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Research Paper|Volume 11, Issue 1|pp 209—229

Oxidative stress induces club cell proliferation and pulmonary fibrosis in Atp8b1 mutant mice

Jutaro Fukumoto1, Joseph Leung1, Ruan Cox Jr1,2, Alexander Czachor1, Prasanna Tamarapu Parthasarathy1, Venu Lagishetty1, Maria Mandry1, Nima Hosseinian1, Priyanshi Patel1, Brittany Perry1, Mason T. Breitzig1, Matthew Alleyn1, Athena Failla1, Young Cho1, Andrew J. Cooke1, Lakshmi Galam1, Ramani Soundararajan1, Nirmal Sharma3, Richard F. Lockey1, Narasaiah Kolliputi1,2
  • 1Division of Allergy and Immunology, Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA
  • 2Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA
  • 3Advanced Lung Diseases & Lung Transplantation, Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA
Received: November 14, 2018Accepted: December 19, 2018Published: January 13, 2019

Copyright: © 2019 Fukumoto et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Atp8b1 (ATPase, aminophospholipid transporter, class I, type 8B, member 1) is a cardiolipin transporter in the apical membrane of lung epithelial cells. While the role of Atp8b1 in pneumonia-induced acute lung injury (ALI) has been well studied, its potential role in oxidative stress-induced ALI is poorly understood. We herein show that Atp8b1G308V/G308V mice under hyperoxic conditions display exacerbated cell apoptosis at alveolar epithelium and aberrant proliferation of club cells at bronchiolar epithelium. This hyperoxia-induced ambivalent response in Atp8b1G308V/G308V lungs was followed by patchy distribution of non-uniform interstitial fibrosis at late recovery phase under normoxia. Since this club cell abnormality is commonly observed between Atp8b1G308V/G308V lungs under hyperoxic conditions and IPF lungs, we characterized this mouse fibrosis model focusing on club cells. Intriguingly, subcellular morphological analysis of IPF lungs, using transmission electron microscopy (TEM), revealed that metaplastic bronchiolar epithelial cells in fibrotic lesions and deformed type II alveolar epithelial cells (AECs) in alveoli with mild fibrosis, have common morphological features including cytoplasmic vacuolation and dysmorphic lamellar bodies. In conclusion, the combination of Atp8b1 mutation and hyperoxic insult serves as a novel platform to study unfocused role of club cells in IPF.