The HO-1 enzyme that may be being made wrong, with glyphosate in place of glycine, promotes another chemical (granulocyte macrophage-colony stimulating factor (GM-CSF) that is seen to be elevated in Covid-19 (1) and the receptor for the chemical may be involved in a lung condition (2) that also has “broken glass” like lung images. The unusual lung images are due to the alveolar areas to be fluid filled and dysfunctional, opaque white areas in the images instead of black/air filled cavities that would normally be visible. (2)
PAP – Pulmonary alveolar proteinosis – “broken glass” lung, or “paving tile”.
Medical opinion: “Clinical data, analytical findings and the few pathological references we have so far suggest SARS-CoV-2 lung disease could be a secondary interferonopathy with pulmonary alveolar proteinosis (PAP)-like features and sometimes thrombotic microangiopathy.” (3)
Treatment with Interferon inhibitors might provide “IFN-γ blockage” and medication trials were recommended.
“The presence of PAP suggests alveolar macrophage dysfunction in clearing surfactant from the alveoli. Whether IL-18 or IFNγ blockage and/or treatments aimed at increasing surfactant phagocytosis/processing by alveolar macrophages are viable treatment strategies, needs further exploration.” (3)
Take home point from clinical trial information and an Abstract-less paper: the PPAR-gamma activator Pioglitazone helped reduce the size of alveolar macrophages in autoimmune pulmonary alveolar proteinosis (PAP). (Vis, Kelly, De Heuvel, MacEachern, 2020) (CTG Labs/NCTO3231033)
GM-CSF promotes growth of alveolar macrophages.
“COVID-19 is a clinical syndrome ranging from mild symptoms to severe pneumonia that often leads to respiratory failure, need for mechanical ventilation, and death. Most of the lung damage is driven by a surge in inflammatory cytokines [interleukin-6, interferon-γ, and granulocyte-monocyte stimulating factor (GM-CSF)]. Blunting this hyperinflammation with immunomodulation may lead to clinical improvement. GM-CSF is produced by many cells, including macrophages and T-cells. GM-CSF-derived signals are involved in differentiation of macrophages, including alveolar macrophages (AMs).” (1)
The authors go on to explain that some GM-CSF can be helpful and promote growth of alveolar macrophages while too much of the GM-CSF stimulation is not. Trials are underway with medication to either block the receptors or antibody medication that combines with the free floating GM-CSF in the blood stream so it is no longer available. (1)
“This blockade can be achieved through antagonism of the GM-CSF receptor or the direct binding of circulating GM-CSF. Initial findings from patients with COVID-19 treated with a single intravenous dose of mavrilimumab, a monoclonal antibody binding GM-CSF receptor α, showed oxygenation improvement and shorter hospitalization. “
Targeting GM-CSF in COVID-19 Pneumonia: Rationale and Strategies https://ncbi.nlm.nih.gov/pmc/articles/PMC7348297/… “HO-1-dependent heme catabolism, regulates GM-CSF synthesis in human airway..”
PPAR-gamma activation helped autoimmune PAP. (Vis, Kelly, De Heuvel, MacEachern, 2020) (CTG Labs/NCTO3231033) See Figure 3, the PPAR alpha, beta/delta, and gamma activate different functions in normal health. Figure 5 shows natural and synthetic ligands of the PPAR receptors, (Grygiel-Gorniak, 2014), but fails to include 9-cis-Retinoic Acid. It was found that both a synthetic and a natural agonist of PPAR gamma only had the desired anti-inflammatory effect when 9-cis-Retinoic acid was also present. (Worley, et al., 2003)
Use of a retinoid medication for a type of leukemia can cause an adverse reaction syndrome that include “ground glass lung” scans. (Weerakkody, et al, 2012) See this post for more info and the full citation: microRNA, elevated homocysteine and is there a role for excess Retinoic Acid? (substack.com) I think there is a role for excess active retinoids in COVID19 and hyperinflammation that seems to be related to the “ground glass lung” scans – fluid filled alveoli – patients drowning in their own body fluids.
We would need to find out if there is an aberrant form of the HO-1 enzyme containing glyphosate in its amino acid construction, that is functional in some new aberrant way, possibly promoting too much GM-CSF – causing a change in the function rather than just making it dysfunctional.
Regulation of IL-1 beta-induced GM-CSF production in human airway smooth muscle cells by CO [Carbon monoxide] — retracted article – need to rethink/read more, https://journals.physiology.org/doi/pdf/10.1152/ajplung.00212.2002 * “The American Physiological Society is retracting this article due to inclusion of data in Figure 4A that were published previously in Figures 5 and 6 of the article “Carbon Monoxide Inhibits Human Airway Smooth Muscle Cell Proliferation via Mitogen-Activated Protein Kinase Pathway” (https:// doi.org/10.1165/rcmb.4851) and represent different results. Due to the length of time since initial publication, the authors were unable to provide original captures for these experiments to resolve the concerns.” (Retraction statement) **So, ignore Figure 4A.
Disclaimer: Opinions are my own and the information is provided for educational purposes within the guidelines of fair use. While I am a Registered Dietitian this information is not intended to provide individual health guidance. Please see a health professional for individual health care purposes.
- Bonaventura A, Vecchié A, Wang TS, et al. Targeting GM-CSF in COVID-19 Pneumonia: Rationale and Strategies. Front Immunol. 2020;11:1625. Published 2020 Jul 3. doi:10.3389/fimmu.2020.01625 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7348297/
- Borie R, Danel C, Debray M-P, et al., Pulmonary alveolar proteinosis. European Respiratory Review 2011 20: 98-107; DOI: 10.1183/09059180.00001311 https://err.ersjournals.com/content/20/120/98
- Julián Fernández-Martín, Pérez-Álvarez Roberto and Lamas-Barreiro José María, COVID-19: An Acute Secondary Interferonophaty? The Mirror of Autoinflammatory Syndromes. Arch of Immunology, Vol 2, Issue 1, DOI: 10.36959/885/368 https://scholars.direct/Articles/immunology/aim-2-005.php?jid=immunology
- Mair, K.M., Robinson, E., Kane, K.A., Pyne, S., Brett, R.R., Pyne, N.J. and Kennedy, S. (2010) Interaction between anandamide and sphingosine-1-phosphate in mediating vasorelaxation in rat coronary artery. British Journal of Pharmacology, 161 (1). pp. 176-192. ISSN 1476-5381 https://core.ac.uk/download/pdf/80831.pdf
- Giacoppo S, Mazzon E. Can cannabinoids be a potential therapeutic tool in amyotrophic lateral sclerosis?. Neural Regen Res. 2016;11(12):1896-1899. doi:10.4103/1673-5374.197125 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5270417/
- ARN14988 (aCDase Inhibitor), https://echelon-inc.com/product/arn14988-acdase-inhibitor/
- Xiao Mei Wang, Hong Pyo Kim, Kiichi Nakahira, Stefan W. Ryter and Augustine M. K. Choi, The Heme Oxygenase-1/Carbon Monoxide Pathway Suppresses TLR4 Signaling by Regulating the Interaction of TLR4 with Caveolin-1. J Immunol March 15, 2009, 182 (6) 3809-3818; DOI: https://doi.org/10.4049/jimmunol.0712437 https://www.jimmunol.org/content/182/6/3809
- Rebecca Gilbert, Update on COVID-19 and Parkinson’s Disease. Oct. 27, 2020, apdaparkinson.org, https://www.apdaparkinson.org/article/newly-published-studies-on-covid-and-pd/
- Fukushima T. Niacin metabolism and Parkinson’s disease. Environ Health Prev Med. 2005;10(1):3-8. doi:10.1265/ehpm.10.3 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2723628/
- Francisco Navarrete, María Salud García-Gutiérrez, Rosa Jurado-Barba, et al., Endocannabinoid System Components as Potential Biomarkers in Psychiatry. Front. Psychiatry, 27 April 2020 | https://doi.org/10.3389/fpsyt.2020.00315 https://www.frontiersin.org/articles/10.3389/fpsyt.2020.00315/full
- Erukainure OL, Matsabisa MG, Salau VF, Islam MS. Tetrahydrocannabinol-Rich Extracts From Cannabis Sativa L. Improve Glucose Consumption and Modulate Metabolic Complications Linked to Neurodegenerative Diseases in Isolated Rat Brains. Front Pharmacol. 2020;11:592981. Published 2020 Nov 24. doi:10.3389/fphar.2020.592981 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7774498/
- CK Eternity, Melatonin: the master antioxidant. August 9, 2020, multiflora-herbs.com, https://www.multiflora-herbs.com/blogs/news/melatonin-the-master-antioxidant
- Yingying Lu,Baixia Hao,Richard Graeff &Jianbo Yue, NAADP/TPC2/Ca2+ Signaling Inhibits Autophagy.
- Article: e27595, Published online: 08 Jan 2014, https://doi.org/10.4161/cib.27595, https://www.tandfonline.com/doi/full/10.4161/cib.27595
- Li R, Li Y, Liang X, Yang L, Su M, Lai KP. Network Pharmacology and bioinformatics analyses identify intersection genes of niacin and COVID-19 as potential therapeutic targets [published online ahead of print, 2020 Nov 10]. Brief Bioinform. 2020;bbaa300. doi:10.1093/bib/bbaa300 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7717147/
- Tweet Thread https://twitter.com/Parsifaler/status/1367148395278856193?s=20
- https://ncbi.nlm.nih.gov/pmc/articles/PMC6399501/… https://medlineplus.gov/genetics/condition/spinal-muscular-atrophy-with-progressive-myoclonic-epilepsy/… https://ncbi.nlm.nih.gov/pmc/articles/PMC3779446/… https://ncbi.nlm.nih.gov/pmc/articles/PMC7382416/… https://ncbi.nlm.nih.gov/pmc/articles/PMC3779446/… https://sciencedaily.com/releases/2016/11/161103122227.htm
- https://www.cedclinic.com/blog/tetrahydrocannabinol-rich-extracts-from-cannabis-sativa-l-improve-glucose-consumption-and-modulate-metabolic-complications-linked-to-neurodegenerative-diseases-in-isolated-rat-brains / pdf https://drive.google.com/file/d/14x6YFb_SoL_2FETSRMrcjfrKga0oNlO_/view
- Targeting GM-CSF in COVID-19 Pneumonia: Rationale and Strategies https://ncbi.nlm.nih.gov/pmc/articles/PMC7348297/… “HO-1-dependent heme catabolism, regulates GM-CSF synthesis in human airway..”
- Regulation of IL-1-induced GM-CSF production in human airway smooth muscle cells by CO — retracted article – need to rethink/read more, https://journals.physiology.org/doi/pdf/10.1152/ajplung.00212.2002
- (Vis, Kelly, De Heuvel, MacEachern, 2020) Vis DC, Kelly MM, De Heuvel E, MacEachern PR. Reduction in Alveolar Macrophage Size in Refractory Autoimmune Pulmonary Alveolar Proteinosis After Treatment With Pioglitazone. J Bronchology Interv Pulmonol. 2020 Jul;27(3):219-222. doi: 10.1097/LBR.0000000000000686. PMID: 32569076. https://pubmed.ncbi.nlm.nih.gov/32569076/ *Might be this clinical trial as there is no Abstract viewable on the Vis, et al. paper: (CTG Labs/NCTO3231033) https://beta.clinicaltrials.gov/study/NCT03231033
- (Grygiel-Gorniak, 2014) Grygiel-Górniak, B. Peroxisome proliferator-activated receptors and their ligands: nutritional and clinical implications – a review. Nutr J 13, 17 (2014). https://doi.org/10.1186/1475-2891-13-17 https://nutritionj.biomedcentral.com/articles/10.1186/1475-2891-13-17
- (Worley, et al., 2003) Worley JR, Baugh MD, Hughes DA, Edwards DR, Hogan A, Sampson MJ, Gavrilovic J. Metalloproteinase expression in PMA-stimulated THP-1 cells. Effects of peroxisome proliferator-activated receptor-gamma (PPAR gamma) agonists and 9-cis-retinoic acid. J Biol Chem. 2003 Dec 19;278(51):51340-6. doi: 10.1074/jbc.M310865200. Epub 2003 Oct 8. PMID: 14534304. https://www.jbc.org/article/S0021-9258(20)75394-9/fulltext