While overt pathology ascribable to the virus infection was not seen in any tissues outside the respiratory tract and associated lymphoid tissues by conventional histology, immunohistochemistry for inflammatory reactants suggested that the effect of at least the H5N1 virus infection was not limited to those tissues. Notably, severe hypoxia, as a result of the pronounced lung pathology [23] , cytokinemia, or both may have given rise to extrapulmonary reactions. Both pathways may be regulated by HIF-1 [28] . HIF-1 was originally discovered as a biological O 2 sensor that enables the organism to adapt to hypoxia. Hypoxia is a reduction in the normal level of oxygen tension and occurs during acute and chronic pulmonary disease, vascular disease and cancer. Under hypoxic conditions, the rate of oxygen supply limits the rate of oxygen consumption, and aerobic metabolism is reduced. In cases of severe O 2 deficiency, the respiratory chain succumbs, and as a consequence, cellular death by necrosis or apoptosis may result. HIF-1 is a heterodimeric transcription factor composed of HIF-1α and HIF-1β subunits. Whereas HIF-1β is constitutively expressed, HIF-1α is targeted to ubiquitinylation by the von Hippel-Lindau tumor suppressor protein and is rapidly degraded in the proteasome. Under hypoxic conditions, hydroxylation of HIF-1α is blocked, which promotes protein stability and transactivation of HIF-1 [26] . Upon translocation to the nucleus, HIF-1 promotes the expression of genes encoding proteins that increase the cellular supply with oxygen and with energy-providing substrates [27] . HIF-1 initiates the defense against hypoxia at different levels, but in virtually all tissues, hypoxia induces the synthesis of proteins controlling local blood flow, notably VEGF and HO-1 [26, 27, 36] .