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Ex-vivo Human Skin Model for Studying Nitrogen Mustard-Induced Skin Damage and Injury Mechanisms
Alexa Rivera del Rio Hernendez, MD; Naresh Mahajan, PhD; Aniekanabasi Ufot, MS; Jose Antonio Arellano, MD; Hamid Malekzadeh, MD; Yusuf Surucu, MD; Samantha Lee Bosco, BS; Ethan Banks, Undergraduate; Fuat Baris Bengur, MD; Shawn Loder, MD; Jeffrey A. Gusenoff, MD; Francesco M. Egro, MBChB, MSc, MRCS; J. Peter Rubin, MD, FACS, MBA; Asim Ejaz, PhD
University of Pittsburgh
2024-12-11
Presenter: Alexa Rivera del Rio Hernandez, MD
Affidavit:
I certify that the material proposed for presentation in this abstract has not been published in any scientific journal or previously presented at a major meeting.
Director Name: J. Peter Rubin
Author Category: Fellow Plastic Surgery
Presentation Category: Basic Science Research
Abstract Category: General Reconstruction
INTRODUCTION: Mustard agents are accessible and toxic chemical warfare agents (CWA) that cause severe skin injuries and blistering, primarily through DNA alkylation. The limited physiological relevance of animals to humans hampers the development and testing of effective therapeutic alternatives for skin damage secondary to mustard agents. Possession of CWAs by militant organizations brings up the need for research efforts to develop potent mitigators. We utilized an ex vivo human skin model to study the effects of nitrogen mustard (NM) within the skin and to delineate molecular pathways of tissue injury and cell death.
METHODS: We applied NM (30 mg/cm2 ) to human skin samples, and utilized acetone as the control intervention. Treated areas were assessed at 0.5, 6, 24, 120 and 200 hours post-application for histological, immunofluorescence and gene expression analyses.
RESULTS: NM exposure led to pyknosis, ballooning and focal epidermis-dermis separation with a significant lymphocytic inflammation. TUNEL staining demonstrated progressive cell death, which was near-complete by 200 hours and affected all layers. Heightened apoptosis and inflammation was demonstrated by increased PARP, Caspase 3 and TNF-alpha expression, while anti-apoptotic gene expression decreased over time.
CONCLUSION: Nitrogen mustard induces characteristic histological and molecular changes in our perfused human skin that mirror sulfur mustard-induced injuries. Gene expression indicates a trend towards apoptosis and inflammation. Our results align with published results on the mechanism of action of NM, establishing our model as a reliable platform to further study NM-induced skin injuries and potential mitigators that will block or reverse the induced damage.
