 99(12)% of reference value, PC20FEV1: > 8(3.7)mg/ml]. A sputum sample was collected from each individual using hypertonic saline. Sputum was separated from saliva and then divided into two portions as uncontaminated as possible by squamous cells. Both portions were treated independently and simultaneously within two hours with a solution of bithiothreitol to disperse the cells, and then centrifuged. The supernatant was poured off and frozen al -70 degrees for later determination of EPC. The sediment was stained with Papanicolaou stain, toluidine blue and eosinhematoxylin. DC count was expressed as a percentage of total inflammatory cells. ECP was determined with a CAP-System and a commercial kit (Pharmacia Diagnostics SA, Uppsala, Sweden). Two subjects in each group were unable to produce valid sputum samples (20% of healthy subjects and 10% of asthmatics). The validity of the method was demonstrated by significant differences between asthmatics and healthy subjects in both eosinophil and EPC levels. The reproducibility of method was verified by comparing the results for the sputum fractions; no significant differences were found in cell counts or EPC levels. The within-group correlation coefficients for the sputum fractions ranges between 48 and 77% for all cell types, except squamous cells, which gave a coefficient of 18%. For EPC the correlation coefficient was 98%. DC and EPC determinations in sputum induced by hypertonic saline are valid and reproducible.

Adult↗
PubMed2002

Lung surgery: identifying the subgroup at risk for sputum retention.

OBJECTIVES: Sputum retention after lung surgery is a potentially lethal condition, which can progress to atelectasis, pneumonia and respiratory failure requiring ventilatory support. Previous studies have concentrated on the treatment of postoperative respiratory complications but few have studied the risk factors for sputum retention. This prospective study was designed to identify the risk factors which may lead to the development of sputum retention after lung surgery. METHODS: Three hundred sixty-one patients underwent lung surgery between January 1997 and December 1999 in a specialist Thoracic Surgery Unit (pneumonectomy, lobectomy, wedge or segmental resection, bullectomy, etc). Preoperative and intraoperative data collected prospectively included potential risk factors: chronic obstructive airway disease (COAD), forced expiratory volume in 1 s (FEV1)<50%, current smokers, ischaemic heart disease (IHD), cerebrovascular disease (CVA), resection of phrenic or recurrent laryngeal nerve, or absence of regional analgesia. Univariate and multivariate analysis was performed. RESULTS: Sputum related complications occurred in 108 patients (30%). There were 17 deaths of which nine were due to complications related to sputum retention. Univariate analysis confirmed current smokers (n=128), COAD (n=103), IHD (n=41), prior history of CVA (n=16), FEV1<50% (n=48), and absence of regional anaesthesia as significant risk factors (P<0.01). The multivariate analysis confirmed current smokers, IHD and absence of regional anaesthesia as risk factors. CONCLUSIONS: A subgroup of lung surgery patients at high risk for postoperative sputum retention can be predicted by the presence of one of the following criteria: current smokers, history of COAD, CVA, or IHD, and absence of regional analgesia. Prophylactic measures should be considered in this group to reduce the incidence of sputum retention.

Aged↗
PubMed2005

Total eosinophil cationic protein levels in induced sputum as a marker of changes in eosinophilic inflammation in a patient with allergic asthma.

BACKGROUND: Counting eosinophils in induced sputum seems to be a better way to survey disease activity than indirect clinical assessments of airway inflammation, such as pulmonary function measurement. The conventional analysis of induced sputum, however, is time-consuming and requires skilled personnel, which have restricted its use. OBJECTIVE: To determine whether measuring eosinophil cationic protein (ECP) levels in the entire sputum sample could replace the method of counting eosinophils and measuring ECP levels in the supernatant only to establish a clinically more applicable method of studying the intraindividual changes in eosinophilic activity in induced sputum. METHODS: In 13 patients with mild, nonsymptomatic allergic asthma, sputum was induced before and 24 hours after allergen challenge. The entire sputum sample was diluted with 0.1% dithiothreitol, incubated, and divided into 2 parts. One part was processed according to the conventional method, and released ECP levels in the supernatant were measured. The second part was treated with a lysing reagent. Cell debris was separated, and total (intracellular and extracellular) ECP levels in the solution were measured. RESULTS: We found good correlation between total ECP levels in the entire sputum sample and released ECP levels in the supernatant before (r = 0.97) and 24 hours after (r = 0.99) allergen challenge (P < .01 for both). We also found a good correlation between the changes in total and released ECP levels (r = 0.99; P < .01). CONCLUSIONS: Total ECP concentration seems to reflect the eosinophilic inflammatory changes in asthma and might be a useful tool in clinical practice.

Adult↗
PubMed2005

Effect of histamine and adenosine 5'-monophosphate provocation on sputum neutrophils and related mediators in atopic patients.

BACKGROUND: Airway hyperresponsiveness and inflammation can be noninvasively studied by bronchial provocation using direct (histamine) or indirect (adenosine 5'-monophosphate [AMP]) stimuli and induced sputum. OBJECTIVE: To report on the immediate effects of histamine and AMP challenge on induced sputum neutrophil counts and related mediator levels. METHODS: We performed a single-masked, randomized, placebo-controlled, 3-way, crossover, methodological study in 14 atopic patients (median age, 25 years; 8 males; mean +/- SD forced expiratory volume in 1 second, 99% +/- 5%) without anti-inflammatory medication use. At baseline, sputum induction was performed. Bronchial challenges with AMP, histamine, or placebo were performed 48 hours later. Thirty minutes after challenge, sputum induction was performed again. Challenge periods in each patient were separated by more than 2 weeks. Sputum cells and the mediators leukotriene B4, interleukin 8, myeloperoxidase, and albumin were quantified. RESULTS: Comparing median challenge-induced relative changes in cells and mediators, neither histamine nor AMP challenge altered the induced sputum neutrophil counts (histamine, 2.7%; AMP, 2.95%; placebo, -2%; P > .07 for all), interleukin 8 levels (histamine, 2.4 ng/mL; AMP, -3.8 ng/mL; placebo, -0.2 ng/mL; P > .06), leukotriene B4 levels (histamine, -4.8 pg/mL; AMP, 3 pg/mL; placebo, 6 pg/mL; P > .08), or myeloperoxidase levels (histamine, 0.16 microg/mL; AMP, 0 microg/mL; placebo, -0.03 microg/mL; P > .07). Sputum albumin levels were increased after histamine challenge compared with AMP and placebo challenge (P < .01 for both). CONCLUSIONS: Histamine and AMP provocation have no major effects on induced neutrophil counts and related mediator levels in atopic patients, whereas histamine challenge induces plasma leakage. Potential interactions of noninvasive methods to evaluate airway reactivity and inflammation should be carefully considered.

Adenosine Monophosphate↗
PubMed2004

Glutathione and nitrite in induced sputum from patients with stable and acute asthma compared with controls.

BACKGROUND: Oxidative stress is believed to play an important role in the pathogenesis of asthma. Determining the reduced glutathione (GSH) and nitric oxide (NO) contents of the airway is useful when investigating oxidative stress in the lung. OBJECTIVE: To explore antioxidant defenses by measuring sputum GSH levels and to evaluate oxidant stress by measuring sputum nitrite (NO2-) levels in asthma patients. METHODS: Sputum GSH, NO2-, cell counts, and plasma NO2- contents were evaluated in 11 patients with stable asthma, 10 patients with acute asthma attacks, and 11 controls. RESULTS: The highest GSH content in sputum samples was in stable asthma patients compared with the other groups (P < .001), and patients with exacerbations of asthma had a greater GSH content than controls (P < .001). Mean sputum NO2- content was significantly lower in controls than in acute (P = .001) and stable (P < .001) asthma patients. There was no significant difference in sputum NO2- contents between acute and stable asthma patients, although there was a trend toward higher levels in acute asthma patients (P = .38). CONCLUSIONS: Sputum induction can be used to obtain bronchial secretions for the evaluation of GSH and NO2- contents. Oxidative stress is chronic and probably less severe in patients with stable asthma. Glutathione and NO2- may serve as markers for determining the extent of the oxidative processes in asthma, which is characterized by chronic airway inflammation.

Acute Disease↗
PubMed1999

Analysis of induced sputum to examine the effects of inhaled corticosteroid on airway inflammation in children with asthma.

BACKGROUND: Analysis of induced sputum can be performed safely in children with asthma and is useful for both cellular and biochemical markers of inflammation. Glucocorticosteroid inhalation has become the first line therapy for chronic asthma by suppressing airway inflammation, which produces the decrease of bronchial hyperreactivity and reduces the number of eosinophil in bronchial submucosa. OBJECTIVE: To determine the characteristics of the inflammatory cells and their markers in sputum and to examine the pharmacokinetic effects of glucocorticoid within 3 hours after inhalation therapy on FEV1 and sputum inflammatory indices in children with clinically defined chronic asthma. METHODS: Thirty subjects with asthma included 14 current symptomatic asthmatics and 14 normal controls inhaled 4.5% hypertonic saline for 10 minutes by nebulizer. The expectorated sputum were collected from all asthmatics before and 3 hours after corticosteroid inhalation for children with asthma and were reduced by dithiotreitol. Total cell counts and differentials were determined. ECP was measured by CAP system. Interleukin-5, GM-CSF and albumin were measured by double sandwich ELISA. RESULTS: The mean eosinophil percentage and ECP in induced sputum of asthmatics were significantly higher than that of controls. The induced sputum samples obtained after glucocorticoid inhalation showed a significant reduction in mean eosinophil percentage, but FEV1, IL-5, GM-CSF, albumin, and ECP values were not significantly decreased. CONCLUSION: The present results in induced sputum may be interpreted to reflect direct steroid action on airways and lack of effect on bone marrow effectors at 3 hours after glucocorticoid inhalation.

Administration, Inhalation↗
PubMed2001

Correlation between airway hyperresponsiveness and airway inflammation in a young adult population: eosinophil, ECP, and cytokine levels in induced sputum.

BACKGROUND: Eosinophil counts and eosinophil cationic protein (ECP) levels in the airway are elevated in asthmatic patients. However, few studies have examined the correlation between various cytokines in the sputum and airway hyperresponsiveness (AHR) in young adults with or without asthma. OBJECTIVE: We examined the correlation between AHR and eosinophil counts or ECP, and levels of several cytokines in the sputum. METHODS: We studied 120 nonsmoker students (group 1: intermittent mild asthmatic patients; group 2: subjects with history of childhood asthma; group 3: subjects sensitized by Dermatophagoides farinae with atopic disease; group 4: normal subjects sensitized by D. farinae; group 5: subjects with cedar pollinosis; and group 6: normal subjects). In each subject, AHR and lung function tests were measured, together with eosinophil count, ECP, granulocyte-macrophage colony-stimulating factor, TNF-alpha, IL-5, and interleukin-1beta in induced sputum. RESULTS: AHR in groups 1 and group 2 were high, in groups 5 and 6 low, and in groups 3 and 4 lower than in groups 1 and 2 but higher than groups 5 and 6. Percentages of eosinophils, ECP, and TNF-alpha in induced sputum in groups 1 and 2 were high, those in groups 5 and 6 were below detection limits, and those in groups 3 and 4 were lower than the percentages in groups 1 and 2. Granulocyte-macrophage colony-stimulating factor in the sputum was elevated only in group 1. The correlations between AHR and sputum eosinophil count, ECP, and TNF-alpha were significant, with the strongest correlation with TNF-alpha. CONCLUSIONS: Our results suggest that TNF-alpha levels in the sputum play an important role in determining the severity of AHR in young individuals. Further once AHR develops, it does not disappear, and the severity of airway inflammation influences the extent of AHR.

Adult↗
PubMed1999

Airway mast-cell activation in asthmatics is associated with selective sputum eosinophilia.

BACKGROUND: Tryptase is a serine endoprotease selectively released from mast cells. Although mast cells are known to be activated after experimental allergic provocation, their role in naturally occurring asthma is still debated. METHODS: We have investigated the levels of tryptase in the whole induced sputum collected from 51 asthmatics (31 atopic and 20 intrinsic) seen in our outpatient clinic and 22 normal nonatopic healthy volunteers. Tryptase was measured by a new immunoassay based on B12 monoclonal antibody recognition of total tryptase (UniCAP System, Pharmacia) with a sensitivity of 1 ng/ml. RESULTS: While being below the threshold of detection in all normal volunteers, tryptase was detectable in the sputum from 9/51 asthmatics (18%) including five atopic and four intrinsic asthma cases. In these patients, among whom three were asymptomatic asthmatics, the values ranged between 1 and 6.1 ng/ml. The asthmatics with detectable sputum tryptase had greater sputum eosinophil counts (P<0.05) but lower neutrophil counts (P<0.05) than those in whom tryptase was undetectable. When compared to control subjects, asthmatics without tryptase had still greater eosinophil counts (P<0.0001) but also raised neutrophil counts (P<0.05). No significant difference could be found between asthmatics with tryptase and those without tryptase with respect to the age, the baseline lung function, the methacholine bronchial responsiveness, and the frequency of treatment with inhaled steroids. CONCLUSIONS: With the UniCAP System, tryptase was detectable in the sputum from 18% of asthmatics irrespective of atopy and current symptoms. Asthmatics with tryptase appeared to have a selective increase in sputum eosinophil counts while those without tryptase displayed a mixed sputum granulocyte infiltration with raised eosinophil and neutrophil counts.

Adolescent↗
PubMed1998

The effect of mucolytic agents on gene transfer across a CF sputum barrier in vitro.

Trials of gene transfer for cystic fibrosis (CF) are currently underway. However, direct application to the airways may be impeded by the presence of airway secretions. We have therefore assessed the effect of CF sputum on the expression of the reporter gene beta-galactosidase complexed with the cationic liposome DC-Chol/DOPE in a number of cell lines in vitro. Transfection was markedly inhibited in the presence of sputum; the effect was concentration dependent and was only partially ameliorated by removal of sputum with phosphate-buffered saline (PBS) washing before gene transfer. However, treatment of the sputum-covered cells with recombinant human DNase (rhDNase, 50 micrograms/ml) but not with N-acetylcysteine, Nacystelyn, lysine (all 20 mM) or recombinant alginase (0.5 U/ml) significantly (P < 0.005) improved gene transfer. Adenovirus-mediated gene transfer efficiency in the presence of sputum was similarly inhibited, and again, treatment with rhDNase before transfection significantly improved gene transfer (P < 0.005). Transfection of Cos 7 cells in the presence of exogenous genomic DNA alone demonstrated similar inhibition to that observed with sputum and was also ameliorated by pre-treatment of DNA-covered cells with rhDNase. In a separate series of experiments performed in the absence of added sputum or genomic DNA, increasing concentrations of rhDNase resulted in a concentration-related decline in transfection efficiency. However, even at the highest concentration (500 micrograms/ml of rhDNase), transfection efficiency remained more than 50% of control. Thus, pre-treatment of CF airways with rhDNase may be appropriate before liposome or adenovirus-mediated gene therapy.

Adenoviridae↗
PubMed1999

The effect of montelukast (MK-0476), a cysteinyl leukotriene receptor antagonist, on allergen-induced airway responses and sputum cell counts in asthma.

BACKGROUND: Cysteinyl leukotrienes are capable of inducing chemotaxis of eosinophils in vitro and within the airways of animals and humans in vivo. OBJECTIVE: We hypothesized that montelukast (MK-0476), a potent cysLT1 receptor antagonist, would protect against allergen-induced early (EAR) and late (LAR) asthmatic responses by virtue of anti-inflammatory properties. Hence, we studied the effect of pretreatment with oral montelukast on allergen-induced airway responses. As an exploratory endpoint, changes in inflammatory cell differentials and eosinophil cationic protein (ECP) were evaluated in hypertonic saline-induced sputum. METHODS: Twelve asthmatic men (20-34 years, FEV1 79-109% predicted, histamine PC20FEV1 <4 mg/mL) with dual responses to inhaled house dust mite extract participated in a two-period, double-blind, placebo-controlled, crossover study. Three oral doses of montelukast (10 mg) or matching placebo were administered 36 and 12 h before, and 12 h post-allergen. The airway response to allergen was measured by FEV1, and the EAR and LAR were expressed as the corresponding areas under the time-response curves (AUC0-3 h and AUC3-8h, respectively). During each study period, sputum was induced with 4.5% NaCl 24 h before and 24 h after a standardized allergen challenge. Processed whole sputum cytospins were stained with Giemsa, and cell counts expressed as percentage nonsquamous cells. ECP was measured by FEIA in sputum supernatants. RESULTS: All subjects completed the study. The changes in baseline FEV1 were not significantly different between the two pretreatments (P = 0.183). Montelukast significantly inhibited the EAR and LAR, reducing the AUC0-3h by 75.4% (P<0.001) and the AUC3-8h by 56.9% (P = 0.003) as compared with placebo. Sputa of nine subjects could be included in the analysis (<80% squamous cells). Allergen challenge significantly increased sputum eosinophils after placebo (mean change +/- SD: 4.8 +/- 5.8%, P = 0.038), with a similar trend after montelukast (mean change +/- SD: 4.1 +/- 5.4%; P = 0.056). The allergen-induced changes in sputum eosinophils and ECP, however, were not significantly different between the two pretreatments (P = 0.652 and P = 0.506, respectively). CONCLUSION: We conclude that oral montelukast protects against allergen-induced early and late airway responses in asthma. However, using the present dosing and sample size, this protection was not accompanied with changes in sputum eosinophil percentage or activity, which may require more prolonged pretreatment with cysLT1 receptor antagonists.

Acetates↗
PubMed2001

Immuno-regulatory cytokines in asthma: IL-15 and IL-13 in induced sputum.

BACKGROUND: The importance of Th2-type lymphocyte function in asthmatic airway inflammation is well recognized, but less is known about the factors which regulate the function of these lymphocytes in asthma. The macrophage-derived cytokine, interleukin (IL)-15 has a number of T cell regulatory properties which might be of relevance to asthma and its treatment. OBJECTIVE: The aims were to identify and quantify the T cell regulatory cytokine IL-15 in induced sputum samples from asthmatic patients, in comparison with IL-13, and to relate the levels of these cytokines to treatment with inhaled steroids. METHODS: Induced sputum was collected from 16 asthmatics (eight steroid and eight non-steroid treated) and eight normal controls. IL-15 and IL-13 levels were measured by enzyme-linked immunoassay (ELISA) in sputum. IL-15 levels were also measured in sputum cell culture supernatants and localized to specific sputum cells by immuno-cytochemistry. RESULTS: IL-15 levels were increased and IL-13 levels were decreased in sputum fluid from steroid-treated compared with non-steroid-treated asthmatics. IL-15 was localized specifically to macrophages and the proportion of these cells expressing IL-15 correlated with sputum fluid IL-15 and IL-15 levels in cell culture supernatants, and all were higher in the steroid-treated asthmatics. CONCLUSION: IL-15 and IL-13 production appears to be reciprocally regulated by steroid therapy in asthma patients. The steroid-associated increase in IL-15 may regulate a fundamental shift away from an inflammatory Th2-type environment in asthma and may be an essential component of the cytokine modulation underlying the therapeutic benefit of corticosteroids in this condition.

Adult↗
PubMed2001

Safety of sputum induction with isotonic saline in adults with acute severe asthma.

BACKGROUND: Sputum induction is a safe and effective technique to study airway inflammation in stable asthma. However, it has the potential to induce bronchospasm and the safety and efficacy of the technique in acute asthma has not been determined. OBJECTIVE: The objective of this study was to evaluate the safety and efficacy of a protocol to induce sputum using isotonic saline in adults with acute exacerbations of asthma. METHODS: Adults (n = 47) presenting to the emergency room with acute asthma and an FEV1 > 1.0 L underwent supervised sputum induction with 0.9% saline delivered by an ultrasonic nebuliser. Induction was ceased if there was a fall of 20% or greater from baseline FEV1. RESULTS: Subjects had moderate to severe exacerbations of acute asthma. An adequate sputum sample was obtained in 87% of subjects. Four subjects ceased induction because of symptom distress. There was a fall > or = 20% in 28% of subjects. Bronchoconstriction was successfully reversed by salbutamol in all subjects. Predictors of significant bronchoconstriction were older age, use of ingested corticosteroids, and a requirement for high-dose nebulized salbutamol for the exacerbation. Maintenance long-acting beta2-agonist therapy protected against bronchoconstriction during sputum induction. CONCLUSIONS: Sputum induction in acute asthma using isotonic saline is highly efficacious in obtaining an adequate sputum sample. There is the potential for significant bronchoconstriction to occur but this can be managed safely with minimal discomfort to subjects.

Acute Disease↗
PubMed2003

Metalloproteinase-9 is increased after toluene diisocyanate exposure in the induced sputum from patients with toluene diisocyanate-induced asthma.

BACKGROUND AND OBJECTIVE: Persistent asthma symptoms are associated with airway inflammation and remodeling, which may be mediated through metalloproteinase (MMP) and tissue inhibitor of metalloproteinase (TIMP). The aim of this study was to evaluate MMPs and TIMP involvement in toluene diisocyanate (TDI)-induced asthma. MATERIALS AND METHOD: Induced sputum was collected in eight newly diagnosed TDI-induced asthma subjects (group I) before and 7 h after the TDI and placebo challenges and in 12 subjects with TDI-induced occupational asthma diagnosed 5 years previously with persistent asthma symptoms (group II). Sera was collected in group I at diagnosis, and in group II, they were collected at the time of the study. 12 nonasthmatic healthy subjects were enrolled as controls. MMP-9, MMP-2 and TIMP-1 levels in both sputum and serum were measured by enzyme-linked immunosorbent assay (ELISA). Gelatinase activity in the sputum was confirmed by zymographic analysis. RESULTS: The serum TIMP-1 level was significantly higher in asthma patients than in healthy controls (P = 0.01), while MMP-9 level was significantly lower in asthmatic patients (P = 0.03). There was no significant difference in MMP-2 level (P = 0.27). MMP-9 level in the sputum was significantly increased after the TDI challenges (P = 0.01). TIMP-1 level in sputum tended to increase after TDI challenges, but no statistical significance was noted (P = 0.09). MMP-9 and MMP-9/TIMP-1 levels in the sputum were significantly higher in group II than in group I (P = 0.04, P = 0.02) with no significant difference in TIMP-1 level. Minimal amount of MMP-2 was found in sputum. Zymography demonstrated that MMP-9 level increased and active form of MMP-9 was generated after the TDI bronchoprovocation test. CONCLUSION: TDI exposure leads to overproduction of MMP-9, which may induce airway inflammation and remodeling, and then contribute to persistent asthmatic symptoms in TDI-induced asthma.

Adult↗
PubMed2003

Increased levels of vascular endothelial growth factor in induced sputum in asthmatic patients.

BACKGROUND: Vascular endothelial growth factor (VEGF) is highly expressed in the airway of asthmatic patients. As VEGF increases airway vascular permeability, consequent thickening of the airway wall mucosa may lead to narrowing of the airway lumen. OBJECTIVE: We evaluated the relationship between VEGF levels in induced sputum and eosinophilic inflammatory profiles, and the degree of airway vascular permeability in asthmatic patients and we evaluated the effect of inhaled corticosteroids on VEGF levels in induced sputum. METHODS: Induced sputum specimens were obtained from 28 glucocorticosteroids free asthmatics and 11 healthy control subjects. We examined VEGF levels and airway vascular permeability index in induced sputum. After the initial sputum induction, 21 asthmatics received 8-week inhaled beclomethasone dipropionate (BDP, 800 micro g/day) therapy, then sputum induction was repeated. RESULTS: The VEGF levels in asthmatics were significantly higher than in healthy control subjects (P < 0.0001). The VEGF levels were negatively correlated with forced expiratory volume of 1 s (FEV1, % predicted, r = - 0.68, P < 0.001), the percentage of eosinophils (r = 0.51, P < 0.01) and ECP levels (r = 0.39, P < 0.05). Moreover, the VEGF levels were significantly correlated with airway vascular permeability index (r = 0.61, P < 0.001). After 8-week inhaled BDP therapy, the VEGF levels were significantly decreased compared to pretreatment levels (P < 0.0001) and the VEGF levels were significantly correlated with airway vascular permeability index even in post-treatment asthmatics (r = 0.62, P < 0.01). CONCLUSION: The VEGF levels in induced sputum were increased in asthmatics and its levels were associated with degree of airway narrowing and airway vascular permeability. These findings provide strong evidence that VEGF may play an important role in the pathogenesis of bronchial asthma.

Adult↗
PubMed2003

A single nasal allergen challenge increases induced sputum inflammatory markers in non-asthmatic subjects with seasonal allergic rhinitis: correlation with plasma interleukin-5.

BACKGROUND: Seasonal allergic rhinitis (SAR) is a risk factor for asthma in affected individuals. Nasal allergic inflammation enhances bone-marrow eosinophil production, mainly via IL-5, and rhinitis patients have increased airway inflammation during the pollen season. OBJECTIVE: To assess the impact of nasal allergy on sputum inflammatory markers. METHODS: In an open-labelled, randomized, placebo-controlled cross-over study with 16 non-asthmatic SAR patients (median age 25 years, 56% males), the effect of a single nasal allergen challenge performed out of season on induced sputum inflammatory parameters was evaluated. SAR patients were identified by history, skin-prick test and specific IgE. All patients had normal lung function/bronchial hyper-responsiveness out of season and a negative asthma/wheezing history. Sputum cells and supernatant levels of ECP, sICAM, IL-5 and IL-10, and plasma levels of IL-5 and ECP, were measured before and 24 h after nasal allergen challenge. After a washout period of at least 4 weeks, the procedure was repeated with placebo challenge (diluent). RESULTS: Nasal allergen challenge led to an increase in sputum ECP (pre = 60 +/- 12, post = 212 +/- 63 micro g/L, P = 0.02 vs. placebo), and sICAM (4.8 +/- 2.7 to 6.5 +/- 2.9 ng/mL, P = 0.02 vs. placebo), whereas IL-10 decreased after provocation (44 +/- 11 to 29 +/- 6 pg/mL, P = 0.06 vs. placebo). Sputum IL-5 was undetectable in all patients. The absolute number of blood and sputum eosinophils did not change significantly after allergen or placebo challenge (P > 0.07, both comparisons). Plasma levels of IL-5 increased after allergen challenge (8.7 +/- 2.9 to 14.5 +/- 3.9 pg/mL, P = 0.001), and the increase in plasma IL-5 was positively correlated with the rise in sputum ECP in a subgroup of 'responders' (n = 12, r = 0.71, P = 0.01). CONCLUSIONS: A single nasal allergen challenge in SAR patients increased markers of allergic inflammation in the lower respiratory tract, possibly via pronounced activation of inflammatory cells through circulating immediate-type reaction cytokines like IL-5. These findings may provide additional explanatory data for the high susceptibility of SAR patients to incident asthma.

Administration, Intranasal↗
PubMed2002

A comparative study of eicosanoid concentrations in sputum and urine in patients with aspirin-intolerant asthma.

BACKGROUND: Although many studies have assumed that the overproduction of cysteinyl- leukotrienes (cys-LTs) and an imbalance of arachidonic acid metabolism may be plausible causes for the pathogenesis of aspirin-intolerant asthma (AIA), there has been little experimental evidence to substantiate this notion in lower airways of patients with AIA. OBJECTIVES: The purpose of this study was to compare the eicosanoid concentrations in sputum and urine from patients with AIA. METHODS: The concentrations of sputum cys-LTs, prostaglandin E2 (PGE2), PGF2alpha, PGD2 and thromboxane B2 were measured to assess local concentrations of eicosanoids in patients with AIA and in those with aspirin-tolerant asthma (ATA). The concentrations of two urinary metabolites, leukotriene E4 (LTE4) and 9alpha11betaPGF2, were also measured to corroborate the relationship between the eicosanoid biosynthesis in the whole body and that in lower airways. RESULTS: The concentration of PGD2 in sputum was significantly higher in patients with AIA than in those with ATA (median, 5.3 pg/mL vs. 3.1 pg/mL, P < 0.05), but there was no significant difference in the concentration of the corresponding metabolite, 9alpha11betaPGF2, between the two groups. No differences were noted in the concentrations of other prostanoids in sputum between the two groups. The sputum cys-LT concentrations showed no differences between the two groups, in spite of the observation that the concentration of urinary LTE4 was significantly higher in patients with AIA than in those with ATA (median, 195.2 pg/mg-cre vs. 122.1 pg/mg-cre, P < 0.05). There was a significant correlation among the concentration of cys-LTs, the number of eosinophils and the concentration of eosinophil-derived neurotoxin (EDN) in sputum. CONCLUSION: The urinary concentration of LTE4 does not necessary reflect cys-LT biosynthesis in lower airways. A significantly higher concentration of PGD2 in sputum from patients with AIA suggests the possible ongoing mast cell activation in lower airways.

Anti-Inflammatory Agents, Non-Steroidal↗