提示: 手机请竖屏浏览!

黏液阻塞性肺疾病
Muco-Obstructive Lung Diseases


Richard C. Boucher ... 呼吸系统疾病 • 2019.05.16
相关阅读
• 慢性阻塞性肺疾病临床特征的最新进展 • 被诊断为COPD的患者中究竟有多少人真正患该病 • 诊断气道阻塞时应遵循指南推荐的0.70阈值 • 哪种抗生素最适合与囊性纤维化无关的支气管扩张发作 • VX-659–tezacaftor–ivacaftor三联疗法用于携带1或2个Phe508del等位基因的囊性纤维化患者 • VX-445–tezacaftor–ivacaftor三联疗法用于携带1或2个Phe508del等位基因的囊性纤维化患者 • COPD患者的三联疗法 • β受体阻滞剂可能改善慢性阻塞性肺疾病患者的结局

累及气道的一系列肺部疾病,包括慢性阻塞性肺疾病(COPD)、囊性纤维化、原发性纤毛运动不良症和非囊性纤维化支气管扩张,可被描述为黏液阻塞性疾病1-4。这些疾病的临床表现包括咳嗽、咳痰和发作性加重,这些通常与慢性支气管炎的诊断相关5。然而,“慢性支气管炎”和“高分泌性疾病”均不能充分描述这些疾病的典型特征:弥漫性黏液阻塞、气道壁扩张、慢性炎症和细菌感染;因此,“黏液阻塞”可能是一个更适合的描述性术语。虽然哮喘也可能与弥漫性气道黏液阻塞相关7,但其具有独特的病理生理机制,因此不能放到这一组疾病中讨论8

气道黏膜阻塞的发病机制如图1A所示。在健康人体内,充分水合的黏液层被迅速地从远端气道运输至气管(速度约为50 μm/s)。在黏液阻塞性疾病中,上皮在离子-液体运输、黏蛋白分泌方面有缺陷,或者有这些缺陷的组合,因而导致黏液超浓缩(脱水)、黏液运输失败以及黏液黏附于气道表面。咳嗽时,气管内积聚的黏液以痰的形式咳出11。小气道内的黏液无法通过咳嗽清除,因而积聚,形成气流阻塞、感染和炎症病灶11





作者信息

Richard C. Boucher, M.D.
From the Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill. Address reprint requests to Dr. Boucher at the Marsico Lung Institute, University of North Carolina at Chapel Hill, 7008 Marsico Hall, Chapel Hill, NC 27599, or at richard_boucher@med.unc.edu.

 

参考文献

1. Han MK, Agusti A, Calverley PM, et al. Chronic obstructive pulmonary disease phenotypes: the future of COPD. Am J Respir Crit Care Med 2010;182:598-604.

2. King PT, Holdsworth SR, Freezer NJ, Villanueva E, Holmes PW. Characterisation of the onset and presenting clinical features of adult bronchiectasis. Respir Med 2006;100:2183-2189.

3. Knowles MR, Zariwala M, Leigh M. Primary ciliary dyskinesia. Clin Chest Med 2016;37:449-461.

4. Rowe SM, Miller S, Sorscher EJ. Cystic fibrosis. N Engl J Med 2005;352:1992-2001.

5. Jones PW, Forde Y. St George’s respiratory questionnaire manual. London: St George’s, University of London, 2009 (http://www.healthstatus.sgul.ac.uk/SGRQ_download/SGRQ%20Manual%20June%202009.pdf).

6. Rogers DF. Physiology of airway mucus secretion and pathophysiology of hypersecretion. Respir Care 2007;52:1134-1146.

7. Dunican EM, Elicker BM, Gierada DS, et al. Mucus plugs in patients with asthma linked to eosinophilia and airflow obstruction. J Clin Invest 2018;128:997-1009.

8. Fahy JV, Dickey BF. Airway mucus function and dysfunction. N Engl J Med 2010;363:2233-2247.

9. Henderson AG, Ehre C, Button B, et al. Cystic fibrosis airway secretions exhibit mucin hyperconcentration and increased osmotic pressure. J Clin Invest 2014;124:3047-3060.

10. Kesimer M, Ford AA, Ceppe A, et al. Airway mucin concentration as a marker of chronic bronchitis. N Engl J Med 2017;377:911-922.

11. Button B, Goodell HP, Atieh E, et al. Roles of mucus adhesion and cohesion in cough clearance. Proc Natl Acad Sci U S A 2018;115:12501-12506.

12. Rose MC, Voynow JA. Respiratory tract mucin genes and mucin glycoproteins in health and disease. Physiol Rev 2006;86:245-278.

13. Button B, Cai LH, Ehre C, et al. A periciliary brush promotes the lung health by separating the mucus layer from airway epithelia. Science 2012;337:937-941.

14. Thornton DJ, Rousseau K, McGuckin MA. Structure and function of the polymeric mucins in airways mucus. Annu Rev Physiol 2008;70:459-486.

15. Rubinstein M, Colby RH. Polymer physics. Oxford, United Kingdom: Oxford University Press, 2003.

16. Anderson WH, Coakley RD, Button B, et al. The relationship of mucus concentration (hydration) to mucus osmotic pressure and transport in chronic bronchitis. Am J Respir Crit Care Med 2015;192:182-190.

17. Lucas A, Douglas LC. Principles underlying ciliary activity in the respiratory tract. Arch Otolaryngol 1934;20:518-541.

18. Okuda K, Chen G, Subramani DB, et al. Localization of secretory mucins MUC5AC and MUC5B in normal/healthy human airways. Am J Respir Crit Care Med 2019;199:715-727.

19. Zhu Y, Ehre C, Abdullah LH, et al. Munc13-2-/- baseline secretion defect reveals source of oligomeric mucins in mouse airways. J Physiol 2008;586:1977-1992.

20. Widdicombe JH, Wine JJ. Airway gland structure and function. Physiol Rev 2015;95:1241-1319.

21. Boucher RC. Human airway ion transport: part one. Am J Respir Crit Care Med 1994;150:271-281.

22. Tarran R, Button B, Picher M, et al. Normal and cystic fibrosis airway surface liquid homeostasis: the effects of phasic shear stress and viral infections. J Biol Chem 2005;280:35751-35759.

23. Leith DE. Cough. Phys Ther 1968;48:439-447.

24. Button B, Okada SF, Frederick CB, Thelin WR, Boucher RC. Mechanosensitive ATP release maintains proper mucus hydration of airways. Sci Signal 2013;6:ra46-ra46.

25. Cole AM, Liao HI, Stuchlik O, Tilan J, Pohl J, Ganz T. Cationic polypeptides are required for antibacterial activity of human airway fluid. J Immunol 2002;169:6985-6991.

26. Cole AM, Dewan P, Ganz T. Innate antimicrobial activity of nasal secretions. Infect Immun 1999;67:3267-3275.

27. Livraghi-Butrico A, Grubb BR, Wilkinson KJ, et al. Contribution of mucus concentration and secreted mucins Muc5ac and Muc5b to the pathogenesis of muco-obstructive lung disease. Mucosal Immunol 2017;10:395-407.

28. Cole PJ. Inflammation: a two-edged sword — the model of bronchiectasis. Eur J Respir Dis Suppl 1986;147:6-15.

29. Tyson JJ, Chen KC, Novak B. Sniffers, buzzers, toggles and blinkers: dynamics of regulatory and signaling pathways in the cell. Curr Opin Cell Biol 2003;15:221-231.

30. Chalmers JD, Moffitt KL, Suarez-Cuartin G, et al. Neutrophil elastase activity is associated with exacerbations and lung function decline in bronchiectasis. Am J Respir Crit Care Med 2017;195:1384-1393.

31. Sly PD, Gangell CL, Chen L, et al. Risk factors for bronchiectasis in children with cystic fibrosis. N Engl J Med 2013;368:1963-1970.

32. Worlitzsch D, Tarran R, Ulrich M, et al. Effects of reduced mucus oxygen concentration in airway Pseudomonas infections of cystic fibrosis patients. J Clin Invest 2002;109:317-325.

33. Cowley ES, Kopf SH, LaRiviere A, Ziebis W, Newman DK. Pediatric cystic fibrosis sputum can be chemically dynamic, anoxic, and extremely reduced due to hydrogen sulfide formation. MBio 2015;6(4):e00767-e00767.

34. Tunney MM, Field TR, Moriarty TF, et al. Detection of anaerobic bacteria in high numbers in sputum from patients with cystic fibrosis. Am J Respir Crit Care Med 2008;177:995-1001.

35. Sze MA, Hogg JC, Sin DD. Bacterial microbiome of lungs in COPD. Int J Chron Obstruct Pulmon Dis 2014;9:229-238.

36. Segal LN, Clemente JC, Tsay JC, et al. Enrichment of the lung microbiome with oral taxa is associated with lung inflammation of a Th17 phenotype. Nat Microbiol 2016;1:16031-16031.

37. Flynn JM, Niccum D, Dunitz JM, Hunter RC. Evidence and role for bacterial mucin degradation in cystic fibrosis airway disease. PLoS Pathog 2016;12(8):e1005846-e1005846.

38. Matsui H, Wagner VE, Hill DB, et al. A physical linkage between cystic fibrosis airway surface dehydration and Pseudomonas aeruginosa biofilms. Proc Natl Acad Sci U S A 2006;103:18131-18136.

39. Rosenfeld M, Emerson J, Williams-Warren J, et al. Defining a pulmonary exacerbation in cystic fibrosis. J Pediatr 2001;139:359-365.

40. Sethi S, Maloney J, Grove L, Wrona C, Berenson CS. Airway inflammation and bronchial bacterial colonization in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2006;173:991-998.

41. Goss CH, Burns JL. Exacerbations in cystic fibrosis. 1: Epidemiology and pathogenesis. Thorax 2007;62:360-367.

42. Boucher RC. On the pathogenesis of acute exacerbations of mucoobstructive lung diseases. Ann Am Thorac Soc 2015;12:Suppl 2:S160-S163.

43. Lee AL, Button BM, Denehy L, et al. Proximal and distal gastro-oesophageal reflux in chronic obstructive pulmonary disease and bronchiectasis. Respirology 2014;19:211-217.

44. Brodlie M, Aseeri A, Lordan JL, et al. Bile acid aspiration in people with cystic fibrosis before and after lung transplantation. Eur Respir J 2015;46:1820-1823.

45. Cox MJ, Turek EM, Hennessy C, et al. Longitudinal assessment of sputum microbiome by sequencing of the 16S rRNA gene in non-cystic fibrosis bronchiectasis patients. PLoS One 2017;12(2):e0170622-e0170622.

46. Leung HM, Birket S, Hyun C, et al. The study of functional microanatomy of CF airways using clinical intranasal micro-OCT imaging. Pediatr Pulmonol 2018;53:Suppl 2:174-174. abstract.

47. Esther CR, Muhlebach MS, Ehre C, et al. Mucus accumulation in the lungs precedes structural changes and infection in children with cystic fibrosis. Sci Transl Med 2019;11(486):eaav3488-eaav3488.

48. Simel DL, Mastin JP, Pratt PC, et al. Scanning electron microscopic study of the airways in normal children and in patients with cystic fibrosis and other lung diseases. Pediatr Pathol 1984;2:47-64.

49. Abdullah LH, Coakley R, Webster MJ, et al. Mucin production and hydration responses to mucopurulent materials in normal versus cystic fibrosis airway epithelia. Am J Respir Crit Care Med 2018;197:481-491.

50. Muhlebach MS, Zorn BT, Esther CR, et al. Initial acquisition and succession of the cystic fibrosis lung microbiome is associated with disease progression in infants and preschool children. PLoS Pathog 2018;14(1):e1006798-e1006798.

51. Hogg JC, Paré PD, Hackett TL. The contribution of small airway obstruction to the pathogenesis of chronic obstructive pulmonary disease. Physiol Rev 2017;97:529-552.

52. Clunes LA, Davies CM, Coakley RD, et al. Cigarette smoke exposure induces CFTR internalization and insolubility, leading to airway surface liquid dehydration. FASEB J 2012;26:533-545.

53. Cantin AM, Bilodeau G, Ouellet C, Liao J, Hanrahan JW. Oxidant stress suppresses CFTR expression. Am J Physiol Cell Physiol 2006;290:C262-C270.

54. Kreda SM, Seminario-Vidal L, van Heusden CA, et al. Receptor-promoted exocytosis of airway epithelial mucin granules containing a spectrum of adenine nucleotides. J Physiol 2010;588:2255-2267.

55. Martinez-Garcia MA, Miravitlles M. Bronchiectasis in COPD patients: more than a comorbidity? Int J Chron Obstruct Pulmon Dis 2017;12:1401-1411.

56. Murphy TF, Brauer AL, Eschberger K, et al. Pseudomonas aeruginosa in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2008;177:853-860.

57. Horani A, Ferkol TW, Dutcher SK, Brody SL. Genetics and biology of primary ciliary dyskinesia. Paediatr Respir Rev 2016;18:18-24.

58. Bush A, Payne D, Pike S, Jenkins G, Henke MO, Rubin BK. Mucus properties in children with primary ciliary dyskinesia: comparison with cystic fibrosis. Chest 2006;129:118-123.

59. Maglione M, Bush A, Nielsen KG, et al. Multicenter analysis of body mass index, lung function, and sputum microbiology in primary ciliary dyskinesia. Pediatr Pulmonol 2014;49:1243-1250.

60. Flume PA, Chalmers JD, Olivier KN. Advances in bronchiectasis: endotyping, genetics, microbiome, and disease heterogeneity. Lancet 2018;392:880-890.

61. Whitwell F. A study of the pathology and pathogenesis of bronchiectasis. Thorax 1952;7:213-239.

62. Roberts HR, Wells AU, Milne DG, et al. Airflow obstruction in bronchiectasis: correlation between computed tomography features and pulmonary function tests. Thorax 2000;55:198-204.

63. Bienvenu T, Sermet-Gaudelus I, Burgel PR, et al. Cystic fibrosis transmembrane conductance regulator channel dysfunction in non-cystic fibrosis bronchiectasis. Am J Respir Crit Care Med 2010;181:1078-1084.

64. Serisier DJ, Martin ML, McGuckin MA, et al. Effect of long-term, low-dose erythromycin on pulmonary exacerbations among patients with non-cystic fibrosis bronchiectasis: the BLESS randomized controlled trial. JAMA 2013;309:1260-1267.

65. Aksamit TR, O’Donnell AE, Barker A, et al. Adult patients with bronchiectasis: a first look at the US Bronchiectasis Research Registry. Chest 2017;151:982-992.

66. Farrell PM, White TB, Ren CL, et al. Diagnosis of cystic fibrosis: consensus guidelines from the Cystic Fibrosis Foundation. J Pediatr 2017;181:Suppl:S4-S15.e1.

67. Ramsey BW, Davies J, McElvaney NG, et al. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med 2011;365:1663-1672.

68. Anderson SD, Daviskas E, Brannan JD, Chan HK. Repurposing excipients as active inhalation agents: the mannitol story. Adv Drug Deliv Rev 2018;133:45-56.

69. Donaldson SH, Bennett WD, Zeman KL, Knowles MR, Tarran R, Boucher RC. Mucus clearance and lung function in cystic fibrosis with hypertonic saline. N Engl J Med 2006;354:241-250.

70. Shei RJ, Peabody JE, Kaza N, Rowe SM. The epithelial sodium channel (ENaC) as a therapeutic target for cystic fibrosis. Curr Opin Pharmacol 2018;43:152-165.

71. Elkins MR, Robinson M, Rose BR, et al. A controlled trial of long-term inhaled hypertonic saline in patients with cystic fibrosis. N Engl J Med 2006;354:229-240.

72. Paff T, Daniels JM, Weersink EJ, Lutter R, Vonk Noordegraaf A, Haarman EG. A randomised controlled trial on the effect of inhaled hypertonic saline on quality of life in primary ciliary dyskinesia. Eur Respir J 2017;49:49-49.

73. Fujimoto K, Yasuo M, Urushibata K, Hanaoka M, Koizumi T, Kubo K. Airway inflammation during stable and acutely exacerbated chronic obstructive pulmonary disease. Eur Respir J 2005;25:640-646.

74. Yuan S, Hollinger M, Lachowicz-Scroggins ME, et al. Oxidation increases mucin polymer cross-links to stiffen airway mucus gels. Sci Transl Med 2015;7:276ra27-276ra27.

75. Tarrant BJ, Le Maitre C, Romero L, et al. Mucoactive agents for chronic, non-cystic fibrosis lung disease: a systematic review and meta-analysis. Respirology 2017;22:1084-1092.

服务条款 | 隐私政策 | 联系我们