Systemic Platelet-activating Factor Receptor Activation Augments Experimental Lung Tumor Growth and Metastasis

Hackler, Patrick C.; Reuss, Sarah M.; Konger, Raymond L.; Travers, Jeffrey B.; Sahu, Ravi P.

doi:10.4137/cgm.s14501

Cited by 30 publications

(51 citation statements)

References 38 publications

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“…107 In an animal model of lung cancer, administration of PAFR agonists led to increased tumor growth and lung metastasis. 106 In a recent animal study the oxidative stress of traditional chemotherapy promoted PAF production and subsequent treatment failure, suggesting a role for PAF signaling in treatment outcomes. 108 Interestingly, these untoward effects were inhibited by antioxidants, COX-2 inhibitors, or depletion of regulatory T cells.…”

Section: Malignancymentioning

confidence: 99%

Platelets in the immune response: Revisiting platelet-activating factor in anaphylaxis

Gill

Jindal

Jagdis

et al. 2015

Journal of Allergy and Clinical Immunology

109

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Anaphylaxis is an acute, severe, life-threatening multisystem allergic reaction resulting from the sudden systemic release of biochemical mediators and chemotactic substances. Release of both preformed granule-associated mediators and newly generated lipid-derived mediators contributes to the amplification and prolongation of anaphylaxis. Platelet-activating factor (PAF) is a potent phospholipid-derived mediator the central role of which has been well established in experimental models of both immune-mediated and non-immune mediated anaphylaxis. It is produced and secreted by several types of cells, including mast cells, monocytes, tissue macrophages, platelets, eosinophils, endothelial cells, and neutrophils. PAF is implicated in platelet aggregation and activation through release of vasoactive amines in the inflammatory response, resulting in increased vascular permeability, circulatory collapse, decreased cardiac output, and various other biological effects. PAF is rapidly hydrolyzed and degraded to an inactive metabolite, lysoPAF, by the enzyme PAF acetylhydrolase, the activity of which has shown to correlate inversely with PAF levels and predispose to severe anaphylaxis. In addition to its role in anaphylaxis, PAF has also been implicated as a mediator in both allergic and nonallergic inflammatory diseases, including allergic rhinitis, sepsis, atherosclerotic disease, and malignancy, in which PAF signaling has an established role. The therapeutic role of PAF antagonism has been investigated for several diseases, with variable results thus far. Further investigation of its role in pathology and therapeutic modulation is highly anticipated because of the pressing need for more selective and targeted therapy for the management of severe anaphylaxis.

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Section: Malignancymentioning

confidence: 99%

Platelets in the immune response: Revisiting platelet-activating factor in anaphylaxis

Gill

Jindal

Jagdis

et al. 2015

Journal of Allergy and Clinical Immunology

109

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“…Several antagonists of PAFR function are available, categorized based on their chemical properties . Most are well tolerated in various experimental settings, including in vitro cultured cells, in vivo mouse models and human trials . The safety and tolerability of WEB‐2086 were examined in two double‐blind, placebo‐controlled, within‐subject crossover studies.…”

Section: Hif‐1α‐induced Pafr‐mediated Bacterial Infections In Copdmentioning

confidence: 99%

“…Another PAFR antagonist (SR27417) inhibited PAF‐induced symptoms in mild bronchial asthmatic patients with only minor side effects . PAFR expression and activation were also shown to accelerate lung cancer progression, and administration of an agonist augmented both tumour growth and lung metastasis in a PAFR‐dependent manner …”

Section: Hif‐1α‐induced Pafr‐mediated Bacterial Infections In Copdmentioning

confidence: 99%

Hypoxia‐inducible factor and bacterial infections in chronic obstructive pulmonary disease

et al. 2019

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COPD is a seriously disabling respiratory condition that inexorably progresses to disability and mortality. It affects approximately 10% of the population globally with a greater prevalence at advanced ages. Airway bacterial infections complicate the disease course in most COPD patients, leading to increased symptoms, more rapid decline in lung function, acute exacerbations and reduced quality of life. With increasing bacterial resistance to antibiotics and adverse effects of conventional treatments, new effective non‐antibiotic antimicrobial therapies are urgently needed to manage COPD. Hypoxia‐inducible factor (HIF)‐1α is an important transcriptional regulator of cellular responses to hypoxia, oxidants and inflammation, and is overexpressed in the lungs of COPD patients. Recent evidence shows that increased HIF‐1α expression can upregulate the platelet‐activating factor receptor (PAFR) on the airway epithelial surface that is increased in smokers and particularly COPD patients. The receptor is utilized by PAFR‐dependent bacteria (Streptococcus pneumoniae, Haemophilus influenzae and Pseudomonas aeruginosa) to induce infection in both the respiratory and gastrointestinal (GI) tracts. However, the importance and mechanism of HIF‐1α in augmenting PAFR‐dependent bacterial infections in COPD are poorly understood. Here, we review the evidence for the roles of local tissue hypoxia‐induced inflammation, HIF‐1α and PAFR in facilitating bacterial infections in COPD. Blocking PAFR may provide a novel antimicrobial approach to manage bacterial infections in COPD.

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“…The ability of UV treatment to suppress both T‐cell mediated antitumor immune responses and CHS is known to occur through the production of antigen‐specific regulatory T‐cells (Tregs) . More recently, UV‐IS was shown to promote the growth of B16F10 melanoma and Lewis lung carcinoma tumors following transplant into UV‐treated syngeneic C57BL/6 hosts . The ability of UV to stimulate tumor growth was shown to be dependent on immune cell function, as the UV‐induced tumor response was not observed in NOD.CB17‐Prkdc SCID /M mice lacking an intact adaptive immune system .…”

Section: Pparγ Plays An Important Role In Regulating Inflammation Andmentioning

confidence: 99%

“…[96][97][98] More recently, UV-IS was shown to promote the growth of B16F10 melanoma and Lewis lung carcinoma tumors following transplant into UV-treated syngeneic C57BL/6 hosts. 98,99 The ability of UV to stimulate tumor growth was shown to be dependent on immune cell function, as the UV-induced tumor response was not observed in NOD.CB17-Prkdc SCID /M mice lacking an intact adaptive immune system. 98 Increased tumor growth also required CD25 + Tregs and interleukin 10 production.…”

Section: Pparγ Plays a Key Role In Cutaneous Immunity And Promotes mentioning

confidence: 99%

Evidence that peroxisome proliferator‐activated receptor γ suppresses squamous carcinogenesis through anti‐inflammatory signaling and regulation of the immune response

Ren

Konger

2019

Molecular Carcinogenesis

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A variety of evidence suggests that peroxisome proliferator‐activated receptor (PPAR)γ agonists may represent a potential pharmacologic target in the prevention or treatment of skin cancer. In particular, recent reports suggest that PPARγ activation may exert at least some of its anti‐neoplastic effects through the suppression of tumor promoting chronic inflammation as well as by strengthening antitumor immune responses. This activity is thought to occur through a distinct mode of ligand interaction with PPARγ that causes transrepression of transcription factors that are involved in inflammatory and immunomodulatory signaling. However, current thiazolidinedione (TZD)‐type PPARγ agonists have significant safety concerns that limit their usefulness as a preventive or therapeutic option. Due to the relatively large ligand binding pocket of PPARγ, a diverse group of ligands can be seen to interact with distinct modes of binding to PPARγ, leading to the phenomenon of partial agonist activity and selective PPARγ modulators (SPPARγM). This has led to the development of ligands that are tailored to deliver desired pharmacologic activity, but lack some of the negative side effects associated with full agonists, such as the currently utilized TZD‐type PPARγ agonists. In addition, there is evidence that a number of phytochemicals that are currently being touted as antineoplastic nutraceuticals also possess PPARγ activity that may partially explain their pharmacologic activity. We propose that one or more of these partial agonists, SPPARγMs, or putative phytochemical PPARγ ligands could presumably be used as a starting point to design more efficacious anti‐neoplastic PPARγ ligands that lack adverse pharmacological effects.

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Systemic Platelet-activating Factor Receptor Activation Augments Experimental Lung Tumor Growth and Metastasis

Cited by 30 publications

References 38 publications

Platelets in the immune response: Revisiting platelet-activating factor in anaphylaxis

Platelets in the immune response: Revisiting platelet-activating factor in anaphylaxis

Hypoxia‐inducible factor and bacterial infections in chronic obstructive pulmonary disease

Evidence that peroxisome proliferator‐activated receptor γ suppresses squamous carcinogenesis through anti‐inflammatory signaling and regulation of the immune response

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