Link to the University of Pittsburgh Homepage
Link to the University Library System Homepage Link to the Contact Us Form

Dysregulation of Pulmonary Surfactant Protein Induced By Arsenic In Acute Promyelocytic Leukemia Chemotherapy

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 (Unpublished)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.

[img] PDF
Submitted Version
Restricted to University of Pittsburgh users only until June 2022.

Download (2MB) | Request a Copy

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.


Share

Citation/Export:
Social Networking:
Share |

Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Cao, Shuoshc87@pitt.edushc87
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairBarchowsky, Aaronaab20@pitt.eduaab20
Thesis Advisorleikauf, georgegleikauf@pitt.edugleikauf
Committee Memberredner, robertredner@pitt.eduredner
Committee Membermallampalli, ramarama.mallampalli2@osumc.edu
Committee Memberdi, yuanpupeterdi@pitt.edupeterdi
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: Graduate 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: 31 Jul 2020 03:05
URI: http://d-scholarship.pitt.edu/id/eprint/39306

Available Versions of this Item

  • Dysregulation of Pulmonary Surfactant Protein Induced By Arsenic In Acute Promyelocytic Leukemia Chemotherapy. (deposited 31 Jul 2020 03:05) [Currently Displayed]

Metrics

Monthly Views for the past 3 years

Plum Analytics


Actions (login required)

View Item View Item