in the previous issue of critical care we read with great interest a report of the first experimental study of recombinant human activated protein c ( rhapc ) in oleic acid - induced nonseptic acute lung injury ( ali ) in sheep .
impairment of the protein c pathway plays a central role in the pathogenesis of sepsis . treatment with rhapc has been reported to increase survival from severe sepsis .
the administration of rhapc may correct the dysregulated anticoagulant mechanism and prevent propagation of thrombin generation and the formation of microvascular thrombosis .
it is likely that the beneficial effects of rhapc observed in experimental and clinical studies of severe sepsis result from a combination of mechanisms that modulate the interdependent processes of coagulation and inflammation .
protein c levels also decrease markedly in ali , of both septic and nonseptic origin .
low levels of protein c in ali are associated with poor clinical outcome . in the present study
, the authors of the well known group of lars bjertnaes ( troms , norway ) showed that simultaneous administration of rhapc ameliorates oleic acid - induced ( non - septic ) lung injury .
the rise in pulmonary artery pressure , the development of pulmonary edema and the derangement of arterial oxygenation subsequent to intravenous bolus infusion of oleic acid all improved significantly during coadministration of rhapc .
we recently reviewed studies of rhapc treatment in sepsis - related ali and found the timing of drug administration to be critical in these experiments .
when given prior to the injury in a porcine model   or given simultaneously in pseudomonas aeruginosa - induced lung injury in rats , the oxygenation further deteriorated  beneficial effects could only be shown when rhapc was given post injury in various ovine models [ 9 - 11 ] .
we hypothesized that rhapc in the early stage of ali may disturb the complex coagulation balance at the alveolar level , and may impede an initially positive effect of coagulation activation , because in the early phase of ali the epithelial side as well as the endothelial side of the capillary barrier are involved with fibrin deposition , reflecting a shift in the alveolar / fibrinolysis balance .
the beneficial effects of the simultaneous treatment in the present study , however , are in contrast to our hypothesis and lead away from the coagulation cascade to the activity of neutrophils in ali . during inflammation ,
activated neutrophils accumulate in the lungs and other organs , thus contributing to organ system dysfunction .
neutrophils express receptors for rhapc and neutrophil chemotaxis is inhibited by exposure to rhapc , explaining its beneficial effects .
our group uses an ovine model of smoke inhalation and sepsis to induce ali , since smoke inhalation and sepsis are major contributors to mortality in burn patients .
the lungs of sheep have a special feature , a single bronchial artery , and a single lymphatic draining of the lung . a 10-fold increase in bronchial blood flow
the venous outflow of the bronchial circulation drains into the pulmonary microcirculation at the precapillary level .
considering the fact that initial damage to the airway appeared to drive the pathophysiology of the parenchyma , investigators hypothesized that the bronchial blood might deliver cytotoxic materials or cells into the pulmonary microcirculation . to test this hypothesis ,
several investigators have tied off the bronchial artery of sheep and then exposed the animals to smoke . in these studies
what could be the linkage between the airway , the bronchial venous drainage and parenchymal injury to the lung ?
many of the neutrophils , however , have been activated in the bronchial areas  their f - actin is activated and the cells are stiff and can not deform .
these stiff cells are carried to the pulmonary microvasculature , where they are impaled by the narrow pulmonary capillaries .
the final proof of this hypothesis was to deplete the animals of their neutrophils and determine how this affected the response to inhalation injury . in these studies of sheep depleted of their leukocytes ,
when rhapc binds to these receptors , before the cells are drained via the bronchial venous system into the pulmonary microvasculature , a reduction of ali may be anticipated .
taking these facts together , the results of waerhaug and colleagues appear in a different light ; of course oleic acid - induced ali is different from smoke inhalation , but , given the direct injury to the lung and the fact that sheep have the single bronchial artery , the beneficial effects of a simultaneous treatment with rhapc might be more advantageous than in other models  especially since only sheep subjected to peritoneal sepsis or endotoxin infusion presented with reduced extravascular lung water .
future studies are warranted to determine the effects of rhapc in an ovine model when the bronchial artery is tied off to clear its mechanism in ali .
 impairment of the protein c pathway plays a central role in the pathogenesis of sepsis . treatment with recombinant human activated protein c ( rhapc ) has been reported to increase survival from severe sepsis . 
 protein c levels also decrease markedly in acute lung injury , of both septic and nonseptic origin . 
 low levels of protein c in acute lung injury are associated with poor clinical outcome . 
 the present article discusses the beneficial effects of rhapc in oleic acid - induced lung injury as well as the controversies between different animal models and the timing of drug administration . 
 the unique bronchial circulation in ovine models seems to be responsible for the beneficial effects of rhapc when given simultaneously to the injury . 
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