American Journal Of Respiratory Cell And Molecular Biology
Am J Respir Cell Mol Biol. 2011 Mar;44(3):309-15. doi: 10.1165/rcmb.2009-0265OC. Epub 2010 Apr 23.
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 μm; CF, 4.52 ± 0.47 μm), 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 μm; 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.