Attenuation of shock-induced acute lung injury by sphingosine kinase inhibition

Cindy Lee, Da Zhong Xu, Eleonora Feketeova, K. B. Kannan, Jong K. Yun, Edwin A. Deitch, Zoltan Fekete, David H. Livingston, Carl J. Hauser

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

Background: Prolonged elevations of cytosolic calcium concentrations ([Ca2+Ji) are required for optimal neutrophil (PMN) activation responses to G-Protein coupled chemoattractants. We recently showed that the coupling of endosomal Ca2+ store depletion to more prolonged entry of external Ca2+ depends on cellular conversion of sphingosine to sphingosine 1-phosphate (S1P) by sphingosine kinase (SK). We therefore hypothesized that inhibition of SK might inhibit PMN activation and thus ameliorate lung injury after trauma and hemorrhagic shock (T/HS). Methods: Chemotaxis (CTX) of human PMN was studied using modified Boyden chambers in the presence or absence of the selective SK inhibitor, SKI-2. After determining the concentration of SKI-2 that inhibited human PMN CTX by 50% (IC50) we subjected rats to T/HS (laparotomy, hemorrhage to 30-40 mm Hg × 90 minutes, 3 hours resuscitation). We then studied rat PMN CD11b expression using flow cytometry and lung injury using the Evans Blue dye technique in the presence of IC50 doses of SKI-2 or vehicle given in pretreatment at laparotomy. Results: Human PMN CTX was suppressed slightly more than 50% by 40 μmol/L SKI-2 (233 ±20 vs103 ± 12 × 103 cells/well, p < 0.001). Rat PMN expression of CD11b after T/HS was decreased from 352 ± 30 to 232 ± 7 MFU (p < 0.001) in the presence 30 μmol/L SKI-2. Lung permeability to Evans Blue was decreased from 9.5 ± 2 to 4.1 ± 0.7% (p = 0.036.). SKI-2 did not cause hemodynamic instability or alter resuscitation requirements. Conclusions: Modulation of PMN Ca2+ entry via SK inhibition inhibits PMN CTX in vitro, and inhibits CD11b expression in vivo without major effects on hemodynamics. These cellular changes were associated with amelioration of lung injury in vivo in a rat model of T/HS. These findings suggest that SK inhibition allows modulation of inflammation via control of [Ca2+]; without the cardiovascular compromise expected with Ca2+ channel blockade. SK inhibition therefore appears to be an important novel candidate therapy for inflammatory organ injury after shock.

Original languageEnglish (US)
Pages (from-to)955-960
Number of pages6
JournalJournal of Trauma - Injury, Infection and Critical Care
Volume57
Issue number5
DOIs
StatePublished - Nov 1 2004

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Acute Lung Injury
Shock
Hemorrhagic Shock
Chemotaxis
Lung Injury
Wounds and Injuries
Evans Blue
Resuscitation
Laparotomy
Inhibitory Concentration 50
Hemodynamics
Neutrophil Activation
Sphingosine
Chemotactic Factors
GTP-Binding Proteins
Inhibition (Psychology)
sphingosine kinase
Permeability
Flow Cytometry
Coloring Agents

All Science Journal Classification (ASJC) codes

  • Surgery
  • Critical Care and Intensive Care Medicine

Cite this

Lee, Cindy ; Xu, Da Zhong ; Feketeova, Eleonora ; Kannan, K. B. ; Yun, Jong K. ; Deitch, Edwin A. ; Fekete, Zoltan ; Livingston, David H. ; Hauser, Carl J. / Attenuation of shock-induced acute lung injury by sphingosine kinase inhibition. In: Journal of Trauma - Injury, Infection and Critical Care. 2004 ; Vol. 57, No. 5. pp. 955-960.
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abstract = "Background: Prolonged elevations of cytosolic calcium concentrations ([Ca2+Ji) are required for optimal neutrophil (PMN) activation responses to G-Protein coupled chemoattractants. We recently showed that the coupling of endosomal Ca2+ store depletion to more prolonged entry of external Ca2+ depends on cellular conversion of sphingosine to sphingosine 1-phosphate (S1P) by sphingosine kinase (SK). We therefore hypothesized that inhibition of SK might inhibit PMN activation and thus ameliorate lung injury after trauma and hemorrhagic shock (T/HS). Methods: Chemotaxis (CTX) of human PMN was studied using modified Boyden chambers in the presence or absence of the selective SK inhibitor, SKI-2. After determining the concentration of SKI-2 that inhibited human PMN CTX by 50{\%} (IC50) we subjected rats to T/HS (laparotomy, hemorrhage to 30-40 mm Hg × 90 minutes, 3 hours resuscitation). We then studied rat PMN CD11b expression using flow cytometry and lung injury using the Evans Blue dye technique in the presence of IC50 doses of SKI-2 or vehicle given in pretreatment at laparotomy. Results: Human PMN CTX was suppressed slightly more than 50{\%} by 40 μmol/L SKI-2 (233 ±20 vs103 ± 12 × 103 cells/well, p < 0.001). Rat PMN expression of CD11b after T/HS was decreased from 352 ± 30 to 232 ± 7 MFU (p < 0.001) in the presence 30 μmol/L SKI-2. Lung permeability to Evans Blue was decreased from 9.5 ± 2 to 4.1 ± 0.7{\%} (p = 0.036.). SKI-2 did not cause hemodynamic instability or alter resuscitation requirements. Conclusions: Modulation of PMN Ca2+ entry via SK inhibition inhibits PMN CTX in vitro, and inhibits CD11b expression in vivo without major effects on hemodynamics. These cellular changes were associated with amelioration of lung injury in vivo in a rat model of T/HS. These findings suggest that SK inhibition allows modulation of inflammation via control of [Ca2+]; without the cardiovascular compromise expected with Ca2+ channel blockade. SK inhibition therefore appears to be an important novel candidate therapy for inflammatory organ injury after shock.",
author = "Cindy Lee and Xu, {Da Zhong} and Eleonora Feketeova and Kannan, {K. B.} and Yun, {Jong K.} and Deitch, {Edwin A.} and Zoltan Fekete and Livingston, {David H.} and Hauser, {Carl J.}",
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Lee, C, Xu, DZ, Feketeova, E, Kannan, KB, Yun, JK, Deitch, EA, Fekete, Z, Livingston, DH & Hauser, CJ 2004, 'Attenuation of shock-induced acute lung injury by sphingosine kinase inhibition', Journal of Trauma - Injury, Infection and Critical Care, vol. 57, no. 5, pp. 955-960. https://doi.org/10.1097/01.TA.0000149495.44582.76

Attenuation of shock-induced acute lung injury by sphingosine kinase inhibition. / Lee, Cindy; Xu, Da Zhong; Feketeova, Eleonora; Kannan, K. B.; Yun, Jong K.; Deitch, Edwin A.; Fekete, Zoltan; Livingston, David H.; Hauser, Carl J.

In: Journal of Trauma - Injury, Infection and Critical Care, Vol. 57, No. 5, 01.11.2004, p. 955-960.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Attenuation of shock-induced acute lung injury by sphingosine kinase inhibition

AU - Lee, Cindy

AU - Xu, Da Zhong

AU - Feketeova, Eleonora

AU - Kannan, K. B.

AU - Yun, Jong K.

AU - Deitch, Edwin A.

AU - Fekete, Zoltan

AU - Livingston, David H.

AU - Hauser, Carl J.

PY - 2004/11/1

Y1 - 2004/11/1

N2 - Background: Prolonged elevations of cytosolic calcium concentrations ([Ca2+Ji) are required for optimal neutrophil (PMN) activation responses to G-Protein coupled chemoattractants. We recently showed that the coupling of endosomal Ca2+ store depletion to more prolonged entry of external Ca2+ depends on cellular conversion of sphingosine to sphingosine 1-phosphate (S1P) by sphingosine kinase (SK). We therefore hypothesized that inhibition of SK might inhibit PMN activation and thus ameliorate lung injury after trauma and hemorrhagic shock (T/HS). Methods: Chemotaxis (CTX) of human PMN was studied using modified Boyden chambers in the presence or absence of the selective SK inhibitor, SKI-2. After determining the concentration of SKI-2 that inhibited human PMN CTX by 50% (IC50) we subjected rats to T/HS (laparotomy, hemorrhage to 30-40 mm Hg × 90 minutes, 3 hours resuscitation). We then studied rat PMN CD11b expression using flow cytometry and lung injury using the Evans Blue dye technique in the presence of IC50 doses of SKI-2 or vehicle given in pretreatment at laparotomy. Results: Human PMN CTX was suppressed slightly more than 50% by 40 μmol/L SKI-2 (233 ±20 vs103 ± 12 × 103 cells/well, p < 0.001). Rat PMN expression of CD11b after T/HS was decreased from 352 ± 30 to 232 ± 7 MFU (p < 0.001) in the presence 30 μmol/L SKI-2. Lung permeability to Evans Blue was decreased from 9.5 ± 2 to 4.1 ± 0.7% (p = 0.036.). SKI-2 did not cause hemodynamic instability or alter resuscitation requirements. Conclusions: Modulation of PMN Ca2+ entry via SK inhibition inhibits PMN CTX in vitro, and inhibits CD11b expression in vivo without major effects on hemodynamics. These cellular changes were associated with amelioration of lung injury in vivo in a rat model of T/HS. These findings suggest that SK inhibition allows modulation of inflammation via control of [Ca2+]; without the cardiovascular compromise expected with Ca2+ channel blockade. SK inhibition therefore appears to be an important novel candidate therapy for inflammatory organ injury after shock.

AB - Background: Prolonged elevations of cytosolic calcium concentrations ([Ca2+Ji) are required for optimal neutrophil (PMN) activation responses to G-Protein coupled chemoattractants. We recently showed that the coupling of endosomal Ca2+ store depletion to more prolonged entry of external Ca2+ depends on cellular conversion of sphingosine to sphingosine 1-phosphate (S1P) by sphingosine kinase (SK). We therefore hypothesized that inhibition of SK might inhibit PMN activation and thus ameliorate lung injury after trauma and hemorrhagic shock (T/HS). Methods: Chemotaxis (CTX) of human PMN was studied using modified Boyden chambers in the presence or absence of the selective SK inhibitor, SKI-2. After determining the concentration of SKI-2 that inhibited human PMN CTX by 50% (IC50) we subjected rats to T/HS (laparotomy, hemorrhage to 30-40 mm Hg × 90 minutes, 3 hours resuscitation). We then studied rat PMN CD11b expression using flow cytometry and lung injury using the Evans Blue dye technique in the presence of IC50 doses of SKI-2 or vehicle given in pretreatment at laparotomy. Results: Human PMN CTX was suppressed slightly more than 50% by 40 μmol/L SKI-2 (233 ±20 vs103 ± 12 × 103 cells/well, p < 0.001). Rat PMN expression of CD11b after T/HS was decreased from 352 ± 30 to 232 ± 7 MFU (p < 0.001) in the presence 30 μmol/L SKI-2. Lung permeability to Evans Blue was decreased from 9.5 ± 2 to 4.1 ± 0.7% (p = 0.036.). SKI-2 did not cause hemodynamic instability or alter resuscitation requirements. Conclusions: Modulation of PMN Ca2+ entry via SK inhibition inhibits PMN CTX in vitro, and inhibits CD11b expression in vivo without major effects on hemodynamics. These cellular changes were associated with amelioration of lung injury in vivo in a rat model of T/HS. These findings suggest that SK inhibition allows modulation of inflammation via control of [Ca2+]; without the cardiovascular compromise expected with Ca2+ channel blockade. SK inhibition therefore appears to be an important novel candidate therapy for inflammatory organ injury after shock.

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