LEADe will report in 2008 and is expected to provide a more definitive evaluation of the potential for statins in the treatment of people with AD.
Background Severe traumatic injury is associated with bone marrow dysfunction that manifests as impaired erythropoiesis and prolonged hematopoietic progenitor cell (HPC) mobilization from the bone marrow. Extramedullary erythropoiesis, the development of red blood cells outside the bone marrow, has not been studied following severe injury and critical illness. This study examined the influence of lung contusion/hemorrhagic shock (LCHS) followed by chronic stress (CS) on the rodent spleen and to investigate the involvement of the splenic erythropoietin/erythropoietin receptor and BMP4 signaling. Methods Male Sprague-Dawley rats were subjected to LCHS and LCHS/CS. Animals underwent two hours of daily restraint stress until the day of sacrifice. On day seven the spleen was assessed for weight, growth of splenic CFU-GEMM, BFU-E, and CFU-E colonies, the presence of HPCs, and splenic mRNA expression of bone morphogenetic protein 4 (BMP4), erythropoietin and its receptor. Data was presented as mean±SD; *p<0.05 vs. naïve and **p<0.05 vs. LCHS by t-test. Results On day seven, the addition of CS to LCHS increased spleen weight by 22%. LCHS/CS increased splenic growth of CFU-GEMM, BFU-E and CFU-E colonies by 28–39% vs. LCHS alone. Seven days after LCHS/CS, splenic HPCs increased from 0.60% to 1.12 % compared to naïve animals. Following LCHS/CS, both BMP4 and EPO expression increased significantly in the spleen. Splenic EPOr expression decreased following LCHS/CS in the presence of a persistent moderate anemia. Conclusions Extramedullary erythropoiesis, manifest by increased splenic weight, splenic erythroid colony growth, splenic HPCs, BMP4, and EPO expression, is present in the spleen after LCHS/CS. Splenic EPOr expression was significantly decreased following LCHS/CS. Extramedullary erythropoiesis may play a key role in identifying new therapies to aid the recovery from acute anemia following severe trauma and chronic stress.
Background Propranolol has been shown previously to restore bone marrow function and improve anemia after lung contusion/hemorrhagic shock. We hypothesized that daily clonidine administration would inhibit central sympathetic outflow and restore bone marrow function in our rodent model of lung contusion/hemorrhagic shock with chronic stress. Methods Male Sprague-Dawley rats underwent six days of restraint stress after lung contusion/hemorrhagic shock during which the animals received clonidine (75μg/kg) after the restraint stress. On post-injury day seven, we assessed urine norepinephrine, blood hemoglobin, plasma granulocyte colony stimulating factor (G-CSF), and peripheral blood mobilization of hematopoietic progenitor cells (HPC), as well as bone marrow cellularity and erythroid progenitor cell growth. Results The addition of clonidine to lung contusion/hemorrhagic shock with chronic restraint stress, significantly decreased urine norepinephrine levels, improved bone marrow cellularity, restored erythroid progenitor colony growth, and improved hemoglobin (14.1±0.6 vs. 10.8±0.6 g/dL). The addition of clonidine to lung contusion/hemorrhagic shock with chronic restraint stress significantly decreased HPC mobilization and restored G-CSF levels. Conclusions After lung contusion/hemorrhagic shock with chronic restraint stress, daily administration of clonidine restored bone marrow function and improved anemia. Alleviating chronic stress and decreasing norepinephrine is a key therapeutic target to improve bone marrow function after severe injury.
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