Sustained Lipopolysaccharide-Induced Lung Inflammation in Mice Is Attenuated by Functional Deficiency of the Fas/Fas Ligand System

ABSTRACT To determine whether the Fas/Fas ligand (FasL) (CD95/CD178) system contributes to the development of an inflammatory response in vivo, 2.5 μg of bacterial lipopolysaccharide (LPS; endotoxin) per g was administered intranasally to healthy mice (C57BL/6) and mutant mice deficient in either Fas (lpr mice) or FasL (gld mice). Sustained LPS-induced neutrophilic inflammation in the lungs was attenuated in both lpr and gld mice. These observations provide further evidence of a proinflammatory role for the Fas/FasL system in the lungs.

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Control of local blood flow in pulmonary inflammation: role for neutrophils, PAF, and thromboxane

Journal of Applied Physiology ◽

10.1152/jappl.1991.70.3.1184 ◽

1991 ◽

Vol 70 (3) ◽

pp. 1184-1193 ◽

Cited By ~ 11

Author(s):

P. G. Hellewell ◽

P. M. Henson ◽

G. P. Downey ◽

G. S. Worthen

Keyword(s):

Blood Flow ◽

Inflammatory Response ◽

Lung Inflammation ◽

Pulmonary Inflammation ◽

Local Blood Flow ◽

Synthesis Inhibitor ◽

Rabbit Lung ◽

Local Inflammatory Response ◽

Paf Antagonists

The intrapulmonary instillation of C5a results in a local inflammatory response that, in this site, is accompanied by a decrease in local blood flow. Reversal of this decrease by vasodilators or the thromboxane synthesis inhibitor dazmegral has been shown to result in enhanced lung inflammation. In the present study the mechanisms underlying the decrease in flow in pulmonary inflammation were investigated in the rabbit in vivo and in the isolated blood-perfused rabbit lung. In vivo, the decrease in local blood flow was shown to be dependent on circulating neutrophils. In the isolated blood-perfused lung, inflammation induced by airway instillation of C5a was similar histologically to that seen in vivo and was also accompanied by a decrease in local blood flow. The decrease in blood flow appeared to require circulating neutrophils and was prevented by dazmegral and the platelet-activating factor (PAF) antagonists WEB 2086 and L-659,989. Furthermore, no decrease occurred in aspirin-treated lungs perfused with normal blood, suggesting that the source of thromboxane was lung rather than circulating cells. The decrease in blood flow in inflammation did not appear to be a consequence of hypoxic vasoconstriction. Inflammation in the guinea pig lung was also accompanied by a decrease in local blood flow and was also prevented by dazmegral and PAF antagonists. We conclude that local inflammation in the lung is accompanied by a decrease in blood flow that involves neutrophils and the lipid mediators PAF and thromboxane. We suggest that this form of negative feedback by the neutrophil serves to control the inflammatory response.

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Antigen-Induced Eosinophilic Lung Inflammation Develops in Mice Deficient in Chemokine Eotaxin

Blood ◽

10.1182/blood.v92.10.3912 ◽

1998 ◽

Vol 92 (10) ◽

pp. 3912-3923 ◽

Cited By ~ 70

Author(s):

Yi Yang ◽

James Loy ◽

Rolf-Peter Ryseck ◽

Daniel Carrasco ◽

Rodrigo Bravo

Keyword(s):

Endothelial Cells ◽

Inflammatory Response ◽

Lung Inflammation ◽

Immunohistochemical Staining ◽

High Selectivity ◽

Allergic Diseases ◽

Mutant Mice ◽

Cc Chemokine ◽

Lung Eosinophilia

Abstract The mechanisms that regulate the selective infiltration of eosinophils in certain allergic diseases are still poorly understood. The CC chemokine eotaxin is a potent chemoattractant, highly specific for eosinophils. Recent studies have implicated that eotaxin plays an important role in the recruitment of eosinophils in different inflammation processes. A number of other chemokines, cytokines, and chemoattractants also have chemotactic activities for eosinophils and some of them present high selectivity for eosinophils. To further study the role of eotaxin in inflammation, we generated mutant mice with the eotaxin gene disrupted and replaced by the Escherichia coliβ-galactosidase gene. These mice developed normally and had no histologic or hematopoietic abnormalities. Furthermore, our studies showed that the lack of eotaxin did not affect the recruitment of eosinophils in the inflammation models induced by Sephadex beads and thioglycollate, as well as in an experimental lung eosinophilia model induced by ovalbumin aerosol challenge, even at the onset of the inflammatory response. The replacement of the eotaxin gene by the β-galactosidase gene provided a useful marker to monitor the activity of the eotaxin promoter under normal conditions and after antigen challenges. Immunohistochemical staining suggested that endothelial cells were the major sources of eotaxin expression.

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Could Arachidonic Acid-Derived Pro-Resolving Mediators Be a New Therapeutic Strategy for Asthma Therapy?

Frontiers in Immunology ◽

10.3389/fimmu.2020.580598 ◽

2020 ◽

Vol 11 ◽

Author(s):

Daniella Bianchi Reis Insuela ◽

Maximiliano Ruben Ferrero ◽

Diego de Sá Coutinho ◽

Marco Aurélio Martins ◽

Vinicius Frias Carvalho

Keyword(s):

Arachidonic Acid ◽

Inflammatory Response ◽

Lung Inflammation ◽

Clinical Investigation ◽

Inflammatory Cells ◽

Airway Epithelial ◽

Asthmatic Patients ◽

Beneficial Effects

Asthma represents one of the leading chronic diseases worldwide and causes a high global burden of death and disability. In asthmatic patients, the exacerbation and chronification of the inflammatory response are often related to a failure in the resolution phase of inflammation. We reviewed the role of the main arachidonic acid (AA) specialized pro-resolving mediators (SPMs) in the resolution of chronic lung inflammation of asthmatics. AA is metabolized by two classes of enzymes, cyclooxygenases (COX), which produce prostaglandins (PGs) and thromboxanes, and lypoxygenases (LOX), which form leukotrienes and lipoxins (LXs). In asthma, two primary pro-resolving derived mediators from COXs are PGE2 and the cyclopentenone prostaglandin15-Deoxy-Delta-12,14-PGJ2 (15d-PGJ2) while from LOXs are the LXA4 and LXB4. In different models of asthma, PGE2, 15d-PGJ2, and LXs reduced lung inflammation and remodeling. Furthermore, these SPMs inhibited chemotaxis and function of several inflammatory cells involved in asthma pathogenesis, such as eosinophils, and presented an antiremodeling effect in airway epithelial, smooth muscle cells and fibroblasts in vitro. In addition, PGE2, 15d-PGJ2, and LXs are all able to induce macrophage reprogramming to an alternative M2 pro-resolving phenotype in vitro and in vivo. Although PGE2 and LXA4 showed some beneficial effects in asthmatic patients, there are limitations to their clinical use, since PGE2 caused side effects, while LXA4 presented low stability. Therefore, despite the strong evidence that these AA-derived SPMs induce resolution of both inflammatory response and tissue remodeling in asthma, safer and more stable analogs must be developed for further clinical investigation of their application in asthma treatment.

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Antigen-Induced Eosinophilic Lung Inflammation Develops in Mice Deficient in Chemokine Eotaxin

Blood ◽

10.1182/blood.v92.10.3912.422k23_3912_3923 ◽

1998 ◽

Vol 92 (10) ◽

pp. 3912-3923 ◽

Cited By ~ 2

Author(s):

Yi Yang ◽

James Loy ◽

Rolf-Peter Ryseck ◽

Daniel Carrasco ◽

Rodrigo Bravo

Keyword(s):

Endothelial Cells ◽

Inflammatory Response ◽

Lung Inflammation ◽

Immunohistochemical Staining ◽

High Selectivity ◽

Allergic Diseases ◽

Mutant Mice ◽

Cc Chemokine ◽

Lung Eosinophilia

The mechanisms that regulate the selective infiltration of eosinophils in certain allergic diseases are still poorly understood. The CC chemokine eotaxin is a potent chemoattractant, highly specific for eosinophils. Recent studies have implicated that eotaxin plays an important role in the recruitment of eosinophils in different inflammation processes. A number of other chemokines, cytokines, and chemoattractants also have chemotactic activities for eosinophils and some of them present high selectivity for eosinophils. To further study the role of eotaxin in inflammation, we generated mutant mice with the eotaxin gene disrupted and replaced by the Escherichia coliβ-galactosidase gene. These mice developed normally and had no histologic or hematopoietic abnormalities. Furthermore, our studies showed that the lack of eotaxin did not affect the recruitment of eosinophils in the inflammation models induced by Sephadex beads and thioglycollate, as well as in an experimental lung eosinophilia model induced by ovalbumin aerosol challenge, even at the onset of the inflammatory response. The replacement of the eotaxin gene by the β-galactosidase gene provided a useful marker to monitor the activity of the eotaxin promoter under normal conditions and after antigen challenges. Immunohistochemical staining suggested that endothelial cells were the major sources of eotaxin expression.

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Opposing Effects of Transmembrane and Soluble FAS Ligand Expression on Inflammation and Tumor Cell Survival

Journal of Experimental Medicine ◽

10.1084/jem.191.7.1209 ◽

2000 ◽

Vol 191 (7) ◽

pp. 1209-1220 ◽

Cited By ~ 147

Author(s):

Andreas M. Hohlbaum ◽

Signa Moe ◽

Ann Marshak-Rothstein

Keyword(s):

Inflammatory Response ◽

Fas Ligand ◽

Physiological Role ◽

Cytotoxic Activities ◽

Inflammatory Reactions ◽

Soluble Fas ◽

Ligand Expression ◽

Soluble Fasl ◽

Neutrophil Response

Fas ligand (FasL) has been shown to mediate both apoptotic and inflammatory reactions. To rigorously assess the physiological role of different forms of the FasL molecule with regard to these two distinct processes, we isolated stably transfected lymphoma cell lines that expressed either murine wild-type FasL, membrane-only FasL, or functionally distinct forms of soluble FasL. First, the ability of these lines to induce an inflammatory response was assessed in vivo by injecting the transfectants intraperitoneally and measuring subsequent neutrophil extravasation into the peritoneal cavity. Second, lines were assessed by injecting the transfectants subcutaneously and monitoring their growth as solid tumors. Our study clearly demonstrated that the extent of inflammation induced by the transfectants directly correlated with their relative cytotoxic activities. A neutrophil response could only be elicited in mice with intact Fas death domains although Fas expression by the neutrophils was not essential. Lymphoma cells expressing the soluble FasL form corresponding to the natural cleavage product could not trigger apoptosis and did not induce a neutrophil response. In contrast to the other FasL transfectants, these cells survived as tumor transplants. However, expression of soluble FasL was not benign, but actually suppressed the inflammatory response and protected other transfectants from the effector mechanisms elicted by membrane-bound FasL.

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Endogenous itaconate is not required for particulate matter-induced NRF2 expression or inflammatory response

eLife ◽

10.7554/elife.54877 ◽

2020 ◽

Vol 9 ◽

Cited By ~ 8

Author(s):

Kaitlyn A Sun ◽

Yan Li ◽

Angelo Y Meliton ◽

Parker S Woods ◽

Lucas M Kimmig ◽

...

Keyword(s):

Air Pollution ◽

Particulate Matter ◽

Inflammatory Response ◽

Lung Inflammation ◽

Mitochondrial Enzyme ◽

Nrf2 Activation ◽

Anti Inflammatory ◽

Nrf2 Expression

Particulate matter (PM) air pollution causes cardiopulmonary mortality via macrophage-driven lung inflammation; however, the mechanisms are incompletely understood. RNA-sequencing demonstrated Acod1 (Aconitate decarboxylase 1) as one of the top genes induced by PM in macrophages. Acod1 encodes a mitochondrial enzyme that produces itaconate, which has been shown to exert anti-inflammatory effects via NRF2 after LPS. Here, we demonstrate that PM induces Acod1 and itaconate, which reduced mitochondrial respiration via complex II inhibition. Using Acod1-/- mice, we found that Acod1/endogenous itaconate does not affect PM-induced inflammation or NRF2 activation in macrophages in vitro or in vivo. In contrast, exogenous cell permeable itaconate, 4-octyl itaconate (OI) attenuated PM-induced inflammation in macrophages. OI was sufficient to activate NRF2 in macrophages; however, NRF2 was not required for the anti-inflammatory effects of OI. We conclude that the effects of itaconate production on inflammation are stimulus-dependent, and that there are important differences between endogenous and exogenously-applied itaconate.

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