Adrenomedullin treatment abolishes ileal mucosal hypoperfusion induced by Staphylococcus aureus α-toxin—An intravital microscopic study on an isolated rat ileum

Abstract

These data suggest that exogenously added adrenomedullin protects ileum mucosa by diminishing alpha-toxin-induced microcirculatory disturbances. Further investigations will have to clarify the therapeutic potential of adrenomedullin in sepsis-related gut dysfunction.

Persistent villi hypoperfusion explains intramucosal acidosis in sheep endotoxemia*

“…The characteristics of intestinal blood flow redistribution are similar to those described by Vallet et al (15). Brell et al (33), using intravital microscopy in rats, showed that Staphylococcus aureus alpha-toxin causes ileal mucosal hypoperfusion. Nakajima et al (34) also showed that endotoxin induces a significant decrease in mucosal perfusion of mouse small intestine, characterized by a reduction in red blood cell velocity and flow in villi.…”

“…Indeed, studies using laser-Doppler flowmetry (6), dyed (16) or fluorescent (16,42) microspheres, and PO 2 measurements using Pd-porphyrin phosphorescence (43) have failed to identify mucosal hypoperfusion. Conversely, direct visualization of intestinal mucosa by intravital microscopy (33)(34)(35)(36), orthogonal spectral polarization (OPS) imaging (24), or the sidestream dark field imaging of our study have almost systematically showed alterations in its microcirculation. It is worth noting that laser Doppler flowmetry provides a relative signal of red blood cell flow from an unknown tissue volume, and thus, it is unable to discriminate capillary stopped flow or flow heterogeneity induced by sepsis.…”

Adrenomedullin reduces intestinal epithelial permeability in vivo and in vitro

“…Doses of AM and ␣-toxin were chosen on the basis of previous studies regarding the analysis of endothelial barrier function (15,16,27). Purified staphylococcal ␣-toxin was generously provided by Prof. Dr. S. Bhakdi (University of Mainz, Germany).…”

“…Interestingly, in sepsis, AM is produced to a great extent in the mucosa of the gastrointestinal tract (49,75), and splanchnic vasculature is highly responsive to AM (15,16,42,52). In previous reports, we demonstrated that AM stabilized endothelial barrier function in vitro, ex vivo, and in vivo (15,16,27,63). Remarkably, AM treatment was shown to abolish ileal mucosal hypoperfusion and to stabilize intramucosal hemoglobin oxygenation in Staphylococcus aureus (S. aureus) ␣-toxin-exposed ileum (15,16).…”

“…In previous reports, we demonstrated that AM stabilized endothelial barrier function in vitro, ex vivo, and in vivo (15,16,27,63). Remarkably, AM treatment was shown to abolish ileal mucosal hypoperfusion and to stabilize intramucosal hemoglobin oxygenation in Staphylococcus aureus (S. aureus) ␣-toxin-exposed ileum (15,16). Therefore, we now tested the hypothesis that AM stabilizes epithelial barrier function.…”