@article{9d4e85b534394d11afb9f48690d202cc,
title = "Complex interplay between autophagy and oxidative stress in the development of pulmonary disease",
abstract = "The autophagic pathway involves the encapsulation of substrates in double-membraned vesicles, which are subsequently delivered to the lysosome for enzymatic degradation and recycling of metabolic precursors. Autophagy is a major cellular defense against oxidative stress, or related conditions that cause accumulation of damaged proteins or organelles. Selective forms of autophagy can maintain organelle populations or remove aggregated proteins. Dysregulation of redox homeostasis under pathological conditions results in excessive generation of reactive oxygen species (ROS), leading to oxidative stress and the associated oxidative damage of cellular components. Accumulating evidence indicates that autophagy is necessary to maintain redox homeostasis. ROS activates autophagy, which facilitates cellular adaptation and diminishes oxidative damage by degrading and recycling intracellular damaged macromolecules and dysfunctional organelles. The cellular responses triggered by oxidative stress include the altered regulation of signaling pathways that culminate in the regulation of autophagy. Current research suggests a central role for autophagy as a mammalian oxidative stress response and its interrelationship to other stress defense systems. Altered autophagy phenotypes have been observed in lung diseases such as chronic obstructive lung disease, acute lung injury, cystic fibrosis, idiopathic pulmonary fibrosis, and pulmonary arterial hypertension, and asthma. Understanding the mechanisms by which ROS regulate autophagy will provide novel therapeutic targets for lung diseases. This review highlights our current understanding on the interplay between ROS and autophagy in the development of pulmonary disease.",
keywords = "Autophagy, Mitochondria, Mitophagy, Oxidative stress, Pulmonary disease, Reactive oxygen species",
author = "Wojciech Ornatowski and Qing Lu and Manivannan Yegambaram and Garcia, {Alejandro E.} and Zemskov, {Evgeny A.} and Emin Maltepe and Fineman, {Jeffrey R.} and Ting Wang and Black, {Stephen M.}",
note = "Funding Information: This research was supported in part by HL60190 ( SMB ), HL137282 ( SMB / JRF ), HL134610 ( SMB ), HL142212 ( SMB / EZ ), HL146369 ( SMB ), and HL061284 ( JRF ) all from the National Institutes of Health . Funding Information: A growing body of evidence supports an important role of autophagy in idiopathic pulmonary fibrosis (IPF) [ 290–292] (Fig. 4). IPF is a chronic progressive lung disease characterized by scar tissue formation, lung function impairment and respiratory failure. Although IPF etiology is unclear, a number of major risk factors have been described including genetics, CS, air pollution, and aging [293]. The prevailing literature suggests that aging mitochondria and impaired autophagy/mitophagy are involved in IPF pathogenesis [ 294–297]. Excessive ROS generation produced by activation of several NOX isoforms induces aberrant redox signaling and disease progression in IPF (reviewed in Ref. [298]). Cross-talk between activated NOX isoforms and mitochondria also affects mitochondrial function and mtROS generation [299]. TGFβ1-mediated activation of NOX4 is a major contributor to IPF development. NOX4 is widely distributed in different types of vascular cells and is the only NOX isoform which is up-regulated by TGFβ. Recent studies demonstrated a functional link between TGFβ-induced NOX4 levels and autophagy rate in bleomycin-exposed mice and fibroblasts derived from IPF patients [300]. NOX4 inhibition by metformin [301], NOX4 degradation by azithromycin [300] or miRNA-directed downregulation of TGFβR2/NOX4 [302] reverse or prevent bleomycin-induced pulmonary fibrosis in animals. The oxidative stress induced by NOX4 induces cell senescence resulting in a pro-apoptotic phenotype in alveolar epithelial cells (AEC) and an anti-apoptotic phenotype in senescent myofibroblasts leading to increased extracellular matrix (ECM) deposition and fibrotic foci formation. AEC senescence is accompanied by the loss of PTEN, and the activation of the NF-κB pathway [303]. Interestingly, fibroblasts cultured in the supernatants collected from senescent AEC also exhibit increased collagen deposition [303]. Mitochondria-targeted antioxidants reverse fibroblast senescence suggesting mtROS contribute to this process [304]. The analysis of lung tissue samples obtained from IPF patients shows an accumulation of p62 and low levels of LC3-II, and TGF-β1 treatment of lung fibroblasts also downregulates autophagy [305]. These data indicate that the molecular mechanisms underlying IPF development include impaired autophagy. Furthermore, stimulating autophagy with rapamycin decreases the expression of fibronectin and α-smooth muscle actin in fibroblasts in vitro and exerts an anti-fibrotic effect in the bleomycin model in vivo [305]. Detailed studies of autophagy in IPF have revealed that the accumulation of dysfunctional mitochondria is associated with Parkin [306] and PINK1 deficiency which, in turn, depends on a decrease in ATF3 transcription factor activity [294,307]. PINK1-deficient mice are prone to lung fibrosis and this is characterized by the accumulation of dysfunctional mitochondria [294]. The anti-fibrotic agent, pirfenidone, has been shown to improve autophagy/mitophagy by enhancing PARK2 expression and by decreasing mtROS levels and attenuating fibrosis in bleomycin-exposed mice [308]. The decrease in mitophagy in IPF also leads to extracellular release of mitochondrial damage associated molecular patterns (mtDAMPs), such as mtDNA, which induces pro-inflammatory cell signaling via TLR9 [309]. These can be been used as a plasma marker of severe IPF in patients [310]. [310]. Molecular mechanisms associated with aging (such as genetic instability, epigenetic changes, aging-related histone PTMs etc.) may also contribute to mitochondria dysfunction and IPF pathogenesis [311]. Mucin 5B overexpression has been shown to enhance lung fibrosis in mice [312], suggesting a cross-talk between autophagy and secretory mechanisms. Further, increased expression of mucin 5B in the lungs of IPF patients has been recently linked to MUC5B promoter polymorphisms and to alterations in its epigenetic regulation by DNA methylation) [313]. Interestingly, in contrast to other hyperproliferative/fibrotic pulmonary diseases (such as PAH and asthma), autophagy impairment is a hallmark of IPF [ 294–297] and also characteristic for CF (see Section 4.3). Indeed, the systematic analysis of data obtained for various pulmonary diseases suggests that both an impaired and hyper-activated autophagy can have a negative impact on cell homeostasis and contribute to the development of disease pathology.This research was supported in part by HL60190 (SMB), HL137282 (SMB/JRF), HL134610 (SMB), HL142212 (SMB/EZ), HL146369 (SMB), and HL061284 (JRF) all from the National Institutes of Health. Publisher Copyright: {\textcopyright} 2020",
year = "2020",
month = sep,
doi = "10.1016/j.redox.2020.101679",
language = "English (US)",
volume = "36",
journal = "Redox Biology",
issn = "2213-2317",
publisher = "Elsevier BV",
}