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      Tight junctions in pulmonary epithelia during lung inflammation

      review-article
      Pflugers Archiv
      Springer Berlin Heidelberg
      Lung, Inflammation, Asthma, COPD, ARDS, Tight junctions

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          Abstract

          Inflammatory lung diseases like asthma bronchiale, chronic obstructive pulmonary disease and allergic airway inflammation are widespread public diseases that constitute an enormous burden to the health systems. Mainly classified as inflammatory diseases, the treatment focuses on strategies interfering with local inflammatory responses by the immune system. Inflammatory lung diseases predispose patients to severe lung failures like alveolar oedema, respiratory distress syndrome and acute lung injury. These life-threatening syndromes are caused by increased permeability of the alveolar and airway epithelium and exudate formation. However, the mechanism underlying epithelium barrier breakdown in the lung during inflammation is elusive. This review emphasises the role of the tight junction of the airway epithelium as the predominating structure conferring epithelial tightness and preventing exudate formation and the impact of inflammatory perturbations on their function.

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          Most cited references132

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          Structure and function of claudins.

          Claudins are tetraspan transmembrane proteins of tight junctions. They determine the barrier properties of this type of cell-cell contact existing between the plasma membranes of two neighbouring cells, such as occurring in endothelia or epithelia. Claudins can completely tighten the paracellular cleft for solutes, and they can form paracellular ion pores. It is assumed that the extracellular loops specify these claudin functions. It is hypothesised that the larger first extracellular loop is critical for determining the paracellular tightness and the selective ion permeability. The shorter second extracellular loop may cause narrowing of the paracellular cleft and have a holding function between the opposing cell membranes. Sequence analysis of claudins has led to differentiation into two groups, designated as classic claudins (1-10, 14, 15, 17, 19) and non-classic claudins (11-13, 16, 18, 20-24), according to their degree of sequence similarity. This is also reflected in the derived sequence-structure function relationships for extracellular loops 1 and 2. The concepts evolved from these findings and first tentative molecular models for homophilic interactions may explain the different functional contribution of the two extracellular loops at tight junctions.
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            Claudin-2 expression induces cation-selective channels in tight junctions of epithelial cells.

            Tight junctions seal the paracellular pathway of epithelia but, in leaky tissues, also exhibit specific permeability. In order to characterize the contribution of claudin-2 to barrier and permeability properties of the tight junction in detail, we studied two strains of Madin-Darby canine kidney cells (MDCK-C7 and MDCK-C11) with different tight junctional permeabilities. Monolayers of C7 cells exhibited a high transepithelial resistance (>1 kOhms cm(2)), compared with C11 cells (<100 Ohms cm(2)). Genuine expression of claudin-1 and claudin-2, but not of occludin or claudin-3, was reciprocal to transepithelial resistance. However, confocal microscopy revealed a marked subjunctional localization of claudin-1 in C11 cells, indicating that claudin-1 is not functionally related to the low tight junctional resistance of C11 cells. Strain MDCK-C7, which endogenously does not express junctional claudin-2, was transfected with claudin-2 cDNA. In transfected cells, but not in vector controls, the protein was detected in colocalization with junctional occludin by means of immunohistochemical analyses. Overexpression of claudin-2 in the originally tight epithelium with claudin-2 cDNA resulted in a 5.6-fold higher paracellular conductivity and relative ion permeabilities of Na(+) identical with 1, K(+)=1.02, NMDG(+)=0.79, choline(+)=0.71, Cl(-)=0.12, Br(-)=0.10 (vector control, 1:1.04:0.95:0.94:0.85:0.83). By contrast, fluxes of (radioactively labeled) mannitol and lactulose and (fluorescence labeled) 4 kDa dextran were not changed. Hence, with regular Ringer's, Na(+) conductivity was 0.2 mS cm(-2) in vector controls and 1.7 mS cm(-2) in claudin-2-transfected cells, while Cl(-) conductivity was 0.2 mS cm(-2) in both cells. Thus, presence of junctional claudin-2 causes the formation of cation-selective channels sufficient to transform a 'tight' tight junction into a leaky one.
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              Regulation of tissue homeostasis by NF-kappaB signalling: implications for inflammatory diseases.

              The nuclear factor-kappaB (NF-kappaB) signalling pathway regulates immune responses and is implicated in the pathogenesis of many inflammatory diseases. Given the well established pro-inflammatory functions of NF-kappaB, inhibition of this pathway would be expected to have anti-inflammatory effects. However, recent studies in mouse models have led to surprising and provocative results, as NF-kappaB inhibition in epithelial cells resulted in the spontaneous development of severe chronic inflammatory conditions. These findings indicate that NF-kappaB signalling acts in non-immune cells to control the maintenance of tissue immune homeostasis. This Review discusses the mechanisms by which NF-kappaB activity in non-immune cells regulates tissue immune homeostasis and prevents the pathogenesis of inflammatory diseases.
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                Author and article information

                Contributors
                0049 (0)731-50023247 , oliver.wittekindt@uni-ulm.de
                Journal
                Pflugers Arch
                Pflugers Arch
                Pflugers Archiv
                Springer Berlin Heidelberg (Berlin/Heidelberg )
                0031-6768
                1432-2013
                5 December 2016
                5 December 2016
                2017
                : 469
                : 1
                : 135-147
                Affiliations
                Institute of General Physiology, Ulm University, Albert-Einstein-Allee 11, 89081 Ulm, Germany
                Article
                1917
                10.1007/s00424-016-1917-3
                5203840
                27921210
                c0d4ab33-47dd-4074-88d1-1b6100bdeea8
                © The Author(s) 2016

                Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                History
                : 23 November 2016
                : 23 November 2016
                : 27 November 2016
                Funding
                Funded by: Ministry of Science, Research and Arts of Baden-Württemberg
                Award ID: 32-7533-6-10
                Award Recipient :
                Funded by: Deutsche Forschungsgemeinschaft (DE)
                Award ID: SFB1149/1.A05
                Funded by: FundRef http://dx.doi.org/10.13039/501100001659, Deutsche Forschungsgemeinschaft;
                Award ID: DI1402/3-1
                Categories
                Invited Review
                Custom metadata
                © Springer-Verlag Berlin Heidelberg 2017

                Anatomy & Physiology
                lung,inflammation,asthma,copd,ards,tight junctions
                Anatomy & Physiology
                lung, inflammation, asthma, copd, ards, tight junctions

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