in the past decade , the angiopoietin ( ang)-1/2-tie2 system has increasingly been suggested to play a major role in the various features of human sepsis and acute lung injury and has thereby been considered as a novel therapeutic target [ 1 - 3 ] .
high circulating ang-2 levels promote inflammation and vascular permeability ( in the lungs ) , while ang-1 has a protective effect , and these associations are confirmed by clinical studies
. the putative role of the ang-2/1 balance is gradually being expanded by studies showing that ang-2 levels may predict acute kidney injury and icu outcome , even independently of disease severity . in the current issue of critical care , davis and
colleagues   provide additional evidence that ang-2 release is associated with impaired vasoreactivity in patients with early sepsis , probably via interference with nitric oxide ( no ) , which can be considered as a pivotal pathophysiologic alteration in human sepsis .
they measured vascular reactivity by the non - invasive reactive hyperemiaperipheral artery tonometry ( rh - pat ) technique , reviewed elsewhere .
based on these observations , the authors conclude that ang-2 is a more meaningful biomarker of endothelial function in sepsis than ' currently used surrogate measures ' , but formal evaluation of predictive values are lacking and the correlations are moderate at best .
also , the authors did not measure ang-1 levels , although the balance between ang-2 and ang-1 may determine the net biological effect .
finally , an intervention targeted at these molecules would be needed to reveal a direct role in microvascular responses in sepsis .
indeed , the angiopoietin-1/2-tie2 system controls the responsiveness of the endothelium via multiple signal transduction pathways , including activation of rho - like small gtpases , protein kinase c - zeta and src , while the protein c system , a therapeutic target of alleged benefit in human septic shock , may also be involved , as recently suggested .
ang-1 may be associated with enhanced and ang-2 with decreased endothelial no synthase and release , even clinically .
conversely , changes in rh - pat are but partly dependent on changes in no levels ; we do not know this relationship in sepsis nor whether changes in the former are of prognostic significance for organ failure and mortality , so can not be certain of their clinical significance .
cytokine - induced exocytosis by weibel - palade bodies of procoagulant factors as well as ang-2 is associated with downregulation of endothelial no synthase and release . the no and ang-2/1 balance may thus be inversely interrelated , both in control of synthesis in the endothelium as well as in pro - inflammatory effects .
hence , this may further explain the inverse relation ( in time ) between endothelial no - dependent vascular reactivity and circulating ang-2 in the study by davis and colleagues .
finally , vasopressin ( v)2 receptors may contribute to exocytosis - a well known effect of selective v2 receptor - stimulating desmopressin and aselective v1/2 receptor - stimulating vasopressin , for instance - but selective v1 receptor stimulation may antagonise it , as suggested by recent experimental work showing that the latter may reduce lung leakage and injury in a grampositive ovine model of septic shock . if that is the case , the excess mortality suggested by the trial on vasopressin in the treatment of septic shock , at least when corticosteroids were not co - administered , can be explained , but ang-2 levels were not measured .
however , anti - inflammatory effects of low dose vasopressin have also been observed but the role of the v1 receptor remains unclear .
taken together , the control of weibel - palade bodies in sepsis deserves further study . in conclusion
, the study by davis and colleagues   suggests that ang-2 plays a role in the pathogenesis of sepsis beyond its well - appreciated role in inflammation and vascular permeability , by interfering with microvascular control of blood flow .
the novel inflamatory route may be a target for future therapeutic studies in human sepsis and acute lung injury , including those with activated protein c , v receptor agonists , statins and agents that improve endothelial no .
ang : angiopoietin ; no : nitric oxide ; rh - pat : reactive hyperemia - peripheral artery tonometry ; v : vasopressin .
 the interesting study by davis and colleagues in the current issue of critical care expands on the increasingly recognized role of angiopoietins in human sepsis but raises a number of questions , which are discussed in this commentary . 
 the authors describe an association between elevated angiopoietin ( ang)-2 levels and impaired vascular reactivity , measured by the partly nitric oxide - dependent finger hyperemic response to forearm vascular occlusion , in patients with sepsis . 
 this suggests that the ang-1/2-tie2 system is involved in a number of pathophysiologic , phenotypic and perhaps prognostic alterations in human sepsis , on top of the effect on pulmonary endothelial barrier function . 
 the novel inflammatory route may be a target for future therapeutic studies in human sepsis and acute lung injury , including those with activated protein c. 
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