Autophagy, Apoptosis, the Unfolded Protein Response, and Lung Function in Idiopathic Pulmonary Fibrosis.

Pawan Sharma,Afshin Samali,Saeid Ghavami,Javad Alizadeh,Maya Juarez,Andrew J Halayko,Nicholas J Kenyon,Amir A Zeki

doi:10.3390/cells10071642

Abstract

Autophagy, apoptosis, and the unfolded protein response (UPR) are fundamental biological processes essential for manifold cellular functions in health and disease. Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal pulmonary disorder associated with aging that has limited therapies, reflecting our incomplete understanding. We conducted an observational study linking molecular markers of cell stress response pathways (UPR: BiP, XBP1; apoptosis: cleaved caspase-3; autophagy: LC3β) in lung tissues from IPF patients and correlated the expression of these protein markers to each subject’s lung function measures. We hypothesized that changes in lung tissue expression of apoptosis, autophagy, and UPR markers correlate with lung function deficits in IPF. The cell stress markers BiP, XBP1, LC3β puncta, and cleaved caspase-3 were found to be elevated in IPF lungs compared to non-IPF lungs, and, further, BiP and cleaved caspase-3 co-localized in IPF lungs. Considering lung function independently, we observed that increased XBP1, BiP, and cleaved caspase-3 were each associated with reduced lung function (FEV1, FVC, TLC, RV). However, increased lung tissue expression of LC3β puncta was significantly associated with increased diffusion capacity (DLCO), an indicator of alveolar–capillary membrane function. Similarly, the co-localization of UPR (XBP1, BiP) and autophagy (LC3β puncta) markers was positively correlated with increased lung function (FEV1, FVC, TLC, DLCO). However, the presence of LC3β puncta can indicate either autophagy flux inhibition or activation. While the nature of our observational cross-sectional study design does not allow conclusions regarding causal links between increased expression of these cell stress markers, lung fibrosis, and lung function decline, it does provide some insights that are hypothesis-generating and suggests that within the milieu of active UPR, changes in autophagy flux may play an important role in determining lung function. Further research is necessary to investigate the mechanisms linking UPR and autophagy in IPF and how an imbalance in these cell stress pathways can lead to progressive fibrosis and loss of lung function. We conclude by presenting five testable hypotheses that build on the research presented here. Such an understanding could eventually lead to the development of much-needed therapies for IPF.

Highlights

Idiopathic pulmonary fibrosis (IPF) is the most common of the interstitial lung diseases affecting the older population [1,2]
Our results suggest that unfolded protein response (UPR), autophagy, and apoptosis protein expression markers are significantly increased in IPF compared to non-IPF lungs
In IPF lungs, we observed significantly increased co-localization of between formation and degradation. GRP78 (BiP) and cleaved caspase-3 compared to non-IPF lungs (Figure 1A), which points toward a co-active UPR and apoptotic signaling pathway in IPF

Summary

Introduction

Idiopathic pulmonary fibrosis (IPF) is the most common of the interstitial lung diseases affecting the older population [1,2]. The fundamental pathological processes involved in IPF may be triggered by chronic and/or repetitive damage to the alveolar epithelium of the lung [1,3]. The injured epithelium results in the activation of other types of lung cells, namely, alveolar fibroblasts. The resultant wound healing response by the activated fibroblasts leads to the accumulation of extracellular matrix (ECM), causing phenotypic yet irreversible lung fibrosis that leads to loss of lung function [1,2,3]. Aging is increasingly recognized as a very important factor in the development of IPF, where fibroblast senescence can contribute to IPF pathogenesis [4]

Methods

Results

Conclusion