Neutralizing Antibody Against Interleukin-6 Attenuates Posthemorrhagic Vasospasm in the Rat Femoral Artery Model

George Bowman, Sanat Dixit, Robert H. Bonneau, Vernon Chinchilli, Kevin Cockroft, J. Max Findlay, Gabriele Schackert, R. Loch Macdonald, E. Sander Connolly

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

OBJECTIVE: The degree to which inflammation contributes to the development of posthemorrhagic vasospasm is controversial. In the present study, we investigated the relationship between various inflammatory cytokines (tumor necrosis factor-α, interleukin [IL]-1α, IL-1β, and IL-6) and the development of experimental vasospasm. METHODS: Posthemorrhagic vasospasm was produced in the rat femoral artery model. A latex pouch was placed around each femoral artery, and one pouch was injected with autologous blood and the other with saline as an internal control. Animals were killed at various time points (1 h to 16 d) after surgery (blood exposure), and the degree of vasospasm was assessed by image analysis of artery cross sectional area. Levels of inflammatory cytokines were determined by enzyme-linked immunosorbent assay, and the ability of a polyclonal antibody against rat IL-6 to inhibit vasospasm was tested. RESULTS: The rat femoral artery model produced a biphasic vasospasm response, with maximal chronic delayed vasospasm occurring at 8 days after hemorrhage. Enzyme-linked immunosorbent assay revealed a significant increase in IL-6 concentrations in blood-exposed arteries relative to saline-exposed arteries at multiple time points (6, 12, 24, and 48 h) after hemorrhage (P < 0.0001). A relative increase in IL-1α levels was noted at 24 hours (P < 0.01). IL-1β levels were similarly elevated in both blood- and saline-exposed arteries, and tumor necrosis factor-α levels were not detectable. Administration of a neutralizing polyclonal antibody against rat IL-6 directly into the blood-exposed periarterial pouch at the time of initial surgery resulted in a dose-dependent reduction in the degree of vasospasm compared with vehicle-treated controls at 8 days after hemorrhage (P < 0.05). CONCLUSIONS: These results indicate that cytokine-mediated inflammation is active in the setting of posthemorrhagic vasospasm produced by the rat femoral artery model. In particular, the profound increase in IL-6 levels after exposure to hemorrhage and the ability of a polyclonal antibody against IL-6 to reduce vasospasm suggest that IL-6 may play a prominent role in the development of vasospasm in this model.

Original languageEnglish (US)
Pages (from-to)719-726
Number of pages8
JournalNeurosurgery
Volume54
Issue number3
DOIs
StatePublished - Jan 1 2004

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Femoral Artery
Neutralizing Antibodies
Interleukin-6
Interleukin-1
Arteries
Hemorrhage
Cytokines
Tumor Necrosis Factor-alpha
Enzyme-Linked Immunosorbent Assay
Inflammation
Antibodies
Latex
Cross-Sectional Studies

All Science Journal Classification (ASJC) codes

  • Surgery
  • Clinical Neurology

Cite this

Bowman, George ; Dixit, Sanat ; Bonneau, Robert H. ; Chinchilli, Vernon ; Cockroft, Kevin ; Findlay, J. Max ; Schackert, Gabriele ; Macdonald, R. Loch ; Connolly, E. Sander. / Neutralizing Antibody Against Interleukin-6 Attenuates Posthemorrhagic Vasospasm in the Rat Femoral Artery Model. In: Neurosurgery. 2004 ; Vol. 54, No. 3. pp. 719-726.
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abstract = "OBJECTIVE: The degree to which inflammation contributes to the development of posthemorrhagic vasospasm is controversial. In the present study, we investigated the relationship between various inflammatory cytokines (tumor necrosis factor-α, interleukin [IL]-1α, IL-1β, and IL-6) and the development of experimental vasospasm. METHODS: Posthemorrhagic vasospasm was produced in the rat femoral artery model. A latex pouch was placed around each femoral artery, and one pouch was injected with autologous blood and the other with saline as an internal control. Animals were killed at various time points (1 h to 16 d) after surgery (blood exposure), and the degree of vasospasm was assessed by image analysis of artery cross sectional area. Levels of inflammatory cytokines were determined by enzyme-linked immunosorbent assay, and the ability of a polyclonal antibody against rat IL-6 to inhibit vasospasm was tested. RESULTS: The rat femoral artery model produced a biphasic vasospasm response, with maximal chronic delayed vasospasm occurring at 8 days after hemorrhage. Enzyme-linked immunosorbent assay revealed a significant increase in IL-6 concentrations in blood-exposed arteries relative to saline-exposed arteries at multiple time points (6, 12, 24, and 48 h) after hemorrhage (P < 0.0001). A relative increase in IL-1α levels was noted at 24 hours (P < 0.01). IL-1β levels were similarly elevated in both blood- and saline-exposed arteries, and tumor necrosis factor-α levels were not detectable. Administration of a neutralizing polyclonal antibody against rat IL-6 directly into the blood-exposed periarterial pouch at the time of initial surgery resulted in a dose-dependent reduction in the degree of vasospasm compared with vehicle-treated controls at 8 days after hemorrhage (P < 0.05). CONCLUSIONS: These results indicate that cytokine-mediated inflammation is active in the setting of posthemorrhagic vasospasm produced by the rat femoral artery model. In particular, the profound increase in IL-6 levels after exposure to hemorrhage and the ability of a polyclonal antibody against IL-6 to reduce vasospasm suggest that IL-6 may play a prominent role in the development of vasospasm in this model.",
author = "George Bowman and Sanat Dixit and Bonneau, {Robert H.} and Vernon Chinchilli and Kevin Cockroft and Findlay, {J. Max} and Gabriele Schackert and Macdonald, {R. Loch} and Connolly, {E. Sander}",
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Neutralizing Antibody Against Interleukin-6 Attenuates Posthemorrhagic Vasospasm in the Rat Femoral Artery Model. / Bowman, George; Dixit, Sanat; Bonneau, Robert H.; Chinchilli, Vernon; Cockroft, Kevin; Findlay, J. Max; Schackert, Gabriele; Macdonald, R. Loch; Connolly, E. Sander.

In: Neurosurgery, Vol. 54, No. 3, 01.01.2004, p. 719-726.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Neutralizing Antibody Against Interleukin-6 Attenuates Posthemorrhagic Vasospasm in the Rat Femoral Artery Model

AU - Bowman, George

AU - Dixit, Sanat

AU - Bonneau, Robert H.

AU - Chinchilli, Vernon

AU - Cockroft, Kevin

AU - Findlay, J. Max

AU - Schackert, Gabriele

AU - Macdonald, R. Loch

AU - Connolly, E. Sander

PY - 2004/1/1

Y1 - 2004/1/1

N2 - OBJECTIVE: The degree to which inflammation contributes to the development of posthemorrhagic vasospasm is controversial. In the present study, we investigated the relationship between various inflammatory cytokines (tumor necrosis factor-α, interleukin [IL]-1α, IL-1β, and IL-6) and the development of experimental vasospasm. METHODS: Posthemorrhagic vasospasm was produced in the rat femoral artery model. A latex pouch was placed around each femoral artery, and one pouch was injected with autologous blood and the other with saline as an internal control. Animals were killed at various time points (1 h to 16 d) after surgery (blood exposure), and the degree of vasospasm was assessed by image analysis of artery cross sectional area. Levels of inflammatory cytokines were determined by enzyme-linked immunosorbent assay, and the ability of a polyclonal antibody against rat IL-6 to inhibit vasospasm was tested. RESULTS: The rat femoral artery model produced a biphasic vasospasm response, with maximal chronic delayed vasospasm occurring at 8 days after hemorrhage. Enzyme-linked immunosorbent assay revealed a significant increase in IL-6 concentrations in blood-exposed arteries relative to saline-exposed arteries at multiple time points (6, 12, 24, and 48 h) after hemorrhage (P < 0.0001). A relative increase in IL-1α levels was noted at 24 hours (P < 0.01). IL-1β levels were similarly elevated in both blood- and saline-exposed arteries, and tumor necrosis factor-α levels were not detectable. Administration of a neutralizing polyclonal antibody against rat IL-6 directly into the blood-exposed periarterial pouch at the time of initial surgery resulted in a dose-dependent reduction in the degree of vasospasm compared with vehicle-treated controls at 8 days after hemorrhage (P < 0.05). CONCLUSIONS: These results indicate that cytokine-mediated inflammation is active in the setting of posthemorrhagic vasospasm produced by the rat femoral artery model. In particular, the profound increase in IL-6 levels after exposure to hemorrhage and the ability of a polyclonal antibody against IL-6 to reduce vasospasm suggest that IL-6 may play a prominent role in the development of vasospasm in this model.

AB - OBJECTIVE: The degree to which inflammation contributes to the development of posthemorrhagic vasospasm is controversial. In the present study, we investigated the relationship between various inflammatory cytokines (tumor necrosis factor-α, interleukin [IL]-1α, IL-1β, and IL-6) and the development of experimental vasospasm. METHODS: Posthemorrhagic vasospasm was produced in the rat femoral artery model. A latex pouch was placed around each femoral artery, and one pouch was injected with autologous blood and the other with saline as an internal control. Animals were killed at various time points (1 h to 16 d) after surgery (blood exposure), and the degree of vasospasm was assessed by image analysis of artery cross sectional area. Levels of inflammatory cytokines were determined by enzyme-linked immunosorbent assay, and the ability of a polyclonal antibody against rat IL-6 to inhibit vasospasm was tested. RESULTS: The rat femoral artery model produced a biphasic vasospasm response, with maximal chronic delayed vasospasm occurring at 8 days after hemorrhage. Enzyme-linked immunosorbent assay revealed a significant increase in IL-6 concentrations in blood-exposed arteries relative to saline-exposed arteries at multiple time points (6, 12, 24, and 48 h) after hemorrhage (P < 0.0001). A relative increase in IL-1α levels was noted at 24 hours (P < 0.01). IL-1β levels were similarly elevated in both blood- and saline-exposed arteries, and tumor necrosis factor-α levels were not detectable. Administration of a neutralizing polyclonal antibody against rat IL-6 directly into the blood-exposed periarterial pouch at the time of initial surgery resulted in a dose-dependent reduction in the degree of vasospasm compared with vehicle-treated controls at 8 days after hemorrhage (P < 0.05). CONCLUSIONS: These results indicate that cytokine-mediated inflammation is active in the setting of posthemorrhagic vasospasm produced by the rat femoral artery model. In particular, the profound increase in IL-6 levels after exposure to hemorrhage and the ability of a polyclonal antibody against IL-6 to reduce vasospasm suggest that IL-6 may play a prominent role in the development of vasospasm in this model.

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