Way above my paygrade but here goes. Statins (and several herbs) have been have been credited to reducing vascular permeability. This leakage contributes to fluid accumulation (edema?) in acute respiratory distress syndrome. I remember seeing information about Sphingosine-1-phosphate.
(Quote from the Lipid Library link.) “Sphingosine-1-phosphate is an important cellular metabolite, derived from ceramide that is synthesized de novo or as part of the sphingomyelin cycle (in animal cells)…Intracellularly, sphingosine-1-phosphate functions also to regulate calcium mobilization and cell growth in response to a variety of extracellular stimuli. Current opinion appears to suggest that the balance between sphingosine-1-phosphate and ceramide and/or sphingosine levels in cells is critical for their viability. In common with the lysophospholipids, especially lysophosphatidic acid with which it has some structural similarities, sphingosine-1-phosphate exerts many of its extra-cellular effects through interaction with five specific G protein-coupled receptors on cell surfaces. These are important for the growth of new blood vessels, vascular maturation, cardiac development and immunity, and for directed cell movement.
Sphingosine-1-phosphate is stored in relatively high concentrations in human platelets, presumably because of the existence of highly active sphingosine kinase and a lack of sphingosine phosphatase, and it is released into the blood stream upon activation by physiological stimuli, such as growth factors, cytokines, and receptor agonists and antigens. It may have a critical role in platelet aggregation and thrombosis and could aggravate cardiovascular disease. On the other hand, the relatively high concentration of the metabolite in high-density lipoproteins (HDL) may have beneficial implications for atherogenesis. For example, there are recent suggestions that sphingosine-1-phosphate, together with other lysolipids such as sphingosylphosphorylcholine and lysosulfatide, are responsible for the beneficial clinical effects of HDL by stimulating the production of the potent antiatherogenic signalling molecule nitric oxide by the vascular endothelium. In addition, like lysophosphatidic acid, it is a marker for certain types of cancer, and there is evidence that its role in cell division or proliferation may have an influence on the development of cancers. These are currently topics that are attracting great interest amongst medical researchers, and the potential for therapeutic intervention in sphingosine-1-phosphate metabolism is under active investigation.”
Pulmonary and vascular pharmacology of sphingosine 1-phosphate. Curr Opin Pharmacol. 2006 Mar 21 Brinkmann V, Baumruker T. Autoimmunity & Transplantation, Novartis Institutes for BioMedical Research, WSJ-386.101, Lichtstrasse 35, CH-4002 Basel, Switzerland.
Dysregulation of vasomotor tone, endothelial barrier function and immune cell trafficking are central to the pathology of many lung diseases, including acute lung injury, adult respiratory distress syndrome, chronic obstructive pulmonary disease and asthma. There is increasing evidence that the serum sphingolipid sphingosine 1-phosphate and its G-protein-coupled receptors are pivotal not only in the regulation of lymphocyte migration, but also in the maintenance of vascular homeostasis and the preservation of permeability barriers that separate discrete compartments in the lung.
It appears the opposite of this is ceramide 1-phosphate (C1P). “Ceramide-1-phosphate, a sphingoid analogue of phosphatidic acid or lysophosphatidic acid, is one of the metabolites in the ‘sphingomyelin cycle’ but is only indirectly related to sphingomyelin as it is formed from ceramide by the action of a specific ceramide kinase. It has been detected in human leukaemia (HL 60) cells and in bone marrow from mice, but the ceramide kinase is present in many other cell types. It is now known to have a number of biological functions, some of which are confined to specific cell types. For example, it is mitogenic for fibroblasts and blocks apoptosis in macrophages. In addition, it is believed to be an important mediator of the inflammatory response, by stimulating the release of arachidonic acid by activating a specific phospholipase A2, i.e. the initial rate-limiting step of eicosanoid synthesis.”
A google search on Ceramide-1-phosphate eicosanoid ards brought this article which appears to describe the Mechanisms of platelet-activating factor-mediated responses in the lung Summary: “Activation of the PAF-receptor leads to the production of other lipid mediators, in particular prostaglandins, thromboxane and ceramide. It are these secondary lipid mediators that finally execute the PAF-signal as is summarized in Figure 5 for vasoconstriction, bronchoconstriction and edema formation. Since PAF is an ubiquitous mediator of inflammation, these pathways provide novel attractive targets for specific pharmacological interventions in inflammatory diseases…”
As a layman I recognize some terms I have seen elsewhere. References to cholesterol. Lipids are related to cholesterol and cell membranes. I have read great detail about nutritional supplementation of essential fatty acids EPA and GLA seem to help reduce lung injury from ARDS in RT The Journal for Respiratory Care Practitioners. Fibrins normally help healing wounds but can cause damage when produced in excess Disseminated intravascular coagulation DIC?. The term Eicosanoid is new to me. Reducing Inflammation With Diet And Supplements The Story of Eicosanoid Inhibition. Apparently there is a relationship between eicosanoids and the antioxidant glutathione (NAC and quercertin are precursors of this). Membrane-associated Proteins in Eicosanoid and Glutathione Metabolism MAPEG. Glutathione described for scientists and for laymen. Selenium is a component of glutathione Selenium Deficiency Causes Flu Virus To Mutate. Antioxidants and Viral Infections: Host Immune Response and Viral Pathogenicity “This work points to the importance of host nutrition in not only optimizing the host immune response, but also in preventing viral mutations which could increase the viral pathogenicity…What is the mechanism that allows the viral pathogen to mutate in the deficient host? One possibility is a selection mechanism. Both coxsackievirus and influenza virus are RNA viruses which have a high mutation rate due to a lack of proofreading enzymes during replication. Thus, mutant viruses will be generated each time the virus replicates and sequencing of the virus reveals only the consensus or dominant sequence. A host deficiency in Se leads to alterations in the immune response of the infected host, which in turn could allow the selection of a new viral variant with more pathogenic properties. A second possibility may involve increased oxidative stress that occurs in the Se-deficient mice due to a lack of the antioxidant glutathione peroxidase. The increased oxidative stress status of the host may cause direct damage to the viral pathogenesis.”
I am trying to comprehend it all. Nutrition sounds important. Anti-oxidants and lipid levels play an important role. Would trying to manipulate S1P or C1P help at all or does that affect too many other things?
Sorry about the formatting. The Glutathione link for scientists was supposed to be http://www.thorne.com/altmedrev/fulltext/glut.html.
from Professional Guide to Diseases from Lippincott Williams & Wilkins…
What Happens in ARDS This flowchart shows the process and progress of acute respiratory distress syndrome (ARDS).
Injury reduces normal blood flow to the lungs, allowing platelets to aggregate. | | These platelets release substances, such as serotonin, bradykinin and, especially, histamine. These substances inflame and damage the alveolar membrane and later increase capillary permeability. At this early stage, signs and symptoms of ARDS are undetectable. | | Histamine and other inflammatory substances increase capillary permeability, allowing fluid to shift into the interstitial space. As a result, the patient may experience tachypnea, dyspnea, and tachycardia. | | As capillary permeability increases, proteins and more fluid leak out, increasing interstitial osmotic pressure and causing pulmonary edema. At this stage, the patient may experience increased tachypnea, dyspnea, and cyanosis. Hypoxia (usually unresponsive to increased fraction of inspired air), decreased pulmonary compliance, and crackles and rhonchi may also develop. | | Fluid in the alveoli and decreased blood flow damage surfactant in the alveoli, reducing the cells’ ability to produce more. Without surfactant, alveoli collapse, impairing gas exchange. Look for thick, frothy sputum and marked hypoxemia with increased respiratory distress. | | The patient breathes faster, but sufficient oxygen (O2) can’t cross the alveolocapillary membrane. Carbon dioxide (CO2), however, crosses more easily and is lost with every exhalation. O2, and CO2, levels in the blood decrease. Look for increased tachypnea, hypoxemia, and hypocapnia. | | Pulmonary edema worsens. Meanwhile, inflammation leads to fibrosis, which further impede, gas exchange. The resulting hypoxemia leads to metabolic acidosis. At this stage, look for increased partial pressure of arterial carbon dioxide, decreased pH and partial pressure of arterial oxygen, and mental confusion.
Fredness at 0735-“Injury reduces normal blood flow to the lungs, allowing platelets to aggregate. | | These platelets release substances, such as serotonin, bradykinin and, especially, histamine.”
Note in regards to the relationship between ARDS and DIC, (disseminated intravascular coagulation). Early investigators, (Roger Bone, my mentor, G.R.H.S.) described ARDS as Limited Intravascular Coagulation, as the same initial process with fibrin laying down in capillaries, (from Shock), hemolytic anemia and release of mediators. The extension of that initial injury can cause the same process in other organs besides the lung, causing the devastating hemorrhagic effects seen in D.I.C. ARDS and DIC in combination carry a 100% mortality the last time I checked.
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