exculpatory wrote:Bad-Thoma wrote:exculpatory wrote:Andy, SD, BT, Fencer & the thoughtful, insightful & responsible amongst us:
Wanna see something that blew MY mind which links pulmonology & endocrinology in an attempt to explain often lethal Covid-induced lung disease.
I have read this article 10 times during the last 6 months & still am having a problem grasping all of it.
From the 3/2021 issue of my primary journal - the JCEM (The Journal of Clinical Endocrinology & Metabolism):
https://academic.oup.com/jcem/article/106/3/622/6009077
ME: ‘Excessive mineralocorticoid receptor activation by cortisol’ in the lungs may be a critical component of a pathophysiologic cascade which results in COVID-related ARDS & thrombotic coagulopathy. It lays the groundwork for evaluating a new & UNiQUE therapeutic intervention (dexamethasone PLUS an aldosterone receptor antagonist).
EXCERPTED FROM THE PUBLICATION:
“The loss of the angiotensin-converting enzyme 2 (ACE2) receptor, which is used by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus to get into endothelial and type II alveolar cells, plays a major role in the development of the complications of the infection, acute respiratory distress syndrome (ARDS) and clotting abnormalities.
The loss of the ACE2 receptor results in high levels of angiotensin II, which stimulate nicotinamide adenine dinucleotide phosphate (NADP) oxidase to produce reactive oxygen species (ROS). This removes a key protective mechanism for the pulmonary mineralocorticoid receptor (MR), which now can be activated by cortisol and is no longer aldosterone selective.
Activation of the MR releases adenosine 5′-triphosphate (ATP) from the cells. This then has a paracrine effect on purinergic receptors resulting in calcium entry into the cells.
Increased intracellular calcium results in exocytosis of Weibel-Palade bodies (WPBs) from the cells. These contain the von Willebrand factor (VWF), which spreads like a spiderweb, attracts platelets, and results in microthrombi. The bodies also contain angiopoietin-2, which markedly increases capillary permeability and hence pulmonary edema.
MR blockade with spironolactone has been shown in vitro to block exocytosis of WPBs.
This paper suggests that, on the basis of these hypotheses, there should be trials of dexamethasone to suppress cortisol secretion together with an MR antagonist such as spironolactone or eplerenone.”
ME: FYI, there is precedence for cortisol ‘taking over’ the MR from aldosterone. There is an unusual hereditary syndrome called SAME (syndrome of apparent mineralocorticoid excess) (consequent to the genetic absence of the 11 beta hydroxysteroid dehydrogenase [HSD] type 2 enzyme - which normally deactivates/converts cortisol to cortisone in the kidney) wherein excessive renal cortisol excessively stimulates the MR resulting in hypertension & hypokalemia (mimicking primary hyperaldosteronism).
The intricacy & nuance literally blows my mind. LOL.
I'm sticking with the excerpt and not even attempting the full article as I just don't have the lexicon to get anything more than a basic understanding. Covid - potential cascading failure - understanding the cascade - new intervention to stop the cascade possible is what I am getting, and all I can say is I'm grateful these people exist and are doing this work.
Thank you for reading what you read.
You got the gist of it.
There is a very complex bad ass cascade of events which leads to Covid respiratory failure & kills many people.
If you can block 1 or more components of the cascade, maybe you can block the entire cascade & the awful end result.
The part that obviously intrigues me the most is the endocrine components of the cascade - if you can decrease the excess cortisol with decadron and simultaneously interfere with the binding of cortisol to a receptor it does not typically utilize (the mineralocorticoid receptor - which is normally predominantly used by a different adrenal gland hormone called aldosterone), maybe you can prevent the entire cascade from happening - so that the lungs do not fill up with fluid & clotted blood vessels.
I understand that many won't understand the "doctor" lingo, but what I don't understand is people don't understand the humanity lingo. Too many selfish, "I know everything", "It's a free country" people. It's really sad.
