Mouse Modeling of Key Clinical Complications of Sickle Cell Disease
The key manifestation of Sickle Cell Disease (SCD) is sickle-shaped erythrocytes (red blood cells), which are prone to adhesion to and blockage of blood vessels. SCD is characterized by acute and chronic pain. Acute pain is associated with episodic vaso-occlusion, referred to as vaso-occlusion crisis (VOC), and can be severe. Indeed, pain from VOC is the primary cause for hospitalization in SCD patients. Due to the lack of understanding underlying the mechanism of this disease-specific acute pain, opioids remain the only current treatment. To further understand pain associated with VOC, it is necessary to develop functional pre-clinical models of VOC. We recently developed a new model of VOC in transgenic mice with SCD in which the mice were exposed to cold ambient temperature. Exposure to cold induced vaso-occlusion and robust acute hyperalgesia. The present study compared the efficacy of the exposure to cold model to the established hypoxia/reoxygenation model, in producing hyperalgesia. It was found that both exposure to cold and hypoxia/reoxygenation produced robust mechanical hyperalgesia, but neither had disease-specific impacts on deep tissue hyperalgesia. Using the exposure to cold model, we explored the role of lysophosphatidic acid (LPA), a pro-nociceptive bioactive lipid molecule, in VOC-associated acute pain. LPA levels in blood were elevated following exposure to cold. Increased LPA following exposure to cold suggests its role in VOC and associated pain, which aligns with previous known actions of LPA as a thrombosis and pain promoting factor. LPA may be a potential therapeutic target for managing VOC and its associated pain, and its effectiveness can be investigated using these new mouse models of VOC in SCD.