The Anti-inflammatory And Pro-resolving Lipid Mediator Resolvin D1 Regulates Cigarette Smoke-induced Lung Inflammation In Vitro And In Vivo

Abstract Purpose:Ulinastatin (UTI) is an endogenous protease inhibitor with potent anti-inflammatory, antioxidant and organ protective effects. The inhibitor has been reported to ameliorate inflammatory lung injury but precise mechanisms remain unclear. Methods: An in vivo model of lung injury has been constructed by intratracheal infusion of lipopolysaccharide (LPS). The number of neutrophils and the phagocytosis of apoptotic neutrophils were observed by Diff- Quick method. Lung injury was observed by HE staining .BALF cells were counted by hemocytometer and concentrations of protein plus inflammatory factors were measured with a BCA test kit. During in vitro experiments, RAW264.7 cells were pretreated with UTI (1000 and 5000U/ mL), stained with CellTrackerTM Green B0DIPYTM and HL60 cells added with UV-induced apoptosis and PKH26 Red staining. The expression of ERK5\Mer related proteins was detected by western blot and immunofluorescence.Results: An in vivo model of lung injury has been constructed by intratracheal infusion of lipopolysaccharide (LPS). UTI treatment enhanced the phagocytotic effect of mouse alveolar macrophages on neutrophils, alleviated lung lesions, decreased the pro-inflammatory factor and total protein content of BALF and increased levels of anti-inflammatory factors. in vitro experiments ，UTI enhanced the phagocytosis of apoptotic bodies by RAW264.7 cells in a dose-dependent manner. Increased expression levels of ERK5 and Mer by UTI were shown by Western blotting and immunofluorescence.Conclusions: UTI mediated the activation of the ERK5/Mer signaling pathway, enhanced phagocytosis of neutrophils by macrophages and improved lung inflammation. The current study indicates potential new clinical approaches for accelerating the recovery from lung inflammation.

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In vitro and in vivo evidence for an inflammatory role of the calcium channel TRPV4 in lung epithelium: Potential involvement in cystic fibrosis

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00442.2015 ◽

2016 ◽

Vol 311 (3) ◽

pp. L664-L675 ◽

Cited By ~ 18

Author(s):

Clémence O. Henry ◽

Emilie Dalloneau ◽

Maria-Teresa Pérez-Berezo ◽

Cristina Plata ◽

Yongzheng Wu ◽

...

Keyword(s):

Cystic Fibrosis ◽

Calcium Channel ◽

Lung Inflammation ◽

Transient Receptor Potential ◽

Biologically Active ◽

Transient Receptor Potential Vanilloid ◽

Anti Inflammatory

Cystic fibrosis (CF) is an inherited disease associated with chronic severe lung inflammation, leading to premature death. To develop innovative anti-inflammatory treatments, we need to characterize new cellular and molecular components contributing to the mechanisms of lung inflammation. Here, we focused on the potential role of “transient receptor potential vanilloid-4” (TRPV4), a nonselective calcium channel. We used both in vitro and in vivo approaches to demonstrate that TRPV4 expressed in airway epithelial cells triggers the secretion of major proinflammatory mediators such as chemokines and biologically active lipids, as well as a neutrophil recruitment in lung tissues. We characterized the contribution of cytosolic phospholipase A2, MAPKs, and NF-κB in TRPV4-dependent signaling. We also showed that 5,6-, 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acids, i.e., four natural lipid-based TRPV4 agonists, are present in expectorations of CF patients. Also, TRPV4-induced calcium mobilization and inflammatory responses were enhanced in cystic fibrosis transmembrane conductance regulator-deficient cellular and animal models, suggesting that TRPV4 is a promising target for the development of new anti-inflammatory treatments for diseases such as CF.

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Paeonol Attenuates Cigarette Smoke-Induced Lung Inflammation by Inhibiting ROS-Sensitive Inflammatory Signaling

Mediators of Inflammation ◽

10.1155/2014/651890 ◽

2014 ◽

Vol 2014 ◽

pp. 1-13 ◽

Cited By ~ 37

Author(s):

Meng-Han Liu ◽

An-Hsuan Lin ◽

Hung-Fu Lee ◽

Hsin-Kuo Ko ◽

Tzong-Shyuan Lee ◽

...

Keyword(s):

Oxidative Stress ◽

Cigarette Smoke ◽

Lung Inflammation ◽

Chinese Herb ◽

Inflammatory Infiltration ◽

Beneficial Effects ◽

Antioxidant Function ◽

Mitogen Activated Protein

Cigarette smoking causes persistent lung inflammation that is mainly regulated by redox-sensitive pathways. We have previously reported that cigarette smoke (CS) activates reactive oxygen species- (ROS-) sensitive mitogen-activated protein kinases (MAPKs)/nuclear factor-κB (NF-κB) signaling leading to induction of lung inflammation. Paeonol, the main phenolic compound present in the Chinese herbPaeonia suffruticosa, has antioxidant and anti-inflammatory properties. However, whether paeonol has similar beneficial effects against CS-induced lung inflammation remains unclear. Using a murine model, we showed that chronic CS exposure for 4 weeks caused pulmonary inflammatory infiltration, increased lung vascular permeability, elevated lung levels of chemokines, cytokines, and 4-hydroxynonenal (an oxidative stress biomarker), and induced lung inflammation; all of these CS-induced events were suppressed by chronic treatment with paeonol. Using human bronchial epithelial cells (HBECs), we demonstrated that cigarette smoke extract (CSE) sequentially increased extracellular and intracellular levels of ROS, activated the MAPKs/NF-κB signaling, and induced interleukin-8 (IL-8); all these CSE-induced events were inhibited by paeonol pretreatment. Our findings suggest a novel role for paeonol in alleviating the oxidative stress and lung inflammation induced by chronic CS exposurein vivoand in suppressing CSE-induced IL-8in vitrovia its antioxidant function and an inhibition of the MAPKs/NF-κB signaling.

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Baicalin is anti-inflammatory in cigarette smoke-induced inflammatory models in vivo and in vitro: A possible role for HDAC2 activity

International Immunopharmacology ◽

10.1016/j.intimp.2012.03.001 ◽

2012 ◽

Vol 13 (1) ◽

pp. 15-22 ◽

Cited By ~ 38

Author(s):

Lulu Li ◽

Hong Bao ◽

Jinfeng Wu ◽

Xiaohong Duan ◽

Baojun Liu ◽

...

Keyword(s):

Cigarette Smoke ◽

Inflammatory Models ◽

Anti Inflammatory

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Activation of the aryl hydrocarbon receptor is essential for mediating the anti-inflammatory effects of a novel low-molecular-weight compound

Blood ◽

10.1182/blood-2007-08-109645 ◽

2008 ◽

Vol 112 (4) ◽

pp. 1158-1165 ◽

Cited By ~ 77

Author(s):

B. Paige Lawrence ◽

Michael S. Denison ◽

Hermann Novak ◽

Beth A. Vorderstrasse ◽

Nathalie Harrer ◽

...

Keyword(s):

Molecular Weight ◽

Aryl Hydrocarbon Receptor ◽

Lung Inflammation ◽

Dominant Negative ◽

Low Molecular Weight ◽

Aryl Hydrocarbon ◽

Allergic Lung Inflammation ◽

Anti Inflammatory

Abstract VAF347 is a low-molecular-weight compound that inhibits allergic lung inflammation in vivo. This effect is likely the result of a block of dendritic cell (DC) function to generate proinflammatory T-helper (Th) cells because VAF347 inhibits interleukin (IL)–6, CD86, and human leukocyte antigen (HLA)–DR expression by human monocyte-derived DC, 3 relevant molecules for Th-cell generation. Here we demonstrate that VAF347 interacts with the aryl hydrocarbon receptor (AhR) protein, resulting in activation of the AhR signaling pathway. Functional AhR is responsible for the biologic activity of VAF347 because (1) other AhR agonists display an identical activity profile in vitro, (2) gene silencing of wild-type AhR expression or forced overexpression of a trans-dominant negative AhR ablates VAF347 activity to inhibit cytokine induced IL-6 expression in a human monocytic cell line, and (3) AhR-deficient mice are resistant to the compound's ability to block allergic lung inflammation in vivo. These data identify the AhR protein as key molecular target of VAF347 and its essential role for mediating the anti-inflammatory effects of the compound in vitro and in vivo.

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A Glucuronic Acid-Palmitoylethanolamide Conjugate (GLUPEA) Is an Innovative Drug Delivery System and a Potential Bioregulator

Cells ◽

10.3390/cells10020450 ◽

2021 ◽

Vol 10 (2) ◽

pp. 450

Author(s):

Emiliano Manzo ◽

Aniello Schiano Moriello ◽

Francesco Tinto ◽

Roberta Verde ◽

Marco Allarà ◽

...

Keyword(s):

Transient Receptor Potential ◽

Glucuronic Acid ◽

Drug Carrier ◽

Receptor Potential ◽

Lipid Mediator ◽

Transient Receptor Potential Vanilloid ◽

Innovative Drug ◽

Anti Inflammatory

Palmitoylethanolamide (PEA) is an endogenous anti-inflammatory lipid mediator and a widely used nutraceutical. In this study, we designed, realized, and tested a drug-carrier conjugate between PEA (the active drug) and glucuronic acid (the carrier). The conjugate, named GLUPEA, was characterized for its capability of increasing PEA levels and exerting anti-inflammatory activity both in vitro and in vivo. GLUPEA treatment, compared to the same concentration of PEA, resulted in higher cellular amounts of PEA and the endocannabinoid 2-arachidonoyl glycerol (2-AG), and increased 2-AG-induced transient receptor potential vanilloid type 1 (TRPV1) channel desensitization to capsaicin. GLUPEA inhibited pro-inflammatory monocyte chemoattractant protein 2 (MCP-2) release from stimulated keratinocytes, and it was almost as efficacious as ultra-micronized PEA at reducing colitis in dinitrobenzene sulfonic acid (DNBS)-injected mice when using the same dose. GLUPEA is a novel pro-drug able to efficiently mimic the anti-inflammatory and endocannabinoid enhancing actions of PEA.

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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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IL36 is a critical upstream amplifier of neutrophilic lung inflammation in mice

Communications Biology ◽

10.1038/s42003-021-01703-3 ◽

2021 ◽

Vol 4 (1) ◽

Author(s):

Carolin K. Koss ◽

Christian T. Wohnhaas ◽

Jonathan R. Baker ◽

Cornelia Tilp ◽

Michèl Przibilla ◽

...

Keyword(s):

Cigarette Smoke ◽

Lung Inflammation ◽

H1n1 Influenza ◽

Poly I:C ◽

Intercellular Signaling ◽

Gm Csf ◽

Primary Mouse ◽

Insight Into

AbstractIL-36, which belongs to the IL-1 superfamily, is increasingly linked to neutrophilic inflammation. Here, we combined in vivo and in vitro approaches using primary mouse and human cells, as well as, acute and chronic mouse models of lung inflammation to provide mechanistic insight into the intercellular signaling pathways and mechanisms through which IL-36 promotes lung inflammation. IL-36 receptor deficient mice exposed to cigarette smoke or cigarette smoke and H1N1 influenza virus had attenuated lung inflammation compared with wild-type controls. We identified neutrophils as a source of IL-36 and show that IL-36 is a key upstream amplifier of lung inflammation by promoting activation of neutrophils, macrophages and fibroblasts through cooperation with GM-CSF and the viral mimic poly(I:C). Our data implicate IL-36, independent of other IL-1 family members, as a key upstream amplifier of neutrophilic lung inflammation, providing a rationale for targeting IL-36 to improve treatment of a variety of neutrophilic lung diseases.

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