TRANSLATIONAL REVIEW Calcium Homeostasis and Ionic Mechanisms in Pulmonary Fibroblasts Luke J. Janssen, Subhendu Mukherjee, and Kjetil Ask Firestone Institute for Respiratory Health, St. Joseph’s Hospital, and Department of Medicine, McMaster University, Hamilton, Ontario, Canada ORCID ID: 0000-0002-0202-735X (K.A.). 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 21 oscillations play a central role in the regulation of gene expression in human pulmonary fibroblasts. However, the mechanisms whereby cytosolic [Ca 21 ] are regulated and [Ca 21 ] oscillations transduced are both poorly understood. In this review, we present the general concepts of [Ca 21 ] homeostasis, of ionic mechanisms responsible for various Ca 21 fluxes, and of regulation of gene expression by [Ca 21 ]. 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 21 , which, in turn, activates membrane conductances, including voltage-dependent Ca 21 influx pathways. Collectively, these events produce recurring Ca 21 oscillations, the frequency of which is transduced by Ca 21 -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-b), 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 21 signaling events and the unfolded protein response and apoptosis are also explored. Keywords: calcium signaling; pulmonary fibrosis; transforming growth factor-b; platelet-derived growth factor; gene expression Clinical Relevance After reviewing the original findings pertaining to Ca 21 handling, electrophysiology, and gene expression specifically within pulmonary fibroblasts, we present a global mechanism that explains the roles of Ca 21 signaling in proliferation, synthesis/secretion of matrix proteins, autoactivation, and transformation to myofibroblasts, and, in the process, identify several novel targets for interventions aimed at controlling unwanted pulmonary fibrosis. This global mechanism has not yet been presented within the scientific community. Importance of Pulmonary Fibroblast Biology Fibroblasts are a highly heterogeneous population of cells, the primary function of which is to mediate structural changes in a variety of organs. This function is crucial for normal repair and wound healing. Unfortunately, in some contexts, fibroblast function is uncontrolled and brings on pathophysiological consequences (1). In fibrotic lung disease, the fibroblast is considered one of the hallmark target cells, as its transformation into a myofibroblast results in deposition of extracellular matrix and subsequent fibrosis. Of the more than 300 interstitial lung diseases of known and unknown origin, the common end-stage disease pattern is often extensive fibrosis. Since the discovery of the myofibroblast in 1969, extensive research has focused on fibroblast and myofibroblast biology in scarring disorders. The role of calcium in lung fibroblast biology has not been reviewed extensively and is the object of this review. Many growth factors and autacoids elevate [Ca 21 ] in pulmonary fibroblasts. More importantly, pharmacological disruption of [Ca 21 ] homeostasis in ( Received in original form July 24, 2014; accepted in final form March 16, 2015 ) This work was supported by the Canadian Lung Association and the Ontario Thoracic Society. Author Contributions: conception and design: L.J.J., S.M., and K.A.; drafting the manuscript for important intellectual content: L.J.J., S.M., and K.A. Correspondence and requests for reprints should be addressed to Luke J. Janssen, M.Sc., Ph.D., St. Joseph’s Hospital, 50 Charlton Avenue East, L-314, Hamilton, ON, L8N 4A6 Canada. E-mail: janssenl@mcmaster.ca Am J Respir Cell Mol Biol Vol 53, Iss 2, pp 135–148, Aug 2015 Copyright © 2015 by the American Thoracic Society Originally Published in Press as DOI: 10.1165/rcmb.2014-0269TR on March 18, 2015 Internet address: www.atsjournals.org Translational Review 135