Quantification of Periciliary Fluid Height in Human Airway Biopsies Is Feasible, but Not Suitable as a Biomarker

被引:8
作者
Griesenbach, Uta [1 ]
Soussi, Samia
Larsen, Mia B.
Casamayor, Isabel
Dewar, Ann [2 ]
Regamey, Nicolas [2 ]
Bush, Andrew [2 ]
Shah, Pallav L. [2 ]
Davies, Jane C.
Alton, Eric W. F. W.
机构
[1] Univ London Imperial Coll Sci Technol & Med, Dept Gene Therapy, Natl Heart & Lung Inst, London SW3 6LR, England
[2] Royal Brompton Hosp, London SW3 6LY, England
关键词
cystic fibrosis; biomarker; lung; epithelial cells; extracellular fluid; SURFACE LIQUID VOLUME; FIBROSIS LUNG-DISEASE; CYSTIC-FIBROSIS; MUCOCILIARY CLEARANCE; ION-TRANSPORT; METABOLISM; EPITHELIA; CILIA; CFTR; NA+;
D O I
10.1165/rcmb.2009-0265OC
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The "low volume hypothesis," stating that imbalanced ion movement across the cystic fibrosis (CF) airway epithelium leads to a reduction in periciliary fluid (PCL) and consequently impaired mucociliary clearance, has been the prevailing theory explaining CF pathophysiology, and has been supported by animal models and ex vivo cell culture systems. However, studies in freshly obtained human tissue have not yet been performed. Methods to quantify PCL height in freshly obtained airway biopsies may be useful to assess efficacy of new treatments aimed at restoring PCL height. Here, we established methods to quantify PCL height in freshly obtained CF and non-CF human lower airway biopsies. More than 90% of biopsies contained ciliated epithelium, and PCL height measurements were feasible in approximately 50% of these. Although the mean PCL height was reduced in CF tissue (non-CF, 5.60 +/- 0.28 mu m; CF, 4.52 +/- 0.47 mu m), this did not reach statistical significance (P = 0.06). To strengthen the data, we performed similar studies in wild-type and CF knockout mice, and confirmed the results (non-CF, 4.70 +/- 0.13; CF, 4.10 +/- 0.09 mu m; P < 0.05). PCL height measurements in freshly obtained human airway biopsies are feasible, and PCL height appears reduced in subjects with CF, thereby further supporting the "low volume hypothesis." However, power calculations indicate that this assay can only be considered as a biomarker in large, late-phase clinical trials, because sample sizes required to achieve sufficient power are comparatively large.
引用
收藏
页码:309 / 315
页数:7
相关论文
共 21 条
[1]  
AFZELIUS BA, 1985, EUR J RESPIR DIS, V66, P173
[2]   Ion and fluid transport properties of small airways in cystic fibrosis [J].
Blouquit, Sabine ;
Regnier, Agathe ;
Dannhoffer, Luc ;
Fermanian, Christophe ;
Naline, Emmanuel ;
Boucher, Richard ;
Chinet, Thierry .
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 2006, 174 (03) :299-305
[3]   Evidence for airway surface dehydration as the initiating event in CF airway disease [J].
Boucher, R. C. .
JOURNAL OF INTERNAL MEDICINE, 2007, 261 (01) :5-16
[4]   Regulation of MUC5AC mucin secretion and airway surface liquid metabolism by IL-1β in human bronchial epithelia [J].
Gray, T ;
Coakley, R ;
Hirsh, A ;
Thornton, D ;
Kirkham, S ;
Koo, JS ;
Burch, L ;
Boucher, R ;
Nettesheim, P .
AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY, 2004, 286 (02) :L320-L330
[5]   Gene transfer to the lung: Lessons learned from more than 2 decades of CF gene therapy [J].
Griesenbach, Uta ;
Alton, Eric W. F. W. .
ADVANCED DRUG DELIVERY REVIEWS, 2009, 61 (02) :128-139
[6]   Correctors promote folding of the CFTR in the endoplasmic reticulum [J].
Loo, Tip W. ;
Bartlett, M. Claire ;
Clarke, David M. .
BIOCHEMICAL JOURNAL, 2008, 413 (01) :29-36
[7]   Increased airway epithelial Na+ absorption produces cystic fibrosis-like lung disease in mice [J].
Mall, M ;
Grubb, BR ;
Harkema, JR ;
O'Neal, WK ;
Boucher, RC .
NATURE MEDICINE, 2004, 10 (05) :487-493
[8]   Dual-energy x-ray absorptiometry in small subjects: Influence of dual-energy x-ray equipment on assessment of mineralization and body composition in newborn piglets [J].
Picaud, JC ;
Nyamugabo, K ;
Braillon, P ;
Lapillonne, A ;
Claris, O ;
Delmas, P ;
Meunier, P ;
Salle, B ;
Rigo, J .
PEDIATRIC RESEARCH, 1999, 46 (06) :772-777
[9]   Safety and ethics of bronchoscopy and endobronchial biopsy in difficult asthma [J].
Payne, D ;
McKenzie, SA ;
Stacey, S ;
Misra, D ;
Haxby, E ;
Bush, A .
ARCHIVES OF DISEASE IN CHILDHOOD, 2001, 84 (05) :423-426
[10]   Metabolism of P2 receptor agonists in human airways - Implications for mucociliary clearance and cystic fibrosis [J].
Picher, M ;
Burch, LH ;
Boucher, RC .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2004, 279 (19) :20234-20241