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A7554 - A Single Cutaneous Exposure to Vesicant Arsenicals Causes Fibrotic Constrictive Bronchiolitis in Mice Lungs
Author Block: R. Surolia1, F. Li1, H. Li1, Z. Wang1, M. P. Kashyap2, R. K. Shrivastava2, H. Kim3, A. Ahmad4, A. Agarwal5, M. Athar2, V. B. Antony6; 1Department of Medicine, Univ of Alabama, Birmingham, AL, United States, 2Department of Dermatology, Univ of Alabama, Birmingham, AL, United States, 3Department of radiology, Univ of Alabama, Birmingham, AL, United States, 4Department of Anesthesiology, University of Alabama at Birmingham, Birmingham, AL, United States, 5Department of Medicine-nephrology, Univ of Alabama, Birmingham, AL, United States, 6Univ of Alabama at Birmingham, Birmingham, AL, United States.
Aim: The class of chemical ‘war-threats’ agents known as vesicants includes among others arsenicals and mustard agents. Stockpiles of weaponized arsenic based vesicants developed for World War II still exist. The exposure to these vesicants causes deleterious effect on skin after a single exposure, and progresses to multi-organ failure and death. The survivors of this exposure may have delayed effects on the lung. The delayed effects of vesicant arsenical exposure on lung health are unknown. We have used four major arsenical vesicants namely Lewisite, Diphenyl chloroarsine (DPCL), Diethyl chloroarsine (DECL), and Diphenyl cynoarsine (DPCY) for the study of the chronic injury effects on lungs after single cutaneous exposure. Methods: Delayed effect of single cutaneous exposure to various arsenicals on lungs was studied 42 weeks post exposure. For the study of chronic lung injury induced by skin exposures to various arsenicals and changes in lung morphology, the experimental mice were subjected to micro computed tomography (Micro-CT) imaging. Respiratory system mechanics following increasing methacholine challenges in arsenicals exposed mice were performed using FlexiVent. Lung tissue samples were used for histology and hydroxyproline assay. Results: In vivo, color-scaled results of micro CT analysis by segmentation based on tissue density into mice lung exposed to Lewisite demonstrated increased density in lung parenchymal region. Increased denser areas were observed in peribronchial region in DPCL and DECL exposed mice lungs. DPCY showed destruction of lung tissue. Minimal injury was observed in DECL exposed mice lung. Following single exposure to various arsenicals, airway resistance to inhaled methacholine increases compared to saline (control) treated mice as a result of fibrotic constrictive bronchiolitis with peribronchial fibrosis. In comparison to control mice, mice exposed to lewisite displayed greater maximal (~2.2 fold) responses at 40 mg/kg b. wt. methacholine. Other arsenicals also demonstrated statistically significant increases in airway resistance. The hydroxyproline content was increased by approximately 3-fold in the Lewisite exposed mice lungs when compared with the controls. DPCL, DPCY and DECL exposed mice demonstrated 2-fold increase in hydroxyproline content. The immunostaining in control and arsenical exposed mice lung sections showed increased collagen I and α-SMA expression around the airways.Conclusion: The micro-CT images, lung function tests and histological data demonstrate the presence of fibrotic constrictive bronchiolitis in arsenical (Lewisite, DPCL, DECL and DPCY) exposed mice.