Abstract
BACKGROUND: The spleen is an important contributor to the uncontrolled, excessive release of proinflammatory signals during sepsis that leads to the development of tissue injury and diffuse end-organ dysfunction. Therapeutic pulsed ultrasound (pUS) has been shown to inhibit splenic leukocyte release and reduce cytokine production in other inflammatory disease processes. We hypothesized that pUS treatment inhibits spleen-derived inflammatory responses and increases survival duration in rats with severe intra-abdominal sepsis leading to septic shock. MATERIALS AND METHODS: Rats with intra-abdominal sepsis, induced by cecal ligation and incision, underwent abdominal washout, intra-peritoneal administration of cefazolin, and then either no further treatment (control), splenectomy, or pUS of the spleen. Animals were observed for the primary endpoint of survival duration. RESULTS: Survival curves were significantly different for all groups (P < 0.01). Median survival increased from 9.5 h in control rats to 19.8 h in pUS rats and 35.0 h in splenectomy rats (P < 0.01). At 4 h after cecal ligation and incision, the pUS group had decreased splenic contraction and leukocyte count (P = 0.03) compared with control, indicating reduced exodus of splenic leukocytes. In addition, elevation in plasma TNF-α and MCP-1 was significantly attenuated in the pUS group (P < 0.05 versus control). Splenic β(2) adrenergic receptor levels and phosphorylated Akt were significantly more elevated in the pUS group (P < 0.01 versus control). CONCLUSIONS: pUS significantly prolonged the survival duration of rats with severe intra-abdominal sepsis. This treatment may be an effective, noninvasive therapy that dampens detrimental immune responses during septic shock by activating β(2) adrenergic receptor-Akt phosphorylation in the cholinergic anti-inflammatory pathway.