Autophagy in the lung

Abstract

Autophagy is a cellular process for the disposal of damaged organelles or denatured proteins through a lysosomal degradation pathway. By reducing endogenous macromolecules to their basic components (i.e., amino acids, lipids), autophagy serves a homeostatic function by ensuring cell survival during starvation. Increased autophagy can be found in dying cells, although the relationships between autophagy and programmed cell death remain unclear. To date, few studies have examined the regulation and functional significance of autophagy in human lung disease. The lung, a complex organ that functions primarily in gas exchange, consists of diverse cell types (i.e., endothelial, epithelial, mesenchymal, inflammatory). In lung cells, autophagy may represent a general inducible adaptive response to injury resulting from exposure to stress agents, including hypoxia, oxidants, inflammation, ischemia-reperfusion, endoplasmic reticulum stress, pharmaceuticals, or inhaled xenobiotics (i.e., air pollution, cigarette smoke). In recent studies, we have observed increased autophagy in mouse lungs subjected to chronic cigarette smoke exposure, and in pulmonary epithelial cells exposed to cigarette smoke extract. Knockdown of autophagic proteins inhibited apoptosis in response to cigarette smoke exposure in vitro, suggesting that increased autophagy was associated with epithelial cell death. We have also observed increased morphological and biochemical markers of autophagy in human lung specimens from patients with chronic obstructive pulmonary disease (COPD). We hypothesize that increased autophagy contributes to COPD pathogenesis by promoting epithelial cell death. Further research will examine whether autophagy plays a homeostatic or maladaptive role in COPD and other human lung diseases.

Figure 1.

Autophagic pathway. The activation of autophagy is a multistep process that involves: (1) vessel nucleation; (2) vessel elongation and autophagosome formation, with assimilation of organelles or proteins to be degraded; (3) autophagosome–lysosome fusion; and (4) autophagolysosomal digestion of encapsulated material. Beclin 1, in complex with class III phosphatidylinositol 3-kinase (PI3K) and Atg14, acts as a major positive regulator of autophagy. The rapamycin-sensitive mammalian target of rapamycin (mTOR)/class I PI3K pathway acts as a major negative regulator of autophagy. Autophagosome formation requires two ubiquitin-like conjugation systems: the Atg8 (microtubule-associated protein-1 light chain [LC] 3) conjugation system, and the Atg5–Atg12 conjugation system. Autophagosome–lysosome fusion requires Rab7 and the lysosomal proteins, lysosome-associated membrane protein (LAMP)-1 and LAMP-2. PE = phosphatidyl-ethanolamine.

Figure 2.

Potential factors leading to autophagy in the lung. A number of environmental factors may trigger the activation of autophagy in the lung, some of which may be associated with the pathogenesis of disease. These include cigarette smoke, particle inhalation, adverse oxygen environments, pharmaceuticals, and xenobiotics. Exposure to these agents may trigger adverse stress responses, including enhanced inflammation, oxidative stress, and perturbation of cellular organelle (i.e., endoplasmic reticulum [ER], mitochondria) function. The activation of autophagy, as an endogenous inducible response to cellular stress, may have both adaptive and maladaptive consequences, depending on the experimental model. The beneficial roles of autophagy are associated with the homeostatic turnover of damaged cellular organelles and protein, thus promoting the recycling of vital metabolic building blocks and the regeneration of energy charge. In this regard, autophagy is regarded as a survival mechanism. On the other hand, excessive autophagy may be associated with aberrant degradation of intracellular constituents, leading to autophagic cell death, or, alternatively, to apoptotic cell death, depending on the cell model, both of which may potentially play a contributory role in disease pathogenesis. ALI = acute lung injury; COPD = chronic obstructive pulmonary disease; PAH = pulmonary arterial hypertension.

Figure 3.

Cigarette smoke exposure induces autophagy and apoptosis. Our recent studies indicate that exposure to cigarette smoke extract (CSE) in lung epithelial cells leads to the activation of autophagy. Specifically, CSE activated microtubule-associated protein-1 light chain (LC) 3B, a regulator of autophagosome formation, through an early growth response (Egr)-1–dependent transcriptional mechanism. Furthermore, CSE stimulated the increased expression of other molecules involved in activation of the autophagic pathway, including Atg4B, Atg5, and Atg7, in cultured epithelial cells. CSE exposure concurrently activated the extrinsic apoptotic pathway in lung epithelial cells, involving the activation of the death-inducing signal complex (DISC), and activation of downstream caspase-8, -9, and -3, leading to cell death by apoptosis. In the CSE model, we demonstrated that activation of the autophagic pathway led to increased apoptosis, as siRNA-directed knockdown of LC3B inhibited DISC formation and caspase activation in this model. Further studies are needed to define the relationship between autophagy and apoptosis in the CSE model. ROS = reactive oxygen species.