- Email: [email protected]
Thick mucus hypothesis in cystic fibrosis
CORRESPONDENCE
Several investigators have reported that the ASL is isotonic rather than hyotonic in healthy individuals and patients with cystic fibrosis.4 The latter hypothesis might be in agreement with one of the earliest hypotheses to eplain cystic fibrosis lung disease—the thick mucus hypothesis. When inhaled antibiotics reach the lower airways, thick mucus impairs the baterial-killing function of antibiotics. The strategy of disruption of thick mucus by recombinant DNase or the restored volume of ASL is necessary to improve the efficacy of antibiotic use for lung disease in cystic fibrosis. ASL in healthy individuals and cysticfibrosis patients is too sparse as yet for reliable analysis of the composition.5 *Shinji Teramoto, Haruki Kume, Yoshinosuke Fukuchi *International University of Health and Welfare, Department of Internal Medicine, San-no Hospital, Minato-ku Tokyo 107-0052, Japan; and Department of Respiratory Medicine, Juntendo University, Tokyo, Japan 1
2
3
4
5
Marshall BC, Liou TG. Elusiveness of ideal approach to Pseudomonas aeruginosa infection complicating cystic fibrosis. Lancet 2000; 356: 613–14. Smith JJ, Travis SM, Greemberg EP, Welsh MJ. Cystic fibrosis airway epithelia fail to kill bacteria because of abnormal airway surface fluid. Cell 1996; 85: 229–36. Matsui H, Grubb BR, Tarran R, et al. Evidence for periciliary liquid layer depletion, no abnormal ion composition, in the pathogenesis of cystic fibrosis airway disease. Cell 1998; 95: 1005–15. Knowles MR, Robinson JM, Wood RE, et al. Ion composition of airway surface liquid of patients with cystic fibrosis as compared with normal and disease-control subjects. J Clin Invest 1997; 100: 2588–95. Teramoto S, Matsuse T, Ouchi Y. Manipulation of volume vs osmolality in cystic fibrosis lung disease. Chest 1999; 116: 1494–95.
Author’s reply Sir—We agree with Shinji Teramoto and colleagues that a greater understanding of the microenvironment in the cystic-fibrosis airway is important to develop new treatments. The extent to which aminoglycosides are inactivated by protein and extracellular DNA in cysticfibrosis sputum is an example of the clinical relevance of the airway environment.1 Such information was critical in establishing the amount of inhaled tobramycin needed to overcome these barriers and this form of therapy proved effective. Teramoto and colleagues summarise the continuing controversy between high-salt and low-volume hypotheses for ASL. There are several formidable challenges to investigators working in this area, including the complexity of the human tracheobronchial tree (eg,
1204
the ASL consists of contributions from the surface epithelium and submucosal glands) and the technical difficulty in sampling the ASL without disturbing the system. Mucociliary clearance and the antimicrobial host defences are inextricably linked to the ASL.2 We must understand this fundamental feature of the pathophysiology of cystic fibrosis to invest resources in the therapeutic approaches with the greatest likelihood of success. The interface between P aeruginosa and the cystic fibrosis airway microenvironment is another exciting area of investigation. Pseudomonas spp are more adherent to cystic-fibrosis epithelial cells than normal cells because differences in cell surface glycoconjugates. CFTR, the protein product of the cystic-fibrosis gene is a bacterial receptor for clearance of Pseudomonas by epithelial phagocytosis in normal cells, whereas cystic-fibrosis epithelial cells lack this capability.3 Once infection is established in the cystic-fibrosis airway. Pseudomonas adopt a biofilm mode of growth and are able to withstand host defences and antimicrobial agents.4 This results in the typical chronic indolent infection. These features of pseudomonal colonisation and infection might prove vulnerable to therapeutic interventions. Efforts to develop such therapies will be facilitated by the completion of the pseudomonas genome project.5 Basic investigation of the airway microenvironment, its impact on host defences, and the mechanisms by which P aeruginosa colonises and adapts to the airway microenvironment will hopefully lead to novel treatment approaches. *Bruce C Marshall, Theodore G Liou * Intermountain Cystic Fibrosis Center, University of Utah Health Sciences Center, Wintrobe 711C, Salt Lake City, UT 84132, USA, and Salt Lake Veteran’s Administration Medical Center, Salt Lake City. (e-mail: [email protected]) 1
2
3
4
5
Ramphal R, Lhermitte M, Filliat M, Roussel P. The binding of antipseudomonal antibodies to macromolecules from cystic fibrosis sputum. J Antimicrob Chemother 1988; 22: 483–89. Wine JJ. The genesis of cystic fibrosis lung disease. J Clin Invest 1999; 103: 309–12. Pier GB. Role of cystic fibrosis transmembrane regulator in innate immunity to Pseudomonas aeruginosa. Proc Natl Acad Sci USA 2000; 97: 8822–28. Singh PK, Schaefer AL, Parsek MR, Moninger TO, Welsh MJ, Greenberg EP. Quorum-sensing signals indicate that cystic fibrosis lungs are infected with bacterial biofilms. Nature 2000; 407: 762–64. Stover CK, Pham XQ, Erwin AL, et al. Complete genome sequence of Pseudomonas aeruginosa PA01, an opportunistic pathogen. Nature 2000, 406: 959–64.
Did Celera invent the internet? Sir—The overtaking of publicly funded research teams by Celera Genomics in its completion of the sequencing of the human genome, to which you refer in your Jan 13 editorial,1 smacks somewhat of the Sputnik episode. The United States of Soviet Russia scaled up the payload of their rocket and put a man into space before the USA, but did not make parallel progress in the other technologies required to capitalise on this advance. Craig Venter, the chief executive officer of Celera, has stated that understanding the genome may help resolve previously unanswerable questions.2 But Celera has merely made available the full text of the genome a little sooner than we might otherwise have had it. Those of us working to understand the genome3 no more need the full text of the genome than you would need the full text of a dictionary if you were trying to understand how a dictionary works. You state that, courtesy of Celera, the entire sequence will be available free of charge;1 a Celera spokesman has declared that academic users will have to pay US$7000 per year.4 That the beneficence, and perhaps the integrity, of Celera might not be relied on, was suggested by a fullpage colour advertisement in Canada’s leading newspaper. This advertisement, in large capital letters, declared “The skeptics were right when they said Craig Venter would never crack the human genetic code on schedule. He was two years early”. We smiled when Al Gore told us he had invented the Internet, and he quickly apologised and expressed remorse. Yet, here is the chief executive officer of Celera claiming to have cracked the genetic code—a feat achieved in the 1960s, and for which Nobel prizes were awarded in 1968. My protest in a letter to the newspaper on Jan 15,5 which was forwarded to Venter’s corporate sponsors, was answered by repeats of the advertisement on Jan 16, 22, and 25. Donald R Forsdyke Department of Biochemistry, Queen’s University, Kingston, Ontario, Canada K7L 3N6 (e-mail: [email protected]) 1 2
3 4 5
Editorial. Human genome draws in journals. Lancet 2001; 357: 81. Broder S, Venter JC. Whole genomes: the foundation of new biology and medicine. Curr Opin Biotech 2000; 11: 581–85. Forsdyke DR, Mortimer JR. Chargaff’s legacy. Gene 2000; 261: 127–37. Marshall E. NIH considers paying to use private database. Science 2001; 291: 223–24. Forsdyke DR. Code already cracked. Toronto: Globe & Mail, 2001; Jan 15.
THE LANCET • Vol 357 • April 14, 2001
For personal use. Only reproduce with permission from The Lancet Publishing Group.
Several investigators have reported that the ASL is isotonic rather than hyotonic in healthy individuals and patients with cystic fibrosis.4 The latter hypothesis might be in agreement with one of the earliest hypotheses to eplain cystic fibrosis lung disease—the thick mucus hypothesis. When inhaled antibiotics reach the lower airways, thick mucus impairs the baterial-killing function of antibiotics. The strategy of disruption of thick mucus by recombinant DNase or the restored volume of ASL is necessary to improve the efficacy of antibiotic use for lung disease in cystic fibrosis. ASL in healthy individuals and cysticfibrosis patients is too sparse as yet for reliable analysis of the composition.5 *Shinji Teramoto, Haruki Kume, Yoshinosuke Fukuchi *International University of Health and Welfare, Department of Internal Medicine, San-no Hospital, Minato-ku Tokyo 107-0052, Japan; and Department of Respiratory Medicine, Juntendo University, Tokyo, Japan 1
2
3
4
5
Marshall BC, Liou TG. Elusiveness of ideal approach to Pseudomonas aeruginosa infection complicating cystic fibrosis. Lancet 2000; 356: 613–14. Smith JJ, Travis SM, Greemberg EP, Welsh MJ. Cystic fibrosis airway epithelia fail to kill bacteria because of abnormal airway surface fluid. Cell 1996; 85: 229–36. Matsui H, Grubb BR, Tarran R, et al. Evidence for periciliary liquid layer depletion, no abnormal ion composition, in the pathogenesis of cystic fibrosis airway disease. Cell 1998; 95: 1005–15. Knowles MR, Robinson JM, Wood RE, et al. Ion composition of airway surface liquid of patients with cystic fibrosis as compared with normal and disease-control subjects. J Clin Invest 1997; 100: 2588–95. Teramoto S, Matsuse T, Ouchi Y. Manipulation of volume vs osmolality in cystic fibrosis lung disease. Chest 1999; 116: 1494–95.
Author’s reply Sir—We agree with Shinji Teramoto and colleagues that a greater understanding of the microenvironment in the cystic-fibrosis airway is important to develop new treatments. The extent to which aminoglycosides are inactivated by protein and extracellular DNA in cysticfibrosis sputum is an example of the clinical relevance of the airway environment.1 Such information was critical in establishing the amount of inhaled tobramycin needed to overcome these barriers and this form of therapy proved effective. Teramoto and colleagues summarise the continuing controversy between high-salt and low-volume hypotheses for ASL. There are several formidable challenges to investigators working in this area, including the complexity of the human tracheobronchial tree (eg,
1204
the ASL consists of contributions from the surface epithelium and submucosal glands) and the technical difficulty in sampling the ASL without disturbing the system. Mucociliary clearance and the antimicrobial host defences are inextricably linked to the ASL.2 We must understand this fundamental feature of the pathophysiology of cystic fibrosis to invest resources in the therapeutic approaches with the greatest likelihood of success. The interface between P aeruginosa and the cystic fibrosis airway microenvironment is another exciting area of investigation. Pseudomonas spp are more adherent to cystic-fibrosis epithelial cells than normal cells because differences in cell surface glycoconjugates. CFTR, the protein product of the cystic-fibrosis gene is a bacterial receptor for clearance of Pseudomonas by epithelial phagocytosis in normal cells, whereas cystic-fibrosis epithelial cells lack this capability.3 Once infection is established in the cystic-fibrosis airway. Pseudomonas adopt a biofilm mode of growth and are able to withstand host defences and antimicrobial agents.4 This results in the typical chronic indolent infection. These features of pseudomonal colonisation and infection might prove vulnerable to therapeutic interventions. Efforts to develop such therapies will be facilitated by the completion of the pseudomonas genome project.5 Basic investigation of the airway microenvironment, its impact on host defences, and the mechanisms by which P aeruginosa colonises and adapts to the airway microenvironment will hopefully lead to novel treatment approaches. *Bruce C Marshall, Theodore G Liou * Intermountain Cystic Fibrosis Center, University of Utah Health Sciences Center, Wintrobe 711C, Salt Lake City, UT 84132, USA, and Salt Lake Veteran’s Administration Medical Center, Salt Lake City. (e-mail: [email protected]) 1
2
3
4
5
Ramphal R, Lhermitte M, Filliat M, Roussel P. The binding of antipseudomonal antibodies to macromolecules from cystic fibrosis sputum. J Antimicrob Chemother 1988; 22: 483–89. Wine JJ. The genesis of cystic fibrosis lung disease. J Clin Invest 1999; 103: 309–12. Pier GB. Role of cystic fibrosis transmembrane regulator in innate immunity to Pseudomonas aeruginosa. Proc Natl Acad Sci USA 2000; 97: 8822–28. Singh PK, Schaefer AL, Parsek MR, Moninger TO, Welsh MJ, Greenberg EP. Quorum-sensing signals indicate that cystic fibrosis lungs are infected with bacterial biofilms. Nature 2000; 407: 762–64. Stover CK, Pham XQ, Erwin AL, et al. Complete genome sequence of Pseudomonas aeruginosa PA01, an opportunistic pathogen. Nature 2000, 406: 959–64.
Did Celera invent the internet? Sir—The overtaking of publicly funded research teams by Celera Genomics in its completion of the sequencing of the human genome, to which you refer in your Jan 13 editorial,1 smacks somewhat of the Sputnik episode. The United States of Soviet Russia scaled up the payload of their rocket and put a man into space before the USA, but did not make parallel progress in the other technologies required to capitalise on this advance. Craig Venter, the chief executive officer of Celera, has stated that understanding the genome may help resolve previously unanswerable questions.2 But Celera has merely made available the full text of the genome a little sooner than we might otherwise have had it. Those of us working to understand the genome3 no more need the full text of the genome than you would need the full text of a dictionary if you were trying to understand how a dictionary works. You state that, courtesy of Celera, the entire sequence will be available free of charge;1 a Celera spokesman has declared that academic users will have to pay US$7000 per year.4 That the beneficence, and perhaps the integrity, of Celera might not be relied on, was suggested by a fullpage colour advertisement in Canada’s leading newspaper. This advertisement, in large capital letters, declared “The skeptics were right when they said Craig Venter would never crack the human genetic code on schedule. He was two years early”. We smiled when Al Gore told us he had invented the Internet, and he quickly apologised and expressed remorse. Yet, here is the chief executive officer of Celera claiming to have cracked the genetic code—a feat achieved in the 1960s, and for which Nobel prizes were awarded in 1968. My protest in a letter to the newspaper on Jan 15,5 which was forwarded to Venter’s corporate sponsors, was answered by repeats of the advertisement on Jan 16, 22, and 25. Donald R Forsdyke Department of Biochemistry, Queen’s University, Kingston, Ontario, Canada K7L 3N6 (e-mail: [email protected]) 1 2
3 4 5
Editorial. Human genome draws in journals. Lancet 2001; 357: 81. Broder S, Venter JC. Whole genomes: the foundation of new biology and medicine. Curr Opin Biotech 2000; 11: 581–85. Forsdyke DR, Mortimer JR. Chargaff’s legacy. Gene 2000; 261: 127–37. Marshall E. NIH considers paying to use private database. Science 2001; 291: 223–24. Forsdyke DR. Code already cracked. Toronto: Globe & Mail, 2001; Jan 15.
THE LANCET • Vol 357 • April 14, 2001
For personal use. Only reproduce with permission from The Lancet Publishing Group.