Hemolysis | Leaders in Pharmaceutical Business Intelligence (LPBI) Group

Posts Tagged ‘Hemolysis’

Low Bioavailability of Nitric Oxide due to Misbalance in Cell Free Hemoglobin in Sickle Cell Disease – A Computational Model

Posted in Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, BioSimilars, CANCER BIOLOGY & Innovations in Cancer Therapy, Cardiovascular Pharmacogenomics, Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, Computational Biology/Systems and Bioinformatics, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Nitric Oxide in Health and Disease, Uncategorized, tagged Bioinformatics, Cardiovascular disease, Cardiovascular Disorders, computational biology, health, Hemoglobin, Hemolysis, Hypertension, nitric oxide, Nitric oxide synthase, NO, Pulmonary hypertension, Sickle Cell disease, systems biology on November 9, 2012| 15 Comments »

Author and Reporter: Anamika Sarkar, Ph.D.

Nitric Oxide (NO) is highly regulated in the blood such that it can be released as vasodilator when needed. The importance and pathway of Nitric Oxide has been nicely reviewed by. “Discovery of NO and its effects of vascular biology”. Other articles which are good readings for the importance of NO are – a) regulation of glycolysis b) NO in cardiovascular disease c) NO and Immune responses Part I and Part II d) NO signaling pathways. The effects of NO in diseased states have been reviewed by the articles – “Crucial role of Nitric Oxide in Cancer”, “Nitric Oxide and Sepsis, Hemodynamic Collapse, and the Search for Therapeutic Options”.. (Also, please see Source for more articles on NO and its significance).

Computational models are very efficient tools to understand complex reactions like NO towards physiological conditions. Among them wall shear stress is one of the major factors which is reviewed in the article – “Differential Distribution of Nitric Oxide – A 3-D Mathematical Model”.

Moreover, decrease in availability of NO can lead to many complications like pulmonary hypertension. Some of the causes of decrease in NO have been identified as clinical hypertension, right ventricular overload which can lead to cardiac heart failure, low levels of zinc and high levels of cardiac necrosis.

Sickle Cell disease patients, a hereditary disease, are also known to have decreased levels of NO which can become physiologically challenging. In USA alone, there are 90,000 people who are affected by Sickle cell disease.

Sickle cell disease is breakage of red blood cells (RBC) membrane and resulting release of the hemoglobin (Hb) into blood plasma. This process is also known as Hemolysis. Sickle cell disease is caused by single mutation of Hb which changes RBC from round shape to sickle or crescent shapes (Figure 1).

Figure 1 (A) shows normal red blood cells flowing freely through veins. The inset shows a cross section of a normal red blood cell with normal hemoglobin. Figure 1 (B) shows abnormal, sickled red blood cells The inset image shows a cross-section of a sickle cell with long polymerized HbS strands stretching and distorting the cell shape. Image Source: http://en.wikipedia.org/wiki/Sickle-cell_disease

Sickle Cell RBCs has much shorter life span of 10-20 days when compared with normal RBCs 100-120 days lifespan. Shorter life span of Sickle cell disease RBC’s are compensated by bone marrow generation of new RBCs. However, many times new blood generation cannot cope with the small life span of Sickle cell RBCs and causes pathological condition of Anemia.

RBCs generally breakdown and release Hbs in blood plasma after they reach their end of life span. Thus, in case of Sickle cell disease, there is more cell free Hb than normal. Furthermore, it is known that NO has a very high affinity towards Hbs, which is one of the ways free NO is regulated in blood. As a result presence of larger amounts of cell free Hb in Sickle cell disease lead to less availability of NO.

However, the question remained “what is the quantitative relationship between cell free Hb and depletion of NO”. Deonikar and Kavdia (J. Appl. Physiol., 2012) addressed this question by developing a 2 dimensional Mathematical Model of a single idealized arteriole, with different layers of blood vessels diffusing nutrients to tissue layers (Figure 2: Deonikar and Kavdia Figure 1).

cell free Hb in 2 dimensional representations of blood vessels.

The authors used steady state partial differential equation of circular geometry to represent diffusion of NO in blood and in tissues. They used first and second order biochemical reactions to represent the reactions between NO and RBC and NO autooxidation processes. Some of their reaction model parameters were obtained from literature, rest of them were fitted to experimental results from literature. The model and its parameters are explained in the previously published paper by same authors Deonikar and Kavdia, Annals of Biomed., 2010. The authors found that the reaction rate between NO and RBC is 0.2 x 10⁵, M^-1 s^-1than 1.4 x 10⁵, M^-1 s^-1 as reported before by Butler et.al., Biochim. Biophys. Acta, 1998.

Their results show that even small increase in cell free Hb, 0.5uM, can decrease NO concentrations by 3-7 folds approximately (comparing Fig1(b) and 1(d) of Deonikar and Kavdia, 2012, as shown in Figure 2 of this article). Moreover, their mathematical analysis shows that the increase in diffusion resistance of NO from vascular lumen to cell free zone has no effect on NO distribution and concentration with available levels of cell free Hb.

Deonikar and Kavdia’s mathematical model is a simple representation of actual physiological scenario. However, their model results show that for Sickle cell disease patients, decrease in levels of bioavailable NO is an attribute to cell free Hb, which is in abundant for these patients. Their results show that small increase by 0.5 uM in cell free Hb can cause large decrease in NO concentrations.

These interesting insights from the model can help in further understanding in the context of physiological conditions, by replicating experiments in-vivo and then relating them to other known diseases of Sickle cell disease patients like Anemia, Pulmonary Hypertension. Further, drugs can be targeted towards decreasing free cell Hbs to keep balance in availability of NO, which in turn may help in other related disease like Pulmonary Hypertension of Sickle Cell disease patients.

Sources:

Deonikar and Kavdia (2012) :http://www.ncbi.nlm.nih.gov/pubmed/22223452

Previous model explaining mathematical representation and parameters used in the model :Deonikar and Kavdia, Annals of Biomed., 2010.

Previous paper stating reaction rate of Hb and NO: Butler et.al., Biochim. Biophys. Acta, 1998.

Causes of decrease in NO

Clinical Hypertension : http://www.ncbi.nlm.nih.gov/pubmed/11311074

Right ventricular overload : http://www.ncbi.nlm.nih.gov/pubmed/9559613

Low levels of zinc and high levels of cardiac necrosis : http://www.ncbi.nlm.nih.gov/pubmed/11243421

Sickle Cell Source:

http://en.wikipedia.org/wiki/Sickle-cell_disease

http://www.nhlbi.nih.gov/health/health-topics/topics/sca/

NO Source: