The overall objective of this research is to understand the mechanisms controlling the proliferation and differentiation of hemopoietic stem cells within the hemopoietic microenvironment. Specifically, we are concerned with the pathogenesis of acquired aplastic anemia and believe that our findings demonstrating that mice with chronic inflammation have impaired recovery from hematosuppressive injury may provide insight about the mechanisms of bone marrow failure. Therefore, we propose to study mice with a chronic inflammatory lesion with three specific aims. In the first, we will determine if chronic inflammation sensitizes stem cells to irradiation by exposing mice with a chronic inflammatory lesion to graded doses of total body irradiation and then measuring the dose-response of surviving hemopoietic stem cells using the Till and Mcculloch stem cell colony assay. Irradiation will be carried out in vivo and in vitro. The slopes of the dose-response curves (Do) from mice with and without chronic inflammation will be compared to evaluate the sensitivity of the stem cells to irradiation. Secondly, repopulation of endogenous and exogenous stem cells within the microenvironments of the bone marrow and spleen will be compared in mice with and without chronic inflammatory lesions. Bone marrow transplantation of exogenous cells will be tested for its ability to replete the total body stem cell deficit in mice with chronic inflammation. If transplantation of exogenous bone marrow cells enhance survival of normal mice exposed to total body irradiation but does not save mice with chronic inflammatory lesions, we will have evidence that chronic inflammation affected hemopoietic recovery in vivo. We will also study the support of hemopoiesis in vitro and the elaboration of prostaglandin-E by marrow stromal cells in the supporting layer of biphasic cultures. Finally, we will determine if continuous administration of indomethacin will enhance survival of mice with chronic inflammation after a sublethal dose of total body irradiation. The important modulation of hemopoiesis provided by prostaglandin-E elaboration from marrow stromal cells and the role of prostaglandins in inflammatory responses focus on a prostaglandin mechanism to explain the cellular interaction of bone marrow stroma and stem cells that impairs hemopoietic stem cell recovery in irradiated mice with a chronic inflammatory lesion.
| DeGowin, R L; Fisher, P G; An, D (1987) Differential elaboration of prostaglandin E2 by cells of the hemopoietic microenvironment in response to endotoxin. J Lab Clin Med 109:679-86 |
| Degowin, R L; Lass, S L (1985) Chronic inflammation impairs hematopoiesis and survival after irradiation. J Lab Clin Med 105:299-304 |
