Novel Therapies for Microvascular Permeability in Sepsis

Abstract

Sepsis is characterized physiologically by an aberrant systemic inflammatory response and microvascular dysfunction. While appropriate antibiotics and supportive care are essential in the management of the septic patient, therapies targeting specific aspects of the pathophysiology could have a significant impact on the morbidity and mortality associated with both sepsis and its sequlea, including acute lung injury (ALI). We have characterized several mediators of endothelial cell (EC) barrier function that may serve as novel therapies for sepsis-induced microvascular dysfunction including simvastatin, adenosine triphosphate (ATP), sphingosine 1-phosphate (S1P), and activated protein C (APC). Notably, APC is already available for the treatment of severe sepsis, however, to date its mechanism of action has been unclear. While distinct in many ways, we have found that these agonists have in common the ability to induce dynamic rearrangement of the EC actin cytoskeleton that corresponds to barrier protection. In addition, we have extended our in vitro findings to relevant animal models of endotoxin-induced acute lung injury and have confirmed beneficial effects of both simvastatin and S1P which are associated with evidence of decreased vascular permeability in this setting. Moreover, our data also indicate that APC effects in sepsis may be largely due to augmentation of EC barrier function affecting decreased microvascular permeability. We speculate that the administration of direct modulators of EC barrier function and microvascular permeability, such as those described here, may ultimately become the standard of care for the septic patient.

Sphingosine-1–Phosphate, FTY720, and Sphingosine-1–Phosphate Receptors in the Pathobiology of Acute Lung Injury

“…S1P binding to S1P 1 or other S1P receptors activates Rac, cortactin translocation, peripheral myosin light chain phosphorylation, focal adhesion, adherens junction rearrangement, and recruits these signaling molecules and cytoskeletal effectors to lipid rafts. S1P also induces tight-junction assembly that further strengthens the endothelial barrier ( Figure 3) (31,34,40). Because caged S1P-mediated barrier enhancement is Rac1-dependent (38), S1P may directly interact or bind with Rac1, and induce the dissociation of the Rho guanosine diphosphate (GDP) dissociation inhibitor (RhoGDI) from Rac1 for activation and redistribution to the cell periphery (41).…”

The role of cytoskeleton in the regulation of vascular endothelial barrier function

“…Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Jacobson, Garcia, 2007]. Below we will analyze these signaling pathways and their target cytoskeletal proteins.…”

ADAM15 deficiency attenuates pulmonary hyperpermeability and acute lung injury in lipopolysaccharide-treated mice

“…This is largely owing to the complexity of the disease and our incomplete understanding of its endpoint cellular mechanisms (6,15). Microvascular barrier dysfunction is a common endpoint of inflammatory response characterized by endothelial hyperpermeability, plasma leakage, and leukocyte infiltration in the lungs, leading to respiratory distress and multiple organ failure (7,16). On the basis of the observation that ADAM15 is involved in several inflammatory conditions, coupled with our results showing thrombin induced barrier dysfunction in umbilical vein endothelium is ADAM15 dependent, we infer that ADAM15 plays a role in endothelial barrier dysfunction during inflammation in other tissues including the lungs.…”