Pulmonary endoplasmic reticulum stress—scars, smoke, and suffocation

Abstract

Protein misfolding within the endoplasmic reticulum (ER stress) can be a cause or consequence of pulmonary disease. Mutation of proteins restricted to the alveolar type II pneumocyte can lead to inherited forms of pulmonary fibrosis, but even sporadic cases of pulmonary fibrosis appear to be strongly associated with activation of the unfolded protein response and/or the integrated stress response. Inhalation of smoke can impair protein folding and may be an important cause of pulmonary ER stress. Similarly, tissue hypoxia can lead to impaired protein homeostasis (proteostasis). But the mechanisms linking smoke and hypoxia to ER stress are only partially understood. In this review, we will examine the role of ER stress in the pathogenesis of lung disease by focusing on fibrosis, smoke, and hypoxia.

The integrated stress response in pulmonary disease

“…The aetiology of pulmonary fibrosis is complex and is likely to involve many different triggers, including the ageing process. Prolonged inflammation or the expression of misfolded mutants of surfactant proteins can also lead to pulmonary fibrosis [2]. It has been noted that treating mice with tunicamycin, a toxin that causes ER stress, promotes lung fibrosis and causes mitochondrial dysfunction in primary type II alveolar epithelial cells (table 2) [82].…”

Endoplasmic reticulum stress: a key player in human disease

“…Because of the critical role played by the ER in many aspects of cellular function, it is perhaps unsurprising that dysfunction of the UPR proved to be a factor in the pathogenesis of many human diseases . Almost no tissues are spared from ER stress‐related damage and in this Special Issue of The FEBS Journal , the roles of ER stress in diseases affecting the lung, liver, skin, muscle and nervous system are each examined in detail .…”

“…IRE 1 can also reduce translation during stress, by degrading ER ‐localized mRNA transcripts in a process termed regulated RIDD (reproduced from Ref. ).…”

“…In our review, we explain how ER dysfunction can induce lung fibrosis by promoting the transdifferentiation of airway epithelial cells into fibroblasts – so‐called epithelial‐to‐mesenchyme transition. Inhaled toxins in smoke and other forms of pollution can trigger ER stress to cause tissue damage through effects on some ER chaperones, contributing to the development of chronic obstructive lung disease and emphysema.…”

“…Adequate respiration is necessary to generate the high levels of ATP consumed in all cells where ER protein folding takes place. In tissues with precarious blood supplies, for example, some solid tumours, inadequate circulation leaves the cell hypoxic and so causes ER stress . Although cancer is not a single disease, common features shared by many malignancies include deregulated translation and increased protein secretion .…”