Bench-to-bedside review: Erythropoietin and its derivatives as therapies in critical care

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Pharmacological preconditioning with erythropoietin attenuates the organ injury and dysfunction induced in a rat model of hemorrhagic shock.

SUMMARY Pre-treatment with erythropoietin (EPO) has been demonstrated to exert tissue-protective effects against ‘ischemia-reperfusion’-type injuries. This protection might be mediated by mobilization of bone marrow endothelial progenitor cells (EPCs), which are thought to secrete paracrine factors. These effects could be exploited to protect against tissue injury induced in cases where hemorrhage is foreseeable, for example, prior to major surgery. Here, we investigate the effects of EPO pre-treatment on the organ injury and dysfunction induced by hemorrhagic shock (HS). Recombinant human EPO (1000 IU/kg/day i.p.) was administered to rats for 3 days. Rats were subjected to HS on day 4 (pre-treatment protocol). Mean arterial pressure was reduced to 35±5 mmHg for 90 minutes, followed by resuscitation with 20 ml/kg Ringer’s lactate for 10 minutes and 50% of the shed blood for 50 minutes. Rats were sacrificed 4 hours after the onset of resuscitation. EPC (CD34+/flk-1+ cell) mobilization was measured following the 3-day pre-treatment with EPO and was significantly increased compared with rats pre-treated with phosphate-buffered saline. EPO pre-treatment significantly attenuated organ injury and dysfunction (renal, hepatic and neuromuscular) caused by HS. In livers from rats subjected to HS, EPO enhanced the phosphorylation of Akt (activation), glycogen synthase kinase-3β (GSK-3β; inhibition) and endothelial nitric oxide synthase (eNOS; activation). In the liver, HS also caused an increase in nuclear translocation of p65 (activation of NF-κB), which was attenuated by EPO. This data suggests that repetitive dosing with EPO prior to injury might protect against the organ injury and dysfunction induced by HS, by a mechanism that might involve mobilization of CD34+/flk-1+ cells, resulting in the activation of the Akt-eNOS survival pathway and inhibition of activation of GSK-3β and NF-κB

X-ray Absorption and Reflection in Active Galactic Nuclei

X-ray spectroscopy offers an opportunity to study the complex mixture of emitting and absorbing components in the circumnuclear regions of active galactic nuclei, and to learn about the accretion process that fuels AGN and the feedback of material to their host galaxies. We describe the spectral signatures that may be studied and review the X-ray spectra and spectral variability of active galaxies, concentrating on progress from recent Chandra, XMM-Newton and Suzaku data for local type 1 AGN. We describe the evidence for absorption covering a wide range of column densities, ionization and dynamics, and discuss the growing evidence for partial-covering absorption from data at energies > 10 keV. Such absorption can also explain the observed X-ray spectral curvature and variability in AGN at lower energies and is likely an important factor in shaping the observed properties of this class of source. Consideration of self-consistent models for local AGN indicates that X-ray spectra likely comprise a combination of absorption and reflection effects from material originating within a few light days of the black hole as well as on larger scales. It is likely that AGN X-ray spectra may be strongly affected by the presence of disk-wind outflows that are expected in systems with high accretion rates, and we describe models that attempt to predict the effects of radiative transfer through such winds, and discuss the prospects for new data to test and address these ideas.Comment: Accepted for publication in the Astronomy and Astrophysics Review. 58 pages, 9 figures. V2 has fixed an error in footnote

A Nonerythropoietic Peptide that Mimics the 3D Structure of Erythropoietin Reduces Organ Injury/Dysfunction and Inflammation in Experimental Hemorrhagic Shock

Recent studies have shown that erythropoietin, critical for the differentiation and survival of erythrocytes, has cytoprotective effects in a wide variety of tissues, including the kidney and lung. However, erythropoietin has been shown to have a serious side effect—an increase in thrombovascular effects. We investigated whether pyroglutamate helix B-surface peptide (pHBSP), a nonerythropoietic tissue-protective peptide mimicking the 3D structure of erythropoietin, protects against the organ injury/ dysfunction and inflammation in rats subjected to severe hemorrhagic shock (HS). Mean arterial blood pressure was reduced to 35 ± 5 mmHg for 90 min followed by resuscitation with 20 mL/kg Ringer Lactate for 10 min and 50% of the shed blood for 50 min. Rats were euthanized 4 h after the onset of resuscitation. pHBSP was administered 30 min or 60 min into resuscitation. HS resulted in significant organ injury/dysfunction (renal, hepatic, pancreas, neuromuscular, lung) and inflammation (lung). In rats subjected to HS, pHBSP significantly attenuated (i) organ injury/dysfunction (renal, hepatic, pancreas, neuromuscular, lung) and inflammation (lung), (ii) increased the phosphorylation of Akt, glycogen synthase kinase-3β and endothelial nitric oxide synthase, (iii) attenuated the activation of nuclear factor (NF)-κB and (iv) attenuated the increase in p38 and extracellular signal-regulated kinase (ERK)1/2 phosphorylation. pHBSP protects against multiple organ injury/dysfunction and inflammation caused by severe hemorrhagic shock by a mechanism that may involve activation of Akt and endothelial nitric oxide synthase, and inhibition of glycogen synthase kinase-3β and NF-κB

Multiwavelength observations of short-timescale variability in NGC 4151 .4. Analysis of multiwavelength continuum variability

This paper combines data from the three preceding papers in order to analyze the multi-wave-band variability and spectral energy distribution of the Seyfert 1 galaxy NGC 4151 during the 1993 December monitoring campaign. The source, which was near its peak historical brightness, showed strong, correlated variability at X-ray, ultraviolet, and optical wavelengths. The strongest variations were seen in medium-energy (similar to 1.5 keV) X-rays, with a normalized variability amplitude (NVA) of 24%. Weaker (NVA = 6%) variations (uncorrelated with those at lower energies) were seen at soft gamma-ray energies of similar to 100 keV. No significant variability was seen in softer (0.1-1 keV) X-ray bands. In the ultraviolet/optical regime, the NVA decreased from 9% to 1% as the wavelength increased from 1275 to 6900 Angstrom These data do not probe extreme ultraviolet (1200 Angstrom to 0.1 keV) or hard X-ray (2-50 keV) variability. The phase differences between variations in different bands were consistent with zero lag, with upper limits of less than or similar to 0.15 day between 1275 Angstrom and the other ultraviolet bands, less than or similar to 0,3 day between 1275 Angstrom and 1.5 keV, and less than or similar to 1 day between 1275 and 5125 Angstrom These tight limits represent more than an order of magnitude improvement over those determined in previous multi-wave-band AGN monitoring campaigns. The ultraviolet fluctuation power spectra showed no evidence for periodicity, but were instead well fitted with a very steep, red power law (a less than or equal to -2.5). If photons emitted at a ''primary'' wave band are absorbed by nearby material and ''reprocessed'' to produce emission at a secondary wave band, causality arguments require that variations in the secondary band follow those in the primary band. The tight interband correlation and limits on the ultraviolet and medium-energy X-ray lags indicate that the reprocessing region is smaller than similar to 0.15 it-day in size. After correcting for strong (a factor of greater than or similar to 15) line-of-sight absorption, the medium-energy X-ray luminosity variations appear adequate to drive the ultraviolet/optical variations. However, the medium-energy X-ray NVA is 2-4 times that in the ultraviolet, and the single-epoch, absorption-corrected X-ray/gamma-ray luminosity is only about one-third of that of the ultraviolet/optical/infrared, suggesting that at most about a third of the total low-energy flux could be reprocessed high-energy emission. The strong wavelength dependence of the ultraviolet NVAs is consistent with an origin in an accretion disk, with the variable emission coming from the hotter inner regions and nonvariable emission from the cooler outer regions. These data, when combined with the results of disk fits, indicate a boundary between these regions near a radius of order R approximate to 0.07 1t-day. No interband lag would be expected, as reprocessing (and thus propagation between regions) need not occur, and the orbital timescale of similar to 1 day is consistent with the observed variability timescale. However, such a model does not immediately explain the good correlation between ultraviolet and X-ray variations