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Adrenomedullin reduces Staphylococcus aureus alpha-toxin-induced rat ileum microcirculatory damage
Bernhard Brell1, Bettina Temmesfeld-Wollbrück, Iris Altzschner
1Department of Internal Medicine/Infectious Diseases, University Medicine Berlin, Berlin, Germany.
Objective:
Increased microvascular permeability and perfusion mismatch are hallmarks of sepsis or septic shock. The intestinal mucosa is very sensitive to tissue hypoxia. Intestinal mucosa dysfunction may allow translocation of bacteria and their products, thereby perpetuating sepsis and inflammation. Staphylococcus aureus alpha-toxin is a major pathogenicity determinant of this bacterium, provoking cardiovascular collapse. Current evidence suggests that the endogenous peptide adrenomedullin stabilizes circulatory homeostasis in systemic inflammatory response. Using alpha-toxin as a well-defined strong initiator of an inflammatory reaction, we tested the hypothesis that exogenously applied adrenomedullin stabilizes gut microcirculation.
Design:
Prospective, experimental study.
Setting:
Research laboratory at a university hospital.
Subjects:
Isolated, perfused ileum from male Sprague-Dawley rats and human umbilical vein endothelial cells.
Interventions:
Administration of S. aureus alpha-toxin before or after infusion of adrenomedullin.
Measurements And Main Results:
Injection of a bolus of 1 microg of alpha-toxin in the superior mesenteric artery in a constant-flow, blood-perfused preparation of rat ileum increased perfusion pressure and relative hemoglobin concentration and decreased mucosal hemoglobin oxygen saturation. Continuous infusion of adrenomedullin (0.1 micromol/L) significantly reduced these alpha-toxin-related effects. Severe microvascular hyperpermeability observed in alpha-toxin-exposed ileum was abolished by adrenomedullin pretreatment. In addition, adrenomedullin blocked alpha-toxin-induced endothelial myosin light chain phosphorylation, endothelial cell contraction, and subsequent loss of endothelial barrier function in vitro. Treatment of alpha-toxin (infusion of 0.05 microg/mL)-exposed ileum with adrenomedullin (0.1 micromol/L) started 10 mins after onset of toxin application also significantly reduced superior mesenteric artery pressure and permeability increase.
Conclusions:
In summary, these data suggest that exogenous adrenomedullin protects ileum by reducing alpha-toxin-induced microcirculatory disturbances and by stabilizing endothelial barrier function.
Insights
Adrenomedullin protects the gut by stabilizing microcirculation and endothelial barrier function against Staphylococcus aureus alpha-toxin. This peptide reduces inflammation and improves blood flow during sepsis-induced shock.
Area of Science:
- Physiology
- Microbiology
- Pharmacology
Background:
- Sepsis and septic shock are characterized by increased microvascular permeability and perfusion mismatch.
- Intestinal dysfunction can exacerbate sepsis by allowing bacterial translocation and perpetuating inflammation.
- Staphylococcus aureus alpha-toxin is a key virulence factor causing cardiovascular collapse, while adrenomedullin may stabilize circulatory homeostasis.
Purpose of the Study:
- To investigate the protective effects of exogenously applied adrenomedullin on gut microcirculation.
- To test the hypothesis that adrenomedullin can stabilize gut microcirculation against Staphylococcus aureus alpha-toxin-induced injury.
Main Methods:
- Prospective experimental study using isolated, perfused rat ileum and human umbilical vein endothelial cells.
- Administration of Staphylococcus aureus alpha-toxin and adrenomedullin in various sequences.
- Measurement of perfusion pressure, hemoglobin concentration, oxygen saturation, and endothelial barrier function.
Main Results:
- Alpha-toxin increased perfusion pressure and decreased oxygen saturation in rat ileum.
- Adrenomedullin significantly reduced alpha-toxin-induced microcirculatory disturbances and hyperpermeability.
- In vitro, adrenomedullin blocked alpha-toxin-induced endothelial cell contraction and loss of barrier function.
Conclusions:
- Exogenous adrenomedullin protects the ileum from alpha-toxin-induced microcirculatory disturbances.
- Adrenomedullin stabilizes endothelial barrier function, mitigating sepsis-related gut injury.
- These findings highlight adrenomedullin's potential therapeutic role in sepsis.
