Senescence and autophagy in usual interstitial pneumonia of different etiology

Florian Gallob,Florian Rumpp,Luka Brcic,Helmut Popper,Andreas Nerlich,Sylvia Eidenhammer

doi:10.1007/s00428-020-02917-2

Abstract

Idiopathic pulmonary fibrosis (IPF) is a disease with a dismal prognosis. Currently, the causing agent(s) are poorly understood. Recent data suggest that senescence and autophagy might play a role in its development, as well as changes in metabolism due to hypoxic conditions. In this study, the expression of senescence markers in 23 cases of usual interstitial pneumonia (UIP)/IPF and UIP/chronic autoimmune diseases (UIP/AuD) was investigated. The status of autophagy was evaluated with respect to either antiinflammatory or antihypoxia function. Formalin-fixed paraffin-embedded tissues of UIP were selected for immunohistochemistry with antibodies for p21, p16, and β-galactosidase (senescence); for LC3, SIRT1, MAP1S, and pAMKα (autophagy); and for LDH and GLUT1 (metabolism). Epithelial cells in cystic remodeled areas of UIP stained for p16 and p21, p16 being more specific compared with p21. Myofibroblasts were negative in all cases. An upregulation of all four autophagy markers was seen not only in epithelia within remodeled areas and proliferating myofibroblasts, but also in bronchial epithelia and pneumocytes. Upregulated autophagy points to a compensatory mechanism for hypoxia; therefore, LDH and GLUT1 were investigated. Their expression was present in epithelia within cystic remodeling and in myofibroblasts. The cells within the remodeled areas stained for cytokeratin 5, but coexpressed TTF1, confirming their origin from basal cells of bronchioles. Within this population, senescent cells arise. Our results indicated that autophagy in UIP very likely helps cells to survive in hypoxic condition. By phagocytosis of cellular debris, they supplement their need for nutrition, and by upregulating LDH and GLUT1, they compensate for local hypoxia.

Highlights

Interstitial lung diseases (ILDs) are a heterogenous group of diseases with different etiology, clinical, radiological, and histologic presentation
Two groups were formed, one (n = 10) with usual interstitial pneumonia (UIP) pattern and clinical diagnosis of Idiopathic pulmonary fibrosis (IPF) (UIP/IPF) and a second group (n = 13), for which clinical data pointed to an underlying immune disease (UIP/AuD)
In UIP, regardless of the underlying etiology, we found high expression of all four markers of autophagy (LC3, SIRT1, microtubule-associated protein 1S (MAP1S), and pAMPKα) in

Summary

Introduction

Interstitial lung diseases (ILDs) are a heterogenous group of diseases with different etiology, clinical, radiological, and histologic presentation. They can be classified based on etiology (known and unknown) or based on histology, with usual interstitial pneumonia (UIP) as the most common pattern [24, Master thesis work of Florian Gallob. Idiopathic pulmonary fibrosis (IPF) is the most severe disease characterized by an UIP pattern. The occurrence of UIP pattern in diseases other than IPF was not accepted; this changed. Current therapy includes deceleration of the disease progression with antifibrotic drugs Nintedanib and Pirfenidon, symptom release with oxygen, and, as ultima ratio, lung transplantation [13, 32]. Two processes might play a key role in development of UIP/IPF: senescence and autophagy [37, 45]

Objectives

Methods

Results

Discussion

Conclusion