title: An autoregulatory mechanism governing mucociliary transport is sensitive to mucus load.
abstract: Mucociliary clearance, characterized by mucus secretion and its conveyance by ciliary action, is a fundamental physiological process that plays an important role in host defense. Although it is known that ciliary activity changes with chemical and mechanical stimuli, the autoregulatory mechanisms that govern ciliary activity and mucus transport in response to normal and pathophysiological variations in mucus are not clear. We have developed a high-speed, 1-μm-resolution, cross-sectional imaging modality, termed micro-optical coherence tomography (μOCT), which provides the first integrated view of the functional microanatomy of the epithelial surface. We monitored invasion of the periciliary liquid (PCL) layer by mucus in fully differentiated human bronchial epithelial cultures and full thickness swine trachea using μOCT. We further monitored mucociliary transport (MCT) and intracellular calcium concentration simultaneously during invasion of the PCL layer by mucus using colocalized μOCT and confocal fluorescence microscopy in cell cultures. Ciliary beating and mucus transport are up-regulated via a calcium-dependent pathway when mucus causes a reduction in the PCL layer and cilia height. When the load exceeds a physiological limit of approximately 2 μm, this gravity-independent autoregulatory mechanism can no longer compensate, resulting in diminished ciliary motion and abrogation of stimulated MCT. A fundamental integrated mechanism with specific operating limits governs MCT in the lung and fails when periciliary layer compression and mucus viscosity exceeds normal physiologic limits.
authors.affiliation: 1 Harvard Medical School, Wellman Center for Photomedicine, and.
authors.forename: Linbo
authors.initials: L
authors.lastname: Liu
authors.forename: Suresh
authors.initials: S
authors.lastname: Shastry
authors.forename: Suzanne
authors.initials: S
authors.lastname: Byan-Parker
authors.forename: Grace
authors.initials: G
authors.lastname: Houser
authors.forename: Kengyeh
authors.initials: K
authors.lastname: K Chu
authors.forename: Susan E
authors.initials: SE
authors.lastname: Birket
authors.forename: Courtney M
authors.initials: CM
authors.lastname: Fernandez
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Gardecki
authors.forename: William E
authors.initials: WE
authors.lastname: Grizzle
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Wilsterman
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Sorscher
authors.forename: Steven M
authors.initials: SM
authors.lastname: Rowe
authors.forename: Guillermo J
authors.initials: GJ
authors.lastname: Tearney
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002923:Cilia / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D009079:Mucociliary Clearance; D009093:Mucus / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000378:metabolism*; D013997:Time Factors; D041623:Tomography, Optical Coherence / Q000379:methods; D014132:Trachea / Q000378:metabolism*; D014783:Viscosity
chemical_list: D002118:Calcium
keywords: cilia; intracellular calcium; micro-optical coherence tomography; mucociliary transport