Roles of Transient Receptor Potential (TRP) cation channels in primary pulmonary fibroblasts

Geiger, Fabienne (2023): Roles of Transient Receptor Potential (TRP) cation channels in primary pulmonary fibroblasts. Dissertation, LMU München: Faculty of Medicine

Abstract

Transient receptor potential (TRP) cation channel-mediated signaling constitutes important pathways for ion homeostasis in mammalian cells. The only member of the ankyrin family of TRP channels, TRPA1, harbors a high number of ankyrin repeat domains (ARDs) in its N-terminus. We showed in paper I that this channel is highly expressed in primary human lung fibroblasts (HLFs) and prevented transforming growth factor beta 1 (TGF-β1)-induced fibroblast to myofibroblast differentiation (FMD) in these cells. FMD is a hallmark in the progression of pulmonary fibrosis (PF) in human patients. TRPA1 mRNA expression was markedly reduced in myofibroblasts and knockdown (KD) of the channel resulted in increased expression of fibrosis markers (e.g. collagen 1A1 (COL1A1), fibronectin 1 (FN1), alpha smooth muscle actin (α-SMA) and plasminogen activator inhibitor 1 (PAI-1)). TRPA1-mediated inhibition of expressed myofibroblast specific proteins was orchestrated by a tight regulation of extracellular signal-regulated kinase 1/2 (ERK1/2) and SMAD2-linker phosphorylation and depended on the availability of extracellular calcium ions (Ca2+). As one of the major second messengers, Ca2+ concentrations in cells underlie a rigid control to ensure the specificity of signals and avoid Ca2+-mediated toxicity. Ca2+ influx into cells occurs either through receptor-operated calcium entry (ROCE) or through store-operated calcium entry (SOCE). Whereas some groups suggested involvement of canonical TRP channels 1 and 6 (TRPC1/6) in SOCE, paper II showed that TRPC1/6 in primary murine lung fibroblasts (pmLFs) contribute exclusively to ROCE and not to SOCE. TRP melastatin 7 (TRPM7) channels differ from TRPA1 and TRPC1/6 in that they exhibit higher selectivity for magnesium ions (Mg2+) than for Ca2+. Activation of TRPM7 channels supported the development of cardiac fibrosis by enhancing TGF-β1-triggered synthesis of extracellular matrix (ECM). Paper III showed that inhibition of TRPM7 in HLFs increased plasmin activity and reduced fibrosis marker expression. Therefore, the results of paper I and III suggest that activation of TRPA1 and blocking of TRPM7 channels may be promising therapeutic strategies in patients suffering from pulmonary fibrosis.

• Item Type: Theses (Dissertation, LMU Munich)
• Subjects: 600 Technology, Medicine; 600 Technology, Medicine > 610 Medical sciences and medicine
• Faculties: Faculty of Medicine
• Language: English
• Date of oral examination: 21. September 2023
• 1. Referee: Dietrich, Alexander
• Signature of the printed copy: 0700/UMD 21432