Cao, Shuo
(2020)
Dysregulation of Pulmonary Surfactant Protein Induced By Arsenic In Acute Promyelocytic Leukemia Chemotherapy.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
This is the latest version of this item.
Abstract
Arsenic chemotherapy for Acute Promyelocytic Leukemia (APL) can lead to pulmonary complications. When severe, acute lung injury can occur, which can be lethal and is a serious public health problem with high incidence and mortality rate in adults, and with few drugs available for the efficient treatment in clinic. However, the mechanism of arsenic-induced respiratory failure is unknown. We hypothesize that the maintenance of alveolar surfactant protein biosynthesis will prevent adverse pulmonary events during arsenic chemotherapy. We examined transcript levels of surfactant proteins and their regulators in C57BL6/J mice and in human alveolar NCI-H441 cells. Arsenic decreased surfactant protein A (SFPTA), SFPTB, SFPTC, SFPTD transcripts in a dose- and time- dependent manner in vivo and in vitro. Of the encoded proteins, SFTPB is critical to the lower surface tension at the air-liquid interface within the alveoli of the lung and mice lacking functional SFPTB succumb to respiratory failure shortly after birth. SFPTB transcription is regulated by NK2 homeobox 1 (NKX2-1) and SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4 (SMARCA4). Arsenic decreased NKX2-1 and SMARCA4 transcripts in a dose- and time-dependent manner in vivo and in vitro. In NCI-H441 cells transfected with a luciferase promoter construct, arsenic inhibited SFPTB promotor activity. 5-Aza-2’-deoxycytidine, an inhibitor of DNA methylation, partially restored SFPTB promotor activity inhibited by arsenic. Arsenic decreased NKX2-1 binding to nuclear protein extract from NCI-H441 cells as assessed by electrophoretic mobility shift assay (EMSA). Treatment of NCI-H441 cells with dexamethasone restored SFTPB, NKX2-1, and SMARCA4 transcripts after arsenic treatment. Because corticosteroid theapy is recommended for pulmonary complications in APL patient, this study supports this approach and suggests the possible mechanism involves surfactant protein maintenance.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
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| ETD Committee: |
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| Date: |
30 July 2020 |
| Date Type: |
Publication |
| Defense Date: |
8 June 2020 |
| Approval Date: |
30 July 2020 |
| Submission Date: |
8 June 2020 |
| Access Restriction: |
2 year -- Restrict access to University of Pittsburgh for a period of 2 years. |
| Number of Pages: |
66 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Public Health > Environmental and Occupational Health |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Acute lung injury, SFTPB, NKX2-1, SMARCA4, arsenic, leukemia, chemotherapy |
| Date Deposited: |
31 Jul 2020 03:05 |
| Last Modified: |
01 Jul 2022 05:17 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/39306 |
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Dysregulation of Pulmonary Surfactant Protein Induced By Arsenic In Acute Promyelocytic Leukemia Chemotherapy. (deposited 31 Jul 2020 03:05)
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