Platelet-derived serotonin links vascular disease and tissue fibrosis

Dees, Clara; Akhmetshina, Alfiya; Zerr, Pawel; Reich, Nicole; Palumbo, Katrin; Horn, Angelika; Jüngel, Astrid; Beyer, Christian; Krönke, Gerhard; Zwerina, Jochen; Reiter, Rudolf; Alenina, Natalia; Maroteaux, Luc; Schett, Georg; Distler, Oliver; Distler, Jörg H W

doi:10.1084/jem.20101629

Cited by 234 publications

(234 citation statements)

References 59 publications

(83 reference statements)

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“…THP-2 isoform is expressed in central nervous system, whereas TPH-1 is expressed in peripheral tissues such as vascular cells. 45,46 In this study, we provide evidence that TPH1-derived 5-HTP is converted primarily and probably exclusively to 5-MTP in ECs as we do not detect serotonin, melatonin, kynurenine, or by guest on May 11, 2018 http://circres.ahajournals.org/ Downloaded from 5-methoxytryptamine on the metabolomic profile of HUVEC-CM. Our unpublished data reveal that HUVECs express TPH-1 and do not have detectable THP-2.…”

Section: Discussionmentioning

confidence: 57%

Endothelium-Derived 5-Methoxytryptophan Is a Circulating Anti-Inflammatory Molecule That Blocks Systemic Inflammation

Wang

Hsu

et al. 2016

Circulation Research

108

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Rationale: Systemic inflammation has emerged as a key pathophysiological process that induces multiorgan injury and causes serious human diseases. Endothelium is critical in maintaining cellular and inflammatory homeostasis, controlling systemic inflammation, and progression of inflammatory diseases. We postulated that endothelium produces and releases endogenous soluble factors to modulate inflammatory responses and protect against systemic inflammation. Objective: To identify endothelial cell–released soluble factors that protect against endothelial barrier dysfunction and systemic inflammation. Methods and Results: We found that conditioned medium of endothelial cells inhibited cyclooxgenase-2 and interleukin-6 expression in macrophages stimulated with lipopolysaccharide. Analysis of conditioned medium extracts by liquid chromatography–mass spectrometry showed the presence of 5-methoxytryptophan (5-MTP), but not other related tryptophan metabolites. Furthermore, endothelial cell–derived 5-MTP suppressed lipopolysaccharide-induced inflammatory responses and signaling in macrophages and endotoxemic lung tissues. Lipopolysaccharide suppressed 5-MTP level in endothelial cell-conditioned medium and reduced serum 5-MTP level in the murine sepsis model. Intraperitoneal injection of 5-MTP restored serum 5-MTP accompanied by the inhibition of lipopolysaccharide-induced endothelial leakage and suppression of lipopolysaccharide- or cecal ligation and puncture–mediated proinflammatory mediators overexpression. 5-MTP administration rescued lungs from lipopolysaccharide-induced damages and prevented sepsis-related mortality. Importantly, compared with healthy subjects, serum 5-MTP level in septic patients was decreased by 65%, indicating an important clinical relevance. Conclusions: We conclude that 5-MTP belongs to a novel class of endothelium-derived protective molecules that defend against endothelial barrier dysfunction and excessive systemic inflammatory responses.

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Section: Discussionmentioning

confidence: 57%

Endothelium-Derived 5-Methoxytryptophan Is a Circulating Anti-Inflammatory Molecule That Blocks Systemic Inflammation

Wang

Hsu

et al. 2016

Circulation Research

108

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“…[26][27][28][29] Older studies identified activated platelets in bronchial biopsies from subjects with asthma, 30 and platelets are essential to the accumulation of eosinophils and the development of inflammation in lungs of allergen-sensitized and challenged mice. 16,31 We initially sought direct evidence for platelet-driven leukocyte recruitment in AERD because of the dramatic tissue eosinophilia that characterizes the disease.…”

Section: Platelet-wbc Adherence Causes Cyslts In Aerd 3795mentioning

confidence: 99%

Cysteinyl leukotriene overproduction in aspirin-exacerbated respiratory disease is driven by platelet-adherent leukocytes

Laidlaw

Kidder

Bhattacharyya

et al. 2012

Blood

221

209

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Cysteinyl leukotriene (cysLT) overproduction is a hallmark of aspirin-exacerbated respiratory disease (AERD), but its mechanism is poorly understood. Because adherent platelets can convert the leukocytederived precursor leukotriene (LT)A 4 to LTC 4 , the parent cysLT, through the terminal enzyme LTC 4 synthase, we investigated the contribution of platelet-dependent transcellular cysLT production in AERD. Nasal polyps from subjects with AERD contained many extravascular platelets that colocalized with leukocytes, and the percentages of circulating neutrophils, eosinophils, and monocytes with adherent platelets were markedly higher in the blood of subjects with AERD than in aspirintolerant controls. Platelet-adherent subsets of leukocytes had higher expression of several adhesion markers than did platelet nonadherent subsets. Adherent platelets contributed more than half of the total LTC 4 synthase activity of peripheral blood granulocytes, and they accounted for the higher level of LTC 4 generation by activated granulocytes from subjects with AERD compared with aspirintolerant controls. Urinary LTE 4 levels, a measure of systemic cysLT production, correlated strongly with percentages of circulating platelet-adherent granulocytes. Because platelet adherence to leukocytes allows for both firm adhesion to endothelial cells and augmented transcellular conversion of leukotrienes, a disturbance in plateletleukocyte interactions may be partly responsible for the respiratory tissue inflammation and the overproduction of cysLTs that characterize AERD. (Blood. 2012;119(16):3790-3798) IntroductionAspirin-exacerbated respiratory disease (AERD) is a distinctive syndrome characterized clinically by a triad of asthma, nasal polyposis, and aspirin sensitivity. It is a chronic inflammatory disease associated with eosinophilic infiltration of respiratory tissues, peripheral eosinophilia, and excessive production of cysteinyl leukotrienes (cysLTs), a class of inflammatory lipid mediators that are thought to contribute to several of the characteristic features of AERD. Individuals with this syndrome account for 4% to 11% of all adult patients with asthma, and for a disproportionate share (ϳ 30%) of patients with severe asthma. 1 The confirmatory diagnostic feature of AERD is an idiosyncratic respiratory reaction, including symptoms of acute bronchoconstriction, nasal congestion, and eye watering, on ingestion of aspirin or another nonselective cyclooxygenase (COX) inhibitor. Despite the strikingly consistent clinical phenotype of AERD, the pathogenesis of the disease remains unclear.CysLTs derive from the metabolism of arachidonic acid by effector cells of the innate immune system. In inflammatory leukocytes (neutrophils, monocytes, eosinophils, mast cells, and basophils), arachidonic acid is oxidized by 5-lipoxygenase (5-LO) to form the unstable intermediate leukotriene (LT)A 4 . 2 In neutrophils, LTA 4 is preferentially hydrolyzed by LTA 4 hydrolase to form LTB 4 , whereas in monocytes, mast cells, eosinophils, and basophils, it i...

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“…In certain cell types, 5-HT has been identified as a growth factor and has been shown to increase the proliferation of fibroblasts and consequent collagen synthesis that can lead to fibrosis (Fabre et al, 2008). These findings have further been substantiated by Dees et al, (2011) who linked elevated 5-HT levels to vascular disease and tissue fibrosis due to its ability to stimulate extracellular matrix production in both sclerotic and healthy fibroblasts. There are two 5-HT receptor subtypes that have been identified to play an important role in the lungs specifically.…”

Section: Introductionmentioning

confidence: 93%

Sibutramine, a serotonin–norepinephrine reuptake inhibitor, causes fibrosis in rats

Oberholzer

Schoor

Bester

2015

Environmental Toxicology and Pharmacology

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Sibutramine hydrochloride monohydrate is a weight loss agent indicated for the treatment of obesity. Although it has been banned from most markets, studies are still relevant as it is often a hidden ingredient in herbal and over the counter slimming products. Sibutramine induces liver fibrosis with steatosis in female Sprague-Dawley rats fed a high-energy diet without significant weight gain. In this study, using the same animal model, the effect of Sibutramine on lung morphology was investigated using histological evaluation of the terminal bronchiole and transmission electron microscopy evaluation of the respiratory tissue. From these results Sibutramine was found to induce lung fibrosis in Sprague-Dawley rats as increased collagen synthesis, mast cell accumulation and aggregates of Bronchus Associated Lymphoid Tissue (BALT) in the terminal bronchiole as well as increased collagen deposition in the respiratory tissue was seen.

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Platelet-derived serotonin links vascular disease and tissue fibrosis

Abstract: Blocking 5-HT2B receptor provides a therapeutic target for fibrotic diseases caused by activated platelet release of serotonin during vascular damage.

Cited by 234 publications

References 59 publications

Endothelium-Derived 5-Methoxytryptophan Is a Circulating Anti-Inflammatory Molecule That Blocks Systemic Inflammation

Endothelium-Derived 5-Methoxytryptophan Is a Circulating Anti-Inflammatory Molecule That Blocks Systemic Inflammation

Cysteinyl leukotriene overproduction in aspirin-exacerbated respiratory disease is driven by platelet-adherent leukocytes

Sibutramine, a serotonin–norepinephrine reuptake inhibitor, causes fibrosis in rats

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