XIE, YANG
(2020)
Tissue-Specific effects of Pregnane X Receptor (PXR) and Estrogen Sulfotransferase (EST) on Hemorrhagic Shock-Induced Multiple Organ Injuries.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Hemorrhagic shock (HS) is a life-threatening condition associated with tissue hypoperfusion. HS may lead to dysfunction of multiple organs, including the liver and lung, as a result of oxidative stress and a secondary inflammatory stimulus. Pregnane X receptor (PXR) is a species-specific xenobiotic receptor that regulates the expression of drug-metabolizing enzymes (DMEs) such as the cytochrome P450 3A (CYP3A). Many clinical drugs, including those often prescribed to trauma patients, are known to activate PXR and induce CYP3A. However, it is unclear whether and how PXR plays a role in the regulation of DMEs in the setting of HS and HS-induced hepatic and extrahepatic injury. The estrogen sulfotransferase (EST, or SULT1E1) is a conjugating enzyme that sulfonates and deactivates estrogens. We have previously reported that the expression of EST is highly inducible in the livers of mouse models of multiple diseases, including obesity and type 2 diabetes, liver ischemia and reperfusion, and sepsis. The induction of EST by these disease conditions led to attenuated estrogen responses and have impact on the outcome of these diseases through varied mechanisms and often in a sex- and tissue-specific manner. It is unclear whether and how EST plays a role in HS-induced liver and lung injury. In this dissertation study, I studied the tissue-specific effects of PXR and EST on HS-induced hepatic injury and acute lung injury, respectively. My results demonstrated that (1) activation of PXR sensitizes mice to HS-induced hepatic injury but not acute lung injury. The unavoidable use of PXR-activating drugs in trauma patients has the potential to exacerbate HS-induced hepatic injury, which can be mitigated by the co-administration of anti-oxidative agents, CYP3A inhibitors, or PXR antagonists. (2) Genetic ablation or pharmacological inhibition of Est effectively protected female mice from HS-induced acute lung injury. The pulmonoprotective effect of Est ablation or inhibition was sex- and tissue-specific. HS-induced hepatic injury was not affected in Est knockout (Est-/-) mice. Pharmacological inhibition of EST may represent an effective approach in female patients to manage HS-induced acute lung injury. In summary, my dissertation research has uncovered the tissue-specific effects of PXR and EST on HS-induced multiple organ injuries.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
|
| Date: |
8 May 2020 |
| Date Type: |
Publication |
| Defense Date: |
3 March 2020 |
| Approval Date: |
8 May 2020 |
| Submission Date: |
17 April 2020 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
124 |
| 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: |
Hemorrhagic Shock, PXR, EST |
| Date Deposited: |
08 May 2020 11:59 |
| Last Modified: |
08 May 2020 11:59 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/38357 |
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