Oral Glucosylceramide Reduces 2,4-Dinitrofluorobenzene Induced Inflammatory Response in Mice by Reducing TNF-Alpha Levels and Leukocyte Infiltration

Background: Current therapies for ischemic stroke focus on reperfusion but do not address the acute inflammatory response. Previous clinical trials aimed at modulating the inflammatory milieu by disrupting leukocyte infiltration failed to show clinical efficacy. One possible explanation for this unexpected shortcoming is an incomplete understanding of the precise spatio-temporal underpinnings of leukocyte extravasation and infiltration. Methods: Here we describe the evolution of the inflammatory response in a mouse transient middle cerebral artery occlusion (tMCAO) stroke model at 0, 1, 2 and 3 days post reperfusion. We used wide field and confocal immunofluorescence microscopy to examine the exact nature and location of the invading myelomonocytic populations, with close examination of the leukocyte position with regard to the brain vasculature and the perivascular space. Results: Our findings suggest that the vast majority of infiltrating myelomonocytic cells escape the perivascular compartment and enter the parenchyma. Interestingly, leukocyte extravasation and accumulation in the subcortex occurred over several days. Dramatic heterogeneity in the inflammatory infiltrate was observed across the infarcted tissue, but also in the surrounding penumbra and adjacent cortical surface. In addition, triphenyl tetrazolium chloride staining, a common indicator for infarcted tissue, did not correlate with the amount or location of leukocyte infiltration. Conclusion: Taken together our findings demonstrate that the infiltration of leukocytes dynamically evolves over several days following reperfusion. Furthermore, leukocytes infiltrate in a heterogeneous pattern that does not correlate well with traditional markers of cellular dysfunction. A better understating of the precise spatio-temporal infiltration of inflammatory cells could help inform the next generation of therapeutic interventions.

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Roles of Specialized Pro-Resolving Lipid Mediators in Autophagy and Inflammation

International Journal of Molecular Sciences ◽

10.3390/ijms21186637 ◽

2020 ◽

Vol 21 (18) ◽

pp. 6637 ◽

Cited By ~ 1

Author(s):

Antonio Recchiuti ◽

Elisa Isopi ◽

Mario Romano ◽

Domenico Mattoscio

Keyword(s):

Inflammatory Response ◽

Cytokine Production ◽

Lipid Mediators ◽

Tissue Homeostasis ◽

Leukocyte Infiltration ◽

Catabolic Pathway ◽

Resolution Of Inflammation ◽

Endogenous Lipid ◽

Inflammation Resolution ◽

Cellular Components

Autophagy is a catabolic pathway that accounts for degradation and recycling of cellular components to extend cell survival under stress conditions. In addition to this prominent role, recent evidence indicates that autophagy is crucially involved in the regulation of the inflammatory response, a tightly controlled process aimed at clearing the inflammatory stimulus and restoring tissue homeostasis. To be efficient and beneficial to the host, inflammation should be controlled by a resolution program, since uncontrolled inflammation is the underlying cause of many pathologies. Resolution of inflammation is an active process mediated by a variety of mediators, including the so-called specialized pro-resolving lipid mediators (SPMs), a family of endogenous lipid autacoids known to regulate leukocyte infiltration and activities, and counterbalance cytokine production. Recently, regulation of autophagic mechanisms by these mediators has emerged, uncovering unappreciated connections between inflammation resolution and autophagy. Here, we summarize mechanisms of autophagy and resolution, focusing on the contribution of autophagy in sustaining paradigmatic examples of chronic inflammatory disorders. Then, we discuss the evidence that SPMs can restore dysregulated autophagy, hypothesizing that resolution of inflammation could represent an innovative approach to modulate autophagy and its impact on the inflammatory response.

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Dehydroepiandrosterone inhibits the TNF-alpha-induced inflammatory response in human umbilical vein endothelial cells

Atherosclerosis ◽

10.1016/j.atherosclerosis.2006.02.031 ◽

2007 ◽

Vol 190 (1) ◽

pp. 90-99 ◽

Cited By ~ 38

Author(s):

Gisela Gutiérrez ◽

Criselda Mendoza ◽

Estrella Zapata ◽

Angélica Montiel ◽

Elba Reyes ◽

...

Keyword(s):

Endothelial Cells ◽

Inflammatory Response ◽

Umbilical Vein ◽

Tnf Alpha ◽

Human Umbilical Vein ◽

Umbilical Vein Endothelial Cells

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Increased expression of the interleukin-10 gene by alveolar macrophages in interstitial lung disease

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.1997.273.3.l676 ◽

1997 ◽

Vol 273 (3) ◽

pp. L676-L683 ◽

Cited By ~ 13

Author(s):

J. A. Martinez ◽

T. E. King ◽

K. Brown ◽

C. A. Jennings ◽

L. Borish ◽

...

Keyword(s):

Inflammatory Response ◽

Alveolar Macrophages ◽

Interleukin 10 ◽

Interstitial Lung Diseases ◽

Tnf Alpha ◽

Mrna Levels ◽

Healthy Controls ◽

Necrosis Factor Alpha ◽

Factor Alpha ◽

Necrosis Factor

Idiopathic pulmonary fibrosis (IPF) and bronchiolitis obliterans with organizing pneumonia (BOOP) are interstitial lung diseases of unknown pathogenesis. Alveolar macrophages play a major role in the regulation of the inflammatory response in these diseases through their ability to produce cytokines that modify the inflammatory response. Tumor necrosis factor-alpha (TNF-alpha) and interleukin-10 (IL-10) exhibit proinflammatory and anti-inflammatory actions, respectively, and thus an imbalance in the expression of these cytokines may contribute to the pathogenesis of IPF and BOOP. Therefore, we quantified IL-10 and TNF-alpha mRNA levels in alveolar macrophages obtained by bronchoalveolar lavage (BAL) from patients with IPF and BOOP and in normal healthy volunteers. The level of TNF-alpha mRNA in macrophages obtained from IPF and BOOP patients was not significantly different from normal healthy subjects. However, macrophages from patients with IPF and BOOP expressed increased levels of IL-10 mRNA compared with healthy controls. In addition, stimulation of alveolar macrophages with lipopolysaccharide in the presence of a neutralizing anti-IL-10 antibody augmented the production of TNF-alpha over that seen in the absence of anti-IL-10 antibody, suggesting that the increased expression of IL-10 by alveolar macrophages may act to control the expression of TNF-alpha. Paradoxically, measurement of IL-10 protein in cell-free BAL fluid revealed lower amounts of the protein in patients with IPF and BOOP compared with healthy controls.

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MO413EFFECTS OF CHRONIC, LONG-TERM ACE-INHIBITOR TREATMENT ON CYTOKINE STORM AND RENAL FUNCTION AFTER CARDIO-PULMONARY BYPASS: A PROSPECTIVE OBSERVATIONAL STUDY

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfab083.005 ◽

2021 ◽

Vol 36 (Supplement_1) ◽

Author(s):

Pierangela Presta ◽

Davide Bolignano ◽

Giuseppe Coppolino ◽

Mariateresa Zicarelli ◽

Filiberto Serraino ◽

...

Keyword(s):

Renal Function ◽

Inflammatory Response ◽

Plasma Levels ◽

Kidney Injury ◽

Tnf Alpha ◽

Initial Decrease ◽

The Absolute ◽

Pulmonary Bypass ◽

Inhibitor Treatment

Abstract Background and Aims Cardiopulmonary bypass (CPB) may trigger organs damage, including kidney injury, due to a massive cytokine release. In this observational, prospective study, we have analyzed the possible impact of chronic treatment with ACE-Inhibitors (ACE-I) on the inflammatory response and renal function after CPB. Method Sixty-nine patients undergoing major cardiac surgery with CPB were enrolled. Patients were stratified according to long-term (>6 mo.) ACE-I use (n=38) or not (n=31). The primary endpoint was to analyze the changes in their IL-1 alpha, IL-1beta, IL-2, IL-4, IL-6, IL-8, IL-10, TNF alpha, EGF and VEGF plasma levels. Secondary (renal) endpoints were: postoperative acute kidney injury (AKI), recovery of baseline GFR values and the absolute changes in renal function indexes. Results After CPB, IL-1alpha, IL-1beta, IL-4 and TNF-alpha remained stable overtime, while a significant decrease in IL-2 plasma levels was noticed in the ACE-I group (p=0.01). IL-6 and IL-8 plasma levels increased after surgery and tended to decrease after 48h. IL-10 plasma levels showed a similar variation, but both their rise and decrease were more pronounced in patients under ACE-I treatment (p=0.007). Finally, VEGF and EGF showed a marked initial decrease with a tendency to normalization 10 days after surgery (p for trend ranging from 0.01 to 0.001) (Figure 1-2). The occurrence of AKI within 2 days after surgery, the rate of GFR recovery and the absolute changes in renal function indexes were not statistically different between groups (Figure 3). Conclusion Chronic, long-term ACE-I treatment may influence the inflammatory response following CPB. On the other hand, this drug class apparently has neutral impact on perioperative renal outcomes.

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Lung Inflammation from Single and Repetitive Exposure to Glyphosate

10.21203/rs.3.rs-168480/v1 ◽

2021 ◽

Author(s):

Upkardeep Singh Pandher ◽

Shelley Kirychuk ◽

David Schneberger ◽

Brooke Thompson ◽

Gurpreet Aulakh ◽

...

Keyword(s):

Inflammatory Response ◽

Lung Inflammation ◽

Leukocyte Infiltration ◽

Th2 Cytokines ◽

Once Daily ◽

Repetitive Exposure ◽

Lung Histology ◽

Relevant Dose ◽

First Time

Abstract Background: Glyphosate is an active ingredient in herbicides used in agriculture worldwide. Exposure to glyphosate has been associated with respiratory dysfunctions in agricultural workers. However, the ability of glyphosate to induce inflammation in the lung is not well studied. Therefore, we evaluated lung inflammatory response to glyphosate at agricultural relevant dose for single and repetitive exposures. Methods: Male C57BL/6 mice were intranasally exposed to glyphosate (1 μg/40 μl) for 1-day or once daily for 5-days, and 10-days. After the exposure periods, mice were euthanized to collect the bronchoalveolar lavage (BAL) fluid and lung tissue. Results: Repetitive exposure to glyphosate for 5-days and 10-days showed an increase of neutrophils in BAL fluid and eosinophil peroxidase levels in lungs, a marker for eosinophils. Leukocyte infiltration in lungs was further confirmed through lung histology. Th2 cytokines including IL-5 and IL-13 were increased in BAL fluid after 10-days of glyphosate exposure whereas IL-4 was not increased. Lung sections from all glyphosate groups showed higher expression for ICAM-1, VCAM-1, and vWF adhesion molecules. TLR-4 and TLR-2 expression was increased in lungs after repetitive exposure to glyphosate. Conclusions: We conclude that repetitive exposure to glyphosate induces migration of neutrophils and eosinophils and release of Th2 cytokines. This study, for the first time, provides evidence for the role of ICAM-1, VCAM-1 and vWF in lungs of glyphosate-treated animals.

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