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14: ROLE OF SUBSTANCE P INHIBITION IN ATTENUATING INFLAMMATION IN MURINE SEPTIC PERITONITIS

Mella, Juan Rodolfo

doi: 10.1097/01.ccm.0000424270.97512.db
Oral Abstract Session: ABSTRACT Only

Introduction: Septic peritonitis accounts for nearly one third of all sepsis cases and contributes to a considerable proportion of intensive care unit admissions. Apart from early goal directed therapy with source control and antibiotics, there is no pharmacological management targeted to control the inflammatory pathways that make up sepsis. Substance P (SP) is a neuropeptide that plays a critical role in the inflammatory cascade when bound to the neurokinin-1 receptor (NK1R) triggering cell proliferation, inflammatory mediators release and tissue injury. Inhibiting SP by blocking NK1R may have beneficial effects of controlling the inflammatory response in sepsis.

Hypothesis: A NK1R antagonist (NK1RA) administered following cecal ligation and puncture (CLP) will reduce inflammation and improve survival in the acute phase of sepsis.

Methods: Female ICR mice underwent CLP and randomized to intra-peritoneal treatment of normal saline or CJ-12255, a NK1RA. Blood was collected by facial vein sampling daily for the first 7 days. Peritoneal lavage was performed at 6 and 24 hours following CLP in a subset of mice to collect peritoneal cell counts, cytokines, and quantify bacterial load. Cytokines were evaluated by ELISA. To discern a mechanism, a novel in vitro phagocytosis assay was performed. Opsonization of enteric bacteria with naïve murine plasma, followed by addition of elicited macrophages in the presence of NK1RA was performed to evaluate macrophage ability to kill bacteria.

Results: Treatment with NK1RA resulted in an improvement in survival (p=0.02). Cytokines (IL-6, MIP-2, KC, IL-1RA) were lower in treated mice in the first 24 hours after CLP with a subsequent reduction in leukocyte recruitment in the peritoneum at 24 hours (p<0.01) and blood at 72 hours (p<0.05). There was also a trend toward decreased bacterial load in the peritoneum. Interestingly, the in vitro phagocytosis assay demonstrated lower CFU counts in the presence of higher NK1RA concentrations in a dose dependent fashion.

Conclusions: Inhibiting SP following CLP attenuates inflammation with subsequent improved survival. This appears to be through a mechanism of reduced bacterial growth, presumably by augmentation of macrophage bacterial killing by NK1RA.

Boston University School of Medicine

© 2012 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins