Advisor(s)
Veena Antony
Mohammad Athar
Committee Member(s)
Fu Jun Li
Han-Fei Ding
Mohammad Athar
Prasanna Krishnamurthy
Yuhua Song
School
Joint Health Sciences (Interdisciplinary)
Document Type
Dissertation
Department (new version)
Biomedical Engineering
Date of Award
9-11-2025
Abstract
Arsenicals are members of one of the most important global environmental vesicants and are a persistent bio accumulative carcinogen. One of the vesicants and chemical warfare agents is lewisite, which causes lung injury with pulmonary edema, hemorrhage, and respiratory failure. A single cutaneous exposure to lewisite in mice induces systemic lung injury through arsenical-mediated mechanisms. Some subjects develop Bronchiolitis Obliterans Syndrome (BOS) where there is evidence of airway dysfunction and pathologic narrowing of the airways with extracellular protein deposition and fibroblast invasion. In vitro for human lung endothelial cells, Phenyl arsine Oxide (PAO) exposure, as surrogate of lewisite, leads to a dose- and time-dependent upregulation of endoplasmic stress-related proteins, including XBP1, GRP78, and CHOP. This ER stress induced barrier dysfunction in endothelial cells increases migration of cells and inhibition of barrier tight junction proteins. Endothelial disruption not only facilitates further systemic distribution of toxicants but can contribute to broader pathological effects. While British anti-lewisite (BAL, dimercaprol) is the only approved therapy for arsenical antidotes, it has two disadvantages of inherent toxicity and difficult administration in the field. Hence, the development of effective antidotes to mitigate injury caused by exposure to these agents is highly essential. A member of the Bromodomain and Extra Terminal (BET) domain family, bromodomain 4 (BRD4) is essential for controlling the transcription of genes related to inflammation, proliferation, and the cell cycle. The bromodomain protein 4 (BRD4) inhibitor, CPI-0610 (Pelabresib), is recognized as an anti-inflammatory agent. The present study elucidates that we found a decrease in the expression of Interleukin-6 (IL-6) and Alpha smooth muscle actin (α-SMA) after treatment of CPI-0610 in lewisite-exposed mice. We provided the first experimental demonstration that inhibition of BRD4 rescues lewisite-induced Peribronchial Fibrosis (PF) in a murine model. Our results suggested that CPI-0610, with a manageable clinical safety profile, maybe a novel therapy for cutaneous arsenical-induced pulmonary peribronchial fibrosis.
ProQuest ID
Recommended Citation
Zeng, Huaxiu, "Pao Induces Er Stress In Endothelial Cells Leading To Barrier Function Dysfunction And Inhibition Of Brd4 Prevents Lewisite-Induced Peribronchial Fibrosis" (2025). All ETDs from UAB. 7406.
https://digitalcommons.library.uab.edu/etd-collection/7406
