title: 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.
authors.affiliation: Firestone Institute for Respiratory Health, St. Joseph's Hospital, and Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Luke J
authors.initials: LJ
authors.lastname: Janssen
authors.affiliation: Firestone Institute for Respiratory Health, St. Joseph's Hospital, and Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Subhendu
authors.initials: S
authors.lastname: Mukherjee
authors.affiliation: Firestone Institute for Respiratory Health, St. Joseph's Hospital, and Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Kjetil
authors.identifier: http://orcid.org/0000-0002-0202-735X
authors.initials: K
authors.lastname: Ask
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D005347:Fibroblasts / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D008168:Lung / Q000378:metabolism / Q000473:pathology; D011658:Pulmonary Fibrosis / Q000378:metabolism / Q000473:pathology; D056811:Unfolded Protein Response
chemical_list: D002118:Calcium
keywords: calcium signaling; gene expression; platelet-derived growth factor; pulmonary fibrosis; transforming growth factor-β