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Arteriosclerosis, Thrombosis, and... May 2011Prostaglandins are lipid autacoids derived from arachidonic acid. They both sustain homeostatic functions and mediate pathogenic mechanisms, including the inflammatory... (Review)
Review
Prostaglandins are lipid autacoids derived from arachidonic acid. They both sustain homeostatic functions and mediate pathogenic mechanisms, including the inflammatory response. They are generated from arachidonate by the action of cyclooxygenase isoenzymes, and their biosynthesis is blocked by nonsteroidal antiinflammatory drugs, including those selective for inhibition of cyclooxygenase-2. Despite the clinical efficacy of nonsteroidal antiinflammatory drugs, prostaglandins may function in both the promotion and resolution of inflammation. This review summarizes insights into the mechanisms of prostaglandin generation and the roles of individual mediators and their receptors in modulating the inflammatory response. Prostaglandin biology has potential clinical relevance for atherosclerosis, the response to vascular injury and aortic aneurysm.
Topics: Animals; Cyclooxygenase Inhibitors; Humans; Inflammation; Inflammation Mediators; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Receptors, Prostaglandin; Signal Transduction; Thromboxanes
PubMed: 21508345
DOI: 10.1161/ATVBAHA.110.207449 -
Biomedicine & Pharmacotherapy =... Jul 2023Thromboxane (TX) and prostaglandins are metabolites of arachidonic acid, a twenty-carbon unsaturated fatty acid, and have a variety of actions that are exerted via... (Review)
Review
Thromboxane (TX) and prostaglandins are metabolites of arachidonic acid, a twenty-carbon unsaturated fatty acid, and have a variety of actions that are exerted via specific receptors. Angiogenesis is defined as the formation of new blood vessels from pre-existing vascular beds and is a critical component of pathological conditions, including inflammation and cancer. Lymphatic vessels play crucial roles in the regulation of interstitial fluid, immune surveillance, and the absorption of dietary fat from the intestine; and they are also involved in the pathogenesis of various diseases. Similar to angiogenesis, lymphangiogenesis, the formation of new lymphatic vessels, is a critical component of pathological conditions. The TP-dependent accumulation of platelets in microvessels has been reported to enhance angiogenesis under pathological conditions. Although the roles of some growth factors and cytokines in angiogenesis and lymphangiogenesis have been well characterized, accumulating evidence suggests that TX induces the production of proangiogenic and prolymphangiogenic factors through the activation of adenylate cyclase, and upregulates angiogenesis and lymphangiogenesis under disease conditions. In this review, we discuss the role of TX as a regulator of angiogenesis and lymphangiogenesis, and its emerging importance as a therapeutic target.
Topics: Humans; Lymphangiogenesis; Thromboxanes; Lymphatic Vessels; Neoplasms; Inflammation
PubMed: 37150029
DOI: 10.1016/j.biopha.2023.114831 -
Molecules (Basel, Switzerland) Sep 2022Over the last two decades, there has been an increasing awareness of the role of eicosanoids in the development and progression of several types of cancer, including... (Review)
Review
Over the last two decades, there has been an increasing awareness of the role of eicosanoids in the development and progression of several types of cancer, including breast, prostate, lung, and colorectal cancers. Several processes involved in cancer development, such as cell growth, migration, and angiogenesis, are regulated by the arachidonic acid derivative thromboxane A (TXA). Higher levels of circulating TXA are observed in patients with multiple cancers, and this is accompanied by overexpression of TXA synthase (, TXAS) and/or TXA receptors (, TP). Overexpression of TXAS or TP in tumor cells is generally associated with poor prognosis, reduced survival, and metastatic disease. However, the role of TXA signaling in the stroma during oncogenesis has been underappreciated. TXA signaling regulates the tumor microenvironment by modulating angiogenic potential, tumor ECM stiffness, and host immune response. Moreover, the by-products of TXAS are highly mutagenic and oncogenic, adding to the overall phenotype where TXA synthesis promotes tumor formation at various levels. The stability of synthetic enzymes and receptors in this pathway in most cancers (with few mutations reported) suggests that TXA signaling is a viable target for adjunct therapy in various tumors to reduce immune evasion, primary tumor growth, and metastasis.
Topics: Arachidonic Acid; Eicosanoids; Humans; Male; Neoplasms; Receptors, Thromboxane; Thromboxane A2; Thromboxane-A Synthase; Thromboxanes; Tumor Microenvironment
PubMed: 36234768
DOI: 10.3390/molecules27196234 -
Science Advances Oct 2023While neutrophil extracellular traps (NETs) have previously been linked to some diabetes-associated complications, such as dysfunctional wound healing, their potential...
While neutrophil extracellular traps (NETs) have previously been linked to some diabetes-associated complications, such as dysfunctional wound healing, their potential role in diabetic vascular dysfunction has not been studied. Diabetic Akita mice were crossed with either or mice to generate NET-deficient diabetic mice. By 24 weeks of age, Akita aortae showed markedly impaired relaxation in response to acetylcholine, indicative of vascular dysfunction. Both Akita- mice and Akita- mice had reduced levels of circulating NETs and improved acetylcholine-mediated aortic relaxation. Compared with wild-type aortae, the thromboxane metabolite TXB was roughly 10-fold higher in both intact and endothelium-denuded aortae of Akita mice. In contrast, Akita- and Akita- aortae had TXB levels similar to wild type. In summary, inhibition of NETosis by two independent strategies prevented the development of vascular dysfunction in diabetic Akita mice. Thromboxane was up-regulated in the vessel walls of NETosis-competent diabetic mice, suggesting a role for neutrophils in driving the production of this vasoconstrictive and atherogenic prostanoid.
Topics: Mice; Animals; Extracellular Traps; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Acetylcholine; Neutrophils; Thromboxanes
PubMed: 37878711
DOI: 10.1126/sciadv.adj1019 -
Journal of the American College of... Jul 2022
Topics: Aspirin; Blood Platelets; Humans; Thromboxane B2; Thromboxanes
PubMed: 35835497
DOI: 10.1016/j.jacc.2022.04.053 -
Marine Drugs Jul 2019Prostaglandins (PGs) are lipid mediators belonging to the eicosanoid family. PGs were first discovered in mammals where they are key players in a great variety of... (Review)
Review
Prostaglandins (PGs) are lipid mediators belonging to the eicosanoid family. PGs were first discovered in mammals where they are key players in a great variety of physiological and pathological processes, for instance muscle and blood vessel tone regulation, inflammation, signaling, hemostasis, reproduction, and sleep-wake regulation. These molecules have successively been discovered in lower organisms, including marine invertebrates in which they play similar roles to those in mammals, being involved in the control of oogenesis and spermatogenesis, ion transport, and defense. Prostaglandins have also been found in some marine macroalgae of the genera and and very recently the PGs pathway has been identified for the first time in some species of marine microalgae. In this review we report on the occurrence of prostaglandins in the marine environment and discuss the anti-inflammatory role of these molecules.
Topics: Animals; Anthozoa; Anti-Inflammatory Agents; Aquatic Organisms; Gracilaria; Laminaria; Microalgae; Prostaglandins; Thromboxanes
PubMed: 31340503
DOI: 10.3390/md17070428 -
Journal of Thrombosis and Haemostasis :... Feb 2004
Topics: Aspirin; Cyclooxygenase 1; Drug Evaluation; Humans; Isoenzymes; Membrane Proteins; Platelet Aggregation; Platelet Function Tests; Prostaglandin-Endoperoxide Synthases; Thromboxanes; Treatment Failure
PubMed: 14996001
DOI: 10.1111/j.1538-7836.2004.0615d.x -
Respiratory Research Oct 2023The standard therapy for bronchial asthma consists of combinations of acute (short-acting ß-sympathomimetics) and, depending on the severity of disease, additional...
INTRODUCTION
The standard therapy for bronchial asthma consists of combinations of acute (short-acting ß-sympathomimetics) and, depending on the severity of disease, additional long-term treatment (including inhaled glucocorticoids, long-acting ß-sympathomimetics, anticholinergics, anti-IL-4R antibodies). The antidepressant amitriptyline has been identified as a relevant down-regulator of immunological T2-phenotype in asthma, acting-at least partially-through inhibition of acid sphingomyelinase (ASM), an enzyme involved in sphingolipid metabolism. Here, we investigated the non-immunological role of amitriptyline on acute bronchoconstriction, a main feature of airway hyperresponsiveness in asthmatic disease.
METHODS
After stimulation of precision cut lung slices (PCLS) from mice (wildtype and ASM-knockout), rats, guinea pigs and human lungs with mediators of bronchoconstriction (endogenous and exogenous acetylcholine, methacholine, serotonin, endothelin, histamine, thromboxane-receptor agonist U46619 and leukotriene LTD4, airway area was monitored in the absence of or with rising concentrations of amitriptyline. Airway dilatation was also investigated in rat PCLS by prior contraction induced by methacholine. As bronchodilators for maximal relaxation, we used IBMX (PDE inhibitor) and salbutamol (ß-adrenergic agonist) and compared these effects with the impact of amitriptyline treatment. Isolated perfused lungs (IPL) of wildtype mice were treated with amitriptyline, administered via the vascular system (perfusate) or intratracheally as an inhalation. To this end, amitriptyline was nebulized via pariboy in-vivo and mice were ventilated with the flexiVent setup immediately after inhalation of amitriptyline with monitoring of lung function.
RESULTS
Our results show amitriptyline to be a potential inhibitor of bronchoconstriction, induced by exogenous or endogenous (EFS) acetylcholine, serotonin and histamine, in PCLS from various species. The effects of endothelin, thromboxane and leukotrienes could not be blocked. In acute bronchoconstriction, amitriptyline seems to act ASM-independent, because ASM-deficiency (Smdp1) did not change the effect of acetylcholine on airway contraction. Systemic as well as inhaled amitriptyline ameliorated the resistance of IPL after acetylcholine provocation. With the flexiVent setup, we demonstrated that the acetylcholine-induced rise in central and tissue resistance was much more marked in untreated animals than in amitriptyline-treated ones. Additionally, we provide clear evidence that amitriptyline dilatates pre-contracted airways as effectively as a combination of typical bronchodilators such as IBMX and salbutamol.
CONCLUSION
Amitriptyline is a drug of high potential, which inhibits acute bronchoconstriction and induces bronchodilatation in pre-contracted airways. It could be one of the first therapeutic agents in asthmatic disease to have powerful effects on the T2-allergic phenotype and on acute airway hyperresponsiveness with bronchoconstriction, especially when inhaled.
Topics: Mice; Rats; Humans; Animals; Guinea Pigs; Bronchoconstriction; Methacholine Chloride; Amitriptyline; Histamine; Bronchodilator Agents; Serotonin; Acetylcholine; Sympathomimetics; 1-Methyl-3-isobutylxanthine; Dilatation; Lung; Asthma; Albuterol; Endothelins; Thromboxanes
PubMed: 37907918
DOI: 10.1186/s12931-023-02580-6 -
American Journal of Respiratory and... Sep 2022Although persistent fibroblast activation is a hallmark of idiopathic pulmonary fibrosis (IPF), mechanisms regulating persistent fibroblast activation in the lungs have...
Although persistent fibroblast activation is a hallmark of idiopathic pulmonary fibrosis (IPF), mechanisms regulating persistent fibroblast activation in the lungs have not been fully elucidated. On the basis of our observation that lung fibroblasts express TBXA2R (thromboxane-prostanoid receptor) during fibrosis, we investigated the role of TBXA2R signaling in fibrotic remodeling. We identified TBXA2R expression in lungs of patients with IPF and mice and studied primary mouse and human lung fibroblasts to determine the impact of TBXA2R signaling on fibroblast activation. We used TBXA2R-deficient mice and small-molecule inhibitors to investigate TBXA2R signaling in preclinical lung fibrosis models. TBXA2R expression was upregulated in fibroblasts in the lungs of patients with IPF and in mouse lungs during experimental lung fibrosis. Genetic deletion of TBXA2R, but not inhibition of thromboxane synthase, protected mice from bleomycin-induced lung fibrosis, thereby suggesting that an alternative ligand activates profibrotic TBXA2R signaling. In contrast to thromboxane, F2-isoprostanes, which are nonenzymatic products of arachidonic acid induced by reactive oxygen species, were persistently elevated during fibrosis. F2-isoprostanes induced TBXA2R signaling in fibroblasts and mediated a myofibroblast activation profile due, at least in part, to potentiation of TGF-β (transforming growth factor-β) signaling. treatment with the TBXA2R antagonist ifetroban reduced profibrotic signaling in the lungs, protected mice from lung fibrosis in three preclinical models (bleomycin, Hermansky-Pudlak mice, and radiation-induced fibrosis), and markedly enhanced fibrotic resolution after bleomycin treatment. TBXA2R links oxidative stress to fibroblast activation during lung fibrosis. TBXA2R antagonists could have utility in treating pulmonary fibrosis.
Topics: Animals; Bleomycin; F2-Isoprostanes; Fibroblasts; Humans; Idiopathic Pulmonary Fibrosis; Lung; Mice; Mice, Inbred C57BL; Prostaglandins; Receptors, Thromboxane; Thromboxanes; Transforming Growth Factor beta
PubMed: 35728047
DOI: 10.1164/rccm.202106-1503OC -
British Journal of Cancer Sep 2023Pre-clinical models demonstrate that platelet activation is involved in the spread of malignancy. Ongoing clinical trials are assessing whether aspirin, which inhibits... (Clinical Trial)
Clinical Trial
BACKGROUND
Pre-clinical models demonstrate that platelet activation is involved in the spread of malignancy. Ongoing clinical trials are assessing whether aspirin, which inhibits platelet activation, can prevent or delay metastases.
METHODS
Urinary 11-dehydro-thromboxane B (U-TXM), a biomarker of in vivo platelet activation, was measured after radical cancer therapy and correlated with patient demographics, tumour type, recent treatment, and aspirin use (100 mg, 300 mg or placebo daily) using multivariable linear regression models with log-transformed values.
RESULTS
In total, 716 patients (breast 260, colorectal 192, gastro-oesophageal 53, prostate 211) median age 61 years, 50% male were studied. Baseline median U-TXM were breast 782; colorectal 1060; gastro-oesophageal 1675 and prostate 826 pg/mg creatinine; higher than healthy individuals (~500 pg/mg creatinine). Higher levels were associated with raised body mass index, inflammatory markers, and in the colorectal and gastro-oesophageal participants compared to breast participants (P < 0.001) independent of other baseline characteristics. Aspirin 100 mg daily decreased U-TXM similarly across all tumour types (median reductions: 77-82%). Aspirin 300 mg daily provided no additional suppression of U-TXM compared with 100 mg.
CONCLUSIONS
Persistently increased thromboxane biosynthesis was detected after radical cancer therapy, particularly in colorectal and gastro-oesophageal patients. Thromboxane biosynthesis should be explored further as a biomarker of active malignancy and may identify patients likely to benefit from aspirin.
Topics: Female; Humans; Male; Middle Aged; Aspirin; Biomarkers; Colorectal Neoplasms; Creatinine; Thromboxanes
PubMed: 37420000
DOI: 10.1038/s41416-023-02310-1