Activated neutrophils have been implicated as pathogenic mediators of injury to tissues and, in particular, to the microcirculation system. The critical common step is the adhesion of the activated neutrophils^[5]. Firm adhesion of neutrophils is mediated byβ₂ integrins (CD11b/CD18) and ICAM-1. The role ofβ₂ integrins in lung injury has been determined by the application of blocking antibodies. Anti-CD11b antibodies were found to reduce complement-mediated lung injury ^[20]. In vitro studies have tested the influence of HES on the expression of the adhesion molecule CD11b on neutrophils and found no significant inhibition effect of HES ^[21]. However, the in vivo function has not been established. We observed that HES could inhibit LPS-induced increases of CD11b expression on neutrophils in a dose-dependent manner. This result is consistent with the hypothesis of Nohe et al.^[22]. They found that HES did not attenuate adhesion molecule expression but showed an immediate decreasing effect on neutrophil adhesion. They thought that this was due to its inhibition on interactions of neutrophilic β₂ integrins with their endothelial counterreceptors.<?xml:namespace prefix = o ns = "urn:schemas-microsoft-com:office:office" />

CINC is structurally and functionally related to human IL-8. It is a potent chemotactic factor for rat neutrophils both in vitro and in vivo. Frevert et al. ^[23]reported that approximately 50% to 70% of neutrophil chemotaxis in LPS-induced pulmonary inflammation is caused by CINC. Because CINC itself can increase the expression of CD11b/CD18 integrin on rat neutrophils ^[23] and because expression of leukocyte adhesion molecules such as E selectin is dependent on CINC ^[24], the inhibition of lung CINC level by HES that we observed in our study may exert both direct and indirect effects on neutrophil vascular adhesion and extravascular migration.

In our study, we found that HES at doses of 3.75 and 7.5 mL/kg significantly reduced LPS-induced NF-_kB activation in both blood neutrophils and lungs. NF-_kB plays a central role in regulating the transcription of cytokines, adhesion molecules, and other mediators involved in acute respiratory distress syndrome, sepsis, and multiple organ system failure ^[10]. Liu et al. ^[25] showed that inhibition of NF-_B activation in vivo suppresses LPS-induced CINC and ICAM expression, reduces neutrophil accumulation, and prevents capillary leak in multiple organs. It seems that HES exerts its actions through the NF-_kB signaling pathway. We also found that HES could reduce the LPS-induced increase of TNF-α levels in plasma (data not shown).TNF-α is involved in NF-_kB activation ^[26]. It is possible that HES inhibits NF-_kB activation by inhibition of TNF-α.

Emphasis should be placed on the hemodynamics, which are obviously important during the procedure because reversal of systemic hypotension woule also influence microvascular disorders and thus would not allow discrimination between the effects of HES on macrohemodynamics and microcirculation per se. We measured the blood pressure of the rats in our pilot study, and this variable did not differ among the seven groups, indicating that the animals were hemodynamically stable. Minor hemodynamic changes probably could not be excluded because other measurements such as cardiac output (CO) and systemic vascular resistance (SVR) were lacking. We did not study CO and SVR in our experiment because, on the one hand, measurements of CO and SVR were invasive procedures and because repeated blood sampling of ＞1 mL during the procedure would likely influence the hemodynamics in such a limited circulating blood volume as in the rat; on the other hand, the changes of blood pressure were similar among the seven groups. However, these presumably minor changes would surely not influence hemodynamic stability. The fact that blood pressure differences among the groups were absent in the model used indicates that the improvements of microvascular permeability and reduction of neutrophilic inflammation by HES are not caused by reversal of macrohemodynamics disturbances.