https://repositorio-aberto.up.pt/bitstream/10216/82052/2/89139.pdf

Primaquine revisited six decades after its discovery.

BACKGROUND:The purpose of this article is to summarize all episodes of local anesthetic-related methemoglobinemia found in the medical literature.METHODS:I performed a search of the American National Library of Medicine's PubMed with the following key words: “local anesthetic” and “methemoglobinemia

Methemoglobinemia related to local anesthetics: a summary of 242 episodes.

The prevention and treatment of acute chest syndrome (ACS) is a major clinical concern in sickle cell disease (SCD). However, the mechanism underlying the pathogenesis of ACS remains elusive. We tested the hypothesis that the hemolysis byproduct hemin elicits events that induce ACS. Infusion of a low dose of hemin caused acute intravascular hemolysis and autoamplification of extracellular hemin in transgenic sickle mice, but not in sickle-trait littermates. The sickle mice developed multiple symptoms typical of ACS and succumbed rapidly. Pharmacologic inhibition of TLR4 and hemopexin replacement therapy prior to hemin infusion protected sickle mice from developing ACS. Replication of the ACS-like phenotype in nonsickle mice revealed that the mechanism of lung injury due to extracellular hemin is independent of SCD. Using genetic and bone marrow chimeric tools, we confirmed that TLR4 expressed in nonhematopoietic vascular tissues mediated this lethal type of acute lung injury. Respiratory failure was averted after the onset of ACS-like symptoms in sickle mice by treating them with recombinant hemopexin. Our results reveal a mechanism that helps to explain the pathogenesis of ACS, and we provide proof of principle for therapeutic strategies to prevent and treat this condition in mice.

/pdf/extracellular-hemin-crisis-triggers-acute-chest-syndrome-in-3xies5wke1.pdf

Extracellular hemin crisis triggers acute chest syndrome in sickle mice

Heme is an essential molecule in aerobic organisms. Heme consists of protoporphyrin IX and a ferrous (Fe2+) iron atom, which has high affinity for oxygen (O2). Hemoglobin, the major oxygen-carrying protein in blood, is the most abundant heme-protein in animals and humans. Hemoglobin consists of four globin subunits (α2β2), with each subunit carrying a heme group. Ferrous (Fe2+) hemoglobin is easily oxidized in circulation to ferric (Fe3+) hemoglobin, which readily releases free hemin. Hemin is hydrophobic and intercalates into cell membranes. Hydrogen peroxide can split the heme ring and release “free” redox-active iron, which catalytically amplifies the production of reactive oxygen species. These oxidants can oxidize lipids, proteins, and DNA; activate cell-signaling pathways and oxidant-sensitive, proinflammatory transcription factors; alter protein expression; perturb membrane channels; and induce apoptosis and cell death. Heme-derived oxidants induce recruitment of leukocytes, platelets, and red blood cells to the vessel wall; oxidize low-density lipoproteins; and consume nitric oxide. Heme metabolism, extracellular and intracellular defenses against heme, and cellular cytoprotective adaptations are emphasized. Sickle cell disease, an archetypal example of hemolysis, heme-induced oxidative stress, and cytoprotective adaptation, is reviewed. Antioxid. Redox Signal. 12, 233–248.

/pdf/heme-degradation-and-vascular-injury-2vci849fxd.pdf

Heme degradation and vascular injury.

One of the least recognized causes of cellular damage during ex vivo preservation of red blood cells is oxidative injury to the hemoglobin. The latter has been associated with hemolysis through the release of toxic substances and oxidation of vital cell components. This review delineates some of the major pathways that link hemoglobin oxidation and cellular damage, and summarizes the incidence of red blood cell oxidative injury during hypothermic storage, cryopreservation and desiccation stress. Red blood cell hypothermic storage, despite its success, is not exempt from oxidative injury. Growing evidence portrays a time-dependant oxidative assault including formation of reactive oxygen species, attachment of denatured hemoglobin to membrane phospholipids and the release of hemoglobin-containing membrane microvesicles throughout storage. Similar symptoms have been observed in attempts to stabilize red blood cells in the dried state, in which methemoglobin levels of reconstituted red blood cells reached 50%. Factors affecting the rate of hemoglobin oxidation during red blood cell ex vivo storage include compromised antioxidant activity, high concentrations of glucose in the storage media and the presence of molecular oxygen. Hemoglobin oxidation largely dictates our ability to effectively preserve red blood cells. Understanding its origins along with investigating methods to minimize it can significantly improve the quality of our future blood products.

https://febs.onlinelibrary.wiley.com/doi/epdf/10.1111/j.1742-4658.2009.07472.x

Biopreservation of red blood cells--the struggle with hemoglobin oxidation.

Hemoglobin has functions besides carrying oxygen to the tissues, and regulates vascular tone and inflammation via a redox couple with methemoglobin. Hemoglobin has iron in the reduced valance Fe(II) and methemoglobin has iron in the oxidized valance Fe (III), with a free energy capable of producing water from oxygen. In generating methemoglobin the couple functions as a nitrite reductase. The degree of oxidation of hemoglobin senses the oxygen level in the blood and uses its ability to produce nitric oxide from nitrite to control vascular tone, increasing blood flood when the proportion of oxygenated hemoglobin falls. Additional cardiovascular damage is produced by methemoglobin mediated oxidation of light density lipoproteins, accelerating arteriosclerosis. In addition, the release of heme from methemoglobin is an important factor in inflammation. These physiologic functions are paralleled by thewell-described role in the oxidation of various drugs resulting in methemoglobinemia. Am. J. Hematol., 2006. © 2006 Wiley-Liss, Inc.

/pdf/methemoglobin-it-s-not-just-blue-a-concise-review-2rixcpemvj.pdf

Jay Umbreit

Papers

Methemoglobin—It's not just blue: A concise review