systemic reaction characterized by fever, leukocytosis, increase in erythrocyte sedimentation rate, increases in Leucocytosis secretion of ACTH and glucocorticoids, activation of Complement activat complement and clotting cascades, decreases in serum levels of iron and zinc, a negative nitrogen balance, and by dramatic changes in the concentration of some plasma ,l' proteins. These proteins are named acute phase proteins. i

Interleukin-6 and the acute phase response

Although COVID-19 is most well known for causing substantial respiratory pathology, it can also result in several extrapulmonary manifestations. These conditions include thrombotic complications, myocardial dysfunction and arrhythmia, acute coronary syndromes, acute kidney injury, gastrointestinal symptoms, hepatocellular injury, hyperglycemia and ketosis, neurologic illnesses, ocular symptoms, and dermatologic complications. Given that ACE2, the entry receptor for the causative coronavirus SARS-CoV-2, is expressed in multiple extrapulmonary tissues, direct viral tissue damage is a plausible mechanism of injury. In addition, endothelial damage and thromboinflammation, dysregulation of immune responses, and maladaptation of ACE2-related pathways might all contribute to these extrapulmonary manifestations of COVID-19. Here we review the extrapulmonary organ-specific pathophysiology, presentations and management considerations for patients with COVID-19 to aid clinicians and scientists in recognizing and monitoring the spectrum of manifestations, and in developing research priorities and therapeutic strategies for all organ systems involved.

/pdf/extrapulmonary-manifestations-of-covid-19-5gbdx3z1ea.pdf

Extrapulmonary manifestations of COVID-19.

Among the fatty acids, it is the omega-3 polyunsaturated fatty acids (PUFA) which possess the most potent immunomodulatory activities, and among the omega-3 PUFA, those from fish oil— eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)—are more biologically potent than -linolenic acid (ALA). Some of the effects of omega-3 PUFA are brought about by modulation of the amount and types of eicosanoids made, and other effects are elicited by eicosanoid-independent mechanisms, including actions upon intracellular signaling pathways, transcription factor activity and gene expression. Animal experiments and clinical intervention studies indicate that omega-3 fatty acids have anti-inflammatory properties and, therefore, might be useful in the management of inflammatory and autoimmune diseases. Coronary heart disease, major depression, aging and cancer are characterized by an increased level of interleukin 1 (IL-1), a proinflammatory cytokine. Similarly, arthritis, Crohn’s disease, ulcerative colitis and lupus erythematosis are autoimmune diseases characterized by a high level of IL-1 and the proinflammatory leukotriene LTB4 produced by omega-6 fatty acids. There have been a number of clinical trials assessing the benefits of dietary supplementation with fish oils in several inflammatory and autoimmune diseases in humans, including rheumatoid arthritis, Crohn’s disease, ulcerative colitis, psoriasis, lupus erythematosus, multiple sclerosis and migraine headaches. Many of the placebocontrolled trials of fish oil in chronic inflammatory diseases reveal significant benefit, including decreased disease activity and a lowered use of anti-inflammatory drugs. Key teaching points:  In Western diets, omega-6 fatty acids are the predominant polyunsaturated fats. The omega-6 and omega-3 fatty acids are metabolically distinct and have opposing physiologic functions.  Eicosapentaenoic acid (EPA) is released to compete with arachidonic acid (AA) for enzymatic metabolism inducing the production of less inflammatory and chemotactic derivatives.  Animal and human studies support the hypothesis that omega-3 PUFA suppress cell mediated immune responses.  In experimental animals and humans, serum PUFA levels predict the response of proinflammatory cytokines to psychologic stress. Imbalance in the omega-6/omega-3 PUFA ratio in major depression may be related to the increased production of proinflammatory cytokines and eicosanoids in that illness.  The increased omega-6/omega-3 ratio in Western diets most likely contributes to an increased incidence of cardiovascular disease and inflammatory disorders.  Patients with autoimmune diseases, such as rheumatoid arthritis, inflammatory bowel disease and asthma, usually respond to eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) supplementation by decreasing the elevated levels of cytokines.

Omega-3 Fatty Acids in Inflammation and Autoimmune Diseases

Heart failure results not only from cardiac overload or injury but also from a complex interplay among genetic, neurohormonal, inflammatory, and biochemical changes acting on cardiac myocytes, the cardiac interstitium, or both. This review focuses on biomarkers for heart failure other than routinely determined laboratory values and discusses how these might be used in assessing and managing heart failure.

/pdf/biomarkers-in-heart-failure-52ugb7jodj.pdf

Biomarkers in heart failure.

Effect of sleep loss on C-Reactive protein, an inflammatory marker of cardiovascular risk ☆

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1016/0014-5793%2889%2980476-4

Interleukin-6 is the major regulator of acute phase protein synthesis in adult human hepatocytes

https://aasldpubs.onlinelibrary.wiley.com/doi/pdf/10.1002/hep.1840120517

Acute-phase response of human hepatocytes: regulation of acute-phase protein synthesis by interleukin-6.

https://aasldpubs.onlinelibrary.wiley.com/doi/pdf/10.1002/hep.1840210506

effects of hepatocyte growth factor on the growth and metabolism of human hepatocytes in primary culture.

The effects of oncostatin M on the expression of different cytochrome P450 (CYP) isozymes has been investigated in human hepatocytes. The dose-response and time-course analyses of effects on CYP1A2 and CYP3A4 isozymes revealed that maximal inhibition was reached after 48 hr of exposure of human hepatocytes to 25 units/ml oncostatin M. Reductions in CYP1A2 and CYP3A4 activity produced by oncostatin M correlated with decreases in protein content, de novo protein synthesis and specific mRNA levels, thus suggesting that oncostatin M could down-regulate CYP expression at the transcriptional level. The inhibitory potency of oncostatin M on CYP expression was compared with that of other cytokines belonging to the interleukin-6 receptor family (interleukin-6, interleukin-11 and leukemia inhibitory factor), and interferon-γ, which is recognized to inhibit human CYP expression, and granulocyte colony-stimulating factor, a cytokine that shares structural homology with the interleukin-6 family but has a different transduction signal. Maximal reductions in CYP1A2 activity were reached after 48 hr of treatment with cytokines. At that time, oncostatin M showed the highest inhibitory effects on CYP1A2 activity (38% of control), followed by interferon (49% of control) and interleukin-6 (60% of control), whereas minor effects were produced by the other cytokines (74–80%). Comparable decreases were observed for CYP2A6, CYP2B6 and CYP3A4 activities. Enzymatic activity and de novo protein synthesis of 3-methylcholanthrene-induced CYP1A2 and dexamethasone-induced CYP3A4 were also reduced to a much greater extent by oncostatin M than by other cytokines. The results show that oncostatin M is the most effective cytokine in down-regulating CYP isozymes in human hepatocytes, and its effects were evident even after removal of the cytokine from the culture medium.

Ricardo Fabra

Papers

Interleukin-6 is the major regulator of acute phase protein synthesis in adult human hepatocytes

Acute-phase response of human hepatocytes: regulation of acute-phase protein synthesis by interleukin-6.

effects of hepatocyte growth factor on the growth and metabolism of human hepatocytes in primary culture.

Oncostatin M Down-regulates Basal and Induced Cytochromes P450 in Human Hepatocytes

Intracellular glutathione in human hepatocytes incubated with S-adenosyl-L-methionine and GSH-depleting drugs.