Impairment of autophagy decreases ventilator-induced lung injury by blockade of the NF-κB pathway

• Published in: American journal of physiology. Lung cellular and molecular physiology 2013-06, Vol.304 (12), p.L844-L852
• Main Authors: López-Alonso, Inés, Aguirre, Alina, González-López, Adrián, Fernández, Álvaro F, Amado-Rodríguez, Laura, Astudillo, Aurora, Batalla-Solís, Estefanía, Albaiceta, Guillermo M
• Format: Article
• Language: English
• Subjects: Animals; Autophagy - genetics; Autophagy-Related Proteins; Cysteine Endopeptidases - deficiency; Cysteine Endopeptidases - genetics; Cytokines - biosynthesis; Gene Expression Regulation; I-kappa B Proteins - genetics; I-kappa B Proteins - metabolism; Inflammation - genetics; Lung - metabolism; Lung - pathology; Mice; Mice, Inbred C57BL; Mice, Knockout; Neutrophil Infiltration - genetics; NF-kappa B - genetics; NF-kappa B - metabolism; Respiration, Artificial - adverse effects; Signal Transduction - genetics; Transcription Factors - genetics; Transcription Factors - metabolism; Ubiquitination; Ventilator-Induced Lung Injury - etiology; Ventilator-Induced Lung Injury - metabolism; Ventilator-Induced Lung Injury - pathology
• ISSN: 1040-0605; 1522-1504
• DOI: 10.1152/ajplung.00422.2012

Excessive lung stretch triggers lung inflammation by activation of the NF-κB pathway. This route can be modulated by autophagy, an intracellular proteolytic system. Our objective was to study the impact of the absence of autophagy in a model of ventilator-induced lung injury. Mice lacking Autophagin-1/ATG4B (Atg4b-/-), a critical protease in the autophagic pathway, and their wild-type counterparts were studied in baseline conditions and after mechanical ventilation. Lung injury, markers of autophagy, and activation of the inflammatory response were evaluated after ventilation. Mechanical ventilation increased autophagy and induced lung injury in wild-type mice. Atg4b-/- animals showed a decreased lung injury after ventilation, with less neutrophilic infiltration than their wild-type counterparts. As expected, autophagy was absent in mutant animals, resulting in the accumulation of p62 and ubiquitinated proteins. Activation of the canonical NF-κB pathway was present in ventilated wild-type, but not Atg4b-deficient, animals. Moreover, these mutant mice showed an accumulation of ubiquitinated IκB. High-pressure ventilation partially restored the autophagic response in Atg4b-/- mice and abolished the differences between genotypes. In conclusion, impairment of autophagy results in an ameliorated inflammatory response to mechanical ventilation and decreases lung injury. The accumulation of ubiquitinated IκB may be responsible for this effect.