Autophagy A Core Cellular Process with Emerging Links to Pulmonary Disease

Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
American Journal of Respiratory and Critical Care Medicine (Impact Factor: 13). 08/2011; 184(11):1237-46. DOI: 10.1164/rccm.201106-0966CI
Source: PubMed


Autophagy is a highly conserved homeostatic pathway by which cells transport damaged proteins and organelles to lysosomes for degradation. Dysregulation of autophagy contributes to the pathogenesis of clinically important disorders in a variety of organ systems but, until recently, little was known about its relationship to diseases of the lung. However, there is now growing evidence at the basic research level that autophagy is linked to the pathogenesis of important pulmonary disorders such as chronic obstructive pulmonary disease, cystic fibrosis, and tuberculosis. In this review, we provide an introduction to the field of autophagy research geared to clinical and research pulmonologists. We focus on the best-studied autophagic mechanism, macroautophagy, and summarize studies that link the regulation of this pathway to pulmonary disease. Last, we offer our perspective on how a better understanding of macroautophagy might be used for designing novel therapies for pulmonary disorders.

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    • "Taken together, we conclude that pneumococcal PLY-induced autophagy is mediated through ROS hypergeneration. Recently, the role of autophagy in bacterial infections disease has garnered increasing inter- est4243 , and it has been shown to play crucial roles in host defense, especially in immunological cells. Moreover, autophagy has a direct impact on immunity and inflammatory response within the whole organism. "
    [Show abstract] [Hide abstract] ABSTRACT: The present study focused on the action mechanism of S. pneumoniae (Sp) in inducing autophagy in human alveolar epithelial cells. Sp, a gram-positive extracellular bacterium, activates autophagy with considerably increased microtuble-associated protein light chain 3 (LC3) punctation in A549 cells. The accumulation of typical autophagosomes and conjugation of LC3 to phosphatidylethanolamine were observed in Sp-infected cells as an indication of autophagy. Using the pneumolysin (PLY) mutant, we successfully demonstrated that PLY is involved in initiating autophagy without affecting the expression levels of PI3K-III and Beclin1. PLY-mediated autophagy depends on the inhibition of the phosphoinositide 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway. Furthermore, Sp could also lead to the reactive oxygen species (ROS) hypergeneration in A549 cells. Taken together, Sp infection-induced autophagy is PLY-mediated through ROS hypergeneration and mTOR inhibition. PI3K-I and rapamycin (autophagy inducers) enhanced bacterial clearance, whereas wortmannin (autophagy inhibitor) and acetylcysteine (ROS inhibitor) reduced intracellular bacteria clearance. Thus, Sp-induced autophagy represents a host-protective mechanism, providing new insight into the pathogenesis of respiratory tract Sp infection.
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    • "Similar effects of autophagy have been observed in others pulmonary diseases such as α1-antitrypsin deficiency, mycobacterium tuberculosis, tuberous sclerosis or acute lung injury and are discussed elsewhere141142143. "
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    • "Thus, the study of autophagy in samples such as whole lung homogenates may not represent what happens in a specific subset of cells. A combination of static and dynamic methods is currently recommended with a careful definition of the type of cell in which autophagy is being measured [7]. "
    [Show abstract] [Hide abstract] ABSTRACT: Idiopathic pulmonary fibrosis is the most common and severe form of idiopathic interstitial pneumonias. Despite an exponential increase in our understanding of potentially important mediators and mechanisms, the pathogenesis remains elusive, and little therapeutic progress has been made in the last few years. Mortality in 3-5 years is still 50%. Autophagy, a highly conserved homeostatic mechanism necessary for cell survival, has been recently implicated in the pathogenesis of pulmonary disorders. In this paper we aim to highlight some key issues regarding the process of autophagy and its possible association with the pathogenesis of idiopathic pulmonary fibrosis.
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