Eicosanoids represent a diverse family of lipid mediators with fundamental roles in physiology and disease. Within the eicosanoid superfamily are prostanoids, which are specifically derived from ...arachidonic acid by the enzyme cyclooxygenase (COX). COX has two isoforms; COX‐1 and COX‐2. COX‐2 is the therapeutic target for the nonsteroidal anti‐inflammatory drug (NSAID) class of pain medications. Of the prostanoids, prostacyclin, first discovered by Sir John Vane in 1976, remains amongst the best studied and retains an impressive pedigree as one of the fundamental cardiovascular protective pathways. Since this time, we have learnt much about how eicosanoids, COX enzymes and prostacyclin function in the cardiovascular system, knowledge that has allowed us, for example, to harness the power of prostacyclin as therapy to treat pulmonary arterial hypertension and peripheral vascular disease. However, there remain many unanswered questions in our basic understanding of the pathways, and how they can be used to improve human health. Perhaps, the most important and controversial outstanding question in the field remains; ‘how do NSAIDs produce their much publicized cardiovascular side‐effects?’ This review summarizes the history, biology and cardiovascular function of key eicosanoids with particular focus on prostacyclin and other COX products and discusses how our knowledge of these pathways can applied in future drug discovery and be used to explain the cardiovascular side‐effects of NSAIDs.
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This article is part of a themed section on Eicosanoids 35 years from the 1982 Nobel: where are we now? To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.8/issuetoc
Because metastasis is associated with the majority of cancer-related deaths, its prevention is a clinical aspiration. Prostanoids are a large family of bioactive lipids derived from the activity of ...cyclooxygenase-1 (COX-1) and COX-2. Aspirin impairs the biosynthesis of all prostanoids through the irreversible inhibition of both COX isoforms. Long-term administration of aspirin leads to reduced distant metastases in murine models and clinical trials, but the COX isoform, downstream prostanoid, and cell compartment responsible for this effect are yet to be determined. Here, we have shown that aspirin dramatically reduced lung metastasis through inhibition of COX-1 while the cancer cells remained intravascular and that inhibition of platelet COX-1 alone was sufficient to impair metastasis. Thromboxane A2 (TXA2) was the prostanoid product of COX-1 responsible for this antimetastatic effect. Inhibition of the COX-1/TXA2 pathway in platelets decreased aggregation of platelets on tumor cells, endothelial activation, tumor cell adhesion to the endothelium, and recruitment of metastasis-promoting monocytes/macrophages, and diminished the formation of a premetastatic niche. Thus, platelet-derived TXA2 orchestrates the generation of a favorable intravascular metastatic niche that promotes tumor cell seeding and identifies COX-1/TXA2 signaling as a target for the prevention of metastasis.
Idiopathic pulmonary fibrosis (IPF) is a progressive scarring disease of the lung with poor survival. The incidence and mortality of IPF are rising, but treatment remains limited. Currently, two ...drugs can slow the scarring process but often at the expense of intolerable side effects, and without substantially changing overall survival. A better understanding of mechanisms underlying IPF is likely to lead to improved therapies. The current paradigm proposes that repetitive alveolar epithelial injury from noxious stimuli in a genetically primed individual is followed by abnormal wound healing, including aberrant activity of extracellular matrix-secreting cells, with resultant tissue fibrosis and parenchymal damage. However, this may underplay the importance of the vascular contribution to fibrogenesis. The lungs receive 100% of the cardiac output, and vascular abnormalities in IPF include (a) heterogeneous vessel formation throughout fibrotic lung, including the development of abnormal dilated vessels and anastomoses; (b) abnormal spatially distributed populations of endothelial cells (ECs); (c) dysregulation of endothelial protective pathways such as prostacyclin signaling; and (d) an increased frequency of common vascular and metabolic comorbidities. Here, we propose that vascular and EC abnormalities are both causal and consequential in the pathobiology of IPF and that fuller evaluation of dysregulated pathways may lead to effective therapies and a cure for this devastating disease.
RATIONALE:MicroRNA (miRNA) biomarkers are attracting considerable interest. Effects of medication, however, have not been investigated thus far.
OBJECTIVE:To analyze changes in plasma miRNAs in ...response to antiplatelet therapy.
METHODS AND RESULTS:Profiling for 377 miRNAs was performed in platelets, platelet microparticles, platelet-rich plasma, platelet-poor plasma, and serum. Platelet-rich plasma showed markedly higher levels of miRNAs than serum and platelet-poor plasma. Few abundant platelet miRNAs, such as miR-24, miR-197, miR-191, and miR-223, were also increased in serum compared with platelet-poor plasma. In contrast, antiplatelet therapy significantly reduced miRNA levels. Using custom-made quantitative real-time polymerase chain reaction plates, 92 miRNAs were assessed in a dose-escalation study in healthy volunteers at 4 different time pointsat baseline without therapy, at 1 week with 10 mg prasugrel, at 2 weeks with 10 mg prasugrel plus 75 mg aspirin, and at 3 weeks with 10 mg prasugrel plus 300 mg aspirin. Findings in healthy volunteers were confirmed by individual TaqMan quantitative real-time polymerase chain reaction assays (n=9). Validation was performed in an independent cohort of patients with symptomatic atherosclerosis (n=33), who received low-dose aspirin at baseline. Plasma levels of platelet miRNAs, such as miR-223, miR-191, and others, that is, miR-126 and miR-150, decreased on further platelet inhibition.
CONCLUSIONS:Our study demonstrated a substantial platelet contribution to the circulating miRNA pool and identified miRNAs responsive to antiplatelet therapy. It also highlights that antiplatelet therapy and preparation of blood samples could be confounding factors in case-control studies relating plasma miRNAs to cardiovascular disease.
Because metastasis is associated with the majority of cancer-related deaths, its prevention is a clinical aspiration. Prostanoids are a large family of bioactive lipids derived from the activity of ...cyclooxygenase-1 (COX-1) and COX-2. Aspirin impairs the biosynthesis of all prostanoids through the irreversible inhibition of both COX isoforms. Long-term administration of aspirin leads to reduced distant metastases in murine models and clinical trials, but the COX isoform, downstream prostanoid, and cell compartment responsible for this effect are yet to be determined. Here, we have shown that aspirin dramatically reduced lung metastasis through inhibition of COX-1 while the cancer cells remained intravascular and that inhibition of platelet COX-1 alone was sufficient to impair metastasis. Thromboxane A.sub.2 (TXA.sub.2) was the prostanoid product of COX- 1 responsible for this antimetastatic effect. Inhibition of the COX-1/TXA.sub.2 pathway in platelets decreased aggregation of platelets on tumor cells, endothelial activation, tumor cell adhesion to the endothelium, and recruitment of metastasis-promoting monocytes/ macrophages, and diminished the formation of a premetastatic niche. Thus, platelet-derived TXA.sub.2 orchestrates the generation of a favorable intravascular metastatic niche that promotes tumor cell seeding and identifies COX- 1/TXA.sub.2 signaling as a target for the prevention of metastasis.
Cyclooxygenase-2 (COX-2) is an inducible enzyme that drives inflammation and is the therapeutic target for widely used nonsteroidal antiinflammatory drugs (NSAIDs). However, COX-2 is also ...constitutively expressed, in the absence of overt inflammation, with a specific tissue distribution that includes the kidney, gastrointestinal tract, brain, and thymus. Constitutive COX-2 expression is therapeutically important because NSAIDs cause cardiovascular and renal side effects in otherwise healthy individuals. These side effects are now of major concern globally. However, the pathways driving constitutive COX-2 expression remain poorly understood. Here we show that in the kidney and other sites, constitutive COX-2 expression is a sterile response, independent of commensal microorganisms and not associated with activity of the inflammatory transcription factor NF-κB. Instead, COX-2 expression in the kidney but not other regions colocalized with nuclear factor of activated T cells (NFAT) transcription factor activity and was sensitive to inhibition of calcineurin-dependent NFAT activation. However, calcineurin/NFAT regulation did not contribute to constitutive expression elsewhere or to inflammatory COX-2 induction at any site. These data address the mechanisms driving constitutive COX-2 and suggest that by targeting transcription it may be possible to develop antiinflammatory therapies that spare the constitutive expression necessary for normal homeostatic functions, including those important to the cardiovascular-renal system.
Interferon (IFN) is widely recognised to be an integral part of the innate immune response to viral infection. Since its initial discovery in 1957 by Isaacs and Lindenmann, various IFN sub-types have ...been identified and there are now three distinct classes recognised-Type I (IFN-α and IFN-β), Type II (IFN-γ) and Type III (IFN-λ), distinguished by their differing receptors. As well as displaying profound antiviral activity in vivo, IFN has anti-proliferative, cytotoxic and anti-tumoural roles. In an attempt to harness their immunomodulatory potential, investigators and clinicians have investigated the use of IFNs for the treatment of human diseases with considerable success. For example, IFN-α preparations are now a critical component in the treatment of chronic Hepatitis C infection and IFN-β therapy is now the first line treatment for relapsing remitting multiple sclerosis. However, IFN therapy is also associated with significant morbidity and in some patients is poorly tolerated. In this review, we explore the scientific basis for IFN therapy and outline its therapeutic scope. We describe the commonly encountered side effects and attempt to explain the less well recognised pulmonary complications including emerging evidence of life threatening and irreversible pulmonary vascular pathology. Finally, we look to the future of interferon drug treatment, examining the potential for emerging therapies.
Cyclooxygenases and the cardiovascular system Mitchell, Jane A.; Kirkby, Nicholas S.; Ahmetaj-Shala, Blerina ...
Pharmacology & therapeutics (Oxford),
January 2021, 2021-01-00, 20210101, Letnik:
217
Journal Article
Recenzirano
Odprti dostop
Cyclooxygenase (COX)-1 and COX-2 are centrally important enzymes within the cardiovascular system with a range of diverse, sometimes opposing, functions. Through the production of thromboxane, COX in ...platelets is a pro-thrombotic enzyme. By contrast, through the production of prostacyclin, COX in endothelial cells is antithrombotic and in the kidney regulates renal function and blood pressure. Drug inhibition of COX within the cardiovascular system is important for both therapeutic intervention with low dose aspirin and for the manifestation of side effects caused by nonsteroidal anti-inflammatory drugs. This review focuses on the role that COX enzymes and drugs that act on COX pathways have within the cardiovascular system and provides an in-depth resource covering COX biology and pharmacology. The review goes on to consider the role of COX in both discrete cardiovascular locations and in associated organs that contribute to cardiovascular health. We discuss the importance of, and strategies to manipulate the thromboxane: prostacyclin balance. Finally within this review the authors discuss testable COX-2-hypotheses intended to stimulate debate and facilitate future research and therapeutic opportunities within the field.
Monoclonal antibodies (mAbs) are now established as targeted therapies for malignancies, transplant rejection, autoimmune and infectious diseases, as well as a range of new indications. However, ...administration of mAbs carries the risk of immune reactions such as acute anaphylaxis, serum sickness and the generation of antibodies. In addition, there are numerous adverse effects of mAbs that are related to their specific targets, including infections and cancer, autoimmune disease, and organ-specific adverse events such as cardiotoxicity. In March 2006, a life-threatening cytokine release syndrome occurred during a first-in-human study with TGN1412 (a CD28-specific superagonist mAb), resulting in a range of recommendations to improve the safety of initial human clinical studies with mAbs. Here, we review some of the adverse effects encountered with mAb therapies, and discuss advances in preclinical testing and antibody technology aimed at minimizing the risk of these events.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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