in the previous issue of critical care , kmpers and colleagues   demonstrated a direct correlation between increased peripheral blood levels of the vascular growth factor , angiopoietin ( angpt)-2 , and mortality in 43 critically ill adults with sepsis .
endothelial injury is one of the main hallmarks of sepsis , leading to capillary leak , microcirculatory dysfunction , organ failure , and eventual death in many critically ill patients . angpt-1 and angpt-2 are two of the best - characterized members of a family of endothelial - derived vascular growth factors necessary for both normal and pathologic angiogenesis and vasculogenesis . both angpt-1 and
angpt-2 appear to bind to the tyrosine kinase receptor , tie-2 , found primarily on the luminal surface of endothelial cells .
recent studies have also shown that the tie-2 receptor may be found on certain populations of peripheral blood monocytes , although the function and role of the tie-2 receptor in the host innate immune response remain relatively unexplored .
angpt-1 is a tie-2 agonist and promotes endothelial stabilization and quiescence , whereas angpt-2 is a tie-2 antagonist and promotes endothelial activation , destabilization , and inflammation . as such , the relative balance between angpt-2 and angpt-1 at the tie-2 receptor may be more relevant to the pathobiology of sepsis than the absolute levels of the individual growth factors .
several studies have demonstrated increased peripheral blood levels of angpt-2 in critically ill patients with sepsis [ 5,7 - 9 ] , multiple trauma , acute lung injury ( ali ) , and cardiopulmonary bypass   when compared with healthy controls .
more importantly , increased angpt-2 levels appear to be associated with adverse outcomes [ 5,6,9 - 12 ] .
for example , the study of kmpers and colleagues   showed that increased peripheral blood angpt-2 levels correlated with surrogate markers of tissue hypoxia , disease severity , and mortality in 43 critically ill adults with sepsis .
also of note , consistent with the opposing roles of angpt-2 and angpt-1 on the tie-2 receptor , peripheral blood levels of angpt-1 were significantly lower in the patients with sepsis compared with healthy controls .
unfortunately , in the study of kmpers and colleagues , similar to the aforementioned studies , the temporal kinetics of angpt-1 and angpt-2 were not assessed as blood samples were collected upon the first day of admission to the intensive care unit only .
angpt-2 is stored in the weibel - palade bodies within endothelial cells   in a more or less prepackaged form .
it is therefore not surprising that angpt-2 levels are increased early in response to endothelial activation or injury . whether angpt-2 levels remain increased in critically ill patients with sepsis has not been directly addressed and is a question for future investigation .
it is certainly tempting to speculate that peripheral blood angpt-2 levels would be an ideal biomarker of early endothelial activation and injury .
similarly , whether angpt-1 levels remain decreased in critically ill patients who eventually succumb to their illness is an interesting question .
angpt-1 may be a biomarker of endothelial recovery ; however , given its purported anti - inflammatory role , angpt-1 would appear to be an attractive therapeutic target as well . to this end
, several studies have suggested that manipulating the ratio of angpt-2 to angpt-1 by augmenting angpt-1 levels may represent an ideal therapeutic strategy for patients with sepsis and ali .
important translational laboratory studies are necessary to show that increased angpt-2 levels in critically ill patients are more than just an epiphenomenon .
the role of angpt-2 in the pathobiology of sepsis and ali needs to be further elucidated by using in vitro cell - based studies and animal models of critical illness .
similarly , the presence of the tie-2 receptor on certain subpopulations of peripheral blood monocytes   suggests a larger role for angpt-2 in the host innate immune response . finally , manipulation of the angpt / tie-2 system may be a rational therapeutic strategy for the management of critically ill patients with sepsis and ali .
all of these questions remain an active focus in several laboratories , including our own .
the authors ' research is funded by the national institutes of health ( bethesda , md , usa ) ( grant numbers 5ko8gm077432 and 1r03hd058246 ) .
 the early recognition and management of sepsis remain the greatest challenges in the field of critical care medicine . 
 endothelial injury is one of the hallmarks of sepsis , leading to capillary leak , microcirculatory dysfunction , organ failure , and eventual death in many critically ill patients . 
 the angiogenic growth factors , angiopoietin ( angpt)-1 and angpt-2 , act upon the tie-2 receptor in opposing roles . 
 angpt-2 has been found in abundance in septic patients when compared with healthy controls . in the study by kmpers and colleagues in the previous issue of critical care , angpt-2 levels correlated with markers of tissue hypoxia , disease severity , and mortality in septic adults . 
 however , the temporal kinetics of the angiopoietins were not assessed . 
 it remains to be seen whether angpt-2 levels will function solely as an early marker of sepsis or whether the manipulation of the angpt / tie-2 system will become a rational therapeutic target for the management of sepsis . 
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Acknowledgements