Autophagy, Unfolded Protein Response and Lung Disease

Abstract

Acute Respiratory Distress Syndrome is a severe disorder affecting thousands of individuals worldwide. The available medical countermeasures do not sufficiently suppress the unacceptable high mortality rates associated with those in need. Thus, intense efforts aim to delineate the function of the lung endothelium, so to deliver new therapeutic approaches against this disease. The present manuscript attempts to shed light on the interrelations between the unfolded protein response and autophagy towards lung disease, to deliver a new line of possible therapeutic approaches against the ferocious Acute Respiratory Distress Syndrome.

Keywords: Acute Lung Injury; COPD; Cystic Fibrosis; Endothelium; Pulmonary Hypertension; Tuberculosis.

Figure 1:. Effects of autophagy and UPR on the pathogenesis of lung disease.

(A) Chronic obstructive pulmonary disease (COPD): Increased levels of autophagy damages the airway epithelium which leads to COPD. OSGIN1 induces the expression of autophagy genes, whereas NADH dehydrogenase suppresses autophagy. However, autophagy protects the alveolar macrophages, and reduces persistent inflammation in COPD. Moreover, reactive oxygen species (ROS) induces UPR, which in turn contributes in COPD pathogenesis. Chaperone-mediated autophagy (CMA) suppresses the production of ROS, and hence, protects against COPD. (B) Pulmonary hypertension (PH): Autophagy protects against hypoxia-induced pulmonary hypertension. On the other hand, it accelerates in pulmonary artery smooth muscle cells (PASMCs) proliferation, inducing PH. Suppression of autophagy by chloroquine reduces PASMCs proliferation, and prevents the development of PH and vascular remodeling. UPR is associated with the PH pathogenesis, and suppression of UPR by 4-phenylbutyric acid (4-PBA) attenuates the PH. (C) Tuberculosis: Rapamycin, IFNγ and vitamin D inhibit tuberculosis by inducing autophagy. BCL2-associated athanogene 2 (BAG2) induces reticulophagy in Mycobacterium tuberculosis (Mtb)-infected macrophages, and protects against tuberculosis. Moreover, UPR promotes apoptosis in macrophages and alveolar epithelial cells (AEC) to suppress tuberculosis. M1 polarized macrophages exhibit higher ER stress, thus resisting against Mtb infection. (D) Cystic fibrosis: UPR induces cystic fibrosis, whereas autophagy defends against this disease. Mutated CFTR enhances ROS production, which suppresses autophagy by activating transglutaminase 2 (TG2). Moreover, Oxidative stress, mutated CFTR and pathogens can cause cystic fibrosis through UPR activation. (E) Acute lung injury/ Acute respiratory distress syndrome (ALI/ARDS): Both autophagy and UPR exert protection against ALI/ARDS. RAB26 suppresses LPS-induced ALI by inducing autophagy.