The critical role of heme oxygenase in neutrophil migration impairment in polymicrobial sepsis

Introduction and objective

During severe sepsis a marked impairment of neutrophil migration into the infectious focus occurs, which is associated with dissemination of infection resulting in high mortality. We recently showed that heme oxygenase (HO) products, carbon monoxide and biliverdin, downregulate neutrophil recruitment by reducing the neutrophil/endothelium rolling and adhesion in a noninfectious inflammatory model. This study aimed to investigate a possible role of the HO-1 pathway on the failure of neutrophil recruitment in mice subjected to severe (S-CLP) polymicrobial sepsis induced by cecal ligation and puncture (CLP).

Methods and results

Balb/c mice were pretreated with vehicle or with specific HO-1 inhibitor (ZnPPIX, 30 mg/kg, s.c.) and subjected to S-CLP. Mice were killed 6 hours after CLP, and HO-1 expression in the mesentery and in circulating neutrophils were determined. In another set of experiments, mice were sacrificed 6 and 12 hours after sepsis induction, and intraperitoneal neutrophil migration, bacteremia, lung neutrophil sequestration, cytokines and mean arterial pressure were evaluated. A significant increase in HO-1 expression was observed in the mesentery and in circulating neutrophils of mice pretreated with vehicle and subjected to S-CLP. The inhibition of HO-1 prevents the failure of neutrophil endothelium rolling, adhesion and migration observed in animals pretreated with vehicle and submitted to S-CLP. As consequence, the HO-1 inhibition promoted a reduction of bacteremia, low levels of circulating cytokine and lung neutrophil sequestration, and improves the mean arterial pressure, resulting in an increase of the survival rate.

Conclusion

These data suggest that during an infectious process HO-1 displays a crucial role in the failure of neutrophil migration to the infectious focus, and consequently in the susceptibility in severe sepsis.