Inhibition of BRD4 prevents peribronchial fibrosis in mice with cutaneous lewisite exposure

Huaxiu Zeng^1,2Pooja Singh^1,2Rajesh Sinha^1,2Crystal T Stephens²Aftab Ahmad^1,3Mohammad Athar⁴Veena B Antony^2*

• ¹University of Alabama at Birmingham, Birmingham, United States
• ²Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, BIRMINGHAM, United States
• ³The University of Alabama at Birmingham Department of Anesthesiology and Perioperative Medicine, Birmingham, United States
• ⁴The University of Alabama at Birmingham Department of Dermatology, Birmingham, United States

Arsenicals are members of the vesicants class of chemical warfare weapons, which are extremely toxic, reactive, and induce a strong inflammatory reaction. One of the vesicants is a lewisite, which is only utilized as a chemical warfare agent and is not found in nature. Lewisite is a strong cutaneous irritant and triggers inflammatory immune response via NF-κB and cytokine release and 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. 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 domain (BET) family, bromodomain 4 (BRD4) is essential for controlling the transcription of genes related to inflammation, proliferation, and the cell cycle. 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 IL6 and α-SMA after treatment of CPI-0610 in lewisite-exposed mice. We provided the first experimental demonstration that inhibition of BRD4 rescues lewisite-induced pulmonary fibrosis 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 fibrosis.