Histologically, the only tissue outside the respiratory tract and lymphoid tissues with discernable changes on HE sections was the liver of animals in the H5N1 group, where the Kupffer cells appeared mildly hypertrophic. This change was more apparent in sections stained for Mac387 and HIF-1α (Fig. 5a , c, and data not shown). Using these same phenotypic markers, it became evident that intravascular blood monocytes in many tissues and resident, interstitial macrophages in kidneys and heart of these animals were likely also activated, or alternatively, these tissues were infiltrated with a small but significant population of activated macrophages (Fig. 5e) . A further indication of extrapulmonary activation of the macrophage lineage was seen in the brains of H5N1 infected animals, where a mild, but very notable hypertrophy, and possible increase in numbers, of microglial cells was apparent in sections labeled for the Iba-1 molecule (Fig. 6) . Moreover, there were signs of astrogliosis in the H5N1-infected animals on days 4 and 7, as reflected by increased GFAP expression (data not shown). VEGF-A expression was more pronounced in the brain in this group from day 2 pi through day 7, although on days 1 and 2, the expression in the other groups was also notable (data not shown).