Calcium Homeostasis and Ionic Mechanisms in Pulmonary Fibroblasts

Abstract

Fibroblasts are key cellular mediators of many chronic interstitial lung diseases, including idiopathic pulmonary fibrosis, scleroderma, sarcoidosis, drug-induced interstitial lung disease, and interstitial lung disease in connective tissue disease. A great deal of effort has been expended to understand the signaling mechanisms underlying the various cellular functions of fibroblasts. Recently, it has been shown that Ca(2+) oscillations play a central role in the regulation of gene expression in human pulmonary fibroblasts. However, the mechanisms whereby cytosolic [Ca(2+)] are regulated and [Ca(2+)] oscillations transduced are both poorly understood. In this review, we present the general concepts of [Ca(2+)] homeostasis, of ionic mechanisms responsible for various Ca(2+) fluxes, and of regulation of gene expression by [Ca(2+)]. In each case, we then also summarize the original findings that pertain specifically to pulmonary fibroblasts. From these data, we propose an overall signaling cascade by which excitation of the fibroblasts triggers pulsatile release of internally sequestered Ca(2+), which, in turn, activates membrane conductances, including voltage-dependent Ca(2+) influx pathways. Collectively, these events produce recurring Ca(2+) oscillations, the frequency of which is transduced by Ca(2+)-dependent transcription factors, which, in turn, orchestrate a variety of cellular events, including proliferation, synthesis/secretion of extracellular matrix proteins, autoactivation (production of transforming growth factor-β), and transformation into myofibroblasts. That unifying hypothesis, in turn, allows us to highlight several specific cellular targets and therapeutic intervention strategies aimed at controlling unwanted pulmonary fibrosis. The relationships between Ca(2+) signaling events and the unfolded protein response and apoptosis are also explored.

Loss of TRPV4 Function Suppresses Inflammatory Fibrosis Induced by Alkali-Burning Mouse Corneas

“…Although the in vivo TGFβ1 level was not affected by the loss of TRPV4 in healing corneas, the decline in myofibroblast transdifferentiation may be due to impaired cognate receptor function or signal transduction coupling inducing transactivation of other Ca 2+ influx pathways besides TRPV4. This is possible since there are numerous other Ca 2+ influx pathways besides TRPV4 which can be activated to induce increases in Ca 2+ influx [30]. The possible involvement of different Ca 2+ influx pathways besides TRPV4 may be a factor contributing to the variable effects of TGFβ receptor activation inducing responses accompanying transdifferentiation of fibroblasts into myofibroblasts.…”

Dust particles-induced intracellular Ca2+signaling and reactive oxygen species in lung fibroblast cell line MRC5

“…Currently, no therapeutic strategy targets [Ca 2+ ] i signaling in fibroblast-mediated pulmonary diseases [48], but our results suggest potential means of controlling fibrotic pulmonary diseases by manipulating [Ca 2+ ] i signaling events. In particular, we suggest antioxidant, [Ca 2+ ] i signaling pathway inhibitor, and TRPM2 inhibitor treatments should be considered for therapeutic trials in fibrotic diseases.…”

Pitx2c inhibition increases atrial fibroblast activity: Implications in atrial arrhythmogenesis

“…Intracellular calcium is critical for regulating various functions of fibroblasts, including cell proliferation, matrix remodelling and myofibroblast transdifferentiation . Cytoplasmic calcium oscillations activate extracellular signal‐regulated kinase (ERK) and enhance fibroblast survival and interstitial fibrosis .…”

“…Intracellular calcium is critical for regulating various functions of fibroblasts, including cell proliferation, matrix remodelling and myofibroblast transdifferentiation. 25 Cytoplasmic calcium oscillations activate extracellular signal-regulated kinase (ERK) and enhance fibroblast survival and interstitial fibrosis. 26 In this study, we found that Pitx2cknockdown cells exhibited greater cytoplasmic calcium concentrations compared to control cells in both the baseline calcium-free solution and the 2 mmol/L calcium-containing solution.…”