title: CaMKII inhibition in type II pneumocytes protects from bleomycin-induced pulmonary fibrosis by preventing Ca2+-dependent apoptosis.
abstract: The calcium and calmodulin-dependent kinase II (CaMKII) translates increases in intracellular Ca(2+) into downstream signaling events. Its function in pulmonary pathologies remains largely unknown. CaMKII is a well-known mediator of apoptosis and regulator of endoplasmic reticulum (ER) Ca(2+). ER stress and apoptosis of type II pneumocytes lead to aberrant tissue repair and progressive collagen deposition in pulmonary fibrosis. Thus we hypothesized that CaMKII inhibition alleviates fibrosis in response to bleomycin by attenuating apoptosis and ER stress of type II pneumocytes. We first established that CaMKII was strongly expressed in the distal respiratory epithelium, in particular in surfactant protein-C-positive type II pneumocytes, and activated after bleomycin instillation. We generated a novel transgenic model of inducible expression of the CaMKII inhibitor peptide AC3-I limited to type II pneumocytes (Tg SPC-AC3-I). Tg SPC-AC3-I mice were protected from development of pulmonary fibrosis after bleomycin exposure compared with wild-type mice. CaMKII inhibition also provided protection from apoptosis in type II pneumocytes in vitro and in vivo. Moreover, intracellular Ca(2+) levels and ER stress were increased by bleomycin and significantly blunted with CaMKII inhibition in vitro. These data demonstrate that CaMKII inhibition prevents type II pneumocyte apoptosis and development of pulmonary fibrosis in response to bleomycin. CaMKII inhibition may therefore be a promising approach to prevent or ameliorate the progression of pulmonary fibrosis.
authors.affiliation: Department of Internal Medicine, University of Iowa, Iowa City, Iowa;
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Winters
authors.affiliation: Department of Internal Medicine, University of Iowa, Iowa City, Iowa;
authors.forename: Olha
authors.initials: O
authors.lastname: Koval
authors.affiliation: Department of Internal Medicine, University of Iowa, Iowa City, Iowa;
authors.forename: Shubha
authors.initials: S
authors.lastname: Murthy
authors.affiliation: Central Microscopy Research Facility, University of Iowa, Iowa City, Iowa;
authors.forename: Chantal
authors.initials: C
authors.lastname: Allamargot
authors.affiliation: Department of Internal Medicine, University of Iowa, Iowa City, Iowa;
authors.forename: Sara C
authors.initials: SC
authors.lastname: Sebag
authors.affiliation: Department of Internal Medicine, University of Iowa, Iowa City, Iowa;
authors.forename: John D
authors.initials: JD
authors.lastname: Paschke
authors.affiliation: Department of Internal Medicine, University of Iowa, Iowa City, Iowa;
authors.forename: Omar A
authors.initials: OA
authors.lastname: Jaffer
authors.affiliation: Department of Internal Medicine, University of Iowa, Iowa City, Iowa; Free Radical and Radiation Biology Graduate Program, University of Iowa, Iowa City, Iowa; Iowa City Veterans Affairs Healthcare System, Iowa City, Iowa; and Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: A Brent
authors.initials: AB
authors.lastname: Carter
authors.affiliation: Department of Internal Medicine, University of Iowa, Iowa City, Iowa; Iowa City Veterans Affairs Healthcare System, Iowa City, Iowa; and isabella-grumbach@uiowa.edu.
authors.forename: Isabella M
authors.initials: IM
authors.lastname: Grumbach
mesh_terms: D056809:Alveolar Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001761:Bleomycin / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors*; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000502:physiology; D008822:Mice, Transgenic; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011658:Pulmonary Fibrosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
chemical_list: D047428:Protein Kinase Inhibitors; D001761:Bleomycin; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D002118:Calcium
keywords: CaMKII; ER stress; apoptosis; bleomycin; pulmonary fibrosis