Heme Degradation in Pathophysiology of and Countermeasures to Inflammation-Associated Disease

Abstract

The class of tetrapyrrol “coordination complexes” called hemes are prosthetic group components of metalloproteins including hemoglobin, which provide functionality to these physiologically essential macromolecules by reversibly binding diatomic gasses, notably O2, which complexes to ferrous (reduced/Fe(II)) iron within the heme porphyrin ring of hemoglobin in a pH- and PCO2-dependent manner—thus allowing their transport and delivery to anatomic sites of their function. Here, pathologies associated with aberrant heme degradation are explored in the context of their underlying mechanisms and emerging medical countermeasures developed using heme oxygenase (HO), its major degradative enzyme and bioactive metabolites produced by HO activity. Tissue deposits of heme accumulate as a result of the removal of senescent or damaged erythrocytes from circulation by splenic macrophages, which destroy the cells and internal proteins, including hemoglobin, leaving free heme to accumulate, posing a significant toxicogenic challenge. In humans, HO uses NADPH as a reducing agent, along with molecular oxygen, to degrade heme into carbon monoxide (CO), free ferrous iron (FeII), which is sequestered by ferritin protein, and biliverdin, subsequently metabolized to bilirubin, a potent inhibitor of oxidative stress-mediated tissue damage. CO acts as a cellular messenger and augments vasodilation. Nevertheless, disease- or trauma-associated oxidative stressors sufficiently intense to overwhelm HO may trigger or exacerbate a wide range of diseases, including cardiovascular and neurologic syndromes. Here, strategies are described for counteracting the effects of aberrant heme degradation, with a particular focus on “bioflavonoids” as HO inducers, shown to cause amelioration of severe inflammatory diseases.

Heme Burden and Ensuing Mechanisms That Protect the Kidney: Insights from Bench and Bedside

“…The hydrophobic nature of heme allows for its passage across cell membranes and subsequent buildup within the hydrophobic milieu of intact cells. A strong body of evidence demonstrates that free heme can cause direct and indirect injurious effects [ 4 , 24 , 57 , 60 , 68 ]. Such injurious effects are mediated by the pro-oxidant, pro-inflammatory and cytotoxic properties of heme.…”

“…Exposure of neutrophils to heme is associated with multiple inflammatory characteristics. These include the organization of cytoskeleton in a manner that is consistent with phagocytic and migratory activities, increase in generation of neutrophil extracellular trap, generation of ROS via NADPH oxidase activity, upregulation of neutrophil survival factors such as IL-8, and stimulation of ERK, PI3K–Akt and nuclear factor-κB signaling pathways, all of which indisputably prolong inflammation [ 68 , 83 , 84 ]. Overall, while heme is a cardinal necessity for aerobic life, a strong body of evidence points towards its potential hazardous effects and obviates the demand for an overhaul mechanism to mitigate these effects, namely the HO-1/ferritin system.…”

“…The ability of free iron to exacerbate kidney injury is well documented as its chelation via deferoxamine is shown to be protective in injury models that are coupled with increased heme burden [ 116 , 117 ]. Moreover, Zager and colleagues delivered evidence using different models of kidney injury that upregulation of ferritin may serve as an advantageous “preconditioning” state [ 68 , 133 ]. There is also mounting clinical substantiation to suggest that higher plasma catalytic iron levels are associated with worse outcomes including AKI and need for kidney replacement therapy [ 134 , 135 ].…”

Induced antigen-binding polyreactivity in human serum IgA

“…A variety of pathological processes cause degradation of hemoglobin and myoglobin, and release free heme into the circulation [18]. Several plasma proteins -hemopexin, albumin, haptoglobin and some lipoproteins are able to bind heme and eliminate it from the plasma [19].…”

Therapeutic potential of pyrrole and pyrrolidine analogs: an update

“…One of the heterocycles, pyrrole, is not naturally derived, but its analogs present in co-factors and natural products such as vitamin B12, bile pigments: bilirubin and biliverdin [6,7], and the porphyrins of heme, chlorophyll, chlorins, bacteriochlorins, and porphyrinogens Fig. 2 Pyrrole analogs isolated from microorganism [8][9][10][11]. Pyrrole-containing secondary metabolites such as makaluvamine M, ryanodine, rhazinilam, lamellarin, prodigiosin, myrmicarin, and sceptrinare also exhibit potential biological activity [12][13][14][15][16][17][18][19].…”