Chest ACCP Member Benefits
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Guest Access | Sign In via User Name/Password
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Article Archive
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (29)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Tsang, K. W.
Right arrow Articles by Lam, W.-k.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Tsang, K. W.
Right arrow Articles by Lam, W.-k.
(Chest. 2000;117:420-426.)
© 2000 American College of Chest Physicians

Sputum Elastase in Steady-State Bronchiectasis*

Kenneth W. Tsang, MD, FCCP; Kwok-ning Chan, MD, PhD; Pak-leung Ho, MRCP; Ling Zheng, MD, PhD; Gaik C. Ooi, FRCR; James C. M. Ho, MRCP and Wah-kit Lam, MD, FCCP

* From the University Departments of Medicine (Drs. Tsang, Zheng, J.C.M. Ho, and Lam), Microbiology (Dr. P. Ho), Diagnostic Radiology (Dr. Ooi), and Paediatrics (Dr. Chan), The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong SAR, China.

Correspondence to: Kenneth W.T. Tsang MD (Hons), FCCP, University Department of Medicine, Queen Mary Hospital, Pokfulam, Hong Kong SAR, China; e-mail: kwttsang{at}hkucc.hku.hk


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objectives: To study the correlations between sputum elastase output with clinical and sputum inflammatory and microbial factors in steady-state bronchiectasis.

Design: Prospective recruitment of patients with bronchiectasis (17 women; 48.5 ± 16.5 years old; FEV1/FVC, 1.3 ± 0.6/2.1 ± 0.9) for assessment of 24-h sputum output of elastase, bacteria, leukocytes, interleukin (IL)-1ß, IL-8, tumor necrosis factor-{alpha}, and leukotriene B4. Clinical variables assessed concomitantly included 24-h sputum volume, lung spirometry, number of lung lobes affected by bronchiectasis, and exacerbation frequency.

Setting: Consecutive recruitment of outpatients (n = 30) in steady-state bronchiectasis.

Measurements and results: Twenty-four-hour sputum elastase output correlated with 24-h sputum volume (r = 0.79, p = 0.0001); number of bronchiectatic lung lobes (r = 0.54, p = 0.0026); percent predicted FEV1 (r = -0.48, p = 0.0068); percent predicted FVC (r = -0.49, p = 0.001); and leukocyte output (r = 0.75, p = 0.0001). There was no correlation between the sputum output of bacteria with either inflammatory or enzymatic factors (p > 0.05).

Conclusion: Our data highlight the importance of elastase and the possibility of independent roles for enzymatic, inflammatory, and microbial components in the pathogenesis of bronchiectasis. Further research on novel therapy targeting each of these components should be pursued.

Key Words: bronchiectasis • elastase • interleukin • leukotriene • sputum


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Bronchiectasis is defined pathologically as permanent dilatation of the bronchi. Affected patients suffer from chronic sputum production, recurrent exacerbations, and sometimes progressive lung destruction. The pathogenesis of bronchiectasis is not well understood, but recent studies have identified infective, inflammatory, and also enzymatic elements that interact with each other leading to a vicious cycle of tracheobronchial destruction.1 The pathogenetic role of common pathogens, such as Pseudomonas aeruginosa, Streptococcus pneumoniae, and Haemophilus influenzae, has received considerable attention recently.2 3 4 Extensive recruitment of neutrophils occurs in the bronchiectatic airways,1 5 6 which is mediated by proinflammatory mediators, including interleukin (IL)-1, IL-8, tumor necrosis factor (TNF)-{alpha}, and leukotriene B4 (LTB4).7 8 9 10 11 Activated neutrophils release intracellular elastase in the bronchiectatic airways, which slows ciliary beating and disrupts respiratory mucosa in vitro.12 13 Elastase might therefore play an important role in the pathogenesis of bronchiectasis although this has not been investigated previously. Inasmuch as there is no "gold standard" for measuring disease severity or activity, researchers have adopted some clinical and laboratory variables as disease markers in bronchiectasis. These include spirometry, sputum volume measurement, exacerbation frequency, and sputum concentrations of proinflammatory mediators. 8 11 14 15 16 17 18 19 Because little is known about the relationship between sputum elastase and these variables, we have performed this prospective study to evaluate these correlations in steady-state bronchiectasis.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Study Design and Patient Recruitment
Patients with proven bronchiectasis diagnosed by high-resolution CT were recruited and gave written informed consent. Inclusion criteria included the absence of asthma or other unstable systemic diseases, no alteration in medication and dose for at least 3 months, and steady-state bronchiectasis. The latter was defined as the presence of < 20% alteration in 24-h sputum volume, FEV1, and FVC, and absence of changes in respiratory symptoms for 3 consecutive weeks. The study protocol had approval from the institutional ethics committee. Each patient entered a baseline period (3 consecutive weekly visits) to ensure that she or he was in steady-state bronchiectasis before being further assessed for clinical and laboratory variables by a research physician and a technician blinded to the study protocol.

Variables Assessed
At each visit, the patients were directly asked about the presence of respiratory symptoms (cough, dyspnea, hemoptysis, sputum production, chest pain, and wheezing) and were examined physically. Clinical assessment included the determination of the exacerbation frequency, spirometry, and the number of bronchiectatic lung lobes for each patient. Exacerbation frequency was defined as the number of exacerbations that had occurred in the preceding 12 months. This was determined by meticulous history taking and review of clinical charts. Occurrence and severity of respiratory symptoms, including cough, dyspnea, hemoptysis, increased sputum purulence or volume, and chest pain, were assessed for each patient. An exacerbation was defined as subjective and persistent (>= 24 h) deterioration in at least three respiratory symptoms, with or without fever (>= 37.5°C), radiographic deterioration, systemic disturbances, or deterioration in percussion note or auscultatory findings in the chest.14 Spirometry (FEV1 and FVC), expressed as percent predicted, was measured between 10:00 AM and 12:00 PM with a SensorMedics 2200 (SensorMedics; Yorba Linda, CA) package. Thoracic high-resolution CT was performed, within 12 months of the study, using a General Electric Hispeed Advantage Scanner (Milwaukee, WI) to perform standard 1-mm-thick sections at 10-mm intervals in the supine position. The number of lung lobes (including lingula) affected by bronchiectasis, as evident by the bronchial segment or subsegment being larger than the accompanying artery,20 was determined for each patient. Laboratory assessment included 24-h sputum volume; sputum leukocyte density (per milliliter); sputum total bacterial densities (colony forming units per milliliter); and sputum (sol phase) concentrations of IL-1{alpha}, IL-8, and TNF-{alpha}, LTB4, and elastase.

Measurement of Sputum Sol Elastase
Fresh sputum was stored at -70°C within 15 min of collection until ultracentrifugation (100,000g for 30 min at 4°C) to obtain the sol phase, which was used for determination of elastase activity (concentration). Briefly, 5 µL of sputum sol was added to a chromogenic peptide substrate succinyl-L-alanyl-L-alanine-p-nitroanilide (Sigma; Dorset, UK), and the rate of change of optical density was determined at 410 nm by using a spectrophotometer.21 This rate was compared with a standard curve for the rate of change in optical density, which was obtained from incubating known concentrations of elastase solutions (Sigma) with the same chromogen. The rate of change in optical density was converted into elastase activity (concentration) and expressed in units per milliliter. The elastase concentration was determined in triplicate, and the mean was determined for each patient.

Assessment of Sputum Physical Characteristics
The volume of a 24-h sputum specimen was determined as the mean of a 3-consecutive-day collection (9:00 AM to 9:00 AM) as described previously.14 Briefly, 24-h sputum collection was made by the patients at home in clear sterile plastic (60 mL) pots and stored at 4°C. Patients were trained to completely empty the contents of their mouth before expectoration. Contamination of sputum with visible saliva and food debris was infrequently encountered after the baseline visits. The volume of a 24-h sputum specimen was determined to the nearest 0.5 mL.14 Patients received chest physiotherapy (at least 15 min of expectoration-aiding maneuvers and until no further sputum was obtained) on arrival at the clinic. Fresh sputum was then collected by the research physician in sterile clear plastic pots between 10:00 AM and 12:00 PM after thorough mouth emptying, and within 1 h of physiotherapy in the semireclined position. Sputum leukocyte density, performed on five randomly selected aliquots of a fresh specimen, was assessed within 2 h of collection by the same technician using light microscopy and a hemocytometer.14

Determination of Sputum Bacterial Densities
Standard microbiological procedures were used to identify all the sputum bacteria and classify them into pathogens (P aeruginosa, H influenzae, S pneumoniae, Staphylococcus aureus, Moraxella catarrhalis, and Mycobacteria species) or nonpathogenic bacteria (Neisseria species, {alpha}-hemolytic streptococci, diphtheroids, and coagulase-negative staphylococci). The following enriched and selective media were used for determining the bacterial density (colony forming units per milliliter) in sputum: blood agar (Oxoid CM271 [Oxoid; Basingstoke, UK] supplemented with 5% defibrinated horse blood), chocolate agar supplemented with 18.9 U/mL bacitracin (Sigma; St. Louis, MO), mannitol salt agar (Oxoid CM85), and cetrimide-nalidixic acid agar (Oxoid CM559 and SR102). Fresh sputum was homogenized by using SPUTASOL (Oxoid SR089A) and inoculated onto the media with a 10-µL standard plastic loop to determine the microbial densities of various bacteria. Incubation was performed for up to 4 days at 37°C in 5% CO2, and the dilution that gave 30 to 300 cfu after overnight incubation was counted.14

Measurement of Sputum Sol Proinflammatory Cytokine and LTB4 Concentrations
Sputum sol was obtained, as described above, for determination of cytokine and LTB4 concentrations by using enzyme-linked immunosorbent assay. Samples were added to a 96-well plate (R&D Systems; Minneapolis, MN) coated with monoclonal antibody against one of the cytokines or LTB4 and incubated for 2 h at room temperature. After this, the samples were removed and washed three times with buffer, and an enzyme-linked antibody specific for a particular cytokine or LTB4 was added to each well and incubated at room temperature for 2 h. After a final wash to remove all unbound antibody, a substrate solution was added to each well and incubated for 20 min before the reaction was terminated by adding a stop solution. The optical density was determined by using a plate reader at 450 nm to determine the concentration of the cytokines or LTB4 in the sputum, and the mean concentration for each sample was obtained from the triplicate measurements.

Data Analysis and Statistical Methods
The physiologic measurements and cytokine concentrations were log-normally distributed, whereas the other microbial variables were highly skewed. The relationships between sputum variables, sputum biochemistry, and clinical variables were examined using Spearman rank correlation. For each patient, the 24-h sputum output of bacteria was calculated, as was the product of the 24-h sputum volume and the sputum bacterial density. The 24-h sputum outputs of the proinflammatory mediators and elastase were calculated likewise for each patient. The effects of sputum pathogens on various clinical, biochemical, and sputum variables were initially examined using analysis of variance. Because of small number and the lack of difference among various pathogen groups other than Pseudomonas, sputum pathogens were reclassified as Pseudomonas and non-Pseudomonas. Comparison between the latter groups was made using unpaired Student’s t test after natural logarithmic transformation of the data. All statistical analyses were performed using Statistical Analysis System software package (Version 6.12; SAS Institute; Cary, NC). A p value < 0.05 was taken as indicative of statistical significance.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Patient Demography and Clinical Details
Between December 1996 and February 1998, 30 non-cystic fibrosis (CF) patients were consecutively recruited. Their clinical features are shown in Table 1 . The majority of patients were never- or ex-smokers. All the patients suffered from bronchiectasis of the cylindrical type on high-resolution CT assessment. The cause of bronchiectasis was classified as idiopathic, posttuberculous, Kartagener’s syndrome, and diffuse panbronchiolitis in 25, 1, 3, and 1 patients, respectively.5 One bone marrow transplant recipient (male, age 33 years) was on maintenance therapy of prednisolone and cyclosporin A. Another patient (female, age 79 years) was on regular therapy of prednisolone and azathioprine for stable idiopathic thrombocytopenic purpura. Each patient received twice daily expectoration-aiding chest physiotherapy at home, which was provided either by the spouse or another designated family member. The cohort of patients had a mean (± SD) of 3.6 ± 3.2 exacerbations in the preceding 12 months. Twenty-one, 7, and 2 patients displayed obstructive, restrictive, and normal spirometry, respectively.


View this table:
[in this window]
[in a new window]

  		Table 1. Clinical Characteristics of Patients in Steady-State Bronchiectasis*

 
Sputum Physical, Microbial, Enzymatic, and Proinflammatory Mediator Profile Assessment
The clinical and sputum variables were log-normally distributed and were subclassified according to the status of P aeruginosa infection (Tables 2 and 3) . Bacteria isolated from the sputum were P aeruginosa (n = 22), H influenzae (n = 4), Mycobacterium chelonae (n = 1), S aureus (n = 1), and S pneumoniae (n = 1). No pathogen was isolated in one case. Patients who had P aeruginosa in their sputum had a significantly higher 24-h sputum output of leukocytes, bacteria, TNF-{alpha}, and LTB4 (p < 0.05), but not elastase (p > 0.05), than their counterparts (Table 3) .


View this table:
[in this window]
[in a new window]

  		Table 2. Clinical and Sputum Factors in 30 Patients With Steady-State Bronchiectasis*

 

View this table:
[in this window]
[in a new window]

  		Table 3. Clinical and Sputum Variables in 30 Patients With Steady-State Bronchiectasis, Which Are Also Classified According to the Status of P aeruginosa Infection*

 
Intercorrelation of Sputum Variables
The intercorrelations among various sputum variables are shown in Table 4 . Elastase correlated with 24-h sputum volume and sputum leukocyte density (p < 0.05). Among the sputum proinflammatory mediators, IL-1ß, IL-8, and TNF-{alpha} significantly correlated with each other and with leukocyte density (p < 0.05, data not shown).


View this table:
[in this window]
[in a new window]

  		Table 4. Correlation Analysis for Sputum Variables From 30 Patients With Steady-State Bronchiectasis*

 
Intercorrelation Between Sputum Variables and Clinical Disease Markers
The intercorrelations among various sputum variables and clinical disease markers, namely number of bronchiectatic lung lobes, exacerbation frequency, FEV1 (percent predicted), and FVC (percent predicted), are shown in Table 5 . Sputum output of elastase correlated with the number of bronchiectatic lung lobes but not exacerbation frequency, and inversely with spirometry (Fig 1 ). The number of bronchiectatic lung lobes also significantly correlated with 24-h sputum leukocyte output. Both 24-h sputum volume and 24-h sputum leukocyte output correlated inversely with FEV1 (percent predicted) and FVC (percent predicted). Among the indices of disease severity (data not shown), the number of bronchiectatic lung lobes correlated with exacerbation frequency (r = 0.40, p = 0.03), and inversely with FEV1 (r = -0.44, p = 0.02) and FVC (r = -0.42, p = 0.02). Exacerbation frequency, however, had no correlation with FEV1 (r = -0.08, p = 0.69) or FVC (r = -0.14, p = 0.06).


View this table:
[in this window]
[in a new window]

  		Table 5. Relationship Between Clinical Markers of Disease Severity and Sputum Variables in 30 Patients With Steady-State Bronchiectasis*

 


View larger version (18K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 1. Results of Spearman rank analysis between 24-h sputum elastase output (U) and FEV1 percent predicted (top, A), FVC percent predicted (middle, B), and 24-h sputum volume (bottom, C).

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
This study was performed to evaluate the intercorrelation between sputum elastase output and other disease factors in a cohort of 30 patients with steady-state bronchiectasis. Sputum elastase output correlated with 24-h sputum volume, number of bronchiectatic lung lobes, spirometry (negatively), and 24-h sputum output of leukocytes, IL-1ß, and TNF-{alpha}. Sputum elastase output therefore appears to correlate with disease activity, severity, and inflammatory markers in steady-state bronchiectasis. There were significant positive correlations among the 24-h sputum outputs of inflammatory markers (including the cytokines IL-1ß, IL-8, and TNF-{alpha}) and leukocytes. An inverse relationship between structural and functional markers was found in that the number of bronchiectatic lung lobes inversely correlated with FEV1 (percent predicted) and FVC (percent predicted). Not withstanding the relatively small sample size and the predominance of P aeruginosa infection (73.3% of patients), there was no difference in the correlation patterns between the P aeruginosa-infected patients and their counterparts. Our data showed no correlation between the number of bronchiectatic lung lobes and 24-h sputum volume. This might have been because of the crude nature of only assessing the number of bronchiectatic lobes, rather than the volume or surface area of bronchi that were affected by bronchiectasis. In addition, the presence of bronchiectasis in a lung lobe does not necessarily indicate an underlying active disease process. Very importantly, our data show no correlation between sputum bacterial output and either inflammatory or enzymatic outputs.

Extensive airway infiltration with neutrophils occurs in bronchiectasis, which is mediated by proinflammatory mediators, particularly IL-1ß, IL-8, TNF-{alpha}, and LTB4.7 9 10 11 22 Most patients with non-CF bronchiectasis suffer from airway colonization with H influenzae and S pneumoniae initially, which is followed by chronic colonization by P aeruginosa. Exotoxins produced by P aeruginosa cause ultrastructural damage,3 4 slowing of ciliary beating,2 upregulation of respiratory mucus secretion,23 and induction of TNF-{alpha}, LTB4, and IL-8 release from respiratory mucosa in vitro.24 25 However, our data did not show any in vivo correlation between sputum output of bacteria and proinflammatory mediators (Tables 4 , 5) . This lack of correlation between sputum proinflammatory mediators, including IL-1ß, IL-8, LTB4, and TNF-{alpha}, and lung function variables and exacerbations in bronchiectasis has been reported previously.18 26 27 The presence of severe pulmonary inflammation without any evidence of infection has also been reported in CF lungs.28 Our data, along with the results from previous studies, 18 26 27 28 therefore suggest that inflammation in bronchiectasis could be partly independent of the infective process.

Neutrophils recruited into the airways release elastase, hydrogen peroxide, and reactive oxygen radicals, which are toxic to respiratory mucosa.29 Elastase digests elastin, basement membrane collagen, and proteoglycan.13 Elastase in the airways, irrespective of its neutrophil or P aeruginosa origin, causes slowing of ciliary beating,12 extrusion of epithelial cells,12 and induction of airway mucus production.30 Sputum elastase concentration has previously been reported to correlate positively with radiographic severity31 and negatively with lung function in CF and non-CF bronchiectasis.19 Our data show a correlation of elastase output with 24-h sputum volume and sputum leukocyte output, but not P aeruginosa output. This strongly suggests that most of the sputum elastase were released by neutrophils rather than P aeruginosa.

There is no effective disease-modifying treatment for bronchiectasis. The use of maintenance antibiotics such as nebulized aminoglycosides and judicial early use of potent antibiotics are undoubtedly effective but only treat infection. Prolonged high-dose antibiotic32 and systemic steroid therapy33 have failed to produce significant clinical improvement. Our results suggest that the enzymatic, inflammatory, and infective pathogenic elements could be individually treated. Nebulized {alpha}1-antitrypsin reduces lung elastase concentration in CF 34 and might be a potentially useful antielastase treatment. Bronchial epithelial cell cytokine products could also be potential targets for anticytokine therapy. For example, aerosolized IL-1 receptor antagonist reduces TNF-{alpha} bioavailability in guinea pigs,35 TNF-{alpha} and IL-1 receptors reduce bacterial endotoxin-induced neutrophil recruitment to rat lungs,36 and F(ab1)2 fragments of IL-8 monoclonal antibody reduce sputum chemotactic activity.11 Our results suggest that novel combinations of these antibacterial, anti-inflammatory, and antienzymatic modes of therapies could be useful.


   Acknowledgements
 
The authors thank Dr. Ian Lauder for expert statistical advice. We are grateful to the patients who participated in this study and the support from Dr. C.S. Ho, Ms. Shelley Chan, and Mr. Raymond Leung for technical assistance.


   Footnotes
 
Abbreviations: CF = cystic fibrosis; IL = interleukin; LTB4 = leukotriene B4; TNF = tumor necrosis factor

Received for publication February 11, 1999. Accepted for publication July 15, 1999.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Cole, PJ (1986) Inflammation: a two edged-sword; the model of bronchiectasis. Eur J Respir Dis 147(suppl),6-15
  2. Tsang, KWT, Rutman, A, Kanthakumar, K, et al (1993) Haemophilus influenzae infection of human respiratory mucosa in low concentrations of antibiotics. Am Rev Respir Dis 148,201-207[ISI][Medline]
  3. Tsang, KWT, Rutman, A, Tanaka, E, et al (1994) Interaction of Pseudomonas aeruginosa with human respiratory mucosa in vitro [see comments]. Eur Respir J 7,1746-1753[Abstract]
  4. Feldman, CR, Read, A, Rutman, PK, et al (1992) The interaction of Streptococcus pneumoniae with intact human respiratory mucosa in vitro. Eur Respir J 5,576-583[Abstract]
  5. Cole, PJ (1995) Bronchiectasis. Brewis, RAL Corrin, B Geddes, DMet al eds. Respiratory medicine ,1286-1317 Saunders London, UK.
  6. Lapa e Silva, JR, Guerreiro, D, Noble, B, et al (1989) Immunopathology of experimental bronchiectasis. Am J Respir Cell Mol Biol 1,297-304
  7. Levine, SJ (1995) Bronchial epithelial cell-cytokine interactions in airway inflammation. J Invest Med 43,241-249[ISI][Medline]
  8. Greally, P, Hussain, MJ, Vergani, D, et al (1994) Interleukin-1{alpha}, soluble interleukin-2 receptor, and IgG concentrations in cystic fibrosis treated with prednisolone. Thorax 71,35-39
  9. Schleimer, RP, Benenati, SV, Friedman, B, et al (1991) Do cytokines play a role in leukocyte recruitment and activation in the lung? Am Rev Respir Dis 143,1169-1174[ISI][Medline]
  10. Ford-Hutchinson, AW, Bray, MA, Doig, MV, et al (1980) Leukotriene B, a potent chemokinetic and aggregating substance released from polymorphonuclear leukocytes. Nature 286,264-265[CrossRef][Medline]
  11. Richman-Eisenstat, JBY, Jorens, PG, Herbert, CA, et al (1993) Interleukin-8: an important chemoattractant in sputum of patients with chronic inflammatory airway diseases. Am J Physiol 264,L413-L418[Abstract/Free Full Text]
  12. Amitani, R, Wilson, R, Rutman, A, et al (1991) Effects of human neutrophil elastase and bacterial proteinases on human respiratory epithelium. Am J Respir Cell Mol Biol 4,26-32
  13. Hutchinson, DCS (1987) The role of proteases and antiproteases in bronchial secretions. Eur J Respir Dis 71(suppl),78-85
  14. Tsang, KW, Ho, PL, Lam, WK, et al (1998) Inhaled fluticasone reduces sputum inflammatory indices in severe bronchiectasis. Am J Respir Crit Med 158,723-727[Abstract/Free Full Text]
  15. Tsang, KW, Lam, SK, Lam, WK, et al (1998) High sero-prevalence of Helicobacter pylori in active bronchiectasis. Am J Respir Crit Med 158,1047-1051[Abstract/Free Full Text]
  16. Kronborg, G, Hansen, MB, Svenson, M, et al (1993) Cytokines in sputum and serum from patients with cystic fibrosis and chronic Pseudomonas aeruginosa infection as markers of destructive inflammation in the lungs. Pediatr Pulmonol 15,292-297[ISI][Medline]
  17. Stockley, RA, Hill, SL, Morrison, HM, et al (1984) Elastolytic activities of sputum and its relation to purulence and to lung function in patients with bronchiectasis. Thorax 39,408-413[Abstract]
  18. Buttle, DJ, Burnett, D, Abrahamson, M, et al (1990) Levels of neutrophil elastase and cathepsin B activities, and cystatins in human sputum: relationship to inflammation. Scand J Clin Lab Invest 50,509-516[ISI][Medline]
  19. Suter, S, Schaad, UB, Tegner, H, et al (1986) Levels of free granulocyte elastase in bronchial secretions from patients with cystic fibrosis: effects of antimicrobial treatment against Pseudomonas aeruginosa. J Infect Dis 153,902-909[ISI][Medline]
  20. McGuniness, G, Naidich, DP, Leitman, BS, et al (1993) Bronchiectasis: CT evaluation. Am J Radiol 160,253-259[Abstract/Free Full Text]
  21. Bieth, J, Spiess, B, Wermuth, CG (1974) The synthesis and analytical use of a highly sensitive and convenient substrate of elastase. Biochem Med 11,350-357[CrossRef][ISI][Medline]
  22. Elias, JA, Gustilo, K, Baeder, W, et al (1987) Synergistic stimulation of fibroblast prostaglandin production by recombinant interleukin 1 and tumor necrosis factor. J Immunol 138,3812-3816[Abstract]
  23. Somerville, M, Taylor, CG, Watson, D, et al (1992) Release of mucus glycoconjugates by Pseudomonas aeruginosa rhamnolipids into feline trachea in vivo and human bronchus in vitro. Am J Respir Cell Mol Biol 6,116-122
  24. Cusumano, V, Tufano, MA, Mancuso, G, et al (1997) Porins of Pseudomonas aeruginosa induce release of tumor necrosis factor alpha and interleukin-6 by human leukocytes. Infect Immun 65,1683-1687[Abstract]
  25. Bedard, M, McClure, CD, Schiller, NL, et al (1993) Release of interleukin-8, interleukin-6 and colony-stimulating factors by upper airway epithelial cells: implications for cystic fibrosis. Am Respir Cell Mol Biol 9,455-462
  26. Salva, PS, Doyle, NA, Graham, L, et al (1996) TNF-{alpha}, IL-8, soluble ICAM-1, and neutrophils in sputum of cystic fibrosis patients. Pediatr Pulmonol 21,11-19[CrossRef][ISI][Medline]
  27. Tsang, KW, Ho, PL, Ip, M, et al (1999) The effects of low dose erythromycin in bronchiectasis: a pilot study. Eur Respir J 13,361-364[Abstract]
  28. Khan, T, Wegener, J, Boat, T, et al (1995) Early pulmonary inflammation in infants with cystic fibrosis. Am J Respir Crit Care Med 151,75-82[Abstract]
  29. Stendahl, O, Coble, BI, Dahlgren, C, et al (1984) Myeloperoxidase modulates the phagocytic activity of polymorphonuclear neutrophil leukocytes: studies with cells from a myeloperoxidase-deficient patient. J Clin Invest 73,366-373
  30. Fahy, JV, Schuster, A, Ueki, I, et al (1992) Mucus hypersecretion in bronchiectasis: the role of neutrophil proteases. Am Rev Respir Dis 146,1430-1433[ISI][Medline]
  31. O’Connor, CM, Gaffney, K, Keane, J, et al (1993) {alpha}1-Proteinase inhibitor, elastase activity, and lung disease severity in cystic fibrosis. Am Rev Respir Dis 148,1665-1670[ISI][Medline]
  32. Currie, DC, Garbett, ND, Chan, KL, et al (1990) Double-blind randomized study of prolonged higher-dose oral amoxycillin in purulent bronchiectasis. QJM 76,799-816[Abstract/Free Full Text]
  33. Auerbach, HS, Williams, M, Kirkpatrick, JA, et al (1985) Alternate-day prednisolone reduces morbidity and improves pulmonary function in cystic fibrosis. Lancet 2,686-688[CrossRef][ISI][Medline]
  34. McElvaney, NG, Hubbard, RC, Birrer, P, et al (1991) Aerosol {alpha}-1 antitrypsin treatment for cystic fibrosis. Lancet 337,392-394[CrossRef][ISI][Medline]
  35. Watson, ML, Smith, D, Bourne, AD, et al (1993) Cytokines contribute to airway dysfunction in antigen-challenged guinea pigs: inhibition of airway hyper-sensitivity pulmonary eosinophilic accumulation, and tumor necrosis factor generated by pre-treatment with an interleukin-1 receptor antagonist. Am J Respir Cell Mol Biol 8,365-369
  36. Ulich, TR, Yin, S, Remick, D, et al (1994) Intra-tracheal administration of endotoxin and cytokines: VII. The soluble interleukin I receptor and the soluble tumor necrosis factor receptor II (p80) inhibit acute inflammation. Clin Immunol Immunopathol 72,137-140[CrossRef][ISI][Medline]



This article has been cited by other articles:


Home page
 ChestHome page
M. A. Martinez-Garcia, J.-J. Soler-Cataluna, M. Perpina-Tordera, P. Roman-Sanchez, and J. Soriano
Factors Associated With Lung Function Decline in Adult Patients With Stable Non-Cystic Fibrosis Bronchiectasis
Chest, November 1, 2007; 132(5): 1565 - 1572.
[Abstract] [Full Text] [PDF]

Home page
 ThoraxHome page
K W Tsang, K C Tan, P L Ho, G C Ooi, J C Ho, J Mak, G L Tipoe, C Ko, C Yan, W K Lam, et al.
Inhaled fluticasone in bronchiectasis: a 12 month study
Thorax, March 1, 2005; 60(3): 239 - 243.
[Abstract] [Full Text] [PDF]

Home page
 ThoraxHome page
A P Watt, V Brown, J Courtney, M Kelly, L Garske, J S Elborn, and M Ennis
Neutrophil apoptosis, proinflammatory mediators and cell counts in bronchiectasis
Thorax, March 1, 2004; 59(3): 231 - 236.
[Abstract] [Full Text] [PDF]

Home page
 ChestHome page
S. L. Chan, M. M. Chan-Yeung, G. C. Ooi, C. L. Lam, T. F. Cheung, W. K. Lam, and K. W. Tsang
Validation of the Hong Kong Chinese Version of the St. George Respiratory Questionnaire in Patients With Bronchiectasis
Chest, December 1, 2002; 122(6): 2030 - 2037.
[Abstract] [Full Text] [PDF]

Home page
 RadiologyHome page
G. C. Ooi, P. L. Khong, M. Chan-Yeung, J. C. M. Ho, P. K. S. Chan, J. C. K. Lee, W. K. Lam, and K. W. T. Tsang
High-Resolution CT Quantification of Bronchiectasis: Clinical and Functional Correlation
Radiology, December 1, 2002; 225(3): 663 - 672.
[Abstract] [Full Text] [PDF]

Home page
 Eur Respir JHome page
L. Zheng, W.K. Lam, G.L. Tipoe, I.H. Shum, C. Yan, R. Leung, J. Sun, G.C. Ooi, and K.W. Tsang
Overexpression of matrix metalloproteinase-8 and -9 in bronchiectatic airways in vivo
Eur. Respir. J., July 1, 2002; 20(1): 170 - 176.
[Abstract] [Full Text] [PDF]

Home page
 NEJMHome page
A. F. Barker
Bronchiectasis
N. Engl. J. Med., May 2, 2002; 346(18): 1383 - 1393.
[Full Text] [PDF]

Home page
 ChestHome page
K. W. Tsang, R. Leung, P. Chin-wan Fung, S. L. Chan, G. L. Tipoe, G. C. Ooi, and W. K. Lam
Exhaled and Sputum Nitric Oxide in Bronchiectasis : Correlation With Clinical Parameters
Chest, January 1, 2002; 121(1): 88 - 94.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Article Archive
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (29)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Tsang, K. W.
Right arrow Articles by Lam, W.-k.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Tsang, K. W.
Right arrow Articles by Lam, W.-k.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS