The PGE2–EP2–mast cell axis: An antiasthma mechanism

Torres, Rosa; Picado, César; Mora, Fernando

doi:10.1016/j.molimm.2014.03.007

Cited by 36 publications

(30 citation statements)

References 86 publications

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“…PGE 2 , which acts through the EP2 receptor, stabilizes mast cells, and therefore the abrupt decrease in PGE 2 levels that occurs with COX-1 inhibition might lead to mediator release from inflammatory cells and the development of symptoms in susceptible subejcts. 21 Furthermore, aspirin can increase Syk kinase phosphorylation of the FcεRI signaling complex, facilitating mast cell activation. 22 Increased mast cell reactivity might also be related to a genetic predisposition because of a variant of the FcεRIa subunit gene (FCER1A2344C>T), which is more common among patients with NECD.…”

Section: Clinical Presentationmentioning

confidence: 99%

Approaches to the diagnosis and management of patients with a history of nonsteroidal anti-inflammatory drug–related urticaria and angioedema

Kowalski

Woessner

Sanak

2015

Journal of Allergy and Clinical Immunology

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Nonsteroidal anti-inflammatory drug (NSAID)-induced urticarial and angioedema reactions are among the most commonly encountered drug hypersensitivity reactions in clinical practice. Three major clinical phenotypes of NSAID-induced acute skin reactions manifesting with angioedema, urticaria, or both have been distinguished: NSAID-exacerbated cutaneous disease, nonsteroidal anti-inflammatory drug-induced urticaria/angioedema (NIUA), and single NSAID-induced urticaria and angioedema. In some patients clinical history alone might be sufficient to establish the diagnosis of a specific type of NSAID hypersensitivity, whereas in other cases oral provocation challenges are necessary to confirm the diagnosis. Moreover, classification of the type of cutaneous reaction is critical for proper management. For example, in patients with single NSAID-induced reactions, chemically nonrelated COX-1 inhibitors can be safely used. However, there is cross-reactivity between the NSAIDs in patients with NSAID-exacerbated cutaneous disease and NIUA, and thus only use of selective COX-2 inhibitors can replace the culprit drug if the chronic treatment is necessary, although aspirin desensitization will allow for chronic treatment with NSAIDs in some patients with NIUA. In this review we present a practical clinical approach to the patient with NSAID-induced urticaria and angioedema.

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Section: Clinical Presentationmentioning

confidence: 99%

Approaches to the diagnosis and management of patients with a history of nonsteroidal anti-inflammatory drug–related urticaria and angioedema

Kowalski

Woessner

Sanak

2015

Journal of Allergy and Clinical Immunology

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“…The fact that AKR1B1 activity can be regulated by PGs poses interesting questions in this context. Remarkably, PGE 2 has been reported to exert protective effects in asthma, mainly through interaction with the PGE receptor (Torres et al, 2015), but an implication of AKR1B1 in these effects has not been explored. It would be relevant to assess whether AKR1B1 can be modulated by endogenously generated PGs, and if so whether this influences inflammatory or allergic responses.…”

Section: Prostaglandins Inhibit Aldose Reductasementioning

confidence: 99%

Molecular Interactions and Implications of Aldose Reductase Inhibition by PGA₁ and Clinically Used Prostaglandins

Díez-Dacal¹,

Sánchez‐Gómez

Sánchez‐Murcia

et al. 2015

Mol Pharmacol

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Aldose reductase (AKR1B1) is a critical drug target because of its involvement in diabetic complications, inflammation, and tumorigenesis. However, to date, development of clinically useful inhibitors has been largely unsuccessful. Cyclopentenone prostaglandins (cyPGs) are reactive lipid mediators that bind covalently to proteins and exert anti-inflammatory and antiproliferative effects in numerous settings. By pursuing targets for modification by cyPGs we have found that the cyPG PGA 1 binds to and inactivates AKR1B1. A PGA 1 -AKR1B1 adduct was observed, both by matrix-assisted laser desorption/ ionization time-of-flight mass spectrometry and by SDS-PAGE using biotinylated PGA 1 (PGA 1 -B). Insight into the molecular interactions between AKR1B1 and PGA 1 was advanced by molecular modeling. This anticipated the addition of PGA 1 to active site Cys298 and the potential reversibility of the adduct, which was supported experimentally. Indeed, loss of biotin label from the AKR1B1-PGA 1 -B adduct was favored by glutathione, indicating a retro-Michael reaction, which unveils new implications of cyPG-protein interaction. PGA 1 elicited only marginal inhibition of aldehyde reductase (AKR1A1), considered responsible for the severe adverse effects of many AKR1B1 inhibitors. Interestingly, other prostaglandins (PGs) inhibited the enzyme, including non-electrophilic PGE 1 and PGE 2 , currently used in clinical practice. Moreover, both PGA 1 and PGE 1 reduced the formation of sorbitol in an ex-vivo model of diabetic cataract to an extent comparable to that attained by the known AKR inhibitor epalrestat. Taken together, these results highlight the role of PGs as AKR1B1 inhibitors and the interest in PG-related molecules as leads for the development of novel pharmacological tools.

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“…Later on, PGE 2 promotes differentiation of macrophages and monocytoid dendritic cells to an anti-inflammatory phenotype that suppresses NK cell and neutrophil inflammatory function and mast cell degranulation[86]. Variances in sensitivity, desensitization and activation of different signaling pathways among several PGE 2 receptors accounts for this adaptable pattern of responses at different stages of the immune response[87]. TGF-β1 also presents biphasic activities, since its strong chemoattractive properties brings about a rapid incoming of T cells, granulocytes and macrophages that can contribute to inflammation but can also exert a potent anti-inflammatory response by constraining the synthesis of inflammatory cytokines and stimulating differentiation of naïve T cells to T reg cells[88].…”

Section: Mscs and Immunomodulationmentioning

confidence: 99%

Immunomodulatory oligonucleotide IMT504: Effects on mesenchymal stem cells as a first-in-class immunoprotective/immunoregenerative therapy

Zorzopulos¹,

Opal²,

Hernando-Insúa³

et al. 2017

WJSC

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The immune responses of humans and animals to insults (i.e., infections, traumas, tumoral transformation and radiation) are based on an intricate network of cells and chemical messengers. Abnormally high inflammation immediately after insult or abnormally prolonged pro-inflammatory stimuli bringing about chronic inflammation can lead to life-threatening or severely debilitating diseases. Mesenchymal stem cell (MSC) transplant has proved to be an effective therapy in preclinical studies which evaluated a vast diversity of inflammatory conditions. MSCs lead to resolution of inflammation, preparation for regeneration and actual regeneration, and then ultimate return to normal baseline or homeostasis. However, in clinical trials of transplanted MSCs, the expectations of great medical benefit have not yet been fulfilled. As a practical alternative to MSC transplant, a synthetic drug with the capacity to boost endogenous MSC expansion and/or activation may also be effective. Regarding this, IMT504, the prototype of a major class of immunomodulatory oligonucleotides, induces in vivo expansion of MSCs, resulting in a marked improvement in preclinical models of neuropathic pain, osteoporosis, diabetes and sepsis. IMT504 is easily manufactured and has an excellent preclinical safety record. In the small number of patients studied thus far, IMT504 has been well-tolerated, even at very high dosage. Further clinical investigation is necessary to demonstrate the utility of IMT504 for resolution of inflammation and regeneration in a broad array of human diseases that would likely benefit from an immunoprotective/immunoregenerative therapy.

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The PGE2–EP2–mast cell axis: An antiasthma mechanism

Cited by 36 publications

References 86 publications

Approaches to the diagnosis and management of patients with a history of nonsteroidal anti-inflammatory drug–related urticaria and angioedema

Approaches to the diagnosis and management of patients with a history of nonsteroidal anti-inflammatory drug–related urticaria and angioedema

Molecular Interactions and Implications of Aldose Reductase Inhibition by PGA₁ and Clinically Used Prostaglandins

Immunomodulatory oligonucleotide IMT504: Effects on mesenchymal stem cells as a first-in-class immunoprotective/immunoregenerative therapy

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The PGE2–EP2–mast cell axis: An antiasthma mechanism

Cited by 36 publications

References 86 publications

Approaches to the diagnosis and management of patients with a history of nonsteroidal anti-inflammatory drug–related urticaria and angioedema

Approaches to the diagnosis and management of patients with a history of nonsteroidal anti-inflammatory drug–related urticaria and angioedema

Molecular Interactions and Implications of Aldose Reductase Inhibition by PGA1 and Clinically Used Prostaglandins

Immunomodulatory oligonucleotide IMT504: Effects on mesenchymal stem cells as a first-in-class immunoprotective/immunoregenerative therapy

Contact Info

Product

Resources

About

Molecular Interactions and Implications of Aldose Reductase Inhibition by PGA₁ and Clinically Used Prostaglandins