Loop Diuretics Diminish Hemolysis Induced by α-Hemolysin from Escherichia coli

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Loop Diuretics Diminish Hemolysis Induced by α-Hemolysin from Escherichia coli. / Söderström, Carl Martin; Fagerberg, Steen K; Brogaard, Mette B; Leipziger, Jens; Skals, Marianne; Praetorius, Helle A.

I: Journal of Membrane Biology, Bind 250, Nr. 3, 06.2017, s. 301-313.

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review

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Söderström, Carl Martin o.a.. "Loop Diuretics Diminish Hemolysis Induced by α-Hemolysin from Escherichia coli". Journal of Membrane Biology. 2017, 250(3). 301-313. https://doi.org/10.1007/s00232-017-9963-0

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Söderström, Carl Martin ; Fagerberg, Steen K ; Brogaard, Mette B ; Leipziger, Jens ; Skals, Marianne ; Praetorius, Helle A. / Loop Diuretics Diminish Hemolysis Induced by α-Hemolysin from Escherichia coli. I: Journal of Membrane Biology. 2017 ; Bind 250, Nr. 3. s. 301-313.

Bibtex

@article{a9560924634645f2866a09df773a4a1a,
title = "Loop Diuretics Diminish Hemolysis Induced by α-Hemolysin from Escherichia coli",
abstract = "Uropathogenic Escherichia coli often produce the virulence factor α-hemolysin (HlyA), and the more severe the infection, the likelier it is to isolate HlyA-producing E. coli from patients. HlyA forms pores upon receptor-independent insertion of the toxin into biological membranes and it has been substantiated that HlyA-induced hemolysis is amplified by toxin-induced ATP release and activation of P2X receptors. Thus, hemolysis inflicted by HlyA is a protracted process involving signal transduction. It consists of early, marked cell shrinkage followed by swelling and eventually lysis. The initially shrinkage is a consequence of a substantial Ca(2+)-influx and activation of Ca(2+)-sensitive K(+) and Cl(-) channels (KCa3.1/TMEM16A). The shrinkage is followed by gradual cell swelling, which ultimately lyses the cells. These findings clearly show that the HlyA pore provides a substantial volume challenge for the cells, and the fate of the given cell is co-determined by intrinsic erythrocytal volume regulation. We therefore speculated that other mechanisms involved in erythrocyte volume regulation may influence the hemolytic process inflicted by HlyA. Strikingly, HlyA-induced hemolysis is markedly reduced in erythrocytes isolated from NKCC1-deficient (NKCC1(-/-)) mice compared to controls. The NKCC1 inhibitors furosemide and bumetanide concentration-dependently inhibit HlyA-induced lysis of human and murine erythrocytes. However, in high concentrations bumetanide further reduced hemolysis in erythrocytes from NKCC1(-/-) mice and, thus, also exhibit indirect effects on hemolysis. The effect of loop diuretics on the hemolysis is not unique to HlyA but is similarly seen in LtxA- and α-toxin-induced hemolysis. Bumetanide clearly potentiates HlyA-induced volume reduction and delays the following erythrocyte swelling. This allows increased phagocytosis of damaged erythrocytes by THP-1 cell as a result of prolonged cell shrinkage. These data suggest that erythrocyte susceptibility to cytolysins is modified by NKCC1 and signifies intrinsic volume regulators as important determinants of cellular outcome of pore-forming toxins.",
keywords = "Journal Article",
author = "S{\"o}derstr{\"o}m, {Carl Martin} and Fagerberg, {Steen K} and Brogaard, {Mette B} and Jens Leipziger and Marianne Skals and Praetorius, {Helle A}",
year = "2017",
month = "6",
doi = "10.1007/s00232-017-9963-0",
language = "English",
volume = "250",
pages = "301--313",
journal = "Journal of Membrane Biology",
issn = "0022-2631",
publisher = "Springer New York LLC",
number = "3",

}

RIS

TY - JOUR

T1 - Loop Diuretics Diminish Hemolysis Induced by α-Hemolysin from Escherichia coli

AU - Söderström, Carl Martin

AU - Fagerberg, Steen K

AU - Brogaard, Mette B

AU - Leipziger, Jens

AU - Skals, Marianne

AU - Praetorius, Helle A

PY - 2017/6

Y1 - 2017/6

N2 - Uropathogenic Escherichia coli often produce the virulence factor α-hemolysin (HlyA), and the more severe the infection, the likelier it is to isolate HlyA-producing E. coli from patients. HlyA forms pores upon receptor-independent insertion of the toxin into biological membranes and it has been substantiated that HlyA-induced hemolysis is amplified by toxin-induced ATP release and activation of P2X receptors. Thus, hemolysis inflicted by HlyA is a protracted process involving signal transduction. It consists of early, marked cell shrinkage followed by swelling and eventually lysis. The initially shrinkage is a consequence of a substantial Ca(2+)-influx and activation of Ca(2+)-sensitive K(+) and Cl(-) channels (KCa3.1/TMEM16A). The shrinkage is followed by gradual cell swelling, which ultimately lyses the cells. These findings clearly show that the HlyA pore provides a substantial volume challenge for the cells, and the fate of the given cell is co-determined by intrinsic erythrocytal volume regulation. We therefore speculated that other mechanisms involved in erythrocyte volume regulation may influence the hemolytic process inflicted by HlyA. Strikingly, HlyA-induced hemolysis is markedly reduced in erythrocytes isolated from NKCC1-deficient (NKCC1(-/-)) mice compared to controls. The NKCC1 inhibitors furosemide and bumetanide concentration-dependently inhibit HlyA-induced lysis of human and murine erythrocytes. However, in high concentrations bumetanide further reduced hemolysis in erythrocytes from NKCC1(-/-) mice and, thus, also exhibit indirect effects on hemolysis. The effect of loop diuretics on the hemolysis is not unique to HlyA but is similarly seen in LtxA- and α-toxin-induced hemolysis. Bumetanide clearly potentiates HlyA-induced volume reduction and delays the following erythrocyte swelling. This allows increased phagocytosis of damaged erythrocytes by THP-1 cell as a result of prolonged cell shrinkage. These data suggest that erythrocyte susceptibility to cytolysins is modified by NKCC1 and signifies intrinsic volume regulators as important determinants of cellular outcome of pore-forming toxins.

AB - Uropathogenic Escherichia coli often produce the virulence factor α-hemolysin (HlyA), and the more severe the infection, the likelier it is to isolate HlyA-producing E. coli from patients. HlyA forms pores upon receptor-independent insertion of the toxin into biological membranes and it has been substantiated that HlyA-induced hemolysis is amplified by toxin-induced ATP release and activation of P2X receptors. Thus, hemolysis inflicted by HlyA is a protracted process involving signal transduction. It consists of early, marked cell shrinkage followed by swelling and eventually lysis. The initially shrinkage is a consequence of a substantial Ca(2+)-influx and activation of Ca(2+)-sensitive K(+) and Cl(-) channels (KCa3.1/TMEM16A). The shrinkage is followed by gradual cell swelling, which ultimately lyses the cells. These findings clearly show that the HlyA pore provides a substantial volume challenge for the cells, and the fate of the given cell is co-determined by intrinsic erythrocytal volume regulation. We therefore speculated that other mechanisms involved in erythrocyte volume regulation may influence the hemolytic process inflicted by HlyA. Strikingly, HlyA-induced hemolysis is markedly reduced in erythrocytes isolated from NKCC1-deficient (NKCC1(-/-)) mice compared to controls. The NKCC1 inhibitors furosemide and bumetanide concentration-dependently inhibit HlyA-induced lysis of human and murine erythrocytes. However, in high concentrations bumetanide further reduced hemolysis in erythrocytes from NKCC1(-/-) mice and, thus, also exhibit indirect effects on hemolysis. The effect of loop diuretics on the hemolysis is not unique to HlyA but is similarly seen in LtxA- and α-toxin-induced hemolysis. Bumetanide clearly potentiates HlyA-induced volume reduction and delays the following erythrocyte swelling. This allows increased phagocytosis of damaged erythrocytes by THP-1 cell as a result of prolonged cell shrinkage. These data suggest that erythrocyte susceptibility to cytolysins is modified by NKCC1 and signifies intrinsic volume regulators as important determinants of cellular outcome of pore-forming toxins.

KW - Journal Article

U2 - 10.1007/s00232-017-9963-0

DO - 10.1007/s00232-017-9963-0

M3 - Journal article

C2 - 28488084

VL - 250

SP - 301

EP - 313

JO - Journal of Membrane Biology

JF - Journal of Membrane Biology

SN - 0022-2631

IS - 3

ER -