Question
Asked 19th Mar, 2020

NADPH oxidase Covid-19 Oxygen treatment?

As I understand Neutrophil ROS generation may be a strong contributing factor for lung injury of immunopathological lunginflamation during infection with covid-19. What effects would oxygen treatment have on the ROS generation? Would it cause a strong increase of ROS generation by the overactive neutrophils? Could one treat with e.g. Apocynin?

Most recent answer

14th May, 2020
Hermann A M Mucke
H.M. Pharma Consultancy
At least one company, AptaBio Co. Ltd from Korea, is already working on Covid-19 from this angle with its NOX inhibitor APX-115 which it also has in prepration for Phase II trials in diabetic nephropathy: https://us.acrofan.com/detail.php?number=266790

All Answers (7)

20th Mar, 2020
Pritam Sadhukhan
Johns Hopkins University
The article suggests that Oxygen treatment can reduce the production of ROS in neutrophils by modulating the MAPK and associated downstream signaling.
10.1371/journal.pone.0161343
1 Recommendation
20th Mar, 2020
Suhad Mohammed
University Of Kufa
Because of oxygen released may be using for treatment
24th Mar, 2020
Manash K Paul
University of California, Los Angeles
Hyperbaric Oxygen Reduces Production of Reactive Oxygen Species in Neutrophils from Polytraumatized Patients. and
Reactive Oxygen Species Production in Peripheral Blood Neutrophils of Obstructive Sleep Apnea Patients. these two papers suggest that ROS production is activated in low oxygen conditions and not at high oxygen concentrations.
The role of neutrophils is important as they are capable of recognizing viruses. A a better understanding of the role of neutrophils, that was previously underappreciated with respect to viral infections needs to be done.
26th Apr, 2020
John M Lawler
Texas A&M University
The key to COVID pathology IMO even without hyperbaric treatment is the high levels of NADPH oxidases. ACE1 inhibitors (lisinopril) and angiotensin receptor blockers (telmisartan) can reduce Nox levels.
5th May, 2020
Luay A. Al-Helaly
University of Mosul
With hyperbaric oxygen therapy, I think there will be an increase in oxidant compounds through the effectiveness of neutrophil cells that increase many oxidant compounds through NADPH Oxidase as well as by Meyloperoxidase which can work greatly in cases of infections that occur in the patient's respiratory system.
6th May, 2020
Firas A. Al-Lolage
University of Mosul
This isn't a new article but it should be helpful in this context

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Repurposing of Sodium Thiosulfate (STS) in the treatment of COVID 19 or SARS Cov-2 Viral pandemic of 2019-2020
Repurposing or repositioning of medications to treat emerging diseases is not a new concept; however, I wish to share the story of utilizing sodium thiosulfate (STS) as a repurposed drug in the treatment of calciphylaxis and how even now this drug could possibly assist in the treatment of COVID 19 viral pandemic of 2019-2020 [1].
Repurposing of STS started out with a paper on vascular ossification calcification that included calciphylaxis in 2005 [2] and subsequent multiple papers regarding the use of STS in the treatment of calciphylaxis [3-7]. Importantly, there have been many other papers dealing with the use of STS in the treatment of calciphylaxis over the years (202 papers in pub med with search terms for sodium thiosulfate and calciphylaxis) and STS is often a part of the multimodal treatment strategy. Recently, 2 days ago, a repurposing of an older malaria drug, hydroxychloroquine, to treat patients with COVID-19 gave me the idea or concept to share this question with an international group of researchers on Research Gate.
Here is a list of other approved medications that are also being considered for repurposing as follows: Tocilizumab - sold under the name Actemra, Kaletra/Aluvia HIV drugs, Hydroxychloroquine as previously mentioned and Remdesivir is a broad spectrum anti-viral medication. There are undoubtedly many more under consideration and are also important in this pandemic crisis.
Sodium Thiosulfate (STS) is a potent antioxidant.
Instead of one unpaired electron as in most antioxidants, STS has (2) unpaired electrons that can be readily donated to sequester reactive oxygen/nitrogen species (RONS). During this chemical reaction process of sequestering RONS, STS also is capable of generating glutathione (GSH) a naturally occurring intracellular antioxidant and thus increases the cellular antioxidant strength in a region actively being damaged (Fig. 1 and 2).
Figure 1. This figure demonstrates the chemical structure of sodium thiosulfate, which is an anti-browning, reducing, and antioxidant agent: Capable of donating electrons to re-pair unpaired damaging electrons to be an effective antioxidant as well as a chelator of cations such as the calcium excess in calcific uremic arteriolopathy – CPLX [2].
Figure 2. Possible chemical reaction of STS to generate glutathione (GSH) [2]
Known side effects of sodium thiosulfate (STS) used to treat calciphylaxis
Here is what we know since sodium thiosulfate has become the standard of care in patients with calciphylaxis globally. Obviously, any known allergy to this or a similar sulfur-containing product would preclude its use see references [2-7]. STS may induce an acidosis early-on and with prolonged use could induce osteoporosis see references [2-7].
Sodium Thiosulfate Protective à To Detrimental Cytokine and Reactive Oxygen/Nitrogen Species Storm and Vascular Collapse
Upon initial infection with COVID 19 there is a cauldron of redox chemistry with excessive RONS (the first line of defense against the COVID 19 virus produced by the body’s protective inflammatory response to infection. The cells of immune response include the 1st responder’s neutrophils, mast cells and chronic persistent macrophages - with monocyte migration and monocyte to macrophage transformation at the infectious site of the nasopharyngeal bronchial lining epithelial cells, pneumocytes and capillary endothelial cells.
As these inflammatory cells attempt to clear the virus from these passageway epithelial cell’s they generate RONS with a staggering amount of unpaired reactive oxygen and nitrogen unpaired electrons and toxic cytokines, which over time creates a cytokine storm and RONS beget RONS and cytokines evoke more inflammatory invasion and thus create the cytokine storm. The healthy surrounding cells of the upper and lower pulmonary epithelial, pneumocytes and capillary (blood-oxygen barrier) endothelial cells become a source of collateral damage that originally was intended to result in deleting the invasion of viral envelope DAMPs and PAMPs recognized by these cells in a response to injury and wound healing mechanism to the invading COVID 19 viruses in the pulmonary tissues.
In turn, this RONS storm and cytokine storm leak into the systemic circulation and the protective lining of the endothelial cells (endothelial glycocalyx (ecGCx)) may become damaged and are attenuated and/or lost, which results in a marked increased vascular permeability and loss of intravascular contents into the surrounding extravascular interstitial capillary space. Unfortunately, this loss of intravascular volume due to a ‘capillary leak syndrome’ [8-10] may result in vascular collapse with decreased cardiac output and decreased perfusion of the brain with relative ischemia over time and result in the death of the host or COVID 19 infected patients that have progressed to being on ventilator life support.
Indeed, the COVID 19 virus infection-induced this pulmonary infection with bilateral pneumonia’s requiring ventilator treatment an acute respiratory distress syndrome (ARDS) syndrome (ARDS is an acute inflammatory lung injury, associated with increased pulmonary vascular permeability, increased lung weight, and loss of aerated lung tissue) but these patients actually may be dying of vascular collapse due to a loss of their local and systemic endothelial glycocalyx due to a cytokine and RONS STORM!
In conclusion sodium thiosulfate (STS) would have to be given intravenously; however, these critically ill patients with all have an intravenous established intravenous port to administer medication so it should not be viewed as invasive since these lines are already available. This antioxidant effect might possibly restore some effective endothelial cell function and even re-establish the endothelial glycocalyx or assist in its restoration. The increase in venous or arterial Syndecans may be a key laboratory readout of endothelial glycocalyx loss and systemic vascular collapse [10]. Additionally, patients on ventilators with COVID 19 certainly apply to these thoughts and concepts. The concept of increased pulmonary and possible systemic microvascular permeability is currently a possibility that is not being discussed a great deal at the moment but should be. Further, novel ideas for the prevention of this are of great importance during the COVID 19 pandemic. Drugs that may help to eliminate the excessive RONS with excessive over-reactive cytokines and cytokine storm (such as sodium thiosulfate STS) need to be considered as it relates to capillary leak syndrome with vascular collapse due to viral sepsis of the COVID 19 virus.
References
1. Xue H, Li J, Xie H, Wang Y. Review of Drug Repositioning Approaches and Resources. Int J Biol Sci. 2018 Jul 13;14(10):1232-1244. doi: 10.7150/ijbs.24612
2. Hayden MR, Tyagi SC, Kolb L, Sowers JR, Khanna R. Vascular ossification-calcification in metabolic syndrome, type 2 diabetes mellitus, chronic kidney disease, and calciphylaxis-calcific uremic arteriolopathy: the emerging role of sodium thiosulfate. Cardiovasc Diabetol. 2005 Mar 18;4:4. Review
3. Hayden MR, Kolb LG, Khanna R. Calciphylaxis and the cardiometabolic syndrome. J Cardiometab Syndr. 2006 Winter;1(1):76-9.
4. Hayden MR. Calciphylaxis and the cardiometabolic syndrome: the emerging role of sodium thiosulfate as a novel treatment option. J Cardiometab Syndr. 2008 Winter;3(1):55-9
5. Hayden MR, Goldsmith D, Sowers JR, Khanna R. Calciphylaxis: calcific uremic arteriolopathy and the emerging role of sodium thiosulfate. Int Urol Nephrol. 2008;40(2):443-51. doi: 10.1007/s11255-008-9373-4. Review.
6. Hayden MR, Goldsmith DJ. Sodium thiosulfate: new hope for the treatment of calciphylaxis. Semin Dial. 2010 May-Jun;23(3):258-62. doi: 10.1111/j.1525-139X.2010.00738.x
7. Sowers KM, Hayden MR. Calcific uremic arteriolopathy: pathophysiology, reactive oxygen species and therapeutic approaches. Oxid Med Cell Longev. 2010 Mar-Apr;3(2):109-21. doi: 10.4161/oxim.3.2.11354. Review.
8. Siddall E, Khatri M, Radhakrishnan J. Capillary leak syndrome: etiologies, pathophysiology, and management. Kidney Int. 2017 Jul;92(1):37-46. doi: 10.1016/j.kint.2016.11.029
9. Colombo R, Wu MA, Castelli A, Fossali T, Rech R, Ottolina D, Cogliati C, Catena E. The effects of severe hemoconcentration on acid-base equilibrium in critically ill patients: the forgotten role of buffers in whole blood. J Crit Care. 2020 Mar 4;57:177-184. doi: 10.1016/j.jcrc.2020.02.016.
10. Bøe OW, Sveen K, Børset M, Druey KM. Raised Serum Levels of Syndecan-1 (CD138), in a Case of Acute Idiopathic Systemic Capillary Leak Syndrome (SCLS) (Clarkson's Disease). Am J Case Rep. 2018 Feb 16;19:176-182. doi:10.12659/ajcr.906514
11. Ranieri VM, Rubenfeld GD, Thompson BT, et al; ARDS Definition Task Force. Acute respiratory distress syndrome: the Berlin Definition. JAMA. 2012;307(23):2526-2533.
THIS CONCEPT OF REPURPOSING – REPOSITIONING OF MEDICATIONS THAT ARE ALREADY AVAILABLE IS OPEN TO DISCUSSION AND COMMENTS
Sincerely with gratitude,
Melvin R Hayden, MD

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