The primary resuscitation strategy for these patients is fluid resuscitation to improve organ perfusion and oxygenation and thereby prevent distal organ failure. Legrand et al. [117] examined the effects of fluid resuscitation on renal perfusion in relation to renal microcirculatory function in endotoxemic rats. The authors observed that infusion of endotoxin resulted in altered microvascular perfusion and oxygenation distributions. Early fluid resuscitation greatly improved renal perfusion compared to late resuscitation, but it did not influence oxygenation distribution. Serum cytokine levels decreased in the resuscitated groups, no matter whether early or late resuscitation was involved. Although the results are interesting, one has to keep in mind that the study was conducted at 300 min after endotoxin administration, and it is unknown whether this time frame is long enough to fully assess the therapeutic value of immediate versus delayed resuscitation in clinical situations. There are several issues that need to be addressed in future studies. For example, the volume and rate of fluid administration could simply have altered the disposition of endotoxin in the kidney. It is unclear how dramatic differences in aortic and renal artery flow and microvascular flow between endotoxin alone and endotoxin with fluid resuscitation had no impact on microvascular oxygen tension. Since the human erythropoietin fusion protein (EPO) gene was cloned over 25 years ago, several variants of the EPO molecule have been developed to improve its pharmacokinetic and pharmacodynamic characteristics and to separate its haemopoietic and neuroprotective properties [118] . For example, carbamylated erythropoietin fusion protein (cEPO-FC) contains two recombinant human EPO (rhEPO) molecules connected by the Fc region of human IgG 1 , and is thought to improve the cytoprotective effects while reducing side effects including hypertension and thrombosis. Simon et al. [119] report that pretreatment with a cEPO-FC is as effective as rhEPO in ameliorating spinal cord injury in a porcine model of acute spinal cord ischaemia and reperfusion. This study assessed short-term outcomes, including motor-evoked potentials and histological damage. Future studies will need to focus on the longer-term neurological outcomes and demonstrate an absence of systemic toxicity, including thrombosis. It is noteworthy that clinical studies raised the possibility that rhEPO could improve some clinical outcomes, including neuronal recovery, but rhEPO failed to show any clinical benefit with respect to the Barthel index, modified Rankin scale and mortality rate in patients with stroke [120, 121] . Thus, further experimental and clinical research is needed to determine if derivatives of rhEPO such as cEPO-FC can improve long-term neurological outcome without having potential adverse effects such as hypertension, thrombosis and mortality. Reactive oxygen species are produced by activated neutrophils during the inflammatory response to stimuli such as endotoxins, can directly or indirectly injure host cells, and have been implicated in the pathogenesis of ALI/ARDS. Hassett et al. [122] described the result of pulmonary overexpression of superoxide dismutase in the response to endotoxin administration in animals. Endotoxin produced a severe lung injury compared to a sham injury. Their results support the conclusion that superoxide dismutase plays an important role in lung injury in terms of neutrophil infiltration, cytokine responses, lung edema and histology. However, the delivery technique for the superoxide dismutase transgene-using adeno-associated virusremains controversial. The conclusion that gene therapy may be appropriate for ALI is a bit premature and need further studies.