Li, Lingjue
(2019)
ALTERATION OF CEREBRAL BLOOD FLOW AFTER NEUROVASCULAR INJURY.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Cardiac arrest (CA) and subarachnoid hemorrhage (SAH) are devastating neurovascular diseases with high mortality. Patients who survive the initial insult frequently have long-term neurological deficits. Delayed ischemia is recognized as one of the important mechanisms underlying poor outcome; however, strategies to improve cerebral perfusion failed to demonstrate efficacy in long-term outcome. Regulation of vascular tone in the cerebral microvasculature is key in determining cerebral blood flow (CBF), therefore, the evaluation of cerebral microcirculation alterations after CA and SAH can provide insights into the pathophysiology of neurovascular diseases and aid in the discovery of promising therapeutic targets.
The aim of this dissertation is to explore the role of cerebral microvascular alterations in an animal model and patients who are subjected to neurovascular diseases. In Chapter 2, we extensively reviewed the pharmacological therapies used for CA and global ischemia. We believe that combination therapy is promising which maximizes the effect of CBF restoration and off-sets potential adverse effects on cerebral microcirculation. In Chapter 3 and 4, we established an in-vivo multiphoton microscopy platform to evaluate the pathophysiology and pharmacology in a pediatric CA model. We observed the capillary no-reflow phenomenon and prolonged plasma mean transit time (MTT) in-vivo, identified arteriolar constriction and red blood cell (RBC) stasis as two potential targets to restore cerebral perfusion after CA. Inhibition of a vessel constrictive fatty acid, 20-HETE, dilated arterioles and attenuated MTT but had no effect on RBC stasis. Our results suggest the need for combination therapy to mitigate both the arteriolar constriction and the no-reflow phenomenon. In Chapter 5, we assessed 20-HETE and CO2 reactivity as two microcirculatory biomarkers in SAH patients. Plasma 20-HETE was not correlated with cerebrospinal fluid level, suggesting that local production of 20-HETE might underline the pathophysiology of SAH. We also found a wide range of CO2 reactivity in SAH patients which paved the way for future clinical biomarker investigation.
Collectively, this work identified new therapeutic targets in cerebral microcirculation, and provides rationale for CBF targeted treatment for neurovascular diseases. The clinical biomarker investigation provides novel insights in identifying vulnerable patient population to enable personalize treatment in the future.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
1 May 2019 |
| Date Type: |
Publication |
| Defense Date: |
5 April 2019 |
| Approval Date: |
1 May 2019 |
| Submission Date: |
29 April 2019 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
173 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Pharmacy > Pharmaceutical Sciences |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Cardiac arrest, subarachnoid hemorrhage, cerebral blood flow, microcirculation, 20-HETE, multiphoton microscopy. |
| Date Deposited: |
01 May 2019 12:47 |
| Last Modified: |
01 May 2019 12:47 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/36590 |
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