Calcium Homeostasis and Ionic Mechanisms in Pulmonary Fibroblasts

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 Ca2+ oscillations play a central role in the regulation of gene expression in human pulmonary fibroblasts. However, the mechanisms whereby cytosolic [Ca2+] are regulated and [Ca2+] oscillations transduced are both poorly understood. In this review, we present the general concepts of [Ca2+] homeostasis, of ionic mechanisms responsible for various Ca2+ fluxes, and of regulation of gene expression by [Ca2+]. 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 Ca2+, which, in turn, activates membrane conductances, including voltage-dependent Ca2+ influx pathways. Collectively, these events produce recurring Ca2+ oscillations, the frequency of which is transduced by Ca2+-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-beta), 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 Ca2+ signaling events and the unfolded protein response and apoptosis are also explored.