Another noteworthy phenomenon in our experiment is that the maximal effect of HES was observed at a dose of 7.5 mL/kg in most cases. This may be because most mediators are regulated by many factors. Besides NF-kB, C/EBP and AP-1 are both important in the expression of cytokines, chemokines, and adhesive molecules. Maybe HES has some reverse effects on these pathways or on other untested mediators, such as selectins, and ICAM. Thus the effects of larger doses may be partially offset by those reverse effects. Further experiments are needed to confirm, in vivo, these and other proinflammatory signaling pathways on which HES might exert an influence. Finally, our experiments suggest the best dose of HES for use in a clinical setting. Because 2.5 mL in rats represents approximately 10% of the blood volume, 7.5 mL/kg is comparable to a human subject weighing 70 kg receiving 500 mL of HES.<?xml:namespace prefix = o ns = "urn:schemas-microsoft-com:office:office" /> In summary, we have shown that HES (200/0.5) at doses of 3.75 and 7.5 mL/kg significantly reduced LPS-induced increases in lung capillary permeability. The proposed mechanism is that HES inhibits LPSinduced NF-kB activation, followed by inhibition of the lung CINC protein level, CD11b expression on the blood neutrophil cell surface, and lung neutrophil accumulation, thus reducing the LPS-induced increase in microvascular endothelial permeability in the lung. References 1. Wisselink W, Patetsios P, Panetta TF, et al. Medium molecular weight pentastarch reduces reperfusion injury by decreasing capillary leak in an animal model of spinal cord ischemia. J Vasc Surg 1998;27:109-16. 2. Chiang CH, Wu CP, Perng WC, et al. Dexamethasone and pentastarch produce additive attenuation of ischaemia/ reperfusion lung injury. Clin Sci (Lond) 2000;99:413-9. 3. Allison KP, Gosling P, Jones S, et al. Randomised trial of hydroxyethyl starch versus gelatine for trauma resuscitation. J Trauma 1999;47:1114-21. 4. Ferrara JJ, Dyess DL, Collins JN, et al. Effects of pentafraction administration on microvascular permeability alterations induced by graded thermal injury. Surgery 1994;115:182-9. 5. Carlos TM, Harlan JM. Leukocyte-endothelial adhesion molecules. Blood 1994;84:2068-101. 6. Blackwell TS, Blackwell TR, Holden EP, et al. In vivo antioxidant treatment suppresses nuclear factor-kappa B activation and neutrophilic lung inflammation. J Immunol 1996;157: 1630-7. 7. Ward PA. Role of complement, chemokines, and regulatory cytokines in acute lung injury. Ann N Y Acad Sci 1996;796: 104-12. 8. Parrillo JE. Pathogenetic mechanisms of septic shock. N Engl J Med 1993;328:1471-7. 9. Bone RC. The pathogenesis of sepsis. Ann Intern Med 1991;115: 457-69. 10. Abraham E. NF-_B activation. Crit Care Med 2000;28(Suppl): N100-4. 11. Ye X, Liu SF. Lipopolysaccharide regulates constitutive and inducible transcription factor activities differentially in vivo in the rat. Biochem Biophys Res Commun 2001;288:927-32. | 
