Targeting the Heme-Heme Oxygenase System to Prevent Severe Complications Following COVID-19 Infections

Abstract

SARS-CoV-2 is causing a pandemic resulting in high morbidity and mortality. COVID-19 patients suffering from acute respiratory distress syndrome (ARDS) are often critically ill and show lung injury and hemolysis. Heme is a prosthetic moiety crucial for the function of a wide variety of heme-proteins, including hemoglobin and cytochromes. However, injury-derived free heme promotes adhesion molecule expression, leukocyte recruitment, vascular permeabilization, platelet activation, complement activation, thrombosis, and fibrosis. Heme can be degraded by the anti-inflammatory enzyme heme oxygenase (HO) generating biliverdin/bilirubin, iron/ferritin, and carbon monoxide. We therefore postulate that free heme contributes to many of the inflammatory phenomena witnessed in critically ill COVID-19 patients, whilst induction of HO-1 or harnessing heme may provide protection. HO-activity not only degrades injurious heme, but its effector molecules possess also potent salutary anti-oxidative and anti-inflammatory properties. Until a vaccine against SARS-CoV-2 becomes available, we need to explore novel strategies to attenuate the pro-inflammatory, pro-thrombotic, and pro-fibrotic consequences of SARS-CoV-2 leading to morbidity and mortality. The heme-HO system represents an interesting target for novel “proof of concept” studies in the context of COVID-19.

Arterial Carboxyhemoglobin Levels In Covid-19 Critically Ill Patients

“…Among them, excess of free heme is a potential offending agent as it has been shown to exacerbate and contribute to the pathogenesis of numerous in ammatory diseases [2]. Therefore, it may be postulated that accumulated free heme and Hb could be involved in the mechanisms mediating pulmonary permeability and in ammation in COVID-19 patients [3].…”

Rationale for the use of N ‐acetylcysteine in both prevention and adjuvant therapy of COVID‐19

“…41 Interestingly, it has been proposed that targeting the heme-heme oxygenase system may prevent severe complications following COVID-19 infection. 42 In parallel, NAC inhibits the oxidative stress-mediated activation of nuclear factor kappa-lightchain-enhancer of activated B cells (NFκB) and biochemical pathways upregulating pro-inflammatory genes. 14 NAC also reduced the intracellular hydrogen peroxide concentration and restored the intracellular total thiol contents by inhibiting NFκB translocation to the cellular nucleus and phosphorylation of p38 mitogen-activated protein kinase (MAPK p38).…”

Hesperidin and SARS-CoV-2: New Light on the Healthy Function of Citrus Fruits

“…Hesperidin contributes significantly to antioxidant defense systems as an effective agent against superoxide and hydroxyl radicals [39], and its derivative hesperetin inhibits nitric oxide production by LPS-stimulated microglial cells [40]. hydroxyl radical (•OH), and promotes the oxidative stress [41,42]. In this pathological process, the dysfunction of mitochondrial oxidative metabolism also plays an important role, leading to platelet damage and promoting the formation of thrombi [43].…”

“…Systemic perturbations associated with the severity of COVID-19 disease include free heme release and hyperferritinemia, a sign of dysregulation of iron metabolism, which in turn induces the production of reactive oxygen species, such as superoxide anion (O 2 − ), hydrogen peroxide (H 2 O 2 ); hydroxyl radical (·OH), and promotes the oxidative stress [ 41 , 42 ]. In this pathological process, the dysfunction of mitochondrial oxidative metabolism also plays an important role, leading to platelet damage and promoting the formation of thrombi [ 43 ].…”