CaMKII inhibition in type II pneumocytes protects from bleomycin-induced pulmonary fibrosis by preventing Ca2+-dependent apoptosis

Christopher J Winters; Olha Koval; Shubha Murthy; Chantal Allamargot; Sara C Sebag; John D Paschke; Omar A Jaffer; A Brent Carter; Isabella M Grumbach

doi:10.1152/ajplung.00132.2015

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CaMKII inhibition in type II pneumocytes protects from bleomycin-induced pulmonary fibrosis by preventing Ca2+-dependent apoptosis

Journal article

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Peer reviewed

CaMKII inhibition in type II pneumocytes protects from bleomycin-induced pulmonary fibrosis by preventing Ca2+-dependent apoptosis

Christopher J Winters, Olha Koval, Shubha Murthy, Chantal Allamargot, Sara C Sebag, John D Paschke, Omar A Jaffer, A Brent Carter and Isabella M Grumbach

American journal of physiology. Lung cellular and molecular physiology, Vol.310(1), pp.L86-L94

01/01/2016

DOI: 10.1152/ajplung.00132.2015

PMCID: PMC4698436

PMID: 26545899

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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.

Endoplasmic Reticulum Stress - drug effects

Apoptosis - drug effects

Calcium - metabolism

Endoplasmic Reticulum - metabolism

Mice, Transgenic

Alveolar Epithelial Cells - metabolism

Pulmonary Fibrosis - pathology

Alveolar Epithelial Cells - drug effects

Calcium-Calmodulin-Dependent Protein Kinase Type 2 - antagonists & inhibitors

Animals

Endoplasmic Reticulum - drug effects

Bleomycin - pharmacology

Protein Kinase Inhibitors - pharmacology

Pulmonary Fibrosis - metabolism

Pulmonary Fibrosis - drug therapy

Endoplasmic Reticulum Stress - physiology

Details

Title: Subtitle: CaMKII inhibition in type II pneumocytes protects from bleomycin-induced pulmonary fibrosis by preventing Ca2+-dependent apoptosis
Creators: Christopher J Winters - Department of Internal Medicine, University of Iowa, Iowa City, Iowa
Olha Koval - Department of Internal Medicine, University of Iowa, Iowa City, Iowa
Shubha Murthy - Department of Internal Medicine, University of Iowa, Iowa City, Iowa
Chantal Allamargot - Central Microscopy Research Facility, University of Iowa, Iowa City, Iowa
Sara C Sebag - Department of Internal Medicine, University of Iowa, Iowa City, Iowa
John D Paschke - Department of Internal Medicine, University of Iowa, Iowa City, Iowa
Omar A Jaffer - Department of Internal Medicine, University of Iowa, Iowa City, Iowa
A Brent Carter - 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
Isabella M Grumbach - Department of Internal Medicine, University of Iowa, Iowa City, Iowa; Iowa City Veterans Affairs Healthcare System, Iowa City, Iowa; and isabella-grumbach@uiowa.edu
Resource Type: Journal article
Publication Details: American journal of physiology. Lung cellular and molecular physiology, Vol.310(1), pp.L86-L94
DOI: 10.1152/ajplung.00132.2015
PMID: 26545899
PMCID: PMC4698436
NLM abbreviation: Am J Physiol Lung Cell Mol Physiol
ISSN: 1040-0605
eISSN: 1522-1504
Grant note: R01 HL108932 / NHLBI NIH HHS 2R01-ES-015981-06 / NIEHS NIH HHS R01 ES015981 / NIEHS NIH HHS I01 BX001135 / BLRD VA I01 BX000163 / BLRD VA T32 HL087738 / NHLBI NIH HHS R01-HL-108932 / NHLBI NIH HHS
Language: English
Date published: 01/01/2016
Academic Unit: Anatomy and Cell Biology; Core Research Facilities; Cardiovascular Medicine; Radiation Oncology; Internal Medicine
Record Identifier: 9984094531602771

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