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.
Highlights
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrotic lung disease of unknown etiology [1]
Hyperoxia was chosen as a mitochondrial stressor and apoptosis inducer, because cardiolipin is a primary target of lipid oxidization in hyperoxic lung [15] and oxidized cardiolipin is a trigger for mitochondria-mediated cell apoptosis [16]
This increase in TUNEL positive cells in hyperoxic Atp8b1G308V/G308V lungs was statistically significant (Fig. 1C). We surmise that this increase is, at least in part, due to the increased number of apoptotic type II alveolar epithelial cells (AECs) based on the observation that there was no statistically significant difference between hyperoxic WT and Atp8b1G308V/G308V lungs regarding the number of TUNEL positive cells in bronchiolar epithelium (Fig. 1D-F; the basement membrane of bronchiolar epithelium is outlined by blue line)
Summary
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrotic lung disease of unknown etiology [1]. The median survival of this fatal disease after diagnosis is approximately 3 years and the outcome is largely unaffected by current therapies [2]. The current, widely used bleomycininduced mouse model of pulmonary fibrosis has helped www.aging-us.com researchers and clinicians understand IPF pathophysiology to a large extent as it mimics many pathological aspects of IPF [3]. The events that occur in the early stages of IPF have not been well investigated in the belomycin model. In this model, fibrosis is preceded by robust inflammation, which is inconsistent with the current consensus that IPF is not triggered by inflammation
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