Abstract
RationaleEndogenous tissue mediators inducing lung inflammation in the context of ventilator-induced lung injury (VILI) and acute respiratory distress syndrome (ARDS) are ill-defined.ObjectivesTo test whether mitochondrial alarmins are released during VILI, and are associated with lung inflammation.MethodsRelease of mitochondrial DNA, adenosine triphosphate (ATP), and formyl-Met-Leu-Phe (fMLP) peptide-dependent neutrophil chemotaxis were measured in conditioned supernatants from human alveolar type II-like (A549) epithelial cells submitted to cyclic stretch in vitro. Similar measurements were performed in bronchoalveolar lavage fluids from rabbits submitted to an injurious ventilatory regimen, and from patients with ARDS.Measurements and main resultsMitochondrial DNA was released by A549 cells during cell stretching, and was found elevated in BAL fluids from rabbits during VILI, and from ARDS patients. Cyclic stretch-induced interleukin-8 (IL-8) of A549 cells could be inhibited by Toll-like receptor 9 (TLR9) blockade. ATP concentrations were increased in conditioned supernatants from A549 cells, and in rabbit BAL fluids during VILI. Neutrophil chemotaxis induced by A549 cells conditioned supernatants was essentially dependent on fMLP rather than IL-8. A synergy between cyclic stretch-induced alarmins and lipopolysaccharide (LPS) was found in monocyte-derived macrophages in the production of IL-1ß.ConclusionsMitochondrial alarmins are released during cyclic stretch of human epithelial cells, as well as in BAL fluids from rabbits ventilated with an injurious ventilatory regimen, and found in BAL fluids from ARDS patients, particularly in those with high alveolar inflammation. These alarmins are likely to represent the proximal endogenous mediators of VILI and ARDS, released by injured pulmonary cells.
Highlights
Mechanical ventilation has been lifesaving in many patients with respiratory failure since its introduction several decades ago
Release of mitochondrial DNA, adenosine triphosphate (ATP), and formyl-Met-Leu-Phe peptide-dependent neutrophil chemotaxis were measured in conditioned supernatants from human alveolar type II-like (A549) epithelial cells submitted to cyclic stretch in vitro
Mitochondrial alarmins are released during cyclic stretch of human epithelial cells, as well as in bronchoalveolar lavage (BAL) fluids from rabbits ventilated with an injurious ventilatory regimen, and found in BAL fluids from acute respiratory distress syndrome (ARDS) patients, in those with high alveolar inflammation
Summary
Mechanical ventilation has been lifesaving in many patients with respiratory failure since its introduction several decades ago. It has been associated with lung damage due to cyclic stretch imposed by positive pressure mechanical ventilation, when the lung is injured or infected. This phenomenon is nowadays known as ventilator-induced lung injury (VILI) [1, 2]. It could be shown that cyclic stretch induces de novo transcription of IL-8 gene [13], it remains unclear whether this was a direct transcriptional effect of the mechanical strain or a secondary effect of endogenous mediator(s) released by lung cells injured by cyclic stretch
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