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A5: Cellular and molecular responses to trauma-induced damage of the distal respiratory epithelium

PI: H. Barth and M. Frick

Direct and indirect trauma to the lung are a major cause for the development of acute lung injury/acute respiratory distress syndrome (ALI/ARDS). A hallmark of ARDS is excessive invasion and activation of neutrophils (PMN) in the alveolar space. The release of toxic mediators from PMNs causes alveolar barrier breakdown, which is central for developing ARDS. Maintaining baseline PMN responsiveness on the other hand, is crucial for efficient host defense. Therefore, understanding and targeted pharmacological modulation of enhanced PMN recruitment, priming, and activation is important for future treatment of trauma-induced ARDS. Amongst others, ATP has been found an important “danger” molecule, able to trigger PMN mobilization and control PMN activation. ATP is suspected to modulate the release and intra-alveolar balance of signaling molecules from epithelial cells (e.g. PGE2) and PMNs (e.g. leukotriene B4), which affect PMN activation. Above all, migration and activation of PMNs also depend on Rho-regulated actin dynamics. Given the importance of understanding the molecular mechanisms that regulate PMN migration/activation and building on our results from the initial funding period, we want to test whether trauma-induced increases in alveolar ATP modulate PMN migration, priming and activation; PGE2 and leukotriene B4 (LTB4) levels are modulated following various injuries and result in excessive activation of PMNs and an aggravation of barrier damage. Moreover, PMN-selective toxins to pharmacologically modulate PMN migration across the alveolar barrier will be developed in this project.

We will use fully humanized in vitro models of the alveolar barrier to investigate the impact of trauma challenges on ATP release, cyto-/chemokine levels, PMN migration, priming and activation and on the barrier properties. We will further develop and characterize the PMN-selective toxins in vitro, ex vivo and in the TxT mouse model to inhibit excessive PMN migration across the alveolar barrier.

Principle investigator

Prof. Dr. Holger Barth
Institut für Pharmakologie und Toxikologie
Universitätsklinikum Ulm
Albert-Einstein-Allee 11
89081 Ulm
Tel: +49 731 500-65503
Fax: +49 731 500-65502

Prof. Dr. Manfred Frick
Institut für Allgemeine Physiologie
Universität Ulm
Albert-Einstein-Allee 11
89081 Ulm
Tel.: +49 731 500 23115
Fax: +49 731 500 23242

[Translate to english:] Purinergic P2X receptors are expressed in primary alveolar epithelial cells
[Translate to english:] Activation of P2X4 receptors in ATII cells facilitates surfactant secretion and drives transepithelial fluid