Arginine Therapy Shows Promise for Treatment of Sickle Cell Disease Clinical Subphenotypes of Hemolysis and Arginine Deficiency

Morris, Claudia R.

doi:10.1213/ane.0000000000001874

Cited by 4 publications

(2 citation statements)

References 5 publications

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“…Clinical studies in patients with PH have shown positive effects of L-arginine supplementation ( Nagaya et al, 2001 ; Brown et al, 2018 ). L -Arginine may also be useful in patients with PH and sickle cell disease ( Morris et al, 2003 ; Morris, 2014 ; Morris, 2017 ). Supplementation with L -citrulline in newborn infants with chronic PH ( Fike et al, 2014 ) and in patients with idiopathic pulmonary arterial hypertension and Eisenmenger Syndrome ( Sharif Kashani et al, 2014 ) have also been shown to result in improved hemodynamics.…”

Section: Increasing Arginine Availabilitymentioning

confidence: 99%

Arginine Therapy for Lung Diseases

et al. 2021

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Nitric oxide (NO) is produced by a family of isoenzymes, nitric oxide synthases (NOSs), which all utilize L-arginine as substrate. The production of NO in the lung and airways can play a number of roles during lung development, regulates airway and vascular smooth muscle tone, and is involved in inflammatory processes and host defense. Altered L-arginine/NO homeostasis, due to the accumulation of endogenous NOS inhibitors and competition for substrate with the arginase enzymes, has been found to play a role in various conditions affecting the lung and in pulmonary diseases, such as asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), pulmonary hypertension, and bronchopulmonary dysplasia. Different therapeutic strategies to increase L-arginine levels or bioavailability are currently being explored in pre-clinical and clinical studies. These include supplementation of L-arginine or L-citrulline and inhibition of arginase.

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Section: Increasing Arginine Availabilitymentioning

confidence: 99%

Arginine Therapy for Lung Diseases

et al. 2021

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“…Биологическая доступность L-аргинина является одним из факторов, которые регулируют активацию и эффекторные функции клеток иммунной системы [3,32,35,37,41]. Более того, биодоступность L-аргинина обеспечивает реали-зацию одного из важнейших механизмов микробицидности фагоцитов.…”

Section: Introductionunclassified

Influence of streptococcal arginine deiminase on the leukocyte infiltration in murine air pouch model

et al. 2021

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Numerous pathogens express arginine deiminase, an enzyme that catalyzes the hydrolysis of L-arginine in a chain of biochemical reactions aimed at the synthesis of ATP in bacterial cells. L-arginine is a semi-essential, proteinogenic amino acid that plays an important role in regulating the functions of the immune system cells in mammals. Depletion of L-arginine may cause a weakening of the immune reaction. In order to improve the conditions of dissemination, many pathogens use a strategy of L-arginine depletion in the microenvironment of host cells. Bacterial arginine deiminase can be a pathogenicity factor aimed for dysregulating the processes of inflammation and immune response. In general, the effect of arginine deiminase on immune cells may result into disturbed production of regulatory proinflammatory molecules, such as NO, and related substances, inhibition of activation, migration and differentiation of individual leukocyte subsets. The aim of this study was to investigate the effect of arginine deiminase on the formation of inflammatory infiltrate in murine air pouch model of streptococcal infection. Materials and methods: The study was performed using S. pyogenes M49-16 expressing arginine deiminase and its isogenic mutant S. pyogenes M49-16delArcA with inactivated arginine deiminase gene. The flow cytometry analysis of the inflammatory infiltrate leukocytes subpopulation in mice infected with the original strain of S. pyogenes M49-16 and its isogenic mutant S. pyogenes M49-16delArcA at different periods of infection was performed. It was shown that the inflammation reached its peak 6 hours after streptococcal inoculation, being more pronounced in mice infected with the mutant strain. Тhis finding was affirmed by a simultaneous and more pronounced increase in the absolute numbers of all leukocyte subsets in the focus of inflammation in this group of mice when compared to mice infected with original bacterial strain. Despite the decrease in the absolute number of all leukocyte types in the inflammatory infiltrate in both groups of mice for 24 hours, this trend was more pronounced in the group of mice infected with mutant microbial strain. Comparison of the inflammatory infiltrates developing in mice infected with original versus mutant strains showed that arginine deiminase may be a pathogenicity factor leading to dysregulation of protective immune response, due to impaired migration of white blood cells to the site of infection.

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Therapeutic Strategies for the Treatment of Sickle Cell Disease

Aljahdali

Burnett

Abraham

et al. 2021

Burger's Medicinal Chemistry and Drug Discovery

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There are many important new advances in the development of clinically viable therapeutic options to mitigate the pathophysiology of sickle cell disease (SCD). Some of the most promising new clinical candidates reported herein directly address the primary cause of the disease by allosterically modifying sickle hemoglobin (HbS). In particular, one family of small molecules stabilizes the high oxygen (O 2 )‐affinity R‐state of the protein, which, unlike the low O 2 ‐affinity T‐state, does not present the polymerization promoting βVal6 residue. Several compounds employing this mechanism are currently at various stages of preclinical and clinical investigations. Another series of compounds that engage in a covalent bond with the surface‐located residue βCys93 of HbS, and thus destabilize the T‐state to increase Hb affinity for oxygen, is currently under preclinical development. Furthermore, promising new compounds that, similar to hydroxyurea also induce fetal Hb production, are at various stages of clinical development. Finally, compounds that target the secondary pathophysiology of SCD, including those that counter the dehydration of sickle erythrocyte; endothelial adhesion and vasculature damage; nitroxide donors providing vasodilatory and anti‐inflammatory effects; and a myriad of anti‐inflammatory and anticoagulation candidate molecules, are also being investigated in early‐ and/or late‐stage clinical trials.

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Arginine Therapy Shows Promise for Treatment of Sickle Cell Disease Clinical Subphenotypes of Hemolysis and Arginine Deficiency

Cited by 4 publications

References 5 publications

Arginine Therapy for Lung Diseases

Arginine Therapy for Lung Diseases

Influence of streptococcal arginine deiminase on the leukocyte infiltration in murine air pouch model

Therapeutic Strategies for the Treatment of Sickle Cell Disease

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