BACKGROUND: Activated protein C (aPC) confers survival benefit in patients with sepsis, yet its protective mechanism(s) remain unclear. Herein, we determined time-dependent severity of renal dysfunction during polymicrobial sepsis. We hypothesized aPC restores renal function by preserving organ architecture and reducing inflammation. MATERIALS AND METHODS: Sprague-Dawley rats underwent sham operation or cecal ligation and puncture (CLP). At 6 or 24 h post-surgery, kidney function was assessed by plasma electrolytes, blood urea nitrogen (BUN), and creatinine levels. Renal architecture was examined histologically. In the next series of experiments, 24-h post-surgery, animals were treated with vehicle or aPC (1 mg/kg) for 4 d, and kidney function and circulating cytokine levels were measured. Plasma was collected and assayed for BUN, creatinine, and lactate dehydrogenase (LDH) levels. Serum cytokine levels were measured by ELISA. RESULTS: Plasma electrolytes, BUN, creatinine, and renal architecture were altered 6 h after CLP. Treatment with aPC significantly inhibited sepsis-induced elevations in BUN, creatinine, LDH levels, and improved renal architecture. After CLP, interferon gamma (INFγ) decreased, while interleukins-1beta and -10 (IL-1β and IL-10) increased; these effects were attenuated by aPC treatment. CONCLUSIONS: Our data demonstrate that renal dysfunction occurs as early as 6 h following sepsis and continues thereafter. Treatment with aPC attenuated INFγ and IL-1β changes, and preserved renal function in sepsis. These data suggest aPC may confer a survival advantage by reducing systemic inflammation and, in doing so, preserving organ function.
BACKGROUND: Activated protein C (aPC) confers survival benefit in patients with sepsis, yet its protective mechanism(s) remain unclear. Herein, we determined time-dependent severity of renal dysfunction during polymicrobial sepsis. We hypothesized aPC restores renal function by preserving organ architecture and reducing inflammation. MATERIALS AND METHODS:Sprague-Dawley rats underwent sham operation or cecal ligation and puncture (CLP). At 6 or 24 h post-surgery, kidney function was assessed by plasma electrolytes, blood ureanitrogen (BUN), and creatinine levels. Renal architecture was examined histologically. In the next series of experiments, 24-h post-surgery, animals were treated with vehicle or aPC (1 mg/kg) for 4 d, and kidney function and circulating cytokine levels were measured. Plasma was collected and assayed for BUN, creatinine, and lactate dehydrogenase (LDH) levels. Serum cytokine levels were measured by ELISA. RESULTS: Plasma electrolytes, BUN, creatinine, and renal architecture were altered 6 h after CLP. Treatment with aPC significantly inhibited sepsis-induced elevations in BUN, creatinine, LDH levels, and improved renal architecture. After CLP, interferon gamma (INFγ) decreased, while interleukins-1beta and -10 (IL-1β and IL-10) increased; these effects were attenuated by aPC treatment. CONCLUSIONS: Our data demonstrate that renal dysfunction occurs as early as 6 h following sepsis and continues thereafter. Treatment with aPC attenuated INFγ and IL-1β changes, and preserved renal function in sepsis. These data suggest aPC may confer a survival advantage by reducing systemic inflammation and, in doing so, preserving organ function.
Authors: Jenell R Smith; Peter A Galie; David R Slochower; Christine L Weisshaar; Paul A Janmey; Beth A Winkelstein Journal: Biomaterials Date: 2015-12-02 Impact factor: 12.479