Pharmacologic ACE-Inhibition Mitigates Radiation-Induced Pneumonitis by Suppressing ACE-Expressing Lung Myeloid Cells

Sharma, Guru Prasad; Fish, Brian L.; Frei, Anne; Narayanan, Jayashree; Gasperetti, Tracy; Scholler, Dana; Pierce, Lauren; Szalewski, Nathan; Blue, Noah; Medhora, Meetha; Himburg, Heather A.

doi:10.1016/j.ijrobp.2022.01.023

Cited by 20 publications

(11 citation statements)

References 61 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition to mediating an improved survival after hematopoietic injury, we observed that DIZE treatment also mitigated late morbidities due to pulmonary and renal failure. After 13.5 Gy PBI, rats in this model manifest morbidity from radiation pneumonitis characterized by rapid respiration (25). Here, we observed DIZE treatment reduces pneumonitis related morbidities and mitigates the increase in respiration rate at day 70 after PBI seen in irradiated control rats.…”

Section: Discussionsupporting

confidence: 50%

“…For example, ACE inhibitors have been shown to increase survival during H-ARS in rodent and pig models (1,43,44). Additionally, extensive studies by our group in the rat PBI model have demonstrated ACE inhibitors mitigate lung and kidney DEARE (8,25,28). It is possible ACE2 agonism may be acting to negate downstream ACE signaling by reducing the available amount of Angiotensin II (Ang II) to bind and activate Angiotensin II type 1 receptor (AT1R).…”

Section: Discussionmentioning

confidence: 99%

“…BALF was collected immediately after euthanasia as previously described (25). Lavage fluid was centrifuged at 300g for 5 min at 48C to remove cellular components and the resulting BALF supernatant was 103 concentrated (Millipore Amicon Ultra-4 Centrifugal Filter Unit) prior to ELISA analysis.…”

Section: Bronchoalveolar Lavage Fluid (Balf) Collectionmentioning

confidence: 99%

See 2 more Smart Citations

Mitigation of Multi-Organ Radiation Injury with ACE2 Agonist Diminazene Aceturate

et al. 2022

Self Cite

View full text Add to dashboard Cite

The renin-angiotensin system (RAS) is known to regulate the pathogenesis of radiation-induced injury as inhibitors of the RAS enzyme angiotensin converting enzyme (ACE) have established function as mitigators of multi-organ radiation injury. To further elucidate the role of RAS signaling during both the acute and delayed syndromes of radiation exposure, we have evaluated whether pharmacologic modulation of alternate RAS enzyme angiotensin converting enzyme 2 (ACE2) reduces the pathogenesis of multi-organ radiation-induced injuries. Here, we demonstrate pharmacologic ACE2 activation with the small molecule ACE2 agonist diminazene aceturate (DIZE) improves survival in rat models of both hematologic acute radiation syndrome (H-ARS) and multi-organ delayed effects of acute radiation exposure (DEARE). In the H-ARS model, DIZE treatment increased 30-day survival by 30% compared to vehicle control rats after a LD50/30 total-body irradiation (TBI) dose of 7.75 Gy. In the mitigation of DEARE, ACE2 agonism with DIZE increased median survival by 30 days, reduced breathing rate, and reduced blood urea nitrogen (BUN) levels compared to control rats after partial-body irradiation (PBI) of 13.5 Gy. DIZE treatment was observed to have systemic effects which may explain the multi-organ benefits observed including mobilization of hematopoietic progenitors to the circulation and a reduction in plasma TGF-beta levels. These data suggest the ACE2 enzyme plays a critical role in the RAS-mediated pathogenesis of radiation injury and may be a potential therapeutic target for the development of medical countermeasures for acute radiation exposure.

show abstract

Section: Discussionsupporting

confidence: 50%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Mitigation of Multi-Organ Radiation Injury with ACE2 Agonist Diminazene Aceturate

et al. 2022

Self Cite

View full text Add to dashboard Cite

show abstract

“…Drugs like angiotensin-converting enzyme (ACE) inhibitors, which block elements that contribute to hypertension as their primary mechanism of action, were shown to reduce lethality associated with radiation exposure (both hematopoietic, 39 and from late lung complications). 40 , 41 It is conceivable that this product could also find use in the mitigation of certain chemical-induced lung complications. Still other products in advanced development for radiation-induced dermal 42 or lung 43 indications could be considered for potential use in an SM exposure scenario, and those under study for SM could be applied to the radiation space.…”

Section: Current Crn Environmentmentioning

confidence: 99%

Radiation and Chemical Program Research for Multi-Utility and Repurposed Countermeasures: A US Department of Health and Human Services Agencies Perspective

Rios,

Garcia,

Hogdahl

et al. 2024

Disaster med. public health prep.

View full text Add to dashboard Cite

Although chemical and radiological agents cause toxicity through different mechanisms, the multiorgan injuries caused by these threats share similarities that convene on the level of basic biological responses. This publication will discuss these areas of convergence and explore “multi-utility” approaches that could be leveraged to address common injury mechanisms underlying actions of chemical and radiological agents in a threat-agnostic manner. In addition, we will provide an overview of the current state of radiological and chemical threat research, discuss the US Government’s efforts toward medical preparedness, and identify potential areas for collaboration geared toward enhancing preparedness and response against radiological and chemical threats. We also will discuss previous regulatory experience to provide insight on how to navigate regulatory paths for US Food and Drug Administration (FDA) approval/licensure/clearance for products addressing chemical or radiological/nuclear threats. This publication follows a 2022 trans-agency meeting titled, “Overlapping Science in Radiation and Sulfur Mustard Exposures of Skin and Lung: Consideration of Models, Mechanisms, Organ Systems, and Medical Countermeasures,” sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), a part of the National Institutes of Health (NIH). Discussions from this meeting explored the overlapping nature of radiation and chemical injury and spurred increased interest in how preparedness for one threat leads to preparedness for the other. Herein, subject matter experts from the NIAID and the Biomedical Advanced Research and Development Authority (BARDA), a part of the Administration for Strategic Preparedness and Response (ASPR), summarize the knowledge gained from recently funded biomedical research, as well as insights from the 2022 meeting. These topics include identification of common areas for collaboration, potential use of biomarkers of injury to identify injuries caused by both hazards, and common and widely available treatments that could treat damage caused by radiological or chemical threats.

show abstract

“…However, there is inadequate evidence to conclude its effect on mortality and long-term outcomes in RP patients. 6,7 Amifostine is another widely studied pharmacological antioxidant reported to reduce RP when administered daily prior to RT. However, further studies have not confirmed this finding, and hence not recommended.…”

Section: Introductionmentioning

confidence: 99%

Amomum subulatum mitigates experimental thoracic radiation-induced lung injury by regulating antioxidant status and inflammatory responses

et al. 2023

View full text Add to dashboard Cite

show abstract

Pharmacologic ACE-Inhibition Mitigates Radiation-Induced Pneumonitis by Suppressing ACE-Expressing Lung Myeloid Cells

Cited by 20 publications

References 61 publications

Mitigation of Multi-Organ Radiation Injury with ACE2 Agonist Diminazene Aceturate

Mitigation of Multi-Organ Radiation Injury with ACE2 Agonist Diminazene Aceturate

Radiation and Chemical Program Research for Multi-Utility and Repurposed Countermeasures: A US Department of Health and Human Services Agencies Perspective

Amomum subulatum mitigates experimental thoracic radiation-induced lung injury by regulating antioxidant status and inflammatory responses

Contact Info

Product

Resources

About