ONSET OF ANEMIA IN PULMONARY DISEASES: ROLE OF HYPOXIA, OXIDATIVE STRESS, IRON METABOLISM AND HEMATOPOIETIC REGULATORS

BACKGROUND: In patients affected by severe hypoxia, such as those with Acute Respiratory Distress Syndrome (ARDS), an acute condition characterized by sudden onset of severe hypoxemia and a severe manifestation of COVID19, anemia is a common complication. It remains to be established weather iron metabolism, especially hepcidin, and oxidative stress are involved in negatively interfering with physiological hematopoietic compensatory mechanisms to hypoxia. AIMS: - To investigate etiology and progression of anemia in ARDS patients, through biomarkers of inflammation, iron metabolism and oxidative stress. - To identify the effects of increased hepcidin and the potentially protective effects of erythropoietin (EPO) in the energetic metabolism of lung and brain cells. METHODS: We collected blood samples at three timepoints from 20 ARDS patients: at the diagnosis (T0), when hemoglobin (Hb) was 3 g/dl less than T0 or <8 g/dL (T1), and two days after T1 (T2). Twenty ambulatory chronic obstructive pulmonary disease (COPD) patients were recruited to compare with non-anemic chronic hypoxia and ten non-hypoxic volunteers represented the control group. We reproduced hypoxia and inflammation in hypoxic lung A549 cells treated with lipopolysaccharide (LPS), and mitochondrial damage in neural SHSY5Y cells. The effect of hepcidin treatment and EPO on energetic metabolism was evaluated by measuring oxygen consumption and extracellular acidification rate (Seahorse technology). RESULTS: In ARDS patients, [Hb] decreased within 7-10 days after T0. We observed that ARDS induced higher IL6, hepcidin and malondialdehyde (MDA) with respect to both COPD and controls. The antioxidant barrier (ferric reducing antioxidant power test, FRAP) was weakened from T0 to T1. COVID19 ARDS values were similar to non-COVID ARDS, except for higher hepcidin and non-transferrin-bound iron (NTBI). EPO values were unchanged despite hypoxia. In hypoxic A549 cells, LPS decreased viability and, in combination with hepcidin, decreased mitochondrial respiration and increased the glycolytic rate. In SHSY5Y challenged cells, EPO partially rescued mitochondrial damage and increased glycolysis. CONCLUSIONS: ARDS is characterized by systemic release of inflammatory mediators, which negatively interfere with the hematopoietic adaptation to hypoxia. Oxidative stress and inflammation increase hepcidin, which induces a dysregulation in iron metabolism, with anemia and mitochondrial damage.