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

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

JOURNAL: American Journal of Physiology – Lung Cellular and Molecular Physiology, 1 January 2016, 310(1):L86-L94 DOI: 10.1152/ajplung.00132.2015

Abstract:

The calcium and calmodulin-dependent kinase II (CaMKII) translates increases in intracellular Ca2+ 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) Ca2+. 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 Ca2+ 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.

Link to journal online: http://ajplung.physiology.org/content/310/1/L86.long

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