Long-acting PGE2 and Lisinopril Mitigate H-ARS.

Thrombocytopenia is a major complication in hematopoietic-acute radiation syndrome (H-ARS) that increases the risk of mortality from uncontrolled hemorrhage. There is a great demand for new therapies to improve survival and mitigate bleeding in H-ARS. Thrombopoiesis requires interactions between megakaryocytes (MKs) and endothelial cells. 16, 16-dimethyl prostaglandin E2 (dmPGE2), a longer-acting analogue of PGE2, promotes hematopoietic recovery after total-body irradiation (TBI), and various angiotensin-converting enzyme (ACE) inhibitors mitigate endothelial injury after radiation exposure. Here, we tested a combination therapy of dmPGE2 and lisinopril to mitigate thrombocytopenia in murine models of H-ARS following TBI. After 7.75 Gy TBI, dmPGE2 and lisinopril each increased survival relative to vehicle controls. Importantly, combined dmPGE2 and lisinopril therapy enhanced survival greater than either individual agent. Studies performed after 4 Gy TBI revealed reduced numbers of marrow MKs and circulating platelets. In addition, sublethal TBI induced abnormalities both in MK maturation and in in vitro and in vivo platelet function. dmPGE2, alone and in combination with lisinopril, improved recovery of marrow MKs and peripheral platelets. Finally, sublethal TBI transiently reduced the number of marrow Lin-CD45-CD31+Sca-1- sinusoidal endothelial cells, while combined dmPGE2 and lisinopril treatment, but not single-agent treatment, accelerated their recovery. Taken together, these data support the concept that combined dmPGE2 and lisinopril therapy improves thrombocytopenia and survival by promoting recovery of the MK lineage, as well as the MK niche, in the setting of H-ARS.

Platelets an inflammatory force in transplantation.

Platelet interactions with dendritic cells, T cells and B cells have been best studied in vasculitis and atherosclerosis, but similar mechanisms may contribute to acute and chronic vascular lesions in transplants. In acute inflammation, platelets adhere to vessels and release mediators that increase endothelial cell activation and leukocyte recruitment. Adherent platelets can also augment antibody and cellular immune responses. Activated platelets recruit T cells and initiate a feedback loop. In this loop, platelets secrete chemokines to recruit T cells, and then activated T cells stimulate platelets through CD40-CD154 interactions to secrete more chemokines thereby recruiting more T cells. The interaction of platelets and T cells is enhanced by P-selectin/PSGL-1 stimulation. Both helper and cytotoxic T cells are stimulated by platelets. Antibody production that is stimulated through increased helper T-cell function can activate complement. This sets up another activation loop because platelets express receptors for antibodies and complement. In addition to inflammation, platelets stimulate repair by releasing growth factors and chemokines to recruit circulating vascular progenitor cells. These repair mechanisms could promote the replacement of donor parenchmal cells with recipient cells and contribute to vascuplopathy. This review discusses the interplay of platelets and the immune system in relation to transplantation.

A carcinoid tumor in the gallbladder of a dog.

A cholecystectomy was performed on a 10-year-old spayed female mixed-breed dog with chronic weight loss, persistently increased liver enzyme activities, and cholecystomegaly identified by ultrasonographic examination. A subsequent diagnosis of a biliary carcinoid was made based on a neuroendocrine-type histologic pattern, cytoplasmic argyrophilia by Grimelius staining, immunopositivity for chromogranin A, and the ultrastructural finding of cytoplasmic secretory granules in neoplastic cells. Extrahepatic biliary carcinoid tumors are rare tumors of humans and have not been documented in domestic animals.