Iron and Sphingolipids as Common Players of (Mal)Adaptation to Hypoxia in Pulmonary Diseases

Abstract

Hypoxia, or lack of oxygen, can occur in both physiological (high altitude) and pathological conditions (respiratory diseases). In this narrative review, we introduce high altitude pulmonary edema (HAPE), acute respiratory distress syndrome (ARDS), Chronic Obstructive Pulmonary Disease (COPD), and Cystic Fibrosis (CF) as examples of maladaptation to hypoxia, and highlight some of the potential mechanisms influencing the prognosis of the affected patients. Among the specific pathways modulated in response to hypoxia, iron metabolism has been widely explored in recent years. Recent evidence emphasizes hepcidin as highly involved in the compensatory response to hypoxia in healthy subjects. A less investigated field in the adaptation to hypoxia is the sphingolipid (SPL) metabolism, especially through Ceramide and sphingosine 1 phosphate. Both individually and in concert, iron and SPL are active players of the (mal)adaptation to physiological hypoxia, which can result in the pathological HAPE. Our aim is to identify some pathways and/or markers involved in the physiological adaptation to low atmospheric pressures (high altitudes) that could be involved in pathological adaptation to hypoxia as it occurs in pulmonary inflammatory diseases. Hepcidin, Cer, S1P, and their interplay in hypoxia are raising growing interest both as prognostic factors and therapeutical targets.

Keywords: ARDS; COPD; Cystic Fibrosis; adaptation; ceramide; hepcidin; hypoxia; iron; sphingolipids.

Figure 1

Iron and sphingolipids interplay in response to inflammation and hypoxia. A correct adaptation to hypoxia results in the inhibition of the regulator peptide hepcidin (line 1). Hepcidin main action is the reduction of the outflow of the intracellular ferrous iron (Fe²⁺), which is mediated by ferroportin (Fpn). Therefore, if Fpn is less inhibited, iron can be released in the blood stream, bound to the trasporter fransferrin (Tf) in its ferric form (Fe³⁺), and then reach the bone marrow, to contribute to the hematopoietic response. On the other hand, inflammation induces an increase in hepcidin, which blocks such adaptation. Both inflammation and hypoxia are sources of oxidative stress (lines 2a and 2b). An excess of intracellular iron can be a further source of oxidative stress, through the Fenton reaction (showed at the bottom). Both inflammation and hypoxia increase the production of Ceramide (Cer, lines 3a and 3b) derived by a de novo biosynthetic pathway, mediated by serin palmitoyl transferase (SPT) in the endoplasmic reticulum (ER), and by the hydrolysis of sphingomyelin (SM), mediated by neutral sphingomyelinase (nSMase). Cer accumulation promotes hepcidin expression (line 4) with a consequent increase in intracellular iron content, which, in turn, triggers Cer production (via activation of SM hydrolysis) in a vicious loop. Furthermore, ceramidase (CDase) converts Cer in sphingosine (Sph), which is phosphorylated by sphingosine kinase 1 (SK1) to produce sphingosine 1 phosphate (S1P). S1P acts as an oxygen-independent regulator of HIFs.