Bone Marrow Transplant Induces Pulmonary Vascular Remodeling in Mice.

Abstract

Abstract 4480 ObjectivePulmonary complications are common in bone marrow transplant (BMT) recipients and often of an infectious etiology or attributed to intensive conditioning regimens. Cases of pulmonary arterial hypertension have been described in the setting of autologous BMT but are believed to be the result of acquired infections or previously-administered chemotherapy. Whether transplanted marrow cells themselves are toxic to the recipient's lungs is unknown. MethodsTo address this, non-irradiated female BALB/C mice were transplanted with 5-6×107 whole bone marrow (WBM) cells from male BALB/C mice daily for four days on week zero, then again on week eight (4.5×108 cells total/mouse), or an equal volume of diluent (control). On week 24, transplanted mice received 1000 cGy of chest-only radiation or no radiation. On week 32, histochemical and immunohistochemical analyses were performed on recipient's lungs. ResultsBone marrow chimerism was not significantly different in the irradiated and non-irradiated cohorts at the time of sacrifice (average 45.11+6.25% Y chromosome+, all mice). Recipient lungs contained few non-hematopoietic donor marrow-derived cells. These cells were exclusively epithelial (Y+/cytokeratin+), primarily type II pneumocytes (Y+/prosurfactant C+), while no endothelial (Y+/von Willebrand+) or vascular smooth muscle (Y+/alpha-actin+) cells were identified. Irradiated and non-irradiated cohorts had similar quantities of these cells (0.80+0.22% vs. 0.51+0.08% Y+/cytokeratin+; 0.37+0.08% vs. 0.32+0.12% Y+/prosurfactant C+, p>0.2). Pulmonary vessel wall thickness-to-blood vessel diameter ratios (PVWT/D) were significantly increased in the non-irradiated cohort compared with controls and these ratios were further increased in the irradiated cohort (141+5.75%, 161+5.34% of control, p<0.05 comparing all groups). ConclusionsThese data indicated that marrow cell infusion alone results in pulmonary vascular remodeling and this effect is augmented by radiation injury. These changes are independent of transplanted marrow cell conversion to pulmonary vascular endothelial, smooth muscle cells. These studies suggest that transplanted cells may be lung toxic entities in the setting clinical BMT. Disclosures:No relevant conflicts of interest to declare.