Role of unfolded proteins in lung disease

Abstract

The lungs are exposed to a range of environmental toxins (including cigarette smoke, air pollution, asbestos) and pathogens (bacterial, viral and fungal), and most respiratory diseases are associated with local or systemic hypoxia. All of these adverse factors can trigger endoplasmic reticulum (ER) stress. The ER is a key intracellular site for synthesis of secretory and membrane proteins, regulating their folding, assembly into complexes, transport and degradation. Accumulation of misfolded proteins within the lumen results in ER stress, which activates the unfolded protein response (UPR). Effectors of the UPR temporarily reduce protein synthesis, while enhancing degradation of misfolded proteins and increasing the folding capacity of the ER. If successful, homeostasis is restored and protein synthesis resumes, but if ER stress persists, cell death pathways are activated. ER stress and the resulting UPR occur in a range of pulmonary insults and the outcome plays an important role in many respiratory diseases. The UPR is triggered in the airway of patients with several respiratory diseases and in corresponding experimental models. ER stress has been implicated in the initiation and progression of pulmonary fibrosis, and evidence is accumulating suggesting that ER stress occurs in obstructive lung diseases (particularly in asthma), in pulmonary infections (some viral infections and in the setting of the cystic fibrosis airway) and in lung cancer. While a number of small molecule inhibitors have been used to interrogate the role of the UPR in disease models, many of these tools have complex and off-target effects, hence additional evidence (eg, from genetic manipulation) may be required to support conclusions based on the impact of such pharmacological agents. Aberrant activation of the UPR may be linked to disease pathogenesis and progression, but at present, our understanding of the context-specific and disease-specific mechanisms linking these processes is incomplete. Despite this, the ability of the UPR to defend against ER stress and influence a range of respiratory diseases is becoming increasingly evident, and the UPR is therefore attracting attention as a prospective target for therapeutic intervention strategies.

Manipulation of the unfolded protein response: a pharmacological strategy against coronavirus infection

“…However, these antiviral therapies do not take into account that the pathophysiology associated with COVID-19 is mostly related to an aberrant cellular response. In some clinical manifestations of COVID-19, an exacerbated UPR could play a key role [86–88]. For example, activation of ER stress and the UPR is one of the major triggers of endothelial dysfunction [89, 90], which is associated with acute respiratory distress syndrome (ARDS) [91], a diffuse inflammatory lung injury present in 20-67% of hospitalised patients [92, 93].…”

Manipulation of the unfolded protein response: A pharmacological strategy against coronavirus infection

“…However, these antiviral therapies do not take into account that the pathophysiology associated with COVID-19 is mostly related to an aberrant cellular response. In some clinical manifestations of COVID-19, an exacerbated UPR could play a key role [94][95][96]. For example, activation of ER stress and the UPR is one of the major triggers of endothelial dysfunction [97,98], which is associated with acute respiratory distress syndrome (ARDS) [99], a diffuse inflammatory lung injury present in 20-67% of hospitalised patients [100,101].…”

Has2 Regulates the Development of Ovalbumin-Induced Airway Remodeling and Steroid Insensitivity in Mice

“…A previous study reported that EIF2 signaling was downregulated in patients with childhood asthma (29). Moreover, pathways associated with ER stress and UPR play a role in modulating inflammatory and immune responses in the development of severe asthma (30). Furthermore, administration of the ER stress inhibitor decreased the IL-17 expression (31).…”