A novel sulfur mustard (HD) vapor inhalation exposure model of pulmonary toxicity for the efficacy evaluation of candidate medical countermeasures

Perry, Mark R.; Neal, Matthew; Hawks, Roger; Pressburger, David; Satola, Jan; Triplett, Cheryl A.; Reed, Beth Glover; Andrews, Meredith; Harvilchuck, Jill A.; Nealy, Michael S.; Platoff, Gennady E.; Yeung, David T.

doi:10.1080/08958378.2021.1951401

Cited by 6 publications

(15 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To detect both beneficial and detrimental effects of the B2M-KO-TSC treatment, a target inhaled SM dose which resulted in 50% death on day 28 was selected. A previous study (Perry et al, 2021) of SM survival reported that the inhaled LD 50 on day 28 was 0.8 mg/kg. The respiratory parameter results for SM challenged rats in the present study are shown in Table 3.…”

Section: Resultsmentioning

confidence: 94%

“…SM Exposure System: SM is a federally regulated agent and SM exposure studies are conducted by a small number of certified laboratories. Battelle Memorial Institute is one such facility and utilizes a custom designed SM inhalation exposure system to simultaneously challenge up to 10 rats simultaneously to controlled SM vapor concentrations (Perry et al, 2021). SM vapor is generated by metering house air through a custom permeation vapor generator containing <10 ml of neat SM while a temperature-controlled aluminum block maintains the vapor generator at 50 C. The dilution airline is heat-traced to prevent vapor condensation.…”

Section: Methodsmentioning

confidence: 99%

“…In addition, animal exposure level (mg x min/m 3 ) was calculated from the mean SM concentration multiplied by the exposure duration. In preparation for the present study, SM lethality was evaluated for both inhaled SM dose and exposure level (Perry et al, 2021) and showed that inhaled SM dose reduced variation in lethality values. This consistency allows for a more reproducible animal model of SM toxicity which is optimal for evaluating MCM.…”

Section: Methodsmentioning

confidence: 99%

“…Conducting airway epithelial damage accounts for most of the mortality and morbidity after SM inhalation. This pathology includes plastic bronchitis, an obstructive condition in which rubbery/chalk-like plugs (casts) occlude the airway lumen and impede gas exchange (White et al, 2016), airway epithelial necrosis (Perry et al, 2021), and depletion of the basal cell pool (Ghanei et al, 2011). Persistent epithelial pathology, including regions of epithelial denudation, indicates that SM exposure causes an aberrant epithelial repair process that lasts months to years.…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Assessment of Beta-2 Microglobulin Gene Edited Airway Epithelial Stem Cells as a treatment for Sulfur Mustard Inhalation

et al. 2022

Self Cite

View full text Add to dashboard Cite

Respiratory system damage is the primary cause of mortality in individuals who are exposed to vesicating agents including sulfur mustard (SM). Despite these devastating health complications, there are no fielded therapeutics that are specific for such injuries. Previous studies reported that SM inhalation depleted the tracheobronchial airway epithelial stem cell (TSC) pool and supported the hypothesis, TSC replacement will restore airway epithelial integrity and improve health outcomes for SM-exposed individuals. TSC express Major Histocompatibility Complex (MHC-I) transplantation antigens which increases the chance that allogeneic TSC will be rejected by the patient’s immune system. However, previous studies reported that Beta-2 microglobulin (B2M) knockout cells lacked cell surface MHC-I and suggested that B2M knockout TSC would be tolerated as an allogeneic graft. This study used a Cas9 ribonucleoprotein (RNP) to generate B2M-knockout TSC, which are termed Universal Donor Stem Cells (UDSC). Whole genome sequencing identified few off-target modifications and demonstrated the specificity of the RNP approach. Functional assays demonstrated that UDSC retained their ability to self-renew and undergo multilineage differentiation. A preclinical model of SM inhalation was used to test UDSC efficacy and identify any treatment-associated adverse events. Adult male Sprague-Dawley rats were administered an inhaled dose of 0.8 mg/kg SM vapor which is the inhaled LD50 on day 28 post-challenge. On recovery day 2, vehicle or allogeneic Fisher rat UDSC were delivered intravenously (n = 30/group). Clinical parameters were recorded daily, and planned euthanasia occurred on post-challenge days 7, 14, and 28. The vehicle and UDSC treatment groups exhibited similar outcomes including survival and a lack of adverse events. These studies establish a baseline which can be used to further develop UDSC as a treatment for SM-induced airway disease.

show abstract

Section: Resultsmentioning

confidence: 94%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Assessment of Beta-2 Microglobulin Gene Edited Airway Epithelial Stem Cells as a treatment for Sulfur Mustard Inhalation

et al. 2022

Self Cite

View full text Add to dashboard Cite

show abstract

“…The program has a robust pipeline of funding to address other areas of concern during a radiation emergency, including the development of de-corporation agents that are amenable to mass casualty use, and the identification of biomarkers of radiation injury to triage and guide patient management and predict severity of late radiation-induced health outcomes. 4 The CCRP, which focuses on discovery research and early development, has supported the development of many animal models, 5 including those addressing ocular, 6 hematologic, 4 and lung 5 injuries arising from SM exposure. The program has also provided guidance and funding to allow the transition of many products to BARDA for further development.…”

Section: Fda Animal Rulementioning

confidence: 99%

Overlapping Science in Radiation and Sulfur Mustard Exposures of Skin and Lung: Consideration of Models, Mechanisms, Organ Systems, and Medical Countermeasures: Overlapping science in radiation and sulfur mustard injuries to lung and skin

Satyamitra,

Andres,

Bergmann

et al. 2023

Disaster med. public health prep.

Self Cite

View full text Add to dashboard Cite

Purpose: To summarize presentations and discussions from the 2022 trans-agency workshop titled “Overlapping Science in Radiation and Sulfur Mustard (SM) Exposures of Skin and Lung: Consideration of Models, Mechanisms, Organ Systems, and Medical Countermeasures.” Methods: Summary on topics includes: 1) an overview of the radiation and chemical countermeasure development programs and missions; 2) regulatory and industry perspectives for drugs and devices; 3) pathophysiology of skin and lung following radiation or SM exposure; 4) mechanisms of action/targets, biomarkers of injury; and 5) animal models that simulate anticipated clinical responses. Results: There are striking similarities between injuries caused by radiation and SM exposures. Primary outcomes from both types of exposure include acute injuries, while late complications comprise chronic inflammation, oxidative stress, and vascular dysfunction, which can culminate in fibrosis in both skin and lung organ systems. This workshop brought together academic and industrial researchers, medical practitioners, U.S. Government program officials and regulators to discuss lung-, and skin-specific animal models and biomarkers, novel pathways of injury and recovery, and paths to licensure for products to address radiation or SM injuries. Conclusions: Regular communications between the radiological and chemical injury research communities can enhance the state-of-the-science, provide a unique perspective on novel therapeutic strategies, and improve overall U.S. Government emergency preparedness.

show abstract

Targeting Tumor Necrosis Factor Alpha to Mitigate Lung Injury Induced by Mustard Vesicants and Radiation

Malaviya,

Laskin,

Businaro

et al. 2023

Disaster med. public health prep.

View full text Add to dashboard Cite

Pulmonary injury induced by mustard vesicants and radiation is characterized by DNA damage, oxidative stress, and inflammation. This is associated with increases in levels of inflammatory mediators including tumor necrosis factor (TNF)α in the lung and upregulation of its receptor TNFR1. Dysregulated production of TNFα and TNFα signaling have been implicated in lung injury, oxidative and nitrosative stress, apoptosis, and necrosis which contribute to tissue damage, chronic inflammation, airway hyperresponsiveness and tissue remodeling. These findings suggest that targeting production of TNFα or TNFα activity may represent an efficacious approach to mitigating lung toxicity induced by both mustards and radiation. This review summarizes current knowledge on the role of TNFα in pathologies associated with exposure to mustard vesicants and radiation, with a focus on the therapeutic potential of TNFα-targeting agents in reducing acute injury and chronic disease pathogenesis.

show abstract

A novel sulfur mustard (HD) vapor inhalation exposure model of pulmonary toxicity for the efficacy evaluation of candidate medical countermeasures

Cited by 6 publications

References 26 publications

Assessment of Beta-2 Microglobulin Gene Edited Airway Epithelial Stem Cells as a treatment for Sulfur Mustard Inhalation

Assessment of Beta-2 Microglobulin Gene Edited Airway Epithelial Stem Cells as a treatment for Sulfur Mustard Inhalation

Overlapping Science in Radiation and Sulfur Mustard Exposures of Skin and Lung: Consideration of Models, Mechanisms, Organ Systems, and Medical Countermeasures: Overlapping science in radiation and sulfur mustard injuries to lung and skin

Targeting Tumor Necrosis Factor Alpha to Mitigate Lung Injury Induced by Mustard Vesicants and Radiation

Contact Info

Product

Resources

About