scholarly journals Beyond just hemoglobin: Red blood cell potentiation of hemoglobin-oxygen unloading in fish

2017 ◽  
Vol 123 (4) ◽  
pp. 935-941 ◽  
Author(s):  
Colin J. Brauner ◽  
Till S. Harter
Keyword(s):  
Blood Cell ◽  
Red Blood Cell ◽  
Ph Regulation ◽  
In Vivo Studies ◽  
Heterogeneous Distribution ◽  
Disease States ◽  
Future Work ◽  
Improve Treatment Efficacy

Teleosts comprise 95% of fish species, almost one-half of all vertebrate species, and represent one of the most successful adaptive radiation events among vertebrates. This is thought to be in part because of their unique oxygen (O2) transport system. In salmonids, recent in vitro and in vivo studies indicate that hemoglobin-oxygen (Hb-O2) unloading to tissues may be doubled or even tripled under some conditions without changes in perfusion. This is accomplished through the short circuiting of red blood cell (RBC) pH regulation, resulting in a large arterial-venous pH difference within the RBC and induced reduction in Hb-O2 affinity. This system has three prerequisites: 1) highly pH-sensitive hemoglobin, 2) rapid RBC pH regulation, and 3) a heterogeneous distribution of plasma-accessible CA in the cardiovascular system (presence in the tissues and absence at the gills). Although data are limited, these attributes may be general characteristics of teleosts. Although this system is not likely operational to the same degree in other vertebrates, some of these prerequisites do exist, and the generation and elimination of pH disequilibrium states at the RBC will likely enhance Hb-O2 unloading to some degree. In human disease states, there are conditions that may partly satisfy those for enhanced Hb-O2 unloading, tentatively an avenue for future work that may improve treatment efficacy.

scholarly journals Anti-tumor effects of RTX-240: an engineered red blood cell expressing 4-1BB ligand and interleukin-15

2021 ◽  
Author(s):  
Shannon L. McArdel ◽  
Anne-Sophie Dugast ◽  
Maegan E. Hoover ◽  
Arjun Bollampalli ◽  
Enping Hong ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Blood Cell ◽  
Nk Cells ◽  
Red Blood Cell ◽  
Safety Profile ◽  
Nk Cell ◽  
Cell Activity ◽  
In Vivo Studies

AbstractRecombinant agonists that activate co-stimulatory and cytokine receptors have shown limited clinical anticancer utility, potentially due to narrow therapeutic windows, the need for coordinated activation of co-stimulatory and cytokine pathways and the failure of agonistic antibodies to recapitulate signaling by endogenous ligands. RTX-240 is a genetically engineered red blood cell expressing 4-1BBL and IL-15/IL-15Rα fusion (IL-15TP). RTX-240 is designed to potently and simultaneously stimulate the 4-1BB and IL-15 pathways, thereby activating and expanding T cells and NK cells, while potentially offering an improved safety profile through restricted biodistribution. We assessed the ability of RTX-240 to expand and activate T cells and NK cells and evaluated the in vivo efficacy, pharmacodynamics and tolerability using murine models. Treatment of PBMCs with RTX-240 induced T cell and NK cell activation and proliferation. In vivo studies using mRBC-240, a mouse surrogate for RTX-240, revealed biodistribution predominantly to the red pulp of the spleen, leading to CD8 + T cell and NK cell expansion. mRBC-240 was efficacious in a B16-F10 melanoma model and led to increased NK cell infiltration into the lungs. mRBC-240 significantly inhibited CT26 tumor growth, in association with an increase in tumor-infiltrating proliferating and cytotoxic CD8 + T cells. mRBC-240 was tolerated and showed no evidence of hepatic injury at the highest feasible dose, compared with a 4-1BB agonistic antibody. RTX-240 promotes T cell and NK cell activity in preclinical models and shows efficacy and an improved safety profile. Based on these data, RTX-240 is now being evaluated in a clinical trial.

scholarly journals Absence of the Adaptor Protein PEA-15 Is Associated with Altered Pattern of Th Cytokines Production by Activated CD4+ T Lymphocytes In Vitro, and Defective Red Blood Cell Alloimmune Response In Vivo

PLoS ONE ◽  
2015 ◽  
Vol 10 (8) ◽  
pp. e0136885 ◽  
Author(s):  
Stéphane Kerbrat ◽  
Benoit Vingert ◽  
Marie-Pierre Junier ◽  
Flavia Castellano ◽  
François Renault-Mihara ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Blood Cell ◽  
Red Blood Cell ◽  
Adaptor Protein

Abstract 372: The Endothelial Glycocalyx Promotes Homogenous Blood Flow Distribution within the Microvasculature

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
P Mason McClatchey
Keyword(s):  
Fluid Dynamics ◽  
Blood Flow ◽  
Blood Viscosity ◽  
Tissue Perfusion ◽  
Microvascular Perfusion ◽  
Endothelial Glycocalyx ◽  
Heterogeneous Distribution ◽  
Disease States

Introduction: Impaired tissue oxygenation is observed in many disease states including congestive heart failure, diabetes, cancer and aging. Decreased tissue perfusion and heterogeneous distribution of blood flow in the microvasculature contributes to this pathology. The physiological mechanisms regulating homogeneity/heterogeneity of microvascular perfusion are presently unknown. We hypothesized that microfluidic properties of the glycocalyx would promote perfusion homogeneity. Methods: To test our hypothesis, we used established empirical formulations for modelling blood viscosity in vivo (blood vessels) and in vitro (glass tubes). We first assess distribution of blood flow in idealized arteriolar networks. We next simulated distribution of blood flow at an idealized capillary bifurcation. Finally, we simulated velocity profiles and pressure gradients within the vessel lumen with varying glycocalyx properties using a computational fluid dynamics approach. Results: We found that transit time heterogeneity (as assessed by STD to mean ratio) was increased approximately 9x (6.9x-10.6x) using in vitro formulations of blood viscosity relative to in vivo formulations. This effect was mathematically accounted for by increased effective blood viscosity in smaller arterioles. We also found that distribution of blood flow at an idealized microvascular bifurcation was more symmetric using the in vivo formulation than the in vitro formulation (approximately 2x greater disparity between flow in downstream vessels). This effect was mathematically accounted for by an increased hematocrit dependence of blood viscosity. Both the diameter- and hematocrit-based changes in blood viscosity were entirely predictable from fluid dynamics simulations incorporating a space-filling, semi-permeable glycocalyx layer. Summary: Our simulations indicate that the mechanical properties of the endothelial glycocalyx promote homogeneous microvascular perfusion. Conclusions: The literature provides evidence of both glycocalyx degradation and impaired tissue perfusion in the same disease states. Preservation or restoration of normal glycocalyx properties may be a viable strategy for improving tissue perfusion in a wide variety of diseases.

ASPIRIN MODIFIES RED BLOOD CELL BEHAVIOUR (RBC) IN THE PLATELET-RBC INTERACTION

1987 ◽  
Author(s):  
M T Santos ◽  
J Aznar ◽  
J Valles ◽  
J L Perez-Reguejo
Keyword(s):  
Single Dose ◽  
Blood Cell ◽  
Platelet Activation ◽  
Red Blood Cell ◽  
Normal Subjects ◽  
Antithrombotic Agent ◽  
Cell Behaviour ◽  
Insight Into

RBC stimulate the initial stages of platelet activation by collagen as evaluated by the BASIC wave (Perez-Requejo et al. Thromb Haemostas 54:799 1985). In order to get some insight into the mechanisms of platelet-RBC interactions, a BASIC wave was induced by lug/ml of collagen after mixing "in vitro" platelets and RBC obtained both before and two hours after a single dose of 500 mg of ASA from normal subjects. The TXB2 formed was also evaluated. The results show (Table) that non aspirinized RBC (non-ASA-RBC) increase the BASIC wave intensity of aspirinized platelets (ASA-PRP) by a cyclooxygenase-independent pathway since no increase in TXB2 was observed (Exp 1), while both non-ASA-RBC (Exp 2) and ASA-RBC (Exp 3) activate non-ASA platelets with theparticipation of the cyclooxygenase system, since an increase in TXA2 was found.A comparison of the effect of non-ASA-RBC (Exp 1) and ASA-RBC (Exp 4) on aspirinized platelets shows that ASA modifies the RBC behaviour associated with estimulation of platelets by a cyclooxygenase-independent pathway. This effect of ASA on RBC is nottransient and lasts at least 48 hours after ASA ingestion. In addition, when asmall proportion of nonASA platelets (10%) is mixed with aspirinized platelets(90%) and ASA-RBC - a situation that can be encountered "in vivo" inthe hours following ASA ingestion - the intensity of the BASIC wave is 89% of that obtained when all the platelets are non aspirinized. This RBC effect on the mixtureof ASA and nonASA platelets, may help explain the sometimes contradictory effect of ASA as an antithrombotic agent.

The Presence of Novel Amino Acids in the Cytoplasmic Domain of Stem Cell Factor Results in Hematopoietic Defects inSteel17H Mice

Blood ◽  
1999 ◽  
Vol 94 (6) ◽  
pp. 1915-1925 ◽  
Author(s):  
Reuben Kapur ◽  
Ryan Cooper ◽  
Xingli Xiao ◽  
Mitchell J. Weiss ◽  
Peter Donovan ◽  
...  
Keyword(s):  
Amino Acids ◽  
Bone Marrow ◽  
Biological Activity ◽  
Stem Cell ◽  
Blood Cell ◽  
Red Blood Cell ◽  
Stem Cell Factor ◽  
Cytoplasmic Domain

Abstract Stem cell factor (SCF) is expressed as an integral membrane growth factor that may be differentially processed to produce predominantly soluble (S) (SCF248) or membrane-associated (MA) (SCF220) protein. A critical role for membrane presentation of SCF in the hematopoietic microenvironment (HM) has been suggested from the phenotype of the Steel-dickie(Sld) mice, which lack MA SCF, and by studies performed in our laboratory (and by others) using long-term bone marrow cultures and transgenic mice expressing different SCF isoforms.Steel17H (Sl17H) is an SCF mutant that demonstrates melanocyte defects and sterility in males but not in females. The Sl17H allele contains a intronic mutation resulting in the substitution of 36 amino acids (aa’s) in the SCF cytoplasmic domain with 28 novel aa’s. This mutation, which affects virtually the entire cytoplasmic domain of SCF, could be expected to alter membrane SCF presentation. To investigate this possibility, we examined the biochemical and biologic properties of the Sl17H-encoded protein and its impact in vivo and in vitro on hematopoiesis and on c-Kit signaling. We demonstrate that compound heterozygous Sl/Sl17H mice manifest multiple hematopoietic abnormalities in vivo, including red blood cell deficiency, bone marrow hypoplasia, and defective thymopoiesis. In vitro, both S and MA Sl17H isoforms of SCF exhibit reduced cell surface expression on stromal cells and diminished biological activity in comparison to wild-type (wt) SCF isoforms. These alterations in presentation and biological activity are associated with a significant reduction in the proliferation of an SCF-responsive erythroid progenitor cell line and in the activation of phosphatidylinositol 3-Kinase/Akt and mitogen-activated protein-Kinase signaling pathways. In vivo, transgene expression of the membrane-restricted (MR) (SCFX9/D3) SCF in Sl/Sl17H mutants results in a significant improvement in peripheral red blood cell counts in comparison toSl/Sl17H mice.

Pathophysiology of Thrombocytopenia and Anemia in Mice Lacking Transcription Factor NF-E2

Blood ◽  
1999 ◽  
Vol 94 (9) ◽  
pp. 3037-3047 ◽  
Author(s):  
Jack Levin ◽  
Jin-Peng Peng ◽  
Georgiann R. Baker ◽  
Jean-Luc Villeval ◽  
Patrick Lecine ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Blood Cell ◽  
Red Blood Cell ◽  
Fetal Life ◽  
Wild Type ◽  
Cell Lineages ◽  
Cell Fragments ◽  
Proliferation Potential

Abstract Expression of the p45 subunit of transcription factor NF-E2 is restricted to selected blood cell lineages, including megakaryocytes and developing erythrocytes. Mice lacking p45 NF-E2 show profound thrombocytopenia, resulting from a late arrest in megakaryocyte differentiation, and a number of red blood cell defects, including anisocytosis and hypochromia. Here we report results of studies aimed to explore the pathophysiology of these abnormalities. Mice lacking NF-E2 produce very few platelet-like particles that display highly disorganized ultrastructure and respond poorly to platelet agonists, features consistent with the usually lethal hemorrhage in these animals. Thrombocytopenia was evident during fetal life and was not corrected by splenectomy in adults. Surprisingly, fetal NF-E2–deficient megakaryocyte progenitors showed reduced proliferation potential in vitro. Thus, NF-E2 is required for regulated megakaryocyte growth as well as for differentiation into platelets. All the erythroid abnormalities were reproduced in lethally irradiated wild-type recipients of hematopoietic cells derived from NF-E2-null fetuses. Whole blood from mice lacking p45 NF-E2 showed numerous small red blood cell fragments; however, survival of intact erythrocytes in vivo was indistinguishable from control mice. Considered together, these observations indicate a requirement for NF-E2 in generating normal erythrocytes. Despite impressive splenomegaly at baseline, mice lacking p45 NF-E2 survived splenectomy, which resulted in increased reticulocyte numbers. This reveals considerable erythroid reserve within extra-splenic sites of hematopoiesis and suggests a role for the spleen in clearing abnormal erythrocytes. Our findings address distinct aspects of the requirements for NF-E2 in blood cell homeostasis and establish its roles in proper differentiation of megakaryocytes and erythrocytes.

Abnormal Erythropoiesis in Microgravity.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3701-3701 ◽  
Author(s):  
Kun Xu ◽  
Keith V. Holubec ◽  
John E. Love ◽  
Thomas J. Goodwin ◽  
Arthur J. Sytkowski
Keyword(s):  
Blood Cell ◽  
Cell Line ◽  
Red Blood Cell ◽  
Bone Marrow Cells ◽  
Cell Mass ◽  
Erythroid Cell ◽  
Specific Marker ◽  
Murine Erythroleukemia

Abstract Humans and experimental animals subjected to microgravity, such as experienced during space flight, exhibit alterations in erythropoiesis, including changes in red blood cell morphology, survival and a reduction in red blood cell mass. Some of these alterations have been attributed to a disruption of normal in vivo erythropoietin physiology. However, human bone marrow cells grown on orbit showed a profound reduction in the number of erythroid cells, suggesting a cellular component. We now report the results of a study carried out on orbit on the International Space Station (ISS UF-1) in which an erythroid cell line was induced to differentiate. Rauscher murine erythroleukemia cells, a continuous cell line that can undergo erythropoietin (Epo)- or chemical-induced differentiation similar to normal erythropoiesis, were cultured for 6 days either in microgravity on board the ISS or on earth and then for 3 days in the absence or presence of 50 U Epo/ml or 0.7% dimethyl sulfoxide (DMSO). The cells were fixed, stored on orbit and returned to earth for study. Compared to ground-based controls, cells cultured in microgravity exhibited a greater degree of differentiation (hemoglobinization) (p<0.01). However, TER-119 antigen, a specific marker of the late stages of murine erythroid differentiation, was not detected on the surface of cells grown in microgravity. A significantly higher percentage (p<0.05) of cell clusters formed on orbit, whereas actin content appeared reduced. Furthermore, there was a more profound loss of actin stress fibers in microgravity following Epo or DMSO treatment. These results demonstrate abnormal erythropoiesis in vitro in microgravity and are consistent with the hypothesis that erythropoiesis is affected by gravitational forces at the cellular level.(Supported by NASA Grants NAG9-1368 and NAG2-1592 to AJS)

scholarly journals Retrovirus-induced feline pure red blood cell aplasia: pathogenesis and response to suramin

Blood ◽  
1991 ◽  
Vol 77 (7) ◽  
pp. 1442-1451
Author(s):  
JL Abkowitz
Keyword(s):  
Blood Cell ◽  
Red Blood Cell ◽  
Mononuclear Cells ◽  
Leukemia Virus ◽  
Transcriptase Inhibitor ◽  
Feline Leukemia Virus ◽  
Erythroid Progenitors ◽  
Marrow Cultures

Feline leukemia virus, subgroup C/Sarma (FeLV-C/Sarma) induces pure red blood cell aplasia in cats. Although erythroid (BFU-E and CFU-E) and granulocyte/macrophage (CFU-GM) progenitors are infected with this virus, only erythropoiesis is impaired. Two to 3 weeks before the onset of anemia, CFU-E become undetectable in marrow cultures while earlier erythroid progenitors (BFU-E) persist, suggesting that FeLV-C/Sarma (presumably via its envelope glycoprotein gp70) inhibits the differentiation of BFU-E to CFU-E in vivo. To correlate in vitro observations with the progression of disease, prospective studies were performed in six cats. These studies showed that at the time that the frequencies of CFU-E decreased in marrow cultures, BFU-E no longer responded to hematopoietic growth factor(s), although the responses of CFU-GM were unchanged. In further studies, anemic cats received suramin, a reverse-transcriptase inhibitor with other diverse effects. Within 4 to 14 days, erythropoiesis improved and up to 1,616 CFU-E were detected per 10(5) marrow mononuclear cells. However, progenitor cells remained infected, suggesting that suramin modulated erythroid differentiation without inhibiting progenitor infection. These observations led to the hypothesis that the gp70 of FeLV-C/Sarma impairs BFU-E differentiation by interference with ligand/receptor interactions or signal transduction pathways unique to erythroid cells. Understanding this mechanism should provide insights into the interactions controlling early erythropoiesis.

Sign in / Sign up

Export Citation Format

Share Document