Blood Cells - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 81

thiol ( S nitrosothiol). Normal erythrocytic ratio of SNO to hemoglobin is lower
than 1:1000 [ 146 ]. S nitrosohemoglobin (Hb SNO ) deficiency aggravates hypoxemia-
mediated pulmonary hypertension [ 147 , 148 ]. However, individuals who are het-
erozygous for a

β

Cys93 mutation are phenotypically silent (without clinical

abnormality) [ 149 ].

3.5.8 Iron Acquisition and Storage

Iron is needed by iron-dependent enzymes. Most of body's iron is found as heme
in red blood cells. Iron can easily gain and lose electrons. This property is used not
only by hemoglobin, but also by myoglobin, cytochromes, and various enzymes.
However, it generates superoxide anions and hydroxyl radicals by electron donation
to oxygen. Because reduced iron can catalyze formation of reactive oxygen species
within cells, cells control the cytosolic amount of iron. Nevertheless, intracellular
iron must be delivered to sites of storage and use, particularly target proteins, such as
enzymes and carriers. Iron delivery is achieved by iron chaperones such as poly(rC)-
binding protein-1 (PCBP1), which delivers iron to iron storage protein ferritin [ 150 ].
Ferritin can store up to 4,500 atoms of iron.
Iron balance is maintained between regulated absorption of dietary iron, iron loss
via exfoliation of enterocytes and skin cells, and bleeding. 44 Iron is absorbed in the
gut, predominantly in the duodenum and upper jejunum, and transported into plasma
by apical importer DMT1 and basolateral exporter ferroportin , respectively [ 151 ]. 45
Iron in senescent RBCs that are ingested by macrophages and degraded is
recycled back into plasma by ferroportin. Plasma iron is carried by glycoprotein
transferrin that delivers iron to cells that express transferrin receptors. 46 At blood
pH, apotransferrin (transferrin iron-free form) can bind 2 Fe 3 + (dissociation con-
stant

K d =

10-23 mol) in the presence of an anion (usually carbonate) that bridges

44 Excess iron damages tissues, as it causes fibrosis. Iron-deficiency disorders generate anemia,
which in turn lead to hypoxia. Iron-deficiency anemias have genetic or acquired (chronic
inflammation) origin. Hereditary hemochromatosis or primary iron-overload disease results from
inadequate hepcidin production. Type-1 hereditary hemochromatosis is associated with increased
iron absorption and deposition in the liver, heart, pancreas, and skin that leads to liver cirrhosis and
diabetes. It is caused by mutations in the HFE gene (hereditary hemochromatosis protein HFE1
forms a proteic complex with transferrin receptor-1). Type-2 hereditary hemochromatosis (juvenile
hemochromatosis) is characterized by severe cardiac and endocrine dysfunction. It results from
mutations in hepcidin (HAMP) or hemojuvelin (HFE2) gene. Type-3 hereditary hemochromatosis
is caused by a mutation in TFR2 gene that encodes transferrin receptor-2. Type-4 hereditary
hemochromatosis is conferred by mutations in ferroportin leading to 2 clinical phenotypes with
iron accumulation in either macrophages or hepatocytes.
45 One to 2 mg of iron is absorbed per day in the gut.
46 Transferrin is synthesized in the liver, retina, testis and brain.