Alveolar Mitochondrial Quality Control during Acute Respiratory Distress Syndrome

Acute respiratory distress syndrome (ARDS) is a leading cause of respiratory failure and death in ICU patients. Experimentally, acute lung injury (ALI) resolution depends on repair of mitochondrial oxidant damage by the mitochondrial quality control (MQC) pathways, mitochondrial biogenesis and mitophagy, but nothing is known about this in human lung. In a case-control autopsy study, we compared lungs of subjects dying of ARDS (n=8; cases) and age/gender-matched subjects dying of non-pulmonary causes (n=7; controls). Slides were examined by light microscopy and immunofluorescence confocal microscopy, randomly probing for co-localization of citrate synthase (CS) with markers of oxidant stress, mitochondrial DNA damage, mitophagy, and mitochondrial biogenesis. ARDS lungs showed diffuse alveolar damage with edema, hyaline membranes, and neutrophils. Compared with controls, a high degree of mitochondrial oxidant damage was seen in type 2 epithelial (AT2) cells and alveolar macrophages by 8-hydroxydeoxyguanosine and malondialdehyde co-staining with CS. In ARDS, anti-oxidant protein heme oxygenase-1 and DNA repair enzyme N-glycosylase/DNA lyase (Ogg1) were found in alveolar macrophages, but not AT2 cells. Moreover, MAP1 light chain-3 (LC3) and serine/threonine-protein kinase (Pink1) staining were absent in AT2 cells, suggesting mitophagy failure. Nuclear respiratory factor-1 (NRF1) staining was missing in the alveolar region, suggesting impaired mitochondrial biogenesis. Widespread hyper-proliferation of AT2 cells in ARDS could suggest defective differentiation into type 1 cells. ARDS lungs show profuse mitochondrial oxidant DNA damage, but little evidence of MQC activity in AT2 epithelium. Since these pathways are important for ALI resolution, our findings support MQC as a novel pharmacologic target for ARDS resolution.