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The major focus of this study was to determine the effect of HES on lung capillary permeability in endotoxic rats and the mechanistic bases that underlie the possible effect. Our results showed that early treatment

of HES (200/0.5) at doses of 3.75 and 7.5 mL/kg significantly reduced LPS-induced increases of lung capillary permeability.

Neutrophils play a central role in experimental models of acute lung leak. After being activated and mediated by adhesion molecules, integrins, and chemotactic factors, neutrophil accumulation is increased in lungs of endotoxic animal models. Neutrophils then release several toxic substances, including reactive oxygen species and proteolytic enzymes, that cause capillary leak and lung injury ^[9]. In this respect, understanding the mechanisms by which HES reduces the increased capillary permeability should provide information on the regulation of processes that can contribute to the pathogenesis of acute lung leak. In this study, we provide evidence that HES could inhibit  LPS-induced increases of lung neutrophil accumulation, CD11b expression on the blood neutrophil cell surface, lung CINC protein level, and NF-_kB activation in both blood neutrophils and lungs in a doserelated manner. These findings provide the first in vivo data supporting a mechanism of HES-elicited reduction of capillary leak involving an anti-inflammatory effect of HES, including inhibition of NF-_kB activation.

Several studies have reported that HES molecules are able to reduce increases in microvascular permeability after ischemic insults in the spinal cord and cremaster muscle or after thermal burn ^[1,14,15]. Our finding in an endotoxic rat model is consistent with these previous reports. In addition, our studies extend these previous observations by showing that the effect of HES is not dose dependent. Although doses of HES 3.75 and 7.5 mL/kg showed a significant reduction in lung capillary permeability, larger doses of 15 and 30 mL/kg did not. The question that arises is as follows: How do starch macromolecules affect the microvascular permeability? Zikria et al. ^[16]postulated that HES macromolecules act by physically sealing the barrier defects created by the injury. This hypothesis was formed on the basis that increased transport is associated with a widening of the interendothelial cleft in postcapillary venules. However, Suval et al. ^[17] found increased extravasation of macromolecules in the presence of normal microvascular ultrastructure. Furthermore, electron microscope evidence confirmed that separation of interendothelial clefts is not a necessary element for increases in microvascular permeability^[18]. Also, the dose-related manner of HES found here is hard to elucidate with only a physically sealing mechanism. There must be additional mechanistic bases that underlie the actions of HES. Oz et al. ^[14]demonstrated that HES might affect microvascular dysfunction by influencing neutrophil binding to stimulatedendothelial cells. However, they did not know the mechanismof this effect. Pascual et al. ^[19] reported that HES could reduce neutrophil-mediated tissue injury through inhibition of neutrophil l-selectin expression. Our present findings suggest the in vivo linkage between improvement in microvascular permeability of HES and its reduction of neutrophilic inflammation, which involves ts inhibition of CD11b expression, CINC level, and NF-_kB activation, giving novel and general insight into the underlying mechanisms.