what happens to red blood cells when it is micriwaved

Claret Transfus. 2010 Jun; eight(Suppl 3): s39–s47.

Aging and death signalling in mature cerise cells: from basic science to transfusion practice

Marianna H. Antonelou

^aneDepartment of Prison cell Biology and Biophysics, Faculty of Biological science, University of Athens, Panepistimiopolis, Athens;

Anastasios Chiliad. Kriebardis

¹Department of Cell Biology and Biophysics, Faculty of Biology, University of Athens, Panepistimiopolis, Athens;

² National Blood Eye, Acharnes, Athens, Greece

Issidora Due south. Papassideri

¹Department of Cell Biology and Biophysics, Kinesthesia of Biology, Academy of Athens, Panepistimiopolis, Athens;

Keywords: aging, senescence, death, red blood jail cell signalling, proteome, apoptosis

Introduction

The red blood cells (RBCs) aging procedure is considered as an outcome of special scientific and clinical interest. It represents a total of unidirectional, time-dependent but non-necessarily linear series of molecular events that finally lead to cell clearance¹. Under normal circumstances, all human RBCs live approximately 120±4 days in blood apportionment, implying the existence of tightly regulated molecular mechanism(southward), responsible for the programming of the lifespan and the nonrandom removal of senescent RBCsⁱⁱ ^, ⁱⁱⁱ. Although the RBCs have already been used as a model for aging study^one, the molecular participants, too every bit the signalling pathways involved, are non yet completely clarified.

RBCs storage under blood depository financial institution conditions is far from being considered analogous to the physiologic in vivo crumbling process. The putative implicated in vivo signalling pathways are expected to be more-or-less preserved under in vitro conditions, nonetheless slightly modulated, in response to a totally different environment. A storage menstruation of up to 35–42 days at 4 °C probably is not a "fraternal interlude" of the physiological maturity process and definitely does not represent an ignorable time period, compared to the RBCs lifespan. Stored RBCs age without the normal adjacency of other cells or plasma, which continuously provide them with survival factors and signals and, moreover, they are obligated to share their living space with their own and other cells' wastes. Since no clearance mechanisms seem to function, senescent RBCs are probably sentenced to "survive" for a longer catamenia than they were probably programmed for. Although there is evidence suggesting that storage disturbs the physiological RBC aging process⁴ ^– ^seven, the mechanistic basis of the aging progress inside the claret unit of measurement and the functional reactivity of the modified RBCs in vivo, remain even so elusive.

Given the fundamental need for prophylactic and efficient transfusions, the clinical affect of stored claret, as a function of the storage parameters, has attracted considerable attention. Clinical trials that focus on the potential adverse clinical consequences of transfusing older storage-age RBCs units vs. younger ones accept already been reported^viii. Autonomously from the skepticism around their blueprint and execution^ix, these studies indicate the necessity of thorough examination of the storage effect on packed RBCs, before analyzing their potential impact on the clinical consequence.

This review focuses on the current cognition on aging and death signalling pathways operating in both in vivo systems and stored RBCs and suggests time to come directions in the preservation science, helpful for addressing what seem to exist the current critical questions in transfusion medicine.

RBC aging, senescence and in vivo death signalling pathways

RBCs experience a range of continuous metabolic and physical damages as they age, such as membrane vesiculation¹⁰, haemoglobin (Hb) modifications and progressive failure of both, cellular homeostasis and antioxidant defenses. The increment in RBCs density¹¹, the nonenzymatic glycation of Hb¹² and the deamidation of protein 4.oneb to 4.1a¹³ ^, ^fourteen accept been widely used as sensitive RBC age markers. In fact, numerous post-translational protein modifications, including phosphorylation, oxidation and assemblage are functionally involved in the regulation of RBCs homeostasis and lifespan.

Despite these cumulative events, the senescent signals, namely the molecular measure of RBCs age, do not seem to gradually express in cells. On the reverse, they appear as a snap, rapid and non-linear cascade of events at the terminal phase of the crumbling process, probably before long earlier RBCs removal by the reticuloendothelial system³. Taken into consideration the inability of mature RBCs to synthesize new proteins, the recognizable markers must derive from modifications in pre-existing molecules. Their generation is near probably the ultimate pace of more than ane signalling pathways, working in a sophisticated context of molecular interplays. To the electric current noesis, the "RBC crumbling phenotype", namely the repertoire of historic period-dependent alterations, can be safely associated with a reported decline in metabolic activity, a progressive cell shape transformation, a membrane remodelling, besides equally with oxidative injury, microvesiculation and exposure of surface removal markers. The only common feature of these modifications is that they all, directly or indirectly, trigger erythrophagocytosis¹⁵.

Microvesiculation

Membrane microvesiculation is part of the RBCs maturation. It represents a well regulated process that is accelerated in older cells^ten. Depending on the circumstances, it may function against (by contributing to irreversible membrane/Hb loss) or in favour (by carrying away damaged and signalling effective jail cell components) of the growing RBCs^sixteen. The exocytosis of non-functional proteins and senescence marks through vesiculation non only protects the RBCs from premature expiry but too indicates that the same recognition signals mediate the rapid removal of old RBCs and vesicles from the circulation^xvi. Through the continuous release of vesicles, RBCs indices change every bit they age¹² and prison cell density progressively increases concomitantly to a subtract in cellular deformability and membrane flexibility. These modifications take been appreciated as major determinants of RBCs premature in vivo removal.

The Band 3-based aging pathway

So far, numerous RBCs crumbling pathways have been proposed based on cellular changes identified in older RBCs. Among them, the clustering¹⁷ and/or the breakdown of Ring 3^eighteen ^, ^nineteen is probably the cardinal pace in the major immunologically mediated pathway, leading to the generation of a powerful senescent indicate, a senescent-specific neo-antigen, in vivo. Similar processes seem to be responsible for premature RBCs clearance in haemoglobinopathies, membrane protein deficiencies, Down syndrome, Alzheimer'south illness etc¹⁷ ^, ^nineteen. Upwards, gratis radical oxidation may be an important factor underlying the formation of the senescent signal. There is show connecting the RBC oxidation levels in vivo to the breakdown of Band iii and to the autologous IgG binding²⁰, as well as the elevated membrane-bound modified Hb to the high incidence of autologous IgG binding²¹. Furthermore, formation of advanced glycation end products²², binding of oxidative denatured Hb to Band three²³ and the following modifications in tyrosine phosphorylation¹⁷, may induce the observed topographic redistribution of Ring 3. Downwardly, the senescence neoantigen appearance induces the binding of both autologous IgGs and probably C3 fraction of the complement to the membrane, triggering erythrophagocytosis¹⁸ ^, ²⁴ ^, ²⁵.

Calcium homeostasis

Distorted calcium (Caⁱⁱ⁺) homeostasis is probably part of some other crumbling-related pathway either as a triggering gene for crumbling or equally its consequence²⁶. Although the path's regulation under physiological conditions is obscured, membrane-associated Bcl-10_L and Bak, which form functional interactions with survival factors of the plasma, might mediate it². Calcium influx is clearly correlated to oxidative damage, vesiculation, aridity and deformability defects suffered by the senescent RBCs²⁷. Furthermore, in that location is an established functional connection betwixt calcium influx and apoptosis-like events in mature erythrocytes²⁷ ^– ³⁰. That calcium-involved set of pathways working in RBCs in response to stress (oxidative, osmotic etc) has been chosen eryptosis. Two underlying signalling pathways have been reported: (i) formation of prostaglandin E2 that leads to the activation of Ca^two+-permeable cation channels and (2) phospholipase A2–mediated release of platelet-activating gene that activates a sphingomyelinase, leading to formation of ceramide. Increased intracellular Ca^two+ and ceramide levels pb to PS exposure. Moreover, calcium activates Ca^two+-sensitive K⁺ channels, leading to cellular KCl loss and cell shrinkage. In addition, Ca^two+ stimulates μ-calpain transglutaminase-2 and, occasionally, caspases that degrade/crosslink the cytoskeleton proteins, resulting in loss of membrane integrity, deformability and blebbing. Finally, Ca^two+ disrupts the critical interaction betwixt phosphotyrosine phosphatase and Band iii³¹. Eryptosis may be a haemolysis escape mechanism of defective erythrocytes²⁹ ^, ^thirty only its relevance - if whatever- to RBC aging process withal has to be firmly established by future studies.

Caspase signalling and PS exposure

Erythrocytic procaspase 3 is in vitro activated under oxidative stress, leading to Band 3 modifications, PS exposure and erythrophagocytosis³² ^, ³³. Such a mechanism is very likely to have an in vivo physiological function in RBCs aging/clearance, as indicated by the active caspase -3 and -eight detection, every bit well equally by the formation of the Fas-signalling death complex in the lipid raft membrane microdomains of aged RBCs³⁴ ^, ³⁵. Aged RBCs nowadays lower aminophospholipid translocase activity and higher levels of externalized PS, in comparison with younger ones³⁵. Activation of caspase 3 during RBCs senescence, under the stimulus of increased oxidative stress, could cleave³⁴ or modulate³⁶ Ring 3, triggering a cascade which leads to RBC removal. Thus, stimulation of caspases in anile or damaged RBCs could induce their phagocytosis in order to prevent haemolysis.

Virtually RBC-derived vesicles expose PS¹⁶ and a number of haematologic diseases²⁹ ^, ³⁷ or in vitro stressful treatments of human RBCs consequence in PS exposure²⁹. Interestingly, PS externalization reflects the charge per unit at which biotinylated RBCs remove from circulation in vivo ³⁷. Still, in vivo PS exposure in healthy individuals senescent RBCs is still a matter of argue, mainly because of the scepticism confronting the techniques used to isolate onetime RBCs¹⁶ ^, ³⁸. Notably, Bratosin et al. take recently detected active caspases in a fraction of PS-exposing senescent RBCs, isolated from claret apportionment³⁹. Considering the powerful thrombogenic effect of externalized PS, it is more likely that it plays a role in the senescence and removal of normal or stressed RBCs, under sure circumstances, through the activation of different signalling pathways. All the same, this postulation should be revaluated past more sophisticated technical skills.

Other mechanisms of RBC in vivo aging

Other mechanisms that accept been proposed in gild to explicate the selective recognition of erstwhile RBCs by macrophages, include the time-dependent desialylation of membrane proteins, which leads to the exposure of "senescence factor glycopeptides" on senescent cells¹. Apart from the mechanism of RBC-bound opsonins, sialic acids and membrane constituents such equally CD47, at to the lowest degree in animal models, are suggested to play a further regulative office in the emptying of senescent RBCs, by inhibiting erythrophagocytosis⁴⁰ ^, ⁴¹. Their normal RBC membrane topology/stoichiometry functions as constructive "non-swallow-me" signals for macrophages bearing their respective receptors. However, such a role for CD47 is probably species-specific²⁸, since in that location is so far no evidence that Rhesus-null human RBCs with reduced CD47 exhibit increased charge per unit of phagocytosis⁴².

Part of the oxidative stress

The RBCs lifespan dependence on an adequate oxidative stress response, imposed by human diseases has been previously established⁴³. The structure of protein-protein interaction networks in the RBC interactome confirmed that RBCs likely suffer of exacerbated oxidative stress and continuously strive against protein and cytoskeletal damage, recruiting a number of alternative pathways related to protein repair, vesiculation or apoptosis⁴⁴ ^, ⁴⁵. Although it currently constitutes an agile topic of inquiry, accumulative information propose a key position for oxidative stress in the RBCs crumbling signalling. Apart from its impact on Band iii-derived neo-antigen germination and the activation of pro-apoptotic components, oxidative stress as well affects Hb and its interactions with membrane components²¹ ^, ²⁷ and caspase-3⁴⁶. Although the major feature of the oxidatively distorted RBC is the bounden of oxidized Hb to high affinity sites on Ring 3, the irreducible complexation of Hb with spectrin is as well a prominent and probably prior marker of in vivo RBCs crumbling process, tightly correlated with increased RBC rigidity, decreased deformability, echinocytosis and erythrophagocytosis⁴⁷ ^– ^fifty. This circuitous might well promote structural modifications in Band 3 past disturbing the cohesion of the cytoskeleton to the bilayer. Moreover, its formation may threaten the normal assembly of the spectrin tetramer and the phospholipid oxidation via a Ca²⁺-promoted quasi-lipoxigenase activity of the oxidized Hb, leading to PS exposure and signalling recognition by the CD36 macrophage receptor²⁷.

In vivo aging remarks

At the present, information technology is difficult to assign the relative contribution of each of the various speculative mechanisms to aging and removal of senescent RBCs, simply it is likely that all of them play a role in this, manifestly complex and tightly regulated, procedure^one. The new era of RBC proteomics revealed an incredible array of RBC proteins involved in intracellular signalling cascades⁵¹ ^, ⁵², while the bachelor refined models of RBC membrane organisation suggest the involvement of other molecules or mechanisms in the aging process. The newly discovered metabolon of Band 3 and glycolytic enzymes complex⁵³ ^, ⁵⁴, the macrocomplex of four.1R, which may contribute to the remodelling of RBC surface⁵⁵, the Ring iii-to-skeleton bridge of adducin with its possible role in the membrane mechanics and vesiculation⁵⁶ and the proposed structural role of glucose transporter-1 in RBCs⁵⁷ (the membrane expression of which is augmented nether RBCs storage in claret banks⁴), are some examples of well organized -past multiple signalling pathways- elements. In one case again, the "whether, how and when" of these factors into the aging process deserve to be the object of time to come endeavours.

Aging, senescence and death signalling pathways in stored RBCs

RBC storage lesion

Biochemical and biomechanical changes in RBCs function and integrity during storage, which affect in vivo survival and function, can be summarized by the term "RBC storage lesion". Easily recognizable biochemical storage effects are the reduction of adenosine triphosphate (ATP), 2,three-diphosphoglycerate (2,3-DPG), pH and glycolysis rate, the accumulation of lactic acid and the increase in Ca^two+ intracellularly. 2,three-DPG depletion leads to increased oxygen affinity just afterward transfusion the ii,3-DPG levels are restored in RBCs. ATP depletion follows the reduction in glycolysis rate, leads to further energetic compromise and is associated -directly or secondary- with a series of biophysical alterations, including cellular shape, membrane stability/deformability and vesiculation⁷. Although membrane deformability has been correlated with RBCs viability later on transfusion⁵⁸, in that location are no direct mechanical fragility measurements as a storage period role. Moreover, the contribution of ATP depletion into the storage lesion and the post-transfusion survival of RBCs accept been challenged. The main biophysical effect of storage is probably the loss of membrane and Hb through the progressively increased vesiculation (Figure one) and the subsequent changes in RBCs mechanical and rheological properties⁵⁹. On the basis of thrombogenetic⁷ and nitric oxide scavenging⁶⁰ potential of vesicles, their transfusion is thought to be continued with adverse clinical outcomes.

An external file that holds a picture, illustration, etc. Object name is BLT-08-s39-g001.jpg

Conventional electron microscopy of RBCs and vesicles released after prolonged storage (35 days) in CPD-A. (A) Membrane blebbing in a RBC that has undergone echinocytic (arrows) transformation. (B) Ultrastructural appearance of a vesicle grooming. Insert: the sediment of the vesicles (5) collected at the final step of the isolation protocol (bars, 0.5 μm).

The release of leukocyte-associated enzymes, cytokines and oxygen radicals accept been associated with the storage lesion. Comparative proteomic assay in stored samples showed predominant accumulation of several bioactive proteins in the supernatant of non-leukofiltered units⁶¹. Furthermore, the oxygen-dependent metabolic modulation is progressively altered during storage and is strongly associated with modifications in Band three poly peptide⁶². In fact, the storage results in remarkable RBC membrane remodelling and vesicular protein variability^four ^, ⁶³ ^, ⁶⁴. Comparative analysis of RBC membranes during the progress of storage revealed changes in the presence/corporeality of proteasomes, chaperones, proteases, kinases, and phosphatases at the membrane^iv ^, ⁶³. Growing show portrays a time-dependent oxidative assault to Hb, membrane and cytoskeleton components, indicating that oxidative injury is a key role of the physiology of stored RBCs^five ^, ⁶⁴ ^– ⁶⁷. Interestingly, the "onset" of the storage impact in the membrane-cytoskeleton network is detected in an earlier time-point than previously appreciated^iv ^, ⁵ ^, ⁶³ ^, ⁶⁶ ^, ⁶⁸, pointing out that any optimization attempt should be applied in the offset weeks of the storage period. Moreover, recent studies showed that aged, stored RBCs have reduced ability to produce nitric oxide, while they suggested that reduction in nitric oxide bioavailability at the endothelium -via the reactivity of the cell-complimentary Hb in stored blood- may underlie the storage lesion. The subsequently may be connected to mail-transfusion pathological outcomes, such as microvascular vasoconstriction, platelet activation and pro-oxidant and pro-inflammatory effects^sixty.

Band 3-related aging machinery and membrane vesiculation during storage

Every bit expected, some profile differences betwixt in vivo and ex vivo aging have been noticed, including the reverse change in Mean Corpuscular Volume (MCV) index^seven and the variation in size and shape of the released vesicles. All the same, stored RBCs progressively limited some of the typical marks of senescence and erythrophagocytosis^{half dozen} ^, ¹⁵. More importantly, all the hallmarks of the Band three-related crumbling machinery accept been documented in stored RBCs: early and progressively increased accumulation of oxidized/denatured Hb to the membrane and the cytoskeleton, early complication of spectrin with Hb, assemblage of Ring 3 at the membrane level and IgG deposition^four ^, ⁶³ ^, ⁶⁶, while removal of transfused RBCs was remarkably delayed after complement aphaeresis during storage⁶⁹. The storage-related vesiculation is a raft-based process that is exacerbated over time in the cold⁷ ^, ⁵⁹. Analysis of the vesicles documented the presence of candy/aggregated Ring three and denatured/oxidized Hb, IgGs and complement components^four ^, ⁵ ^, ⁶⁴, verifying the beneficial role of vesiculation in the survival of stored RBCs. Information technology should be noted that the lasting coexistence of vesicles with their cells of origin represents another "novelty" of the ex vivo storage system, the consequences of which to the RBCs are still obscure.

Eryptosis/apoptosis signalling in stored RBCs

The vesicles shed by the stored RBCs expose PS⁶ ^, ⁷ but there is all the same no clear consensus whether this likewise applies for the RBCs per se ²⁸ ^, ⁷⁰ ^– ⁷². This matter is probably analogous to the previously stated argumentation of in vivo crumbling, farther augmented in ex vivo conditions, because of the express storage duration and the smaller RBC population that contains proportionally less prone to clearance cells. Notably, the storage-dependent remodelling of the RBC membrane includes the Ca²⁺-promoted binding of sorcin and synexin⁶³. Moreover, prolonged storage has been associated with modifications in Fas-associated proteins and caspase activation in both, RBCs^v ^, ⁶³ and vesicles⁵. This element is pregnant, because that WBC-derived functional soluble Fas ligand has been detected in the RBC supernatants later prolonged storage⁷³. Furthermore, semi-quantitative proteomic analysis verified the differences in the expression of lipid rafts-associated proteins between RBC membrane and vesicles⁴ ^, ^seven, suggesting that alterations in membrane lipid organization are involved in vesicle germination and in storage-associated increment in PS exposure⁶.

The effect of RBC membrane remodelling³⁹ and Hb oxidation⁴⁶ on caspase activation has already been suggested. Until today, information technology is not clear whether caspase activation is related or not to apoptosis/eryptosis in stored RBCs. Interestingly, their stimulation coincides with the detection of membrane/cytoskeleton modifications in stored RBCs⁵. Those presumptive caspase-induced membrane modifications might interfere with the mechanical properties of the membrane⁷⁴, the extent of vesiculation⁷ and the signalling of the aging per se ⁷⁵. The apoptotic death of RBCs during storage might work equally a beneficial alternative to haemolysis, provided that apoptosis is not exacerbated by the storage. Otherwise, apoptosis of RBCs inside the storage purse volition be a direct mensurate for in vitro age/stress-related RBCs changes, with a clear event on RBCs recovery and survival, following RBCs transfusion.

CD47-related phagocytosis of stored RBCs

Regarding other signalling pathways, loss of CD47 markers has been documented in RBCs, especially in the older ones⁷¹, during the storage period^iv ^, ⁶⁴ ^, ⁷² ^, ⁷⁶. Obviously, this modification may render RBCs more susceptible to clearance when transfused, merely the to a higher place association has to be firmly established. CD47 has also been detected in the released vesicles⁴ ^, ⁶⁴, showing an ongoing interplay among their various phagocytosis-related signals.

Oxidative stress relevance to the RBC ex vivo crumbling

As storage progresses, antioxidant defence and oxidative injures on RBC membrane, cytoskeleton and cytoplasm components are getting worse^v ^, ⁶⁵ ^, ⁶⁶ ^, ⁷⁷. Oxidative mechanisms that atomic number 82 to normal in vivo crumbling (see above) are currently considered every bit the underlying correspondent to storage lesions⁶⁷ and are probably related to accelerated and/or aberrant aging of stored RBCs. There is evidence that oxidative stress plays significant function in storage-related vesiculation⁷⁸ and in protein degradation, specially of cytoskeleton proteins⁶⁸. The oxidative state of Hb and the incidence of Hb-induced membrane damage are modulated every bit a function of the storage menses, signifying the primal role of Hb oxidation not merely in the physiology of stored RBCs but too in the progression of irreversible signalling mechanisms⁵ ^, ⁶⁴ ^, ⁶⁶ ^, ⁶⁷. All these factors might contribute to trigger the formation of neoantigens in claret units. Although the direct link betwixt the oxidative stress response and the RBC senescence/removal in stored RBCs remains to be firmly established, at that place is evidence that RBCs stored under the antioxidant and membrane-stabilizing issue of mannitol showroom a different expression pattern of senescence marks⁵. In the same context, the storage-related variation in proteasome or protein repair molecules⁴ ^, ⁵, likely represents responsive mechanisms confronting the aging-related set on in major RBC membrane proteins. In the absenteeism of clearance mechanisms inside the claret bag, the terminal effect of the in a higher place functional mechanisms might be multiplied in the recipients, especially in massively transfused ones.

Concluding remarks

Under the continuous pressure of raised clinical questions concerning the safety and efficacy of stored RBCs, there is a potent demand for a more than thorough and updated investigation of the RBCs storage result. Clinical practice demands for recruitment of novel biomarkers, equally accurate in vitro predictors, non simply for RBC in vivo survival only besides for functional capability and effects. The proteomic and in silico approaches are valuable for performing a global screening of the storage- and aging- related RBC modifications, their course during the storage period and the impact of storage variations on it. The currently provided information on RBCs aging indicate that RBCs are highly dynamic blood components and provide the basis for further proteomic experiments with a direct touch on on transfusion medicine. The future research efforts in RBCs preservation scientific discipline should be enriched with emerging principles, techniques and noesis regarding the RBCs interactome, the germination of lipid rafts and other functionally important multiprotein complexes, the repair/destroy mechanisms, the response to oxidative stress, the mail-translational processing, the protein sorting into the vesicles and the membrane as a place of execution of the senescence-related apoptosis-like events. This advanced, sophisticated arroyo would benefit the understanding of the mechanisms that define life and death of RBCs in vivo, in the plastic numberless and in the circulation afterwards transfusion. Information technology also represents the safer manner to the successful optimization of RBCs preservation protocols and transfused RBCs.

We very much regret that many important studies which fabricated significant contributions to ruddy jail cell enquiry could not exist cited or discussed in this review article due to strict infinite limitations.

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