Mast Cells in Sulfur Mustard Exposure: Novel Targets for Modulation to Develop Therapies Against the Long-Term Health Effects in Gulf War Veterans
Abstract
Objective and Rationale: The objective of this Tier I Discovery award is to identify a novel immune mechanism of sulfur mustard [mustard gas; bis(2-chloroethyl) sulfide); SM] pathophysiological effects that could contribute to Gulf War Illness (GWI) mediated through mast cells. Hence, under this proposal to obtain pilot data, we will embark on understanding the role of mast cell-induced immune responses in vesicant inhalation and skin exposures using nitrogen mustard [NM; bis(2-chloroethyl) methylamine] as a surrogate for SM. It is reported that during the Gulf War (GW; 1990-1991) U.S. troops could have been exposed to a number of chemicals including the low-level chemical warfare agents like SM released by the destruction of Iraqi facilities. Studies in the U.S. and other locations have dependably established that approximately 25%-32% of GW Veterans suffer from a disorder with variable symptoms including fatigue, headaches, cognitive dysfunction, musculoskeletal pain, and respiratory, gastrointestinal, and dermatologic complaints. These symptoms of GWI relate closely to the long-term consequences observed with SM exposure. Mast cells are well known to contribute to allergic inflammatory diseases, but also have wide-ranging effects on many physiological systems that are affected in GWI including pulmonary, dermal, gastrointestinal, and nervous systems when activated (e.g., degranulation). Importantly, a role for mast cells has been suggested in the mechanism of vesicating chemical agents like SM-induced inflammatory response and tissue damage. Therefore, we aim to uncover a novel mechanism of SM toxicity that is mediated by mast cells and that could also be applicable to other chemical exposures in GWI. Potential clinical applications, benefits, and risks for Veterans with GWI: The proposed studies will have a strong potential to aid in understanding the mechanism of the inflammatory process and immune response following low exposures to mustard warfare agent SM and identification of applicable and effective markers for therapeutic approaches with a strong translational impact to treat some problems of GWI. Since there are no effective treatments for GWI, therapeutics targeted towards mast cells and their products could be beneficial in GWI Veterans instead of treating symptoms. The mast cell inhibitors therapies can be important targeted therapies to treat inflammatory and immune-related multiple symptoms in GWI Veterans, which can be from chemical exposures alone or in combination with other warzone environmental factors such as silica and oil fires. Projected time to achieve a patient-related outcome: The current proposal is aimed to generate initial pilot data to identify mast cell activation as contributor to GWI, which could serve as an important biomarker and therapeutic target using NM a surrogate of SM. Based on the results obtained from studies under this proposal, we plan to conduct further comprehensive studies with mast cells with SM to obtain relevant pre-clinical data to proceed further for any clinical studies. Thus, this timeline is not defined at this time. Likely contributions of this study in advancing the field of GWI research: Identification of mast cell activation can significantly contribute to GWI by serving as an important biomarker and therapeutic target in vesicating agents-related GWI pathogenesis. In addition, the other biomarkers related to mast cell activation could also be important in GWI and help in this area of research by identifying targeted therapies to effectively treat GWI. Also, the development of vesicating chemical agent-induced animal model will not only contribute in elucidating the possible molecular and physiological mechanisms underlying GWI but also can be used for efficacy studies to identify effective therapies by us and other research groups. We plan to further study the role of mast cells in other exposures including extreme heat, silic
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810169
Entities
People
- Neera Tewari-Singh
Organizations
- United States Army
- University of Colorado Denver