Bromine (Br2) is a highly toxic dark-reddish liquid, which evaporates readily to a red vapor with a suffocating odor. World production of Br2 exceeds 300,000 tons per year. Exposure to Br2 causes acute lung injury, death from respiratory failure, and fibrosis. Because of the potential for industrial and transportation accidents to release of large amounts of Br2 in populated areas, Br2 presents a clear and present danger to public health. Few published studies have evaluated the acute and chronic sequelae of Br2 inhalation; treatment remains symptomatic and no effective countermeasures exist. Similar to human pathology, exposure of mice to Br2 causes reactive airway disease syndrome (RADS), increased permeability of the blood gas barrier to plasma proteins, and inflammation followed by sub-epithelial airway fibrosis and significant mortality. The overall purpose of this application is to identify the biochemical and molecular mechanisms responsible for these events and develop appropriate countermeasures. We propose that Br2 and hypobromous acid (HOBr-) interact with and fragment high molecular weight hyaluronan (H-HA), a ubiquitous matrix glycosaminoglycan, to generate highly inflammatory low molecular weight hyaluronan fragments (L-HA). L- HA binds to CD44 and Toll like receptor (TLR)-4, increases intracellular Ca+2 and activates TGF-?1, and RhoA in lung epithelial and airway smooth muscle cells. These events lead to RADS, increased epithelial permeability to plasma proteins, epithelial-mesenchymal cell transition (EMT) of airway cells, sub-epithelial fibrosis, an death from respiratory failure. In addition, we demonstrate for the first time the formation of brominated lipids in the lungs and plasma of mice exposed to Br2. These compounds, formed by the interaction of Br2 with lung plasmalogens, mediate and amplify Br2 lung injury and act as biomarkers of Br2 exposure. Based on solid data we posit that post-Br2 exposure administration of aerosolized Yabro? (a form of H-HA, currently in clinical trials in Europe for asthma), attenuates lung damage, enhances repair and decreases mortality. Experiments proposed in the first specific aim will assess physiological, biochemical, and morphological changes in mice exposed to Br2 and returned to room air for up to three weeks and test the effectiveness of aerosolized Yabro? administered post exposure to decrease lung injury and mortality. We will then identify the mechanisms by which Br2 damages rodent and human airway smooth muscle (ASM), bronchial and alveolar type II (ATII) cells. We posit that Br2, brominated lipids, and L-HA increase intracellular Ca2+ and activate RhoA, which lead to increased airway contractility and epithelial permeability. Experiments will: (i) determine membrane potentials by patch clamp; (ii) intracellular Ca+2 by fura-2 fluorescence; (iii) RhoA and ROCK activation; (iv) myosin light chain phosphorylation; and (v) (for epithelial cells) permeability to fluorescent dextrans. Finally, we wll isolate mouse tracheal rings at 1, 24, and 72 hr. post Br2 exposure and measure smooth muscle contraction in response to methacholine.

Public Health Relevance

World production of Br2 exceeds 300,000 tons per year and accidental spills into the environment during transportation and industrial accidents are common. Br2 inhalation may cause severe injury to the lungs and death from respiratory failure. The purpose of this application is to understand how bromine damages the lungs and find appropriate countermeasures.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project--Cooperative Agreements (U01)
Project #
1U01ES026458-01A1
Application #
8927967
Study Section
Special Emphasis Panel (ZRG1-MDCN-B (50))
Program Officer
Nadadur, Srikanth
Project Start
2015-08-15
Project End
2020-06-30
Budget Start
2015-08-15
Budget End
2016-06-30
Support Year
1
Fiscal Year
2015
Total Cost
$734,836
Indirect Cost
$188,243
Name
University of Alabama Birmingham
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Zhou, Ting; Yu, Zhihong; Jian, Ming-Yuan et al. (2018) Instillation of hyaluronan reverses acid instillation injury to the mammalian blood gas barrier. Am J Physiol Lung Cell Mol Physiol 314:L808-L821
Aggarwal, Saurabh; Ahmad, Israr; Lam, Adam et al. (2018) Heme scavenging reduces pulmonary endoplasmic reticulum stress, fibrosis, and emphysema. JCI Insight 3:
Jilling, Tamas; Ren, Changchun; Yee, Aaron et al. (2018) Exposure of neonatal mice to bromine impairs their alveolar development and lung function. Am J Physiol Lung Cell Mol Physiol 314:L137-L143
Duerr, Mark A; Palladino, Elisa N D; Hartman, Celine L et al. (2018) Bromofatty aldehyde derived from bromine exposure and myeloperoxidase and eosinophil peroxidase modify GSH and protein. J Lipid Res 59:696-705
Brand, Jeffrey D; Lazrak, Ahmed; Trombley, John E et al. (2018) Influenza-mediated reduction of lung epithelial ion channel activity leads to dysregulated pulmonary fluid homeostasis. JCI Insight 3:
Zhou, Ting; Song, Wei-Feng; Shang, You et al. (2018) Halogen Inhalation-Induced Lung Injury and Acute Respiratory Distress Syndrome. Chin Med J (Engl) 131:1214-1219
Collawn, James F; Bartoszewski, Rafal; Lazrak, Ahmad et al. (2018) Therapeutic attenuation of the epithelial sodium channel with a SPLUNC1-derived peptide in airway diseases. Am J Physiol Lung Cell Mol Physiol 314:L239-L242
Honavar, Jaideep; Doran, Stephen; Ricart, Karina et al. (2017) Nitrite therapy prevents chlorine gas toxicity in rabbits. Toxicol Lett 271:20-25
Lambert, James A; Carlisle, Matthew A; Lam, Adam et al. (2017) Mechanisms and Treatment of Halogen Inhalation-Induced Pulmonary and Systemic Injuries in Pregnant Mice. Hypertension 70:390-400
Ahmed, Khandaker A; Nichols, Alexandria L; Honavar, Jaideep et al. (2017) Measuring nitrate reductase activity from human and rodent tongues. Nitric Oxide 66:62-70

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