Cardiac mitochondrial damage and inflammation responses in sepsis.
OBJECTIVE
Studies in sepsis suggest that mitochondria mediate multiple organ dysfunction, including cardiac failure; however, the underlying molecular mechanisms remain elusive. This study examined changes in mitochondrial membrane integrity, antioxidant activities, and oxidative stress in the heart after infectious challenge (intratracheal Streptococcus pneumoniae, 4 x 10(6) colony-forming units). Inflammation responses also were examined.


METHODS
Cardiac tissues were harvested from Sprague-Dawley rats 4, 8, 12, and 24 h after bacterial challenge (or intratracheal vehicle for sham-treated animals) and homogenized, followed by preparation of subcellular fractions (mitochondrial, cytosol, and nuclei) or whole-tissue lysate. We examined mitochondrial outer membrane damage and cytochrome C translocation to evaluate mitochondrial integrity, mitochondrial lipid and protein oxidation to assess oxidative stress, and mitochondrial superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities to estimate antioxidant defense. In addition, we measured nuclear factor-kappa B (NF-kappaB) activation in myocardium and cytokine production to investigate inflammatory responses to septic challenge.


RESULTS
Oxidation of mitochondrial protein and lipid was evident 4 h through 24 h after bacterial challenge. Mitochondrial outer membrane damage and cytochrome C release were accompanied by down-regulation of mitochondrial SOD and GPx activity. After bacterial challenge, systemic and myocardial cytokine production increased progressively, and NF-kappaB was activated gradually.


CONCLUSIONS
Sepsis impaired cardiac mitochondria by damaging membrane integrity, increasing oxidative stress, and altering defenses against reactive oxygen species. These alterations occur earlier than or simultaneously with inflammatory responses in myocardium after infectious challenge, suggesting that mitochondria play a role in modulating inflammation in sepsis.
Zang
Qun
Q
Department of Surgery, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
Maass
David L
DL
Tsai
Sue Jean
SJ
Horton
Jureta W
JW
D000818:Animals; D045304:Cytochromes c / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005979:Glutathione Peroxidase / Q000378:metabolism; D007249:Inflammation; D008297:Male; D008563:Membrane Lipids / Q000737:chemistry; D008929:Mitochondria, Heart / Q000737:chemistry / Q000201:enzymology / Q000502:physiology* / Q000648:ultrastructure*; D051336:Mitochondrial Membranes / Q000648:ultrastructure; D024101:Mitochondrial Proteins / Q000378:metabolism; D009206:Myocardium / Q000473:pathology*; D016328:NF-kappa B / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D011008:Pneumococcal Infections / Q000150:complications / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018805:Sepsis / Q000150:complications / Q000503:physiopathology*; D012769:Shock / Q000209:etiology; D013296:Streptococcus pneumoniae; D013482:Superoxide Dismutase / Q000378:metabolism
D016207:Cytokines; D008563:Membrane Lipids; D024101:Mitochondrial Proteins; D016328:NF-kappa B; D045304:Cytochromes c; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase