Suicidal erythrocyte death in sepsis

Kempe, Daniela S.; Akel, Ahmad; Lang, Philipp A.; Hermle, Tobias; Biswas, Raja; Muresanu, Juliana; Friedrich, Björn; Dreischer, Peter; Wolz, Christiane; Schumacher, Ulrike; Peschel, Andreas; Götz, Friedrich; Döring, Gerd; Wieder, Thomas; Gulbins, Erich; Läng, Florian

doi:10.1007/s00109-006-0123-8

Cited by 290 publications

(260 citation statements)

References 35 publications

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“…A wide variety of clinical disorders is known to stimulate eryptosis, including iron deficiency [36], phosphate depletion [6], hemolytic uremic syndrome [43], sepsis [35], malaria [10,37,38], or Wilson's disease [46]. Some of these diseases may cause eryptosis by stimulating the formation of hemin.…”

Section: Discussionmentioning

confidence: 99%

Hemin-induced suicidal erythrocyte death

2009

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Several diseases, such as malaria, sickle cell disease, and ischemia/reperfusion may cause excessive formation of hemin, which may in turn trigger hemolysis. A variety of drugs and diseases leading to hemolysis triggers suicidal erythrocyte death or eryptosis, i.e., cell membrane scrambling and cell shrinkage. Eryptosis is elicited by increased cytosolic Ca 2+ activity and by ceramide. The present study explored whether hemin stimulates eryptosis. Cell membrane scrambling was estimated from annexin Vbinding to phosphatidylserine exposed at the cell surface, cell shrinkage from forward scatter in fluorescence-activated cell sorter analysis, cytosolic Ca 2+ activity from Fluo3 fluorescence and ceramide formation from fluorescencelabeled antibody binding. Exposure to hemin (1-10 μM) within 48 h significantly increased annexin V-binding, decreased forward scatter, increased cytosolic Ca 2+ activity, and stimulated ceramide formation. In conclusion, hemin stimulates suicidal cell death, which may in turn contribute to the clearance of circulating erythrocytes and thus to anemia.

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Section: Discussionmentioning

confidence: 99%

Hemin-induced suicidal erythrocyte death

2009

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“…Gram-negative sepsis is usually not associated with massive intravascular hemolysis. Sepsis is, however, in general followed by a reduced amount of red blood cells, partly as a result of hemolysis and partly because of eryptosis (''apoptosis'' in erythrocytes) (51). It is known that pore-forming toxins activate human platelets (52), and that platelet ADP receptors contribute to the initiation of intravascular coagulation (29).…”

Section: Hlya-induced Hemolysis Is Prevented By Pannexin1mentioning

confidence: 99%

α-Hemolysin from Escherichia coli uses endogenous amplification through P2X receptor activation to induce hemolysis

Skals

Jørgensen

Leipziger

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

115

165

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Escherichia coli is the dominant facultative bacterium in the normal intestinal flora. E. coli is, however, also responsible for the majority of serious extraintestinal infections. There are distinct serotypical differences between facultative and invasive E. coli strains. Invasive strains frequently produce virulence factors such as ␣-hemolysin (HlyA), which causes hemolysis by forming pores in the erythrocyte membrane. The present study reveals that this pore formation triggers purinergic receptor activation to mediate the full hemolytic action. Non-selective ATP-receptor (P2) antagonists (PPADS, suramin) and ATP scavengers (apyrase, hexokinase) concentration dependently inhibited HlyA-induced lysis of equine, murine, and human erythrocytes. The pattern of responsiveness to more selective P2-antagonists implies that both P2X 1 and P2X7 receptors are involved in HlyA-induced hemolysis in all three species. In addition, our results also propose a role for the pore protein pannexin1 in HlyA-induced hemolysis, as non-selective inhibitors of this channel significantly reduced hemolysis in the three species. In conclusion, activation of P2X receptors and possibly also pannexins augment hemolysis induced by the bacterial toxin, HlyA. These findings potentially have clinical perspectives as P2 antagonists may ameliorate symptoms during sepsis with hemolytic bacteria.alpha-hemolysin ͉ E. coli ͉ erythrocytes ͉ hemolysis ͉ P2X

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“…7,8 PS exposure, as a result of membrane scrambling, can be induced on RBC in multiple ways such as oxidative damage, (inherited) intracorpuscular defects, infection, intravascular drugs or toxic compounds, and mechanical stress. 4,[9][10][11] Ultimately, this initiates recognition and subsequent removal, via phagocytosis, by phagocytes in the spleen and liver.…”

Section: Introductionmentioning

confidence: 99%

A role for activated endothelial cells in red blood cell clearance: implications for vasopathology

Fens¹,

Wijk²,

Andringa³

et al. 2011

Haematologica

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The online version of this article has a Supplementary Appendix. BackgroundPhosphatidylserine exposure by red blood cells is acknowledged as a signal that initiates phagocytic removal of the cells from the circulation. Several disorders and conditions are known to induce phosphatidylserine exposure. Removal of phosphatidylserine-exposing red blood cells generally occurs by macrophages in the spleen and liver. Previously, however, we have shown that endothelial cells are also capable of erythrophagocytosis. Key players in the erythrophagocytosis by endothelial cells appeared to be lactadherin and αv-integrin. Phagocytosis via the phosphatidylserine-lactadherin-αv-integrin pathway is the acknowledged route for removal of apoptotic innate cells by phagocytes. Design and MethodsEndothelial cell phagocytosis of red blood cells was further explored using a more (patho)physiological approach. Red blood cells were exposed to oxidative stress, induced by tert-butyl hydroperoxide. After opsonization with lactadherin, red blood cells were incubated with endothelial cells to study erythrophagocytosis and examine cytotoxicity. ResultsRed blood cells exposed to oxidative stress show alterations such as phosphatidylserine exposure and loss of deformability. When incubated with endothelial cells, marked erythrophagocytosis occurred in the presence of lactadherin under both static and flow conditions. As a consequence, intracellular organization was disturbed and endothelial cells were seen to change shape ('rounding up'). Increased expression of apoptotic markers indicated that marked erythrophagocytosis has cytotoxic effects. ConclusionsActivated endothelial cells show significant phagocytosis of phosphatidylserine-exposing and rigid red blood cells under both static and flow conditions. This results in a certain degree of cytotoxicity. We postulate that activated endothelial cells play a role in red blood cell clearance in vivo. Significant erythrophagocytosis can induce endothelial cell loss, which may contribute to vasopathological effects as seen, for instance, in sickle cell disease.

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Suicidal erythrocyte death in sepsis

Cited by 290 publications

References 35 publications

Hemin-induced suicidal erythrocyte death

Hemin-induced suicidal erythrocyte death

α-Hemolysin from Escherichia coli uses endogenous amplification through P2X receptor activation to induce hemolysis

A role for activated endothelial cells in red blood cell clearance: implications for vasopathology

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