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Interrelations/Cross Talk Between Transcellular Transport Function and Paracellular Tight Junctional Properties in Lung Epithelial and Endothelial Barriers

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Interrelations/Cross Talk Between Transcellular Transport Function and Paracellular Tight Junctional Properties in Lung Epithelial and Endothelial Barriers Am J Physiol Lung Cell Mol Physiol 293: L520–L524, 2007. First published June 29, 2007; doi:10.1152/ajplung.00218.2007. EB2007 SYMPOSIUM REPORT Interrelations/cross talk between transcellular transport function and paracellular tight junctional properties in lung epithelial and endothelial barriers Willy Van Driessche,1 James L. Kreindler,2 Asrar B. Malik,3 Susan Margulies,4 Simon A. Lewis,5 and Kwang-Jin Kim6 1Laboratory of Physiology, Campus Gasthuisberg O&N, K.U. Leuven, Leuven, Belgium; 2Division of Pulmonary Medicine, Allergy, and Immunology, Department of Pediatrics, Children’s Hospital of Pittsburgh/University of Pittsburgh, Pittsburgh, Pennsylvania; 3Department of Pharmacology, University of Illinois, Chicago, Illinois; 4Department of Bioengineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, Pennsylvania; 5Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, Texas; and 6Will Rogers Institute Pulmonary Research Center, Departments of Medicine, Physiology and Biophysics, Pharmacology and Pharmaceutical Sciences, and Biomedical Engineering, Keck School of Medicine, School of Pharmacy, and Viterbi School of Engineering, University of Southern California, Los Angeles, California Van Driessche W, Kreindler JL, Malik AB, Margulies S, Lewis movement of some substances between these compartments, SA, Kim K-J. Interrelations/cross talk between transcellular trans- and, last, they permit the movement of selected substances port function and paracellular tight junctional properties in lung between the compartments by either active transport or modi- epithelial and endothelial barriers. Am J Physiol Lung Cell Mol fication of the passive permeability. Various techniques have Physiol 293: L520–L524, 2007. First published June 29, 2007; been applied over the years to investigate how lung epithelia doi:10.1152/ajplung.00218.2007.—In this synopsis of a symposium at EB2007, we start with an overview of noise and impedance analyses and endothelia perform these basic functions. These techniques that have been applied to various epithelial barriers. Noise analysis include but are not limited to fluorescence-based techniques for yields specific information about ion channels and their regulation in unraveling Ca-signaling mechanisms, Ussing chamber tech- epithelial and endothelial barriers. Impedance analysis can yield niques for characterization of active and passive ion transport information about apical and basolateral membrane conductances and properties, and patch-clamp studies for deducing kinetics of paracellular conductance of both epithelial and endothelial barriers. ion channels in both isolated and in situ cells of the lungs. In Using a morphologically based model, impedance analysis has been the past, the transcellular and paracellular routes were treated used to assess changes in apical and basolateral membrane surface as two distinct and independent parallel entities. It is becoming areas and dimensions of the lateral intercellular space. Impedance clear that this is not the case, and to understand the physiology analysis of an in vitro airway epithelial barrier under normal, nucle- of solute and solvent movement across the lung epithelia and otide-stimulated, and cigarette smoke-exposed conditions yielded in- formation on how activation and inhibition of secretion occur in endothelia, one must consider these two pathways as two airway epithelial cells. Similarly, impedance analysis of primary rat dynamic and interacting parallel pathways. Studies of transcel- alveolar epithelial cell monolayer model under control and EGTA lular-paracellular cross talk in lung epithelial and endothelial exposure conditions indicate that EGTA causes decreases in resis- barriers are relatively new, and interesting and important ob- tances of tight junctional routes as well as apical and basolateral cell servations are starting to emerge. membranes without causing much change in cell capacitances. In a stretch-caused injury model of alveolar epithelium, transcellular ion TRANSEPITHELIAL AND TRANSENDOTHELIAL NOISE AND transport function and paracellular permeability of solute transport IMPEDANCE MEASUREMENTS: STRENGTHS appear to be differentially regulated. Finally, inhibition of caveolae- AND SHORTCOMINGS mediated transcytosis in lung endothelium led to disruption of para- cellular routes, increasing the physical dimension and permeability of Noise analysis has been successfully applied to study ion tight junctional region. These data together demonstrate the cross talk channel activity in a variety of tight epithelia. Two categories between transcellular and paracellular transport (function and routes) of fluctuation in current were considered: spontaneous noise of lung epithelial and endothelial barriers. Mechanistic (e.g., signaling (SN), which is caused by the spontaneous open-close kinetics cascades) information on such cross talk remain to be determined. of ion channels, and blocker-induced noise (BIN), which is caused by random interaction of a blocker with the channel. SN spectra are particularly useful in characterizing ion conductive EPITHELIA AND ENDOTHELIA PERFORM three basic functions. They pathways that are not detectable with macroscopic current separate two fluid compartments, they selectively restrict the recordings. The benefits of studies of BIN spectra are 1) unbiased measurement of the kinetics of the interaction of Address for reprint requests and other correspondence: K.-J. Kim, Will the blocker with the channel, and 2) determination of the single Rogers Institute Pulmonary Research Center, Depts. of Medicine, Physiology and Biophysics, Pharmacology and Pharmaceutical Sciences, and Biomedical Engineering, Keck School of Medicine, School of Pharmacy, and Viterbi The costs of publication of this article were defrayed in part by the payment School of Engineering, Univ. of Southern California, Los Angeles, CA 90033 of page charges. The article must therefore be hereby marked “advertisement” (e-mail: [email protected]). in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. L520 1040-0605/07 $8.00 Copyright © 2007 the American Physiological Society http://www.ajplung.org EB2007 SYMPOSIUM REPORT L521 (12). Changes in RT will therefore be masked by both the solution resistance (Rsol) in series with epithelial or endothelial barrier per se and resistance of the substratum on which epithelial or endothelial cells grow or subepithelial or suben- dothelial compartment comprised of connective tissues and Fig. 1. Illustration of the impedance that is represented in a Cole-Cole plot. other components (Rsub). As illustrated in Fig. 1, RT can be Because the distribution of the capacitance in the lateral interspace, the center determined as the difference between the impedance at low and of the semicircle is depressed. Data are calculated for transepithelial resistance high frequencies. This method has been successfully applied in (RT) ϭ 20 ⍀, solution resistance (Rsol) ϩ subepithelial/subendothelial resis- studies of biopsies of human colon to estimate RT (28). tance (Rsub) ϭ 40 ⍀, and transepithelial capacitance (CT) ϭ 4 ␮F. The upward shift of the center of the semicircle is simulated by a Cole-Cole dispersion with TRANSPORT AND BARRIER FUNCTIONAL CHANGES IN ␣ϭ0.95. At high frequencies, impedance equals Rsol ϩ Rsub.Atlow frequencies, the impedance becomes RT ϩ Rsol ϩ Rsub. Thus RT equals AIRWAY EPITHELIA REVEALED BY TRANSEPITHELIAL impedance at lowest frequency used minus impedance at highest frequency IMPEDANCE ANALYSIS used. X, imaginary part or reactance. Reprinted with permission from Ghanem et al., Ref. 12. Polarized human bronchial epithelial (HBE) cells, estab- lished and refined by Gray et al. (13) following the procedures of Adler et al. (1), have a mucociliary phenotype and recapit- channel current and channel density. Requirements for a suc- ulate many of the functions of the native epithelium including cessful application of BIN recording are that the induced noise mucus secretion and vectorial ion transport (8, 13). Individual gives rise to relaxation noise in the frequency range of 0.1– membrane conductances and capacitances of HBE cells can be 1,000 Hz and that the magnitude of the inhibition of macro- estimated noninvasively using the system of transepithelial scopic current component can be recorded. A separate but impedance analysis engineered by Dr. Willy van Driessche, in equally powerful technique of impedance analysis of various which current is passed across the epithelium at 100 frequen- epithelial and endothelial barriers has been used over the years. cies, and the lumped model of a simple epithelium is employed Impedance of a biological barrier can be measured by imposing to fit the resulting data (25). When data are expressed as voltage (or current) pulses across the barrier and recording the Cole-Cole plots, two membranes can be distinguished after the current (or voltage) responses in the time domain and then apical membrane conductance has been increased by activation convert the voltage and current data from the time domain to of the cystic fibrosis transmembrane conductance regulator the frequency domain to yield the ratio of voltage and current (CFTR) (Fig. 2). Therefore, transepithelial impedance analysis data in the frequency domain, i.e., the impedance. Sinusoids, can be used to estimate real-time conductance and capacitance for which frequencies vary from very slow (e.g., 0.01 Hz) to changes induced by both stimuli
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