Sepsis is the 7th leading cause of death in infants in the United States. Sepsis often causes cardiorenal syndrome (CRS), defined as simultaneous acute cardiac dysfunction (ACD) and acute kidney injury (AKI), which greatly increases mortality. There are no targeted therapies for sepsis-induced CRS and physicians must rely on supportive therapy usually begun only after the onset of symptoms. Two potential targets are microvascular dysfunction and oxidant generation, which are hallmarks of sepsis. I hypothesized that clinically relevant delayed therapy, which targets both the microcirculation and mitochondrial oxidants, would afford the most effective protection from sepsis-induced CRS in an infant model of sepsis. Two agents were evaluated: rolipram, a phosphodiesterase 4 inhibitor, which improved microvascular function, and MitoTEMPO, a mitochondria-targeted antioxidant.
I first characterized the development of CRS in an infant model of sepsis using cecal ligation and puncture (CLP) to induce sepsis in the 17 to 18-day-old rat pups. I found that both ACD and AKI occur by 6h post-CLP and persisted through 18h post-CLP. There is also increased capillary dysfunction and increased oxidant generation. Dose-finding studies were performed to evaluate the effectiveness of rolipram to prevent the capillary dysfunction and the effectiveness of MitoTEMPO to prevent oxidant generation. Rolipram (0.1 mg/kg) effectively prevented the decline in renal capillary perfusion and also prevented acute cardiac dysfunction. MitoTEMPO (10 mg/kg) effectively prevented the increase in mitochondrial superoxide generation and also prevented acute kidney injury.
Rolipram and MitoTEMPO were also evaluated in a clinically relevant delayed dosing paradigm and in combination therapy. MitoTEMPO only improved renal function when administrated at the time of CLP. Rolipram only improved cardiac function and was effective even with delay administration. Consequently, survival studies were performed with MitoTEMPO administered at the time of surgery (which prevented AKI) and rolipram administered at 6h post-CLP (which prevented ACD). Using this dosing paradigm, administration of rolipram or a combination of both therapies improved survival. Administration of MitoTEMPO had no effect on survival.
In summary, these studies demonstrate that combination therapy with rolipram and MitoTEMPO should be evaluated further as a therapy to treat infant sepsis-induced CRS.
|Advisor:||Mayeux, Philip R.|
|Commitee:||MacMillan-Crow, Lee Ann, Nguyen, Trung C., Rhee, Sung W., Rusch, Nancy J.|
|School:||University of Arkansas for Medical Sciences|
|School Location:||United States -- Arkansas|
|Source:||DAI-B 78/12(E), Dissertation Abstracts International|
|Keywords:||Cardiorenal syndrome, Infant, Mitochondria-targeted antioxidant, Rolipram, Sepsis|
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