Radiation-induced production of pro-inflammatory and pro-fibrotic cytokines results in chronic and irreversible damage to the lungs. To date, no agent has demonstrated a sufficient safety profile to be utilized as a clinical drug for mitigating damage from exposure to radiation from accidental or terroristic nuclear events. Consequently, there is a great need for new, mechanistically-targeted drugs that can be utilized to mitigate radiation poisoning of humans following unintended exposure. Many studies have implicated sphingolipid metabolism as a critical mediator of inflammatory and fibrotic processes. Inflammatory and pro-fibrotic cytokines produced by radiation exposure (e.g. TNF¿ and TGF¿) activate sphingomyelinases and ceramidases to produce sphingosine, which is phosphorylated by sphingosine kinases (SK1 and SK2) to produce sphingosine 1-phosphate (S1P). It is established that SK activation and production of S1P are essential for signaling responses to inflammatory cytokines, including their ability to induce adhesion molecule expression via activation of NF?B. Similarly, collagen synthesis in response to TGF¿ is dependent on S1P production by SKs. Therefore, SKs are rational new targets for drugs that attenuate damaging inflammation and fibrosis. Apogee Biotechnology Corporation has identified the first orally-available SK inhibitors with activity in vitro and in vivo. The lead SK2 inhibitor, designated as ABC294640, has antitumor and anti-inflammatory activities in several in vivo models, while exhibiting very low toxicity to the animal. Our Preliminary Studies indicate that treatment of mice with ABC294640 protects against toxicity from total body or abdominal irradiation when the compound is given either pre-exposure or post-exposure. We hypothesize that suppression of SK2 activity by ABC294640 will mitigate pulmonary fibrotic damage from exposure to ionizing radiation. To establish justification for moving ABC294640 toward clinical trials for radiomitigation, we will conduct the following Specific Aims: 1) To determine the mechanism for ABC294640 protection against cytokine-induced fibrotic responses in cultured human fibroblasts; and 2) To characterize the ability of ABC294640 to protect against pulmonary fibrosis from thoracic irradiation. These studies will provide the experimental validation needed to justify future confirmatory studies in non- human primates, and ultimately clinical trials in humans.
Public Health Relevance Statement: Public Health Relevance: Exposure to ionizing radiation, which can occur through accidental or terroristic nuclear events, causes damage to a variety of organs including the lungs because of chronic inflammation and fibrosis. We have developed an orally-available inhibitor of the enzyme sphingosine kinase-2 that has anti-inflammatory activity in several animal models. We will examine the effects of this compound in mice to determine its ability to reduce radiation-induced lung damage.
Project Terms: Abdomen; Animal Model; Animals; Anti-inflammatory; Anti-Inflammatory Agents; Attenuated; base; Biochemical; Biological Assay; Biotechnology; C57BL/6 Mouse; Cancer Patient; Cell Adhesion Molecules; Cell membrane; Ceramidase; Ceramides; Chest; Chronic; Clinical; Clinical Trials; Collagen; cytokine; Data; Development; Dose; Drug Kinetics; Drug Targeting; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Event; Exhibits; Exposure to; Fibroblasts; Fibronectins; Fibrosis; Future; Gastrointestinal tract structure; Head Start Program; Histologic; Human; In Vitro; in vitro activity; in vivo; in vivo Model; Inflammation; Inflammation Mediators; Inflammatory; inhibitor/antagonist; insight; Interleukin-4; Ionizing radiation; irradiation; Lead; Lipids; Lung; Malignant Neoplasms; Measurement; Metabolism; Mus; nonhuman primate; Nuclear; Organ; Pathway interactions; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Poisoning; Process; Production; public health relevance; Pulmonary Fibrosis; Radiation; Reactive Oxygen Species; research clinical testing; response; Safety; Signal Transduction; Signaling Protein; Small Business Innovation Research Grant; Smooth Muscle Actin Staining Method; Sphingolipids; Sphingomyelinase; Sphingomyelins; Sphingosine; sphingosine 1-phosphate; sphingosine kinase; stability testing; Time; Tissues; TNF gene; Toxic effect; Toxicology; Validation; Wo
