Abstract
Trauma and sepsis can cause acute lung injury (ALI) and Acute Respiratory Distress Syndrome (ARDS) in part by triggering neutrophil (PMN)-mediated increases in endothelial cell (EC) permeability. We had shown that mitochondrial (mt) damage-associated molecular patterns (DAMPs) appear in the blood after injury or shock and activate human PMN. So we now hypothesized that mitochondrial DAMPs (MTD) like mitochondrial DNA (mtDNA) and peptides might play a role in increased EC permeability during systemic inflammation and proceeded to evaluate the underlying mechanisms. MtDNA induced changes in EC permeability occurred in two phases: a brief, PMN-independent ‘spike’ in permeability was followed by a prolonged PMN-dependent increase in permeability. Fragmented mitochondria (MTD) caused PMN-independent increase in EC permeability that were abolished with protease treatment. Exposure to mtDNA caused PMN-EC adherence by activating expression of adherence molecule expression in both cell types. Cellular activation was manifested as an increase in PMN calcium flux and EC MAPK phosphorylation. Permeability and PMN adherence were attenuated by endosomal TLR inhibitors. EC lacked formyl peptide receptors but were nonetheless activated by mt-proteins, showing that non-formylated mt-protein DAMPs can activate EC. Mitochondrial DAMPs can be released into the circulation by many processes that cause cell injury and lead to pathologic endothelial permeability. We show here that mitochondria contain multiple DAMP motifs that can act on EC and/or PMN via multiple pathways. This can enhance PMN adherence to EC, activate PMN-EC interactions and subsequently increase systemic endothelial permeability. Mitochondrial DAMPs may be important therapeutic targets in conditions where inflammation pathologically increases endothelial permeability.
Highlights
Cellular damage due to mechanical trauma, hemorrhage and sepsis can release mitochondrial damage motifs like mitochondrial DNA (mtDNA) and formyl peptides
MtDNA and formyl peptides clearly act as systemic alarmins or damage-associated molecular patterns (DAMPs) [3,4] The mechanisms by which mt-DAMPs (MTD) act on other cells and the molecular events by which MTD induce the systemic inflammatory response syndrome (SIRS) and organ dysfunction are poorly understood
For the first time we test the hypothesis that human mitochondrial ‘damage’ motifs released following cell injury in vivo can trigger endothelial permeability changes observed in acute lung injury and acute respiratory distress syndrome (ARDS) (ALI/ARDS)
Summary
Cellular damage due to mechanical trauma, hemorrhage and sepsis can release mitochondrial (mt) damage motifs like mtDNA and formyl peptides. MtDNA and formyl peptides clearly act as systemic alarmins or damage-associated molecular patterns (DAMPs) [3,4] The mechanisms by which mt-DAMPs (MTD) act on other cells and the molecular events by which MTD induce the systemic inflammatory response syndrome (SIRS) and organ dysfunction are poorly understood. It is known though, that a major mechanism by which innate immunity causes organ dysfunction is instigation of PMNmediated increases in endothelial cell (EC) permeability. We focused on the molecular biologic and cell signaling events that led to the alterations in EC permeability seen in the translational models we had created
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