Transregional Collaborative Research Centre 152

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P16 - Reactive oxygen species (ROS)-signaling by TRP channels in the lung

Oxygen (O2) plays a pivotal role in body homeostasis and the function of the lung as the central organ for gas exchange is regulated by O2 levels in the air. Both, ischaemia in and irradiation of the lung induce the production of reactive oxygen species (ROS), which control complex signal transduction cascades essential for physiological and also for pathophysiological processes like edema formation and lung fibrosis. Recent publications by us and other laboratories favor TRPA1, TRPM2, TRPV4 and TRPC6 channels as important effectors in ROS-mediated signalling pathways. In the first funding period, a protective role of TRPV4 in the development of lung ischemia-reperfusion(I/R)-induced edema (LIRE) has been identified by us which still lacks a mechanistic explanation on the cellular and molecular level. Moreover, TRPC6 and TRPA1 function was deciphered in bleomycin-induced and hyperoxia-mediated lung fibrosis, respectively. By further analysis of TRP-deficient mouse models, essential functions of TRPA1, TRPC6, TRPM2 and TRPV4 in ROS signalling in the lung will now be defined. Along these lines, the impact of these TRP channels on two different pathophysiological scenarios in the lung will be investigated:

Aim 1: Role of TRPV4 for the integrity and barrier function of the lung:



Aim 2: Identification of TRP channels involved in radiation-induced lung fibrosis


Fig. 1: (above) Hypothetical function of TRPV4 in gene expression and protein translocation in alveolar epithelial cells. AQP5, aquaporin 5; CaM, calmodulin; Cdh, cadherin; CnA, calcineurin A; NFAT, nuclear factor of activated T-cells; ZO-P, zona occludens protein. (below) Hypothetical signal-transduction pathways mediating radiation induced lung fibrosis (RILF) by activation of TRP channels. PARG, poly(ADP-ribose)glycohydrolase; PARP-1, poly(ADP-ribose)polymerase-1; PLC, phospholipase C; DAG-K, Diacylglyerol-kinase; blue ↑, activation; red ↓, inhibition.

Defining TRP channel function in these pathophysiological processes will help identify new pharmacological targets to restore pulmonary homeostasis and functional gas exchange.

Alexander Dietrich

Prof. Dr. Alexander Dietrich

Ludwig-Maximilians-Universität in Munich