Lc3 Over-Expression Improves Survival and Attenuates Lung Injury Through Increasing Autophagosomal Clearance in Septic Mice

In Brief Objective: To clarify the role of autophagy in sepsis-induced lung injury. Background: The role of autophagy as a protective or maladaptive response in lung cells during sepsis has not yet been determined. The lack of specificity of the autophagic process has driven the development of new approaches that assessautophagosomes from formation to fusion with lysosomes. Methods: Sepsis was induced by cecal ligation and puncture (CLP). The autophagic process was manipulated using the pharmacological inhibitors of the autophagy pathway. Green fluorescent protein (GFP)-microtubule-associated protein 1 light chain 3 (LC3) transgenic mice were further used to determine the role of autophagy. Results: The formation of autophagosomal protein LC3-II progressively accumulated in the lungs over 24 hours after CLP, with the Lc3 gene expression returning to baseline levels at 24 hours. Autophagosome-lysosome fusion, however, gradually decreased from 8 to 24 hours after CLP, suggesting impaired clearance of autophagosomes rather than upregulation of autophagy in the septic lung. In contrast, transgenic mice overexpressing the Lc3 gene exhibited increased clearance of autophagosomes and improved survival after CLP. This protective effect was also seen in decreased cell death, inflammatory responses, neutrophil accumulation, albumin leakage, and edema formation. However, blockade of autophagosome-lysosome fusion with bafilomycin A1 abolished the protective effects in transgenic mice. This indicates that Lc3 transgene attenuates lung injury/inflammation in sepsis, possibly through increasing the clearance of autophagosomes. Conclusions: Autophagy in the septic lung represents a protective response. However, autophagy, by virtue of excessive autophagosome accumulation, may play a maladaptive role in the late stage of sepsis, leading to acute lung injury. Insufficient completion of autophagy may play a contributing role in sepsis-induced lung injury. Overexpression of the Lc3 gene ameliorates lung injury/inflammation after sepsis, possibly through increasing the clearance of autophagosomes. Autophagy plays a protective role in sepsis; however, it may become maladaptive because of maximal accumulation of autophagosomes in the late-stage septic lung.