Anti-inflammatory lipid mediators and insights into the resolution of inflammation

Lawrence, Toby; Willoughby, D. A.; Gilroy, Derek W.

doi:10.1038/nri915

Cited by 774 publications

(590 citation statements)

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“…Multiple functions, dependent on concentration, location and timing have been described for the prostaglandins (e.g.PGD 2 and PGE 2 ) [1-3,24,25]. In order to examine the immunological responses triggered by the 603600∆/∆, 800020∆/∆ and 807710∆/∆ , we stimulated human PBMC-DMs for 24 hours with each strain and determined the amount of cytokine and chemokine production.…”

Section: Resultsmentioning

confidence: 99%

“…During vasodilation prostaglandins and leukotrienes induce increased permeability of post capillary venules and also recruit complement components and leukocytes to the site of inflammation [2]. In contrast, lipoxins act as pro-resolving lipid mediators, as for example, LXA 4 inhibits the recruitment of neutrophil and eosinophil granulocytes in post capillary venules [3]. Previously, it has been hypothesized that, during fungal infection the invading fungi induce host prostaglandin biosynthesis that causes a local anti-inflammatory response, which in turn could contribute to fungal invasion [26].…”

Section: Discussionmentioning

confidence: 99%

“…Several drugs can block these enzymes and inhibit the generation of bioactive lipid mediators. For example, nonsteroidal anti-inflammatory drugs (NSAIDs), such as indomethacin or ibuprofen, target mainly the COX enzymes, thus prostaglandin biosynthesis, to alleviate inflammation [1–3]. Interestingly, the recognition of the C. albicans cell wall β-glucan by dectin-1 on the surface of macrophages enhances macrophage cytosolic phospholipase A2 activity and COX expression, thus promoting prostaglandin biosynthesis in the host [4,5].…”

Section: Introductionmentioning

confidence: 99%

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Eicosanoid biosynthesis influences the virulence of Candida parapsilosis

et al. 2018

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Lipid mediators, derived from arachidonic acid metabolism, play an important role in immune regulation. The functions of bioactive eicosanoids range from modulating cytokine signaling and inflammasome formation to anti-inflammatory and pro-resolving activities. Human pathogenic fungi such as Candida albicans, Candida parapsilosis, Cryptococcus neoformans and Aspergillus fumigatus have been shown to produce such lipid mediators, associated with their virulence. To date, investigations into the molecular mechanisms of fungal eicosanoid biosynthesis in different species have revealed that several genes are associated with prostaglandin production. However, these routes remain uncharacterized in C. parapsilosis with early results suggesting it uses pathways distinct from those found in C. albicans. Therefore, we aimed to identify and characterize C. parapsilosis genes involved in eicosanoid biosynthesis. Following arachidonic acid treatment of C. parapsilosis cells, we identified several genes interfering with prostaglandin production. Out of the identified genes, homologues of a multi copper oxidase (FET3), an Acyl-CoA thiolase (POT1) and an Acyl-CoA oxidase (POX1-3) were found to play a significant role in prostaglandin synthesis. Furthermore, all three genes were confirmed to enhance C. parapsilosis pathogenicity, as the corresponding deletion mutants were cleared more efficiently by human macrophages and induced higher levels of pro-inflammatory cytokines. In addition, the mutants were less virulent than the wild-type strain in a mouse model of systemic infection. Taken together, we identified three genes that regulate eicosanoid biosynthesis in C. parapsilosis and impact the fungus’ virulence.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Eicosanoid biosynthesis influences the virulence of Candida parapsilosis

et al. 2018

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“…In vitro studies have shown that repetitive mechanical loading of tendon fibroblasts induces the release of PGE 2 and LTB 4 (Almekinders et al, 1995;Li et al, 2004). Both are also produced in substantial amounts at the sites of inflammation (Henderson, 1994;Lawrence et al, 2002). PGE 2 and LTB 4 are inflammatory mediators and have been implicated in the pathogenesis of several inflammatory diseases such as tendinopathy and rheumatoid arthritis (Davidson et al, 1983;Almekinders et al, 1993;Trebino et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Leukotriene B4 at low dosage negates the catabolic effect of prostaglandin E2 in human patellar tendon fibroblasts

Thampatty¹,

Im²,

Wang³

2006

Gene

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Tendinopathy often involves inflammation and matrix degeneration. The inflammatory mediators such as prostaglandin E 2 (PGE 2 ) and leukotriene B 4 (LTB 4 ) are implicated in the development of tendinopathy. Therefore, the purpose of this study was to determine the effect of PGE 2 and LTB 4 on the proliferation of human patellar tendon fibroblasts (HPTFs), the gene expression of collagen type I, MMP-1 and MMP-3, as well as the protein secretion of these gene products by the cells. The results showed that LTB 4 at low doses (0.1 and 1 nM) significantly increased cell proliferation compared to controls and LTB 4 at 0.1 nM negated the PGE 2 -induced decrease in cell proliferation. In addition, PGE 2 at 100 ng/ml significantly increased the expression of MMP-1 and MMP-3 at both mRNA and protein levels. These stimulatory effects were significantly diminished by co-treatment with LTB 4 at 0.1 nM. Finally, neither PGE 2 nor LTB 4 treatment affected collagen type I gene expression. These results suggest that low levels of LTB 4 counterbalance the negative effects mediated by PGE 2 on tendon fibroblast proliferation and MMP production, which may lead to matrix degradation. Thus, our findings suggest that although LTB 4 is generally thought to be pathogenic, low levels of LTB 4 are actually beneficial in maintaining tendon tissue homeostasis.

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“…Several studies indicated that inflammation resolution depends greatly on the expression of specific cytokines [42][43][44] such as interleukin (IL)-10 and transforming growth factor-β (TGF-β), and lipid mediators such as lipoxins [43], protectins, and resolvins [45][46][47]. Moreover, self-limited inflammation resolution following acute inflammation is a coordinated event initiated by an active "class switch" from prostaglandins and leukotrienes inflammatory mediators to resolvins, lipoxins, protectins, and maresins through complex processes involving multiple enzymes and cell types [48].…”

Section: Inflammation Resolution Mediatorsmentioning

confidence: 99%

Targeting Inflammation to Improve Tumor Drug Delivery

2017

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Inefficient delivery of drugs is a main cause of chemotherapy failure in hypo-perfused tumors. To enhance perfusion and drug delivery in these tumors, two strategies have been developed: vascular normalization, aiming at normalizing tumor vasculature and blood vessel leakiness; and stress alleviation, aiming at decompressing tumor vessels. Vascular normalization is based on antiangiogenic drugs, whereas stress alleviation on stroma-depleting agents. Here, an alternatively approach to normalize vessels is presented, considering that malignant tumors tend to develop at chronic inflammation sites. Similarly to tumor vessel leakiness, inflammation is also characterized by vascular hyper-permeability. Therefore, testing the ability of anti-inflammatory agents, such as non-steroidal anti-inflammatory drugs or inflammation resolution mediators, as an alternative way to increase tumor drug delivery, might prove promising.Keywords stress alleviation; vascular normalization; tumor perfusion; anti-inflammatory agents; inflammation resolution The Tumor microenvironment and drug deliveryTumors are complex tissues consisting of cancer cells and their microenvironment [1,2], which includes structural and cellular components. Structural components of the tumor microenvironment comprise tumor blood and lymphatic vessels, and the extracellular matrix (ECM) (see Glossary); while the stromal cell constituents [3] include angiogenic vascular cells (endothelial cells and pericytes), infiltrating immune cells, and cancer-associated fibroblasts (CAFs). Naturally, interactions between cancer cells and the various components of tumor microenvironment affect fundamental cancer cell properties such as proliferation, apoptosis, migration and invasion.It has been postulated that components and features of the tumor microenvironment may also set certain barriers with regard to the effective delivery of therapeutic agents, resulting in compromised therapeutic outcomes and decreased survival [4]. Chemotherapeutic drugs are, without a doubt, potent cytotoxic agents. However, they often fail to cure cancer due to the fact that they are unable to reach cancer cells within the tumor in sufficient amounts [5,6]. Hence, the discovery of more efficient approaches to enhance tumor drug delivery is imperative. Here, the main obstacles in drug delivery to the tumor are presented along with the approaches currently used to overcome them. Furthermore, the use of anti-inflammatory agents is proposed as a promising alternative approach to normalize vessels and improve therapy. Europe PMC Funders Group Causes of insufficient drug delivery to tumorsInefficient drug delivery may arise due to barriers posed by abnormal structure and function of tumor stroma, known as desmoplasia. Desmoplastic tumors are characterized by a dense ECM, containing increased levels of total fibrillar collagen, hyaluronan, fibronectin, proteoglycans and tenascin C [4], which also provides the tumor with a reservoir of growth factors eventually promoting its growth. The dense ...

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Anti-inflammatory lipid mediators and insights into the resolution of inflammation

Cited by 774 publications

References 61 publications

Eicosanoid biosynthesis influences the virulence of Candida parapsilosis

Eicosanoid biosynthesis influences the virulence of Candida parapsilosis

Leukotriene B4 at low dosage negates the catabolic effect of prostaglandin E2 in human patellar tendon fibroblasts

Targeting Inflammation to Improve Tumor Drug Delivery

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