| Budget Amount *help |
¥3,800,000 (Direct Cost: ¥3,800,000)
Fiscal Year 2005: ¥1,900,000 (Direct Cost: ¥1,900,000)
Fiscal Year 2004: ¥1,900,000 (Direct Cost: ¥1,900,000)
|
|---|
| Research Abstract |
Milk fat globule-EGF-factor 8 (MFG-E8), secreted by activated macrophages and immature dendritic cells, links apoptotic cells and phagocytes, and promotes phagocytosis of apoptotic cells. We found that an MFG-E8 mutant, designated as D89E, carrying a point mutation in an RGD motif, inhibited the phagocytosis of apoptotic cells by a wide variety of phagocytes. When intravenously injected into mice, the D89E protein induced the production of auto-antibodies including anti-phospholipids antibodies and anti-nuclear antibodies. The production of auto-antibodies was enhanced by the co-injection of syngeneic apoptotic thymocytes. Following the induction of auto-antibody production by D89E, the treated mice showed a long-term elevation of the titer for auto-antibodies, and developed IgG deposition in the gromeruli. These results indicated that the impairment of apoptotic cell phagocytosis led to auto-antibody production.
We generated transgenic mice in which type II lung epithelial cells as well as macrophages were transiently ablated. Human diphtheria toxin receptor was expressed under the control of the lysozyme M gene promoter in the mice. When diphtheria toxin was administrated to the mice, they suffered from acute lung injury, and died within 4 days. Type II cells as well as alveolar macrophages were deleted in the mice treated with diphtheria toxin. The amount of surfactant proteins A and B in bronchoalveolar lavage fluid was greatly reduced in the diphtheria toxin-treated transgenic mice. When the bone marrow from wild-type mice was transplanted into the irradiated transgenic mice, the alveolar macrophages became resistant to diphtheria toxin, but the mice still suffered from acute lung injury. These results indicated that ablation of type II cells caused lethal acute respiratory distress in association with the reduced amount of surfactant proteins.
|
