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Published in: Journal of Neuroinflammation 1/2012

Open Access 01-12-2012 | Research

Functional analysis of Pro-inflammatory properties within the cerebrospinal fluid after subarachnoid hemorrhage in vivo and in vitro

Authors: Ulf C Schneider, Jennifer Schiffler, Nahid Hakiy, Peter Horn, Peter Vajkoczy

Published in: Journal of Neuroinflammation | Issue 1/2012

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Abstract

Background

To functionally characterize pro-inflammatory and vasoconstrictive properties of cerebrospinal fluid after aneurysmal subarachnoid hemorrhage (SAH) in vivo and in vitro.

Methods

The cerebrospinal fluid (CSF) of 10 patients suffering from SAH was applied to the transparent skinfold chamber model in male NMRI mice which allows for in vivo analysis of the microcirculatory response to a superfusat. Microvascular diameter changes were quantified and the numbers of rolling and sticking leukocytes were documented using intravital multifluorescence imaging techniques. Furthermore, the pro-inflammatory properties of CSF were assessed in vitro using a monocyte transendothelial migration assay.

Results

CSF superfusion started to induce significant vasoconstriction on days 4 and 6 after SAH. In parallel, CSF superfusion induced a microvascular leukocyte recruitment, with a significant number of leukocytes rolling (day 6) and sticking (days 2-4) to the endothelium. CSF of patients presenting with cerebral edema induced breakdown of blood vessel integrity in our assay as evidenced by fluorescent marker extravasation. In accordance with leukocyte activation in vivo, significantly higher in vitro monocyte migration rates were found after SAH.

Conclusion

We functionally characterized inflammatory and vasoactive properties of patients' CSF after SAH in vivo and in vitro. This pro-inflammatory milieu in the subarachnoid space might play a pivotal role in the pathophysiology of early and delayed brain injury as well as vasospasm development following SAH.
Literature
1.
go back to reference Barth M, Capelle H-H, Weidauer S, Weiss C, Münch E, Thomé C, Luecke T, Schmiedek P, Kasuya H, Vajkoczy P: Effect of nicardipine prolonged-release implants on cerebral vasospasm and clinical outcome after severe aneurysmal subarachnoid hemorrhage: a prospective, randomized, double-blind phase IIa study. Stroke 2007, 38:330–336.CrossRefPubMed Barth M, Capelle H-H, Weidauer S, Weiss C, Münch E, Thomé C, Luecke T, Schmiedek P, Kasuya H, Vajkoczy P: Effect of nicardipine prolonged-release implants on cerebral vasospasm and clinical outcome after severe aneurysmal subarachnoid hemorrhage: a prospective, randomized, double-blind phase IIa study. Stroke 2007, 38:330–336.CrossRefPubMed
2.
go back to reference Vajkoczy P, Meyer B, Weidauer S, Raabe A, Thomé C, Ringel F, Breu V, Schmiedek P: Clazosentan (AXV-034343), a selective endothelin A receptor antagonist, in the prevention of cerebral vasospasm following severe aneurysmal subarachnoid hemorrhage: results of a randomized, double-blind, placebo-controlled, multicenter phase IIa study. J Neurosurg 2005, 103:9–17.CrossRefPubMed Vajkoczy P, Meyer B, Weidauer S, Raabe A, Thomé C, Ringel F, Breu V, Schmiedek P: Clazosentan (AXV-034343), a selective endothelin A receptor antagonist, in the prevention of cerebral vasospasm following severe aneurysmal subarachnoid hemorrhage: results of a randomized, double-blind, placebo-controlled, multicenter phase IIa study. J Neurosurg 2005, 103:9–17.CrossRefPubMed
3.
go back to reference Hansen-Schwartz J, Vajkoczy P, Macdonald RL, Pluta RM, Zhang JH: Cerebral vasospasm: looking beyond vasoconstriction. Trends Pharmacol Sci 2007, 28:252–256.CrossRefPubMed Hansen-Schwartz J, Vajkoczy P, Macdonald RL, Pluta RM, Zhang JH: Cerebral vasospasm: looking beyond vasoconstriction. Trends Pharmacol Sci 2007, 28:252–256.CrossRefPubMed
4.
go back to reference Osuka K, Suzuki Y, Tanazawa T, Hattori K, Yamamoto N, Takayasu M, Shibuya M, Yoshida J: Interleukin-6 and development of vasospasm after subarachnoid haemorrhage. Acta Neurochir (Wien) 1998, 140:943–951.CrossRef Osuka K, Suzuki Y, Tanazawa T, Hattori K, Yamamoto N, Takayasu M, Shibuya M, Yoshida J: Interleukin-6 and development of vasospasm after subarachnoid haemorrhage. Acta Neurochir (Wien) 1998, 140:943–951.CrossRef
5.
go back to reference Polin RS, Bavbek M, Shaffrey ME, Billups K, Bogaev CA, Kassell NF, Lee KS: Detection of soluble E-selectin, ICAM-1, VCAM-1, and L-selectin in the cerebrospinal fluid of patients after subarachnoid hemorrhage. J Neurosurg 1998, 89:559–567.CrossRefPubMed Polin RS, Bavbek M, Shaffrey ME, Billups K, Bogaev CA, Kassell NF, Lee KS: Detection of soluble E-selectin, ICAM-1, VCAM-1, and L-selectin in the cerebrospinal fluid of patients after subarachnoid hemorrhage. J Neurosurg 1998, 89:559–567.CrossRefPubMed
6.
go back to reference Hagen AA, Gerber JN, Sweeley CC, White RP, Robertson JT: Levels and disappearance of prostaglandin F2a in cerebral spinal fluid: a clinical and experimental study. Stroke 1977, 8:672–675.CrossRefPubMed Hagen AA, Gerber JN, Sweeley CC, White RP, Robertson JT: Levels and disappearance of prostaglandin F2a in cerebral spinal fluid: a clinical and experimental study. Stroke 1977, 8:672–675.CrossRefPubMed
7.
go back to reference Boullin DJ, Bunting S, Blaso WP, Hunt TM, Moncada S: Responses of human and baboon arteries to prostaglandin endoperoxides and biologically generated and synthetic prostacyclin: their relevance to cerebral arterial spasm in man. Br J Clin Pharmacol 1979, 7:139–147.CrossRefPubMedPubMedCentral Boullin DJ, Bunting S, Blaso WP, Hunt TM, Moncada S: Responses of human and baboon arteries to prostaglandin endoperoxides and biologically generated and synthetic prostacyclin: their relevance to cerebral arterial spasm in man. Br J Clin Pharmacol 1979, 7:139–147.CrossRefPubMedPubMedCentral
8.
go back to reference Brandt L, Ljunggren B, Andersson KE, Hindfelt B, Uski T: Prostaglandin metabolism and prostacyclin in cerebral vasospasm. Gen Pharmac 1982, 14:141–143.CrossRef Brandt L, Ljunggren B, Andersson KE, Hindfelt B, Uski T: Prostaglandin metabolism and prostacyclin in cerebral vasospasm. Gen Pharmac 1982, 14:141–143.CrossRef
9.
go back to reference Rodriguez-y-Baena R, Gaetani P, Folco G, Vigano T, Paoletti P: Arachidonate metabolites and vasospasm after subarachnoid hemorrhage. Neurol Res 1986, 8:25–32.CrossRefPubMed Rodriguez-y-Baena R, Gaetani P, Folco G, Vigano T, Paoletti P: Arachidonate metabolites and vasospasm after subarachnoid hemorrhage. Neurol Res 1986, 8:25–32.CrossRefPubMed
10.
go back to reference Rodriguez-y-Baena R, Gaetani P, Grignani G, Pacchiarini L: Effect of nimodipine on arachidonic acid metabolites after subarachnoid hemorrhage. Acta Neurol Scand 1987, 76:267–271.CrossRef Rodriguez-y-Baena R, Gaetani P, Grignani G, Pacchiarini L: Effect of nimodipine on arachidonic acid metabolites after subarachnoid hemorrhage. Acta Neurol Scand 1987, 76:267–271.CrossRef
11.
go back to reference Paoletti P, Gaetani P, Grignain G, Pacchiarini L, Silvani V, Rodriguez-y-Baena R: CSF leukotriene C4 following subarachnoid hemorrhage. J Neurosurg 1988, 69:488–493.CrossRefPubMed Paoletti P, Gaetani P, Grignain G, Pacchiarini L, Silvani V, Rodriguez-y-Baena R: CSF leukotriene C4 following subarachnoid hemorrhage. J Neurosurg 1988, 69:488–493.CrossRefPubMed
12.
go back to reference Rodriguez-y-Baena R, Gaetani P, Paoletti P: A study on cisternal CSF levels of arachidonic acid metabolites after aneurysmal subarachnoid hemorrhage. J Neurol Sci 1988, 84:329–335.CrossRefPubMed Rodriguez-y-Baena R, Gaetani P, Paoletti P: A study on cisternal CSF levels of arachidonic acid metabolites after aneurysmal subarachnoid hemorrhage. J Neurol Sci 1988, 84:329–335.CrossRefPubMed
13.
go back to reference Chehrazi BB, Giri S, Joy RM: Prostaglandins and vasoactive amins in cerebral vasospasm after aneurysmal subarachnoid hemorrhage. Stroke 1989, 20:217–224.CrossRefPubMed Chehrazi BB, Giri S, Joy RM: Prostaglandins and vasoactive amins in cerebral vasospasm after aneurysmal subarachnoid hemorrhage. Stroke 1989, 20:217–224.CrossRefPubMed
14.
go back to reference Minami N, Tani E, Yokota Y, Maeda Y, Yamaura I: Immunohistochemistry of leukotriene C4 in experimental cerebral vasospasm. Acta Neuropathol 1991, 81:401–407.CrossRefPubMed Minami N, Tani E, Yokota Y, Maeda Y, Yamaura I: Immunohistochemistry of leukotriene C4 in experimental cerebral vasospasm. Acta Neuropathol 1991, 81:401–407.CrossRefPubMed
15.
go back to reference Pradilla G, Chaichana KL, Hoang S, Huang J, Tamargo RJ: Inflammation and cerebral vasospasm after subarachnoid hemorrhage. Neurosurg Clin N Am 2010, 21:365–379.CrossRefPubMed Pradilla G, Chaichana KL, Hoang S, Huang J, Tamargo RJ: Inflammation and cerebral vasospasm after subarachnoid hemorrhage. Neurosurg Clin N Am 2010, 21:365–379.CrossRefPubMed
16.
go back to reference Vajkoczy P, Menger MD, Simpson E, Messmer K: Angiogenesis and vascularization of murine pancreatic islet isografts. Transplantation 1995, 60:123–127.CrossRefPubMed Vajkoczy P, Menger MD, Simpson E, Messmer K: Angiogenesis and vascularization of murine pancreatic islet isografts. Transplantation 1995, 60:123–127.CrossRefPubMed
17.
go back to reference Laird AD, Vajkoczy P, Shawver LK, Thurnher A, Liang C, Mohammadi M, Schlessinger J, Ullrich A, Hubbard SR, Blake RA, Fong TA, Strawn LM, Sun L, Tang C, Hawtin R, Tang F, Shenoy N, Hirth KP, McMahon G, Cherrington : SU6668 is a potent antiangiogenic and antitumor agent that induces regression of established tumors. Cancer Res 2000, 60:4152–4160.PubMed Laird AD, Vajkoczy P, Shawver LK, Thurnher A, Liang C, Mohammadi M, Schlessinger J, Ullrich A, Hubbard SR, Blake RA, Fong TA, Strawn LM, Sun L, Tang C, Hawtin R, Tang F, Shenoy N, Hirth KP, McMahon G, Cherrington : SU6668 is a potent antiangiogenic and antitumor agent that induces regression of established tumors. Cancer Res 2000, 60:4152–4160.PubMed
18.
go back to reference Laschke MW, Elitzsch A, Vollmar B, Vajkoczy P, Menger MD: Combined inhibition of vascular endothelial growth factor (VEGF), fibroblast growth factor and platelet-derived growth factor, but not inhibition of VEGF alone, effectively suppresses angiogenesis and vessel maturation in endometriotic lesions. Hum Reprod 2006, 21:262–268.CrossRefPubMed Laschke MW, Elitzsch A, Vollmar B, Vajkoczy P, Menger MD: Combined inhibition of vascular endothelial growth factor (VEGF), fibroblast growth factor and platelet-derived growth factor, but not inhibition of VEGF alone, effectively suppresses angiogenesis and vessel maturation in endometriotic lesions. Hum Reprod 2006, 21:262–268.CrossRefPubMed
19.
go back to reference Fiedler U, Reiss Y, Scharpfenecker M, Grunow V, Koidl S, Thurston G, Gale NW, Witzenrath M, Rosseau S, Suttorp N, Sobke A, Herrmann M, Preissner KT, Vajkoczy P, Augustin HG: Angiopoietin-2 sensitizes endothelial cells to TNF-alpha and has a crucial role in the induction of inflammation. Nat Med 2006, 12:235–239.CrossRefPubMed Fiedler U, Reiss Y, Scharpfenecker M, Grunow V, Koidl S, Thurston G, Gale NW, Witzenrath M, Rosseau S, Suttorp N, Sobke A, Herrmann M, Preissner KT, Vajkoczy P, Augustin HG: Angiopoietin-2 sensitizes endothelial cells to TNF-alpha and has a crucial role in the induction of inflammation. Nat Med 2006, 12:235–239.CrossRefPubMed
20.
go back to reference Choi EY, Chavakis E, Czabanka MA, Langer HF, Fraemohs L, Economopoulou M, Kundu RK, Orlandi A, Zheng YY, Prieto DA, Ballantyne CM, Constant SL, Aird WC, Papayannopoulou T, Gahmberg CG, Udey MC, Vajkoczy P, Quertermous T, Dimmeler S, Weber C, Chavakis T: Del-1, an endogenous leukocyte-endothelial adhesion inhibitor, limits inflammatory cell recruitment. Science 2008, 322:1101–1104.CrossRefPubMedPubMedCentral Choi EY, Chavakis E, Czabanka MA, Langer HF, Fraemohs L, Economopoulou M, Kundu RK, Orlandi A, Zheng YY, Prieto DA, Ballantyne CM, Constant SL, Aird WC, Papayannopoulou T, Gahmberg CG, Udey MC, Vajkoczy P, Quertermous T, Dimmeler S, Weber C, Chavakis T: Del-1, an endogenous leukocyte-endothelial adhesion inhibitor, limits inflammatory cell recruitment. Science 2008, 322:1101–1104.CrossRefPubMedPubMedCentral
21.
go back to reference Rasi K, Piuhola J, Czabanka M, Sormunen R, Ilves M, Leskinen H, Rysä J, Kerkelä R, Janmey P, Heljasvaara R, Peuhkurinen K, Vuolteenaho O, Ruskoaho H, Vajkoczy P, Pihlajaniemi T, Eklund L: Collagen XV is necessary for modeling of the extracellular matrix and its deficiency predisposes to cardiomyopathy. Circ Res 2010, 107:1241–1252.CrossRefPubMed Rasi K, Piuhola J, Czabanka M, Sormunen R, Ilves M, Leskinen H, Rysä J, Kerkelä R, Janmey P, Heljasvaara R, Peuhkurinen K, Vuolteenaho O, Ruskoaho H, Vajkoczy P, Pihlajaniemi T, Eklund L: Collagen XV is necessary for modeling of the extracellular matrix and its deficiency predisposes to cardiomyopathy. Circ Res 2010, 107:1241–1252.CrossRefPubMed
22.
go back to reference Ostrowski RP, Colohan AR, Zhang JH: Molecular mechanisms of early brain injury after subarachnoid hemorrhage. Neurol Res 2006, 28:399–414.CrossRefPubMed Ostrowski RP, Colohan AR, Zhang JH: Molecular mechanisms of early brain injury after subarachnoid hemorrhage. Neurol Res 2006, 28:399–414.CrossRefPubMed
23.
go back to reference Tulamo R, Frösen J, Junnikkala S, Paetau A, Pitkäniemi J, Kangasniemi M, Niemelä M, Jääskeläinen J, Jokitalo E, Karatas A, Hernesniemi J, Meri S: Complement activation associates with saccular cerebral artery aneurysm wall degeneration and rupture. Neurosurgery 2006, 59:1069–1076. discussion 1076–7PubMed Tulamo R, Frösen J, Junnikkala S, Paetau A, Pitkäniemi J, Kangasniemi M, Niemelä M, Jääskeläinen J, Jokitalo E, Karatas A, Hernesniemi J, Meri S: Complement activation associates with saccular cerebral artery aneurysm wall degeneration and rupture. Neurosurgery 2006, 59:1069–1076. discussion 1076–7PubMed
24.
go back to reference Frösen J, Piippo A, Paetau A, Kangasniemi M, Niemelä M, Hernesniemi J, Jääskeläinen J: Remodeling of saccular cerebral artery aneurysm wall is associated with rupture: histological analysis of 24 unruptured and 42 ruptured cases. Stroke 2004, 35:2287–2293.CrossRefPubMed Frösen J, Piippo A, Paetau A, Kangasniemi M, Niemelä M, Hernesniemi J, Jääskeläinen J: Remodeling of saccular cerebral artery aneurysm wall is associated with rupture: histological analysis of 24 unruptured and 42 ruptured cases. Stroke 2004, 35:2287–2293.CrossRefPubMed
25.
go back to reference Kataoka K, Taneda M, Asai T, Kinoshita A, Ito M, Kuroda R: Structural fragility and inflammatory response of ruptured cerebral aneurysms. A comparative study between ruptured and unruptured cerebral aneurysms. Stroke 1999, 30:1396–1401.CrossRefPubMed Kataoka K, Taneda M, Asai T, Kinoshita A, Ito M, Kuroda R: Structural fragility and inflammatory response of ruptured cerebral aneurysms. A comparative study between ruptured and unruptured cerebral aneurysms. Stroke 1999, 30:1396–1401.CrossRefPubMed
26.
go back to reference Sarrafzadeh A, Schlenk F, Gericke C, Vajkoczy P: Relevance of cerebral interleukin-6 after aneurysmal subarachnoid hemorrhage. Neurocrit Care 2010, 13:339–346.CrossRefPubMed Sarrafzadeh A, Schlenk F, Gericke C, Vajkoczy P: Relevance of cerebral interleukin-6 after aneurysmal subarachnoid hemorrhage. Neurocrit Care 2010, 13:339–346.CrossRefPubMed
27.
go back to reference Fassbender K, Hodapp B, Rossol S, Bertsch T, Schmeck J, Schütt S, Fritzinger M, Horn P, Vajkoczy P, Wendel-Wellner M, Ragoschke A, Kuehl S, Brunner J, Schürer L, Schmiedeck P, Hennerici M: Endothelin-1 in subarachnoid hemorrhage: an acute-phase reactant produced by cerebrospinal fluid leukocytes. Stroke 2000, 31:2971–2975.CrossRefPubMed Fassbender K, Hodapp B, Rossol S, Bertsch T, Schmeck J, Schütt S, Fritzinger M, Horn P, Vajkoczy P, Wendel-Wellner M, Ragoschke A, Kuehl S, Brunner J, Schürer L, Schmiedeck P, Hennerici M: Endothelin-1 in subarachnoid hemorrhage: an acute-phase reactant produced by cerebrospinal fluid leukocytes. Stroke 2000, 31:2971–2975.CrossRefPubMed
Metadata
Title
Functional analysis of Pro-inflammatory properties within the cerebrospinal fluid after subarachnoid hemorrhage in vivo and in vitro
Authors
Ulf C Schneider
Jennifer Schiffler
Nahid Hakiy
Peter Horn
Peter Vajkoczy
Publication date
01-12-2012
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2012
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/1742-2094-9-28

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