Abstract
BackgroundSeptic shock is the leading cause of death in intensive care units. The pathophysiological complexity of this syndrome contributes to an absence of specific treatment. Several preclinical studies in murine models of septic shock have shown improvements to organ injury and survival after administration of mesenchymal stem cells (MSCs). To better mimic a clinical approach in humans, we investigated the impact of randomized controlled double-blind administration of clinical-grade umbilical cord-derived MSCs to a relevant pig model of septic shock.MethodsSeptic shock was induced by fecal peritonitis in 12 male domestic pigs. Animals were resuscitated by an experienced intensivist including fluid administration and vasopressors. Four hours after the induction of peritonitis, pigs were randomized to receive intravenous injection of thawed umbilical cord-derived MSCs (UCMSC) (1 × 106 UCMSCs/kg diluted in 75 mL hydroxyethyl starch (HES), (n = 6) or placebo (HES alone, n = 6). Researchers were double-blinded to the treatment administered. Hemodynamic parameters were continuously recorded. Gas exchange, acid-base status, organ function, and plasma cytokine concentrations were assessed at regular intervals until 24 h after the onset of peritonitis when animals were sacrificed under anesthesia.ResultsPeritonitis induced profound hypotension, hyperlactatemia, and multiple organ failure. These disorders were significantly attenuated when animals were treated with UCMSCs. In particular, cardiovascular failure was attenuated, as attested by a better mean arterial pressure and reduced lactatemia, despite lower norepinephrine requirements. As such, UCMSCs improved survival in this very severe model (60% survival vs. 0% at 24 h).ConclusionUCMSCs administration is beneficial in this pig model of polymicrobial septic shock.
Highlights
Septic shock is the leading cause of death in intensive care units
Characteristics of UCMSCs According to the standards described by the International Society for Cellular Therapy [24], the immunophenotype for UCMSCs is CD14neg-CD34neg-HLA-DRneg-CD11bneg-CD19neg-CD73+-CD90+-CD105+-CD44+
UCMSCs attenuate hemodynamic failure associated with septic shock Peritonitis induced a rapid drop in Mean arterial pressure (MAP) (Fig. 2) despite volume resuscitation (8.16 mL/kg/h for controls vs. 7.48 mL/kg/h for UCMSC group, p = 0.667)
Summary
Septic shock is the leading cause of death in intensive care units. The pathophysiological complexity of this syndrome contributes to an absence of specific treatment. In the initial stages, simultaneous production of pro-inflammatory and anti-inflammatory mediators is observed [3, 4], and it is accepted that sepsis is not a succession of hyper- and hypo-inflammatory states, but that the two are intertwined This new paradigm may explain the failure of many therapies targeting this deregulated host response [5]. Several studies indicated that MSCs can increase bacterial clearance [10] and modulate cytokine production by decreasing pro-inflammatory mediators and increasing anti-inflammatory cytokines [11,12,13,14,15,16] Through their immunomodulatory capacities and antibacterial properties, they can improve renal, pulmonary, liver, cardiac, and muscular function, as well as coagulopathy associated with septic shock [11, 17,18,19,20,21]
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