Continuous Infusion of Pyridoxalated Hemoglobin Polyoxyethylene Conjugate in Hyperdynamic Septic Sheep

Bone, Hans G.; Fischer, Stefanie R.; Schenarts, Paul J.; McGuire, Roy; Traber, Lillian D.; Traber, Daniel L.

doi:10.1097/00024382-199807000-00012

Cited by 29 publications

(20 citation statements)

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“…Of these articles, 52 (38.0%) showed a decreased RVR [25, 28, 30, 31, 32, 33, 34, 36, 45, 46, 47, 51, 52, 53, 58, 62, 63, 68, 69, 70, 71, 72, 73, 74, 75, 78, 84, 85, 87, 92, 95, 98, 99, 100, 101, 109, 111, 112, 114, 115, 120, 122, 124, 125, 126, 130, 131, 135, 143, 144, 154, 155], 16 (11.7%) an unchanged RVR [23, 29, 35, 37, 60, 64, 80, 97, 106, 108, 110, 113, 116, 119, 140, 145,] and 69 (50.3%) an increased RVR [20, 21, 22, 24, 26, 27, 38, 39, 40, 41, 42, 43, 44, 48, 49, 50, 54, 55, 56, 57, 59, 61, 65, …”

Section: Resultsmentioning

confidence: 99%

“…We found 56 experiments performed in small animals [20, 24, 26, 27, 39, 42, 43, 44, 55, 57, 58, 59, 62, 63, 64, 67, 68, 72, 77, 79, 81, 82, 87, 88, 89, 90, 93, 94, 96, 97, 99, 100, 103, 104, 105, 110, 116, 120, 121, 122, 129, 132, 133, 134, 137, 138, 139, 141, 142, 143, 147, 148, 149, 150, 151] and 81 performed in large animals [21, 22, 23, 25, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 40, 41, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 56, 60, 61, 65, 66, 69, 70, 71, 73, 74, ...…”

Section: Resultsmentioning

confidence: 99%

“…Of 59 studies using other methods [20, 29, 30, 33, 34, 36, 37, 38, 39, 40, 43, 44, 46, 47, 48, 55, 57, 59, 61, 64, 67, 68, 70, 76, 77, 79, 82, 84, 87, 88, 93, 94, 96, 97, 98, 101, 103, 104, 105, 107, 116, 120, 122, 123, 125, 129, 130, 132, 133, 134, 136, 137, 138, 139, 147, 148, 149, 150, 151], 16 (27.1%) reported a decreased RVR, 5 (8.5%) an unchanged RVR, and 38 (64.4%) an increased RVR (fig. 3; p =0.017).…”

Section: Resultsmentioning

confidence: 99%

“…Of 29 studies conducted in conscious animals [20, 29, 30, 31, 32, 33, 34, 35, 36, 44, 46, 47, 48, 51, 53, 54, 55, 61, 79, 87, 92, 96, 97, 98, 101, 106, 124, 144, 149], 16 (55.2%) reported a decreased RVR, 4 (13.8%) an unchanged RVR, and 9 (31%) an increased RVR (fig. 4; p = 0.057).…”

Section: Resultsmentioning

confidence: 99%

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Renal Vascular Resistance in Sepsis

et al. 2006

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Aims: To assess changes in renal vascular resistance (RVR) in human and experimental sepsis and to identify determinants of RVR. Methods: We performed a systematic interrogation of two electronic reference libraries using specific search terms. Subjects were animals and patients involved in experimental and human studies of sepsis and septic acute renal failure, in which the RVR was assessed. We obtained all human and experimental articles reporting RVR during sepsis. We assessed the role of various factors that might influence the RVR during sepsis using statistical methods. Results: We found no human studies, in which the renal blood flow (and, therefore, the RVR) was measured with suitably accurate direct methods. Of the 137 animal studies identified, 52 reported a decreased RVR, 16 studies reported no change in RVR, and 69 studies reported an increased RVR. Consciousness of animals, duration of measurement, method of induction of sepsis, and fluid administration had no effect on the RVR. On the other hand, on univariate analysis, size of the animals (p<0.001), technique of measurement (p = 0.017), recovery after surgery (p = 0.004), and cardiac output (p <0.001) influenced the RVR. Multivariate analysis, however, showed that only cardiac output (p = 0.028) and size of the animals (p = 0.031) remained independent determinants of the RVR. Conclusions: Changes in RVR during sepsis in humans are unknown. In experimental sepsis, several factors not directly related to sepsis per se appear to influence the RVR. A high cardiac output and the use of large animals predict a decreased RVR, while a decreased cardiac output and the use of small animals predict an increased RVR.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Renal Vascular Resistance in Sepsis

et al. 2006

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“…Increased NO production principally through the increased expression of inducible NO synthase is thought to mediate many of the adverse hemodynamic consequences in severe sepsis (2). Some investigators have sought to exploit the NO-scavenging ability of hemoglobin in the development of acellular hemoglobin-based therapeutics for sepsis (4). However, clinical trials with a relatively nonselective NO synthase inhibitor suggest that nonspecific NO scavenging in septic shock may have deleterious effects (27).…”

Section: Discussionmentioning

confidence: 99%

Redox active hemoglobin enhances lipopolysaccharide-induced injury to cultured bovine endothelial cells

D’Agnillo¹

2004

American Journal of Physiology-Heart and Circulatory Physiology

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D'Agnillo, Felice. Redox active hemoglobin enhances lipopolysaccharide-induced injury to cultured bovine endothelial cells. Am J Physiol Heart Circ Physiol 287: H1875-H1882, 2004. First published June 17, 2004 10.1152/ajpheart.00164.2004.-The interaction of cell-free hemoglobin with lipopolysaccharide (LPS) is thought to aggravate the pathophysiology of sepsis and/or septic shock. This study examines the possible modulatory role of cell-free hemoglobin on LPS-induced apoptosis of cultured bovine aortic endothelial cells. Experiments were performed with or without fetal bovine serum, a source of LPS-binding protein and soluble CD14. In the absence of serum, LPS alone or coincubated with purified bovine hemoglobin (BvHb), human hemoglobin (Hb), or ␣-cross-linked Hb (␣␣Hb) did not induce apoptosis. In the presence of serum, LPS induced significant apoptosis. LPS combined with BvHb, Hb, or ␣␣Hb produced the same extent of apoptosis as LPS alone. To examine whether the H 2O2-driven redox activity of hemoglobin alters LPS-induced apoptosis, glucose oxidase was added to the system to generate a subtoxic flux of H2O2. The combined treatment of LPS, glucose oxidase, and BvHb, Hb, or ␣␣Hb enhanced apoptosis compared with LPS alone. These findings support a possible mechanism whereby the redox cycling of hemoglobin, and not its direct interaction with LPS, contributes to the hemoglobin-mediated enhancement of LPS-related pathophysiology.apoptosis; ferryl hemoglobin; hydrogen peroxide; glucose oxidase CELL-FREE HEMOGLOBIN resulting from intravascular hemolysis or the administration of hemoglobin-based oxygen therapeutics is thought to exacerbate the pathophysiology of sepsis or endotoxemia. Previous studies implicate the interaction of hemoglobin with lipopolysaccharide (LPS), a cell wall component of gram-negative bacteria and the primary mediator of gram-negative sepsis (3, 26, 39 -41). Understanding how hemoglobin enhances the effects of LPS may be critical in the management of sepsis and/or septic shock given the likely occurrence of hemoglobin-LPS interactions during trauma, infection, injury, or surgery.Several studies have demonstrated that hemoglobin enhances the toxicity or lethality of LPS. Rabbits infused with hemoglobin containing LPS exhibited increased mortality compared with rabbits infused with hemoglobin or LPS (41). Intraperitoneal injection of LPS combined with an intravascular infusion of unmodified or cross-linked hemoglobins induced greater mortality in mice compared with the hemoglobins or LPS alone (39,40). Intravenous administration of ␣-cross-linked human hemoglobin (␣␣Hb) and LPS caused significantly greater mortality and cardiovascular dysfunction than ␣␣Hb or LPS alone in a rabbit model of nonlethal endotoxemia (26). Coinjection of purified hemoglobin and LPS enhanced the LPS-induced ocular inflammatory response in rabbits (30). Increased LPS sensitivity in hypophysectomized rats was linked to an increase in circulating plasma hemoglobin levels (3). Another recent study (20) reported increased ...

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Nitrogen Monoxide (Nitric Oxide): Bioinorganic Chemistry

Fricker¹

2019

Encyclopedia of Inorganic and Bioinorganic Chemistry

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The discovery of nitrogen monoxide (nitric oxide, NO) as the vasodilator molecule endothelium‐derived relaxing factor revealed a major physiological role for this simple diatomic molecule. We now know that NO regulates cardiovascular function, is a neurotransmitter, and is a component of the innate immune response to infection and cancer. The physiological effects of NO are mediated by its varied chemistry which includes redox chemistry and interaction with transition metals. NO can interact with iron‐heme‐containing proteins including hemoglobin and cytochrome c oxidase, and nonheme iron proteins such as aconitase and bacterial transcription regulatory proteins. NO reacts with superoxide to form the highly reactive peroxynitrite which decomposes to give the hydroxyl radical. Nitrosothiols, thiol adducts of NO, act to control NO release, and to shuttle NO between proteins and transport NO across cell membranes. NO is produced by one of three nitric oxide synthase (NOS) enzymes, endothelial NOS, neuronal NOS, and inducible NOS. Signaling functions are mediated via interaction with the heme‐containing protein soluble guanylate cyclase (GC), which produces the cell signaling molecule cyclic guanosine monophosphate (cGMP). This, in turn, is hydrolyzed by phosphodiesterase 5 (PDE5), which turns off NO signaling. Perturbation in NO function contributes to the pathophysiology of many disease states. Endothelial dysfunction and subsequent reduced NO production contribute to hypertension and atherosclerosis. Excess NO is a mediator of inflammatory disease, and neurodegenerative disease, due in part to the production of peroxynitrite. The cardiovascular collapse observed in septic shock is caused by the vasodilator action of NO. Targeting the NO pathway theoretically provides many opportunities for therapeutic intervention. The NO donor drugs glyceryl trinitrate, isosorbide mononitrate, isosorbide dinitrate, and amyl nitrate are used to treat acute angina; and inhaled NO is used to treat persistent pulmonary hypertension in new born infants. Conversely, NOS inhibitors and NO scavengers have been explored to counteract NO as a mediator of disease. Though promising results have been obtained in animal models of disease these latter approaches have had little clinical success. However, targeting downstream of NO has been more successful with new clinically approved classes of drugs such as the inhibitors of PDE5 sildenafil, tadalafil, and vardenafil; and the stimulator of the NO receptor soluble GC, riociguat. It has become apparent that the biological actions, and biological chemistry, of NO are very complex. New opportunities for drug discovery could result from an improved understanding of the biology of NO.

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Continuous Infusion of Pyridoxalated Hemoglobin Polyoxyethylene Conjugate in Hyperdynamic Septic Sheep

Cited by 29 publications

References 0 publications

Renal Vascular Resistance in Sepsis

Renal Vascular Resistance in Sepsis

Redox active hemoglobin enhances lipopolysaccharide-induced injury to cultured bovine endothelial cells

Nitrogen Monoxide (Nitric Oxide): Bioinorganic Chemistry

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