Chronic obstructive pulmonary disease (COPD) is a debilitating disease caused by chronic exposure to cigarette smoke (CS), which involves airway obstruction and alveolar loss (i.e., emphysema). The mechanisms of COPD pathogenesis remain unclear. Our previous studies demonstrated elevated autophagy in human COPD lung, and as a cellular and tissue response to CS exposure in an experimental model of emphysema in vivo. We identified the autophagic protein microtubule-associated protein 1 light chain-3B (LC3B) as a positive regulator of CS-induced lung epithelial cell death. We now extend these initial observations to explore the mechanism by which LC3B mediates CS-induced apoptosis and emphysema development in vivo. Here, we observed that LC3B −/− mice had significantly decreased levels of apoptosis in the lungs after CS exposure, and displayed resistance to CS-induced airspace enlargement, relative to WT littermate mice. We found that LC3B associated with the extrinsic apoptotic factor Fas in lipid rafts in an interaction mediated by caveolin-1 (Cav-1). The siRNA-dependent knockdown of Cav-1 sensitized epithelial cells to CS-induced apoptosis, as evidenced by enhanced death-inducing signaling complex formation and caspase activation. Furthermore, Cav-1 −/− mice exhibited higher levels of autophagy and apoptosis in the lung in response to chronic CS exposure in vivo. In conclusion, we demonstrate a pivotal role for the autophagic protein LC3B in CS-induced apoptosis and emphysema, suggestive of novel therapeutic targets for COPD treatment. This study also introduces a mechanism by which LC3B, through interactions with Cav-1 and Fas, can regulate apoptosis.

BackgroundAutophagy is a basic cellular homeostatic process important to cell fate decisions under conditions of stress. Dysregulation of autophagy impacts numerous human diseases including cancer and chronic obstructive lung disease. This study investigates the role of autophagy in idiopathic pulmonary fibrosis.MethodsHuman lung tissues from patients with IPF were analyzed for autophagy markers and modulating proteins using western blotting, confocal microscopy and transmission electron microscopy. To study the effects of TGF-β1 on autophagy, human lung fibroblasts were monitored by fluorescence microscopy and western blotting. In vivo experiments were done using the bleomycin-induced fibrosis mouse model.ResultsLung tissues from IPF patients demonstrate evidence of decreased autophagic activity as assessed by LC3, p62 protein expression and immunofluorescence, and numbers of autophagosomes. TGF-β1 inhibits autophagy in fibroblasts in vitro at least in part via activation of mTORC1; expression of TIGAR is also increased in response to TGF-β1. In the bleomycin model of pulmonary fibrosis, rapamycin treatment is antifibrotic, and rapamycin also decreases expression of á-smooth muscle actin and fibronectin by fibroblasts in vitro. Inhibition of key regulators of autophagy, LC3 and beclin-1, leads to the opposite effect on fibroblast expression of á-smooth muscle actin and fibronectin.ConclusionAutophagy is not induced in pulmonary fibrosis despite activation of pathways known to promote autophagy. Impairment of autophagy by TGF-β1 may represent a mechanism for the promotion of fibrogenesis in IPF.

Air pollution reduction policies can also mitigate CO2 emissions simultaneously in the industrial sector, but the extent of these co-benefits is understudied. We analyse the potential co-benefits for SO2, NOx, particulate matter (PM) and CO2 emissions reduction in major industrial sectors in China. We construct and analyse a firm-level database covering more than 75 thousand observations and scenario simulations are used to estimate the co-benefits. The findings show that substantial co-benefits could be achieved with three specific interventions. Energy intensity improvement can reduce SO2, NOx, PM and CO2 emissions by 26-44%, 19-44%, 25-46% and 18-50% respectively. Reductions from scale structure adjustment such as phasing out small firms and developing large ones can amount to 1-8%, 1-6%, 2-20% and 0.2-3%. Electrification can reduce emissions by 19-25%, 4-28%, 20-29% and 11-12% if the share of electricity generated from nonfossil fuel sources is 70%. The former two interventions have already been put into practice while the third intervention is regarded as a significant contributor for realizing China's carbon neutrality target. Since firm heterogeneity is the essential source for realizing the co-benefits and it directly determines the magnitude of the co-benefits, stricter and sensible environmental policies targeting industrial firms can accelerate China's sustainable transformation.China is seizing opportunities to achieve its climate commitment to the Pairs Agreement of UNFCCC, while the overall energy-related CO2 emission continues to rise after a small trough in 2016. Domestically, China has battled air pollution for more than thirty years 1 . Although great achievements have been made, China is still facing severe environmental challenges 2,3 . In 2018, only 121 out of 338 cities at and above the prefecture level met the national air quality standard 4 . Among all emission sources, industrial sectors contributed more than 80% of national sulphur dioxide (SO2) emission, more than 60% of national nitrous oxide (NOx) emissions 5 , and more than 80% of national carbon dioxide (CO2) emissions 6 ; therefore, it is still the first priority to strengthen

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AM, Shen H. Interaction of caveolin-1 with ATG12-ATG5 system suppresses autophagy in lung epithelial cells. Am J Physiol Lung Cell Mol Physiol 306: L1016 -L1025, 2014. First published April 11, 2014 doi:10.1152/ajplung.00268.2013.-Autophagy plays a pivotal role in cellular homeostasis and adaptation to adverse environments, although the regulation of this process remains incompletely understood. We have recently observed that caveolin-1 (Cav-1), a major constituent of lipid rafts on plasma membrane, can regulate autophagy in cigarette smoking-induced injury of lung epithelium, although the underlying molecular mechanisms remain incompletely understood. In the present study we found that Cav-1 interacted with and regulated the expression of ATG12-ATG5, an ubiquitin-like conjugation system crucial for autophagosome formation, in lung epithelial Beas-2B cells. Deletion of Cav-1 increased basal and starvation-induced levels of ATG12-ATG5 and autophagy. Biochemical analyses revealed that Cav-1 interacted with ATG5, ATG12, and their active complex ATG12-ATG5. Overexpression of ATG5 or ATG12 increased their interactions with Cav-1, the formation of ATG12-ATG5 conjugate, and the subsequent basal levels of autophagy but resulted in decreased interactions between Cav-1 and another molecule. Knockdown of ATG12 enhanced the ATG5-Cav-1 interaction. Mutation of the Cav-1 binding motif on ATG12 disrupted their interaction and further augmented autophagy. Cav-1 also regulated the expression of ATG16L, another autophagy protein associating with the ATG12-ATG5 conjugate during autophagosome formation. Altogether these studies clearly demonstrate that Cav-1 competitively interacts with the ATG12-ATG5 system to suppress the formation and function of the latter in lung epithelial cells, thereby providing new insights into the molecular mechanisms by which Cav-1 regulates autophagy and suggesting the important function of Cav-1 in certain lung diseases via regulation of autophagy homeostasis.caveolin-1; ATG12-ATG5; ATG16L; autophagy; lung diseases AUTOPHAGY IS A DYNAMIC PROCESS responsible for the turnover of cellular organelles and long-lived proteins. During this process, cytosolic proteins and organelles (e.g., mitochondria and endoplasmic reticulum) are engulfed into double-membranebound vesicles, autophagosomes. The outer membrane of the autophagosome subsequently fuses with lysosomes to form autolysosomes in which the engulfed components are degraded by lysosomal hydrolases, regenerating metabolic precursors that are recycled for macromolecular synthesis and ATP generation (20, 42). Autophagy is induced above basal levels in response to diverse stimuli including nutrient starvation, genotoxic agents, cytokines, and oxidative stress. This process provides an essential function in the maintenance of cellular homeostasis and adaptation to adverse environments (16,29,35).More than 30 autophagy-related genes and gene products critical in the regulation of autophagy, designated "ATG," have been identified heretofore in yeast and hi...

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I ntegrated assessment models that combine geophysics and economics features are often used to evaluate and compare global warming policies. Because there are typically profound uncertainties in these models, a simulation approach is often used. This approach requires the distribution of the uncertain parameters clearly specified. However, this is typically impossible because there is often a significant amount of ambiguity (e.g., estimation error) in specifying the distribution. In this paper, we adopt the widely used multivariate normal distribution to model the uncertain parameters. However, we assume that the mean vector and covariance matrix of the distribution are within some ambiguity sets. We then show how to find the worst-case performance of a given policy for all distributions constrained by the ambiguity sets. This worst-case performance provides a robust evaluation of the policy. We test our algorithm on a famous integrated model of climate change, known as the Dynamic Integrated Model of Climate and the Economy (DICE model). We find that the DICE model is sensitive to the means and covariance of the parameters. Furthermore, we find that, based on the DICE model, moderately tight environmental policies robustly outperform the no controls policy and the famous aggressive policies proposed by Stern and Gore.