Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 6 de 6
Filter
1.
PLoS Pathog ; 18(4): e1010468, 2022 04.
Article in English | MEDLINE | ID: covidwho-1779781

ABSTRACT

An overreactive inflammatory response and coagulopathy are observed in patients with severe form of COVID-19. Since increased levels of D-dimer (DD) are associated with coagulopathy in COVID-19, we explored whether DD contributes to the aberrant cytokine responses. Here we show that treatment of healthy human monocytes with DD induced a dose dependent increase in production of pyrogenic mediator, Prostaglandin E2 (PGE2) and inflammatory cytokines, IL-6 and IL-8. The DD-induced PGE2 and inflammatory cytokines were enhanced significantly by co-treatment with immune complexes (IC) of SARS CoV-2 recombinant S protein or of pseudovirus containing SARS CoV-2 S protein (PVCoV-2) coated with spike-specific chimeric monoclonal antibody (MAb) containing mouse variable and human Fc regions. The production of PGE2 and cytokines in monocytes activated with DD and ICs was sensitive to the inhibitors of ß2 integrin and FcγRIIa, and to the inhibitors of calcium signaling, Mitogen-Activated Protein Kinase (MAPK) pathway, and tyrosine-protein kinase. Importantly, strong increase in PGE2 and in IL-6/IL-8/IL-1ß cytokines was observed in monocytes activated with DD in the presence of IC of PVCoV-2 coated with plasma from hospitalized COVID-19 patients but not from healthy donors. The IC of PVCoV-2 with convalescent plasma induced much lower levels of PGE2 and cytokines compared with plasma from hospitalized COVID-19 patients. PGE2 and IL-6/IL-8 cytokines produced in monocytes activated with plasma-containing IC, correlated well with the levels of spike binding antibodies and not with neutralizing antibody titers. Our study suggests that a combination of high levels of DD and high titers of spike-binding antibodies that can form IC with SARS CoV-2 viral particles might accelerate the inflammatory status of lung infiltrating monocytes leading to increased lung pathology in patients with severe form of COVID-19.


Subject(s)
COVID-19 , Monocytes , Animals , Antigen-Antibody Complex , COVID-19/therapy , Cytokines/metabolism , Dinoprostone/metabolism , Fibrin Fibrinogen Degradation Products , Humans , Immunization, Passive , Immunologic Factors/metabolism , Interleukin-6/metabolism , Interleukin-8/metabolism , Mice , Spike Glycoprotein, Coronavirus/metabolism
2.
J Immunol ; 207(5): 1275-1287, 2021 09 01.
Article in English | MEDLINE | ID: covidwho-1771322

ABSTRACT

The airway epithelial cells (AECs) lining the conducting passageways of the lung secrete a variety of immunomodulatory factors. Among these, PGE2 limits lung inflammation and promotes bronchodilation. By contrast, IL-6 drives intense airway inflammation, remodeling, and fibrosis. The signaling that differentiates the production of these opposing mediators is not understood. In this study, we find that the production of PGE2 and IL-6 following stimulation of human AECs by the damage-associated molecular pattern extracellular ATP shares a common requirement for Ca2+ release-activated Ca2+ (CRAC) channels. ATP-mediated synthesis of PGE2 required activation of metabotropic P2Y2 receptors and CRAC channel-mediated cytosolic phospholipase A2 signaling. By contrast, ATP-evoked synthesis of IL-6 occurred via activation of ionotropic P2X receptors and CRAC channel-mediated calcineurin/NFAT signaling. In contrast to ATP, which elicited the production of both PGE2 and IL-6, the uridine nucleotide, UTP, stimulated PGE2 but not IL-6 production. These results reveal that human AECs employ unique receptor-specific signaling mechanisms with CRAC channels as a signaling nexus to regulate release of opposing immunomodulatory mediators. Collectively, our results identify P2Y2 receptors, CRAC channels, and P2X receptors as potential intervention targets for airway diseases.


Subject(s)
Dinoprostone/metabolism , Inflammation/immunology , Interleukin-6/metabolism , Respiratory Mucosa/metabolism , Adenosine Triphosphate/pharmacokinetics , Alarmins/metabolism , Calcium Release Activated Calcium Channels/metabolism , Cells, Cultured , Humans , Immunomodulation , Interleukin-6/genetics , NFATC Transcription Factors/metabolism , Phospholipases A2/metabolism , Receptors, Purinergic P2X/metabolism , Respiratory Mucosa/pathology , Signal Transduction , Uracil Nucleotides/metabolism
3.
Biomolecules ; 11(12)2021 12 14.
Article in English | MEDLINE | ID: covidwho-1572361

ABSTRACT

Arachidonic acid (AA) metabolism is critical in the initiation and resolution of inflammation. Prostaglandin E2 (PGE2) and leukotriene B4/D4/E4 (LTB4/LD4/LTE4), derived from AA, are involved in the initiation of inflammation and regulation of immune response, hematopoiesis, and M1 (pro-inflammatory) macrophage facilitation. Paradoxically, PGE2 suppresses interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) production and triggers the production of lipoxin A4 (LXA4) from AA to initiate inflammation resolution process and augment regeneration of tissues. LXA4 suppresses PGE2 and LTs' synthesis and action and facilitates M2 macrophage generation to resolve inflammation. AA inactivates enveloped viruses including SARS-CoV-2. Macrophages, NK cells, T cells, and other immunocytes release AA and other bioactive lipids to produce their anti-microbial actions. AA, PGE2, and LXA4 have cytoprotective actions, regulate nitric oxide generation, and are critical to maintain cell shape and control cell motility and phagocytosis, and inflammation, immunity, and anti-microbial actions. Hence, it is proposed that AA plays a crucial role in the pathobiology of ischemia/reperfusion injury, sepsis, COVID-19, and other critical illnesses, implying that its (AA) administration may be of significant benefit in the prevention and amelioration of these diseases.


Subject(s)
Fatty Acids, Essential/metabolism , Inflammation/metabolism , Animals , COVID-19/metabolism , COVID-19/pathology , Dinoprostone/metabolism , Humans , Inflammation/pathology , Leukotriene B4/metabolism , Lipoxins/metabolism , SARS-CoV-2/metabolism
4.
Int J Mol Sci ; 22(13)2021 Jun 23.
Article in English | MEDLINE | ID: covidwho-1282518

ABSTRACT

The usefulness of anti-inflammatory drugs as an adjunct therapy to improve outcomes in COVID-19 patients is intensely discussed in this paper. Willow bark (Salix cortex) has been used for centuries to relieve pain, inflammation, and fever. Its main active ingredient, salicin, is metabolized in the human body into salicylic acid, the precursor of the commonly used pain drug acetylsalicylic acid (ASA). Here, we report on the in vitro anti-inflammatory efficacy of two methanolic Salix extracts, standardized to phenolic compounds, in comparison to ASA in the context of a SARS-CoV-2 peptide challenge. Using SARS-CoV-2 peptide/IL-1ß- or LPS-activated human PBMCs and an inflammatory intestinal Caco-2/HT29-MTX co-culture, Salix extracts, and ASA concentration-dependently suppressed prostaglandin E2 (PGE2), a principal mediator of inflammation. The inhibition of COX-2 enzyme activity, but not protein expression was observed for ASA and one Salix extract. In activated PBMCs, the suppression of relevant cytokines (i.e., IL-6, IL-1ß, and IL-10) was seen for both Salix extracts. The anti-inflammatory capacity of Salix extracts was still retained after transepithelial passage and liver cell metabolism in an advanced co-culture model system consisting of intestinal Caco-2/HT29-MTX cells and differentiated hepatocyte-like HepaRG cells. Taken together, our in vitro data suggest that Salix extracts might present an additional anti-inflammatory treatment option in the context of SARS-CoV-2 peptides challenge; however, more confirmatory data are needed.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Aspirin/pharmacology , COVID-19/drug therapy , COVID-19/immunology , Plant Extracts/pharmacology , Anti-Inflammatory Agents/chemistry , Benzyl Alcohols/metabolism , COVID-19/virology , Caco-2 Cells , Cyclooxygenase 2/drug effects , Cytokines/metabolism , Dinoprostone/metabolism , Glucosides/metabolism , HT29 Cells , Humans , Inflammation , Leukocytes, Mononuclear/drug effects , Lipopolysaccharides/immunology , Plant Bark/chemistry , Plant Extracts/chemistry , SARS-CoV-2/immunology
6.
Bioessays ; 42(12): e2000198, 2020 12.
Article in English | MEDLINE | ID: covidwho-917076

ABSTRACT

The outbreak of a new, potentially fatal virus, SARS-COV-2, which started in December 2019 in Wuhan, China, and since developed into a pandemic has stimulated research for an effective treatment and vaccine. For this research to be successful, it is necessary to understand the pathology of the virus. So far, we know that this virus can harm different organs of the body. Although the exact mechanisms are still unknown, this phenomenon may result from the body's secretion of prostaglandin E2 (PGE2), which is involved in several inflammation and immunity pathways. Noticeably, the expression of this molecule can lead to a cytokine storm causing a variety of side effects. In this paper, we discuss those side effects in SARS-COV-2 infection separately to determine whether PGE2 is, indeed, an important causative factor. Lastly, we propose a mechanism by which PGE2 production increases in response to COVID-19 disease and suggest the possible direct relation between PGE2 levels and the severity of this disease. Also see the video abstract here: https://youtu.be/SnPFAcjxxKw.


Subject(s)
COVID-19/epidemiology , COVID-19/pathology , Dinoprostone/physiology , Pandemics , SARS-CoV-2/pathogenicity , Aging/physiology , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/immunology , Dinoprostone/metabolism , Female , Humans , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Inflammation/complications , Inflammation/epidemiology , Inflammation/pathology , Inflammation/virology , Male , Phenotype , SARS-CoV-2/immunology , Severity of Illness Index , Signal Transduction/immunology
SELECTION OF CITATIONS
SEARCH DETAIL