Broken Barriers: A New Take on Sepsis Pathogenesis

Abstract

Despite intense research into the pathogenesis of sepsis, the current therapy for this devastating syndrome is primarily supportive and mortality remains high. The paucity of specific therapies is not for lack of effort; countless clinical trials in sepsis patients have failed despite promising preclinical data obtained from in vitro and animal models. Human sepsis is characterized by diffuse microvascular leak and tissue edema-features that have been largely ignored in animal models. Moreover, there have been no clinical trials of agents designed to prevent or treat leaky vasculature. Recent compelling evidence suggests that the breakdown in endothelial barrier function plays a crucial role in the pathogenesis of sepsis. In particular, these data suggest that preventing vascular leak can reduce mortality from sepsis. In this Perspective, we highlight the endothelial barrier as a new target for sepsis therapeutics, examining three potential strategies: enhancement of endothelial junctions; reinforcement of the endothelial cytoskeleton; and modulation of endothelial activation.

Development of a Zebrafish Sepsis Model for High-Throughput Drug Discovery

“…Cytokine levels are known to be temporally regulated in response to infection, and we might have missed the peak levels in proinflammatory cytokine expression typically observed in the first few hours following immune insult (40). Moreover, the significantly high expression of the antiinflammatory cytokine IL-10 suggests altered expression and distribution of cellular junction proteins (18,33). Increased vascular permeability in our model was accompanied by reduced expression of tight junction proteins occludin a and b, claudin 5a and b, and their intracellular partner ZO-1.…”

Studies on cell junctions in an ex vivo human lung infection model

“…A severe complication of pneumonia is systemic spreading of the invading pathogen finally resulting in acute respiratory distress syndrome (ARDS), septic shock and sepsis [37][38][39]. A plethora of clinical studies has shown that pathogenesis of ARDS and sepsis include the influx of protein-rich fluid into the air spaces as a consequence of increased permeability of the blood-air barrier leading to fatal lung edema formation [40][41][42][43]. Experimental studies in animals and cultured cells strengthened the hypothesis that junctional disruption of the lung barrier significantly contributes to a deleterious outcome [44][45][46].…”

Management of sepsis: from evidence to clinical practice

“…Proinflammatory reactions are thought to be responsible for collateral tissue damage in severe sepsis such as dysfunction of the vascular endothelium, accompanied by cell death and loss of barrier integrity, giving rise to subcutaneous and bodycavity edema. 91 Further several factors (hypotension, reduced red-cell deformability and microvascular thrombosis) contribute to diminished oxygen delivery in septic shock. 92 As well known, the major pathophysiologic changes in patients with severe sepsis and septic shock include vasoplegic shock (distributive shock), myocardial depression, altered microvascular flow, and a diffuse endothelial injury.…”