Role of TLR4 in Radiation-Induced Cardiomyopathy
Abstract
The continued threat of nuclear bombs or terrorist attacks puts deployed military Service members at risk of exposure to radiation to a large part of their body. Individuals who survive the acute injury from radiation will experience delayed adverse effects that occur within months to years after radiation. The heart is one of the organs that is sensitive to developing such adverse effects. Radiation-induced heart disease also occurs in cancer patients and cancer survivors, as a side effect of radiation therapy of the chest. Radiation-induced cardiomyopathy is therefore a clinical problem in both active military Service members and Veterans. Nonetheless, biological mechanisms by which radiation injures the heart are largely unknown, and medical treatments that prevent or reverse radiation-induced cardiomyopathy are not available. In our studies in mouse and rat models of radiation exposure, we have observed an increase in the proinflammatory mediator toll-like receptor 4 (TLR4), coinciding with increased expression of markers of immune cells in the heart from 4-7 days up to 6 months after irradiation. TLR4 plays a known role in myocardial inflammation after a heart attack and in heart failure, and inhibitors of TLR4 have been shown to reduce cardiac injury in many animal models, including cardiomyopathy due to trauma. Despite this extensive knowledge on the role of TLR4 in heart disease, its role in radiation-induced cardiomyopathy is unknown. We will use our well-established mouse models to examine whether inhibiting TLR4 will reduce inflammation, scar tissue formation, and cardiac function loss, both in the scenario of accidental whole body radiation exposure and in a mouse model that mimics radiation therapy. The topic area addressed is cardiomyopathy. If successful, our proposed studies will be the first to provide evidence that TLR4 inhibition reduces the adverse effects of radiation in the heart. These outcomes will be the basis of the development of TLR4 inhibitors as countermeasures against delayed effects in individuals who are accidentally exposed to radiation, as well as a pharmaceutical intervention in cancer survivors who suffer from radiation-induced heart disease as a late side effect of radiation therapy. Since TLR4 inhibitors are already being developed for other disease conditions, we expect that their path into the clinic as medical interventions of cardiomyopathy due to radiation exposure will be rapid.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910737
Entities
People
- Snehalata A Pawar
Organizations
- United States Army
- University of Arkansas for Medical Sciences