Suboptimal Erythropoietic Response to Hypoxemia in Idiopathic Pulmonary Fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF) is a chronic inflammatory process characterized by severe derangement of gas exchange in the advanced stages of disease. However, erythrocytosis is infrequent in IPF. The aim of this study was to investigate the potential relation between the blunted erythropoietic response and the chronic inflammation. Nine patients (6 men and 3 women) with IPF and profound hypoxemia (PO(2) < 65 mm Hg) and 34 sex- and age-matched healthy volunteers participated in the study. We evaluated the hematologic parameters, serum erythropoietin, tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and IL-8 levels. We also studied the development of burst-forming unit-erythroid (BFU-E)-derived colonies in semisolid methylcellulose cultures in blood samples from all patients. Hemoglobin and serum erythropoietin levels were almost comparable between the two studied groups. On the contrary, serum TNF-alpha, IL-6, and IL-8 values were significantly higher in patients with IPF (p < 0.05, p < 0.01, and p < 0.001, respectively). IPF sera induced a significant growth inhibition of erythroid bursts arising from mononuclear cells of either patients or control subjects compared with heat-inactivated AB serum (p < 0.05 and p < 0.01, respectively). Moreover, there was an apparent increment in the number of BFU-E colonies when patients' mononuclear cells were cultured in comparison with those of healthy subjects (p < 0.05). Our findings suggest that in IPF there is an increased number of primitive erythroid progenitors, which fail to proliferate and differentiate in vivo, suggesting a kind of ineffective erythropoiesis. As a consequence, hemoglobin levels do not rise in proportion to the severity of hypoxemia. Cytokines released from alveolar macrophages seem to have not only local but also systemic effects, since the serum of these patients directly suppressed erythropoiesis; however, the suboptimal erythropoietic response to hypoxia cannot be entirely attributed to this suppression. It is possible that several other factors interfere, synergistically or additively.