We seek to understand the pathogenesis of delayed cerebral arterial construction after subarachnoid hemorrhage (SAH) due to aneurysmal rupture and develop an effective treatment regimen for patients. Recent in vivo and in vitro experiments lead us to propose a specific hypothesis for an important underlying mechanism of chronic cerebral vasospasm after SAH: Complement protein extravasated into the subarachnoid clot is activated by erythrocytes denatured due to """"""""aging"""""""" in this non- supportive environment, which stimulates inflammation and greatly accelerates hemolysis in the subarachnoid clot. We have shown that both inflammation and hemolysis provide major vasoconstrictive stimuli to cerebral arteries surrounded by subarachnoid blood. This hypothesis will be tested studying the movement of serum complement protein into subarachnoid clot and its dependence on """"""""aging"""""""" of subarachnoid erythrocytes using non-specific tracers, radiolabelled complement protein, and immunohistochemistry. A correlation between inflammation and generation of activated chemotactic complement will be sought. The rate of hemolysis in subarachnoid blood clot will be determined as a function of time, an a specific dependence on complement- induced hemolysis determined by immunohistochemical identification of """"""""membrane attack complex."""""""" The prophylactic value of immunosuppression by partial specific decomplementation will be determined in our animal model of cerebral vasospasm, angiographically as well as more specifically against hemolysis and subarachnoid inflammation. By inhibiting rapid hemolysis and activation of complement, a whole cycle of threatening events may be averted. In vitro studies will focus on identification of the vasoactive factors in erythrocyte lysate and their possible role in activation of the protein kinase C system.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL022573-16
Application #
3336983
Study Section
Neurology A Study Section (NEUA)
Project Start
1978-12-01
Project End
1995-06-30
Budget Start
1993-07-01
Budget End
1994-06-30
Support Year
16
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02199
Tummala, Ramachandra P; Sheth, Rishi N; Heros, Roberto C (2006) Hemodilution and fluid management in neurosurgery. Clin Neurosurg 53:238-51
Kawamata, T; Peterson, J W; Bun, T et al. (1997) Augmentation of both hemolysate-induced contraction and activation of protein kinase C by submaximum activation in canine cerebral arteries in vitro. J Neurosurg 87:908-15
Manno, E M; Gress, D R; Ogilvy, C S et al. (1997) The safety and efficacy of cyclosporine A in the prevention of vasospasm in patients with Fisher grade 3 subarachnoid hemorrhages: a pilot study. Neurosurgery 40:289-93
Vacanti, F X; Kwun, B D (1996) Carbon dioxide at anesthetic levels protects against irreversible damage during spinal cord ischemia. J Surg Res 62:59-62
Vacanti, F X; Kwun, B D (1996) Vascular occlusion produced over 24 hours increases spinal cord tolerance to occlusion. J Surg Res 62:29-31
Bulter, W E; Peterson, J W; Zervas, N T et al. (1996) Intracellular calcium, myosin light chain phosphorylation, and contractile force in experimental cerebral vasospasm. Neurosurgery 38:781-7;discussion 787-8
Sakas, D E; Whittaker, K W; Crowell, R M et al. (1996) Perfluorocarbons: recent developments and implications for neurosurgery. J Neurosurg 85:248-54
Kaoutzanis, M C; Peterson, J W; Anderson, R R et al. (1995) Basic mechanism of in vitro pulsed-dye laser-induced vasodilation. J Neurosurg 82:256-61
Kwun, B D; Vacanti, F X (1995) Mild hypothermia protects against irreversible damage during prolonged spinal cord ischemia. J Surg Res 59:780-2
Yokota, M; Peterson, J W; Kaoutzanis, M C et al. (1995) Protein kinase C and diacylglycerol content in basilar arteries during experimental cerebral vasospasm in the dog. J Neurosurg 82:834-40

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