Cerebral blood flow during hypoxic hypoxia  with plasma-based hemoglobin at reduced hematocrit

Ulatowski, John A.; Bucci, Enrico; Razynska, Anna; Traystman, Richard J.; Koehler, Raymond C.

doi:10.1152/ajpheart.1998.274.6.h1933

Cited by 36 publications

(38 citation statements)

References 41 publications

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“…It is intriguing, however, to speculate regarding whether acute changes in CBF might be involved in hypoxic response and EPO generation, since it is known that acute hypoxia and anemia increase CBF (44,45). Furthermore, there remain mechanistic questions concerning how CNS-derived EPO acts in the systemic erythropoietic response.…”

Section: Figurementioning

confidence: 99%

The glial cell response is an essential component of hypoxia-induced erythropoiesis in mice

Weidemann¹,

Kerdiles²,

Knaup³

et al. 2009

J. Clin. Invest.

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A key adaptation to environmental hypoxia is an increase in erythropoiesis, driven by the hormone erythropoietin (EPO) through what is traditionally thought to be primarily a renal response. However, both neurons and astrocytes (the largest subpopulation of glial cells in the CNS) also express EPO following ischemic injury, and this response is known to ameliorate damage to the brain. To investigate the role of glial cells as a component of the systemic response to hypoxia, we created astrocyte-specific deletions of the murine genes encoding the hypoxia-inducible transcription factors HIF-1α and HIF-2α and their negative regulator von Hippel-Lindau (VHL) as well as astrocyte-specific deletion of the HIF target gene Vegf. We found that loss of the hypoxic response in astrocytes does not cause anemia in mice but is necessary for approximately 50% of the acute erythropoietic response to hypoxic stress. In accord with this, erythroid progenitor cells and reticulocytes were substantially reduced in number in mice lacking HIF function in astrocytes following hypoxic stress. Thus, we have demonstrated that the glial component of the CNS is an essential component of hypoxia-induced erythropoiesis. IntroductionThe erythropoietin (EPO) hormone is the chief regulator of red blood cell production in mammals, and its rate of synthesis is highly responsive to changes in physiologic oxygenation (1). Studies of this relationship between oxygen and red blood cell production date back to Viault's work at the end of the nineteenth century (2). Dissection of the mechanisms for induction of the Epo gene by low-oxygen conditions led to the discovery of a hypoxia responsive element (HRE) in the 3′ enhancer region of the gene; a binding site within the Epo gene was found for a family of transcription factors, which were subsequently termed hypoxia-inducible factors (HIFs) (3).HIF is a heterodimeric DNA-binding complex composed of 2 basic helix-loop-helix proteins of the PAS family: the constitutive non-oxygen-responsive subunit HIF-1β (also termed ARNT) and 1 of either hypoxia-inducible α-subunits, HIF-1α or HIF-2α (reviewed in refs. 4, 5). HIF-α subunits are rapidly degraded in normoxia but highly inducible by hypoxia. The interface between oxygen and the HIF-α subunits in normoxia is in part the hydroxylation of 2 prolyl residues in the oxygen-dependent degradation domain of the α subunits. HIF-α hydroxylation under normoxia regulates the interaction with the von Hippel-Lindau tumor suppressor protein (pVHL), which targets HIF-α for proteolysis by the ubiquitin-proteasome pathway (6).EPO synthesis is only detectable in a small number of tissues, including the kidney, liver, and the CNS (reviewed in refs. 7, 8). The kidney produces a large fraction of the circulating EPO in adult mammals (9), and it is clear that nonrenal EPO does not compensate for the loss of renal EPO production in patients with chronic

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Section: Figurementioning

confidence: 99%

The glial cell response is an essential component of hypoxia-induced erythropoiesis in mice

Weidemann¹,

Kerdiles²,

Knaup³

et al. 2009

J. Clin. Invest.

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“…The model is validated by using results from in vivo studies of oxygen transport in whole organs with administration of HBOCs. We used the data on oxygen transport with HBOC transfusion in cat brain (22,23) and hamster dorsal skinfold (7). We briefly summarize the experimental parameters and results and present our model predictions.…”

Section: Equationmentioning

confidence: 99%

Theoretical analysis of effects of blood substitute affinity and cooperativity on organ oxygen transport

Kavdia

Pittman

Popel

2002

Journal of Applied Physiology

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Kavdia, Mahendra, Roland N. Pittman, and Aleksander S. Popel. Theoretical analysis of effects of blood substitute affinity and cooperativity on organ oxygen transport. J Appl Physiol 93: 2122-2128, 2002. First published September 6, 2002 10.1152 10. /japplphysiol.00676.2002 O 2 carriers (HBOCs), which are developed as an alternative to blood transfusion, provide O 2 delivery. At present, there is no model to predict the O 2 transport for a red blood cell-HBOC mixture on a whole organ basis. On the basis of the first principles of mass balance, a model of O 2 transport for an organ was derived to calculate venous PO 2 (PvO 2 ) for a given inlet arterial PO 2 (PaO 2 ), blood flow, and oxygen consumption. The model was validated by using several in vivo animal studies on HBOC administration for a wide range of HBOC oxygen-binding parameters and predicted Pv O 2 for various Pa O 2 in the same species. The model was also used to predict the effect of HBOC affinity and cooperativity on Pv O 2 for humans. The results indicate that PvO 2 can be increased at a constant blood flow-to-oxygen consumption ratio by reducing the affinity of HBOC for normoxia and mild hypoxia; however, a high-affinity HBOC would be more efficient in maintaining higher Pv O 2 for severe hypoxia (PaO 2 Ͻ 40 Torr).hemoglobin based oxygen carrier; oxygen affinity; exchange transfusion; partial pressure of oxygen at 50% hemoglobin saturation; oxygen dissociation curve; cat; hamster

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“…Blood flow of infused cats was directly proportional to the amount of oxygen transported by the infused cell-free hemoglobins [11][12]. Thus, it appears that the efficacy of hemoglobin based carriers is little dependent on their oxygen affinity characteristics, being very good between P50's of 4 to 30 mmHg.…”

Section: Resultsmentioning

confidence: 99%

Development of Zero-Link Polymers of Hemoglobin, Which do not Extravasate and do not Induce Pressure Increases upon Infusion

Bucci¹,

Kwansa²,

Koehler³

et al. 2007

Artificial Cells, Blood Substitutes, and Biotechnology

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Intramolecular crosslink of hemoglobin tetramers solved the problem of urine elimination and short intravascular retention time of cell free hemoglobin infusion. It also produced a family of crosslinked hemoglobins with P50 between 18 and 30 mmHg. However, it did not solve the problem of MAP increases in infused animals. It was proven that extravasation of hemoglobin into interstitial fluid was responsible for MAP increases. Extravasation and the MAP increase was avoided using a hemoglobin polymer with average size near 25 MDa. In spite of a very high oxygen affinity, this polymer delivered oxygen to tissues, producing either vasodilation or vasoconstriction according to oxygen needs. It was also proven that cell free hemoglobins are more efficient than red cells in delivering oxygen to tissues.

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Cerebral blood flow during hypoxic hypoxia with plasma-based hemoglobin at reduced hematocrit

Cited by 36 publications

References 41 publications

The glial cell response is an essential component of hypoxia-induced erythropoiesis in mice

The glial cell response is an essential component of hypoxia-induced erythropoiesis in mice

Theoretical analysis of effects of blood substitute affinity and cooperativity on organ oxygen transport

Development of Zero-Link Polymers of Hemoglobin, Which do not Extravasate and do not Induce Pressure Increases upon Infusion

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