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

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.

Biological interacting units identified in human protein networks reveal tissue-functional diversification and its impact on disease

“…To simplify the analysis, we collapsed the BioInt units (dots) presenting a Wang's Semantic similarity coefficient >0.6 into functional clusters (top 10 largest clusters are arranged in Y axes). In particular, the BioInt units most targeted by fibrosis-related DEg in lung included membrane permeability, proteolysis and apoptosis signaling-related functions [35] . In the case of psoriasis, stress-related protein folding and degradation-regulatory pathways were consistently altered in immune-related organs [39] .…”

The Role of BiP and the IRE1α–XBP1 Axis in Rhabdomyosarcoma Pathology

“…TMA slides (5-µm thick) were deparaffinized in 60 °C for 30min and subsequently rehydrated in Xylene with a gradient alcohol series. Heat-mediated antigen retrieval (0.01 M sodium citrate buffer, pH 6.0) was performed as described previously [ 22 , 26 , 27 ]. In order to eliminate background interference, the slides were washed with Phosphate buffered saline (PBS) and blocked with blocking solution (1.5 mL Maleic Acid Buffer, 0.5 mL FBS, 0.5 mL stock blocking solution, 50 µL 10% Tween-20 and 2.5 mL PBS) at room temperature for 30 min.…”

The role of PD-1/PD-L1 axis in idiopathic pulmonary fibrosis: Friend or foe?

“…It maintains the homeostasis of the intracellular environment by forming autophagosome vesicles, engulfing dysfunctional cytoplasm and organelles, and forming autolysosomes to degrade the contents of vesicles (89,90). Autophagy disorder involves various diseases, also including IPF (91)(92)(93)(94)(95)(96). Accumulating evidence revealed that autophagy activity was impaired in IPF, and inhibition of autophagy could induce myofibroblast proliferation and ECM deposition, thus leading to fibrosis (97,98).…”