Mitochondrial DAMPs Increase Endothelial Permeability through Neutrophil Dependent and Independent PathwaysReportar como inadecuado




Mitochondrial DAMPs Increase Endothelial Permeability through Neutrophil Dependent and Independent Pathways - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

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.



Autor: Shiqin Sun, Tolga Sursal, Yasaman Adibnia, Cong Zhao, Yi Zheng, Haipeng Li, Leo E. Otterbein, Carl J. Hauser , Kiyoshi Itagaki

Fuente: http://plos.srce.hr/



DESCARGAR PDF




Documentos relacionados