Severe trauma and chronic stress activates extramedullary erythropoiesis.

Abstract

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 after 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 (EPO)/EPO receptor and BMP4 signaling. Male Sprague-Dawley rats were subjected to LCHS and LCHS/CS. Animals underwent 2 hours of daily restraint stress until the day of sacrifice. On day 7, the spleen was assessed for weight, growth of splenic colony-forming units (CFU)-granulocyte-, erythrocyte-, monocyte- megakaryocyte (GEMM), burst-forming unit-erythroid (BFU-E), and CFU-E colonies, the presence of HPCs, and splenic mRNA expression of bone morphogenetic protein 4 (BMP4), EPO and its receptor. Data were presented as mean ± SD; *p < 0.05 vs. naïve and **p < 0.05 vs. LCHS by t test. On day 7, 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% to 39% versus LCHS alone. Seven days after LCHS/CS, splenic HPCs increased from 0.60% to 1.12 % compared with naïve animals. After LCHS/CS, both BMP4 and EPO expression increased significantly in the spleen. Splenic EPO receptor (EPOr) expression decreased after LCHS/CS in the presence of a persistent moderate anemia. 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 after LCHS/CS. Extramedullary erythropoiesis may play a key role in identifying new therapies to aid the recovery from acute anemia after severe trauma and chronic stress.