In vivo modulation of the inflammatory response by nonsteroidal antiinflammatory drug‐related compounds that trigger <i><scp>L</scp></i>‐selectin shedding

Herrera-García, Ada; Domínguez-Luis, María Jesús; Arce-Franco, Mayte; López-Fernández, Judith; Feria, Manuel; Barreiro, Olga; Sánchez-Madrid, Francisco; Dı́az-González, Federico

doi:10.1002/eji.201242805

Cited by 14 publications

(19 citation statements)

References 45 publications

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“…shedding of L-selectin has been demonstrated not only in vivo in both humans and mice [5,11], but also in vitro, where the concentration of NSAIDs required to induce L-selectin shedding in human neutrophils [5,12] are within the range (micromolars) reached in plasma by oral administration of NSAIDs in humans [49,50].…”

Section: Inhibition Of Cell Adhesion By Nsaidsmentioning

confidence: 99%

“…In healthy human volunteers, the basal surface expression of L-selectin on circulating neutrophils is significantly reduced by therapeutic doses of indomethacin [5]. In the zymosan air pouch model of acute inflammation, intramuscular treatment with N-phenylanthranilic acid, a diphenylamine-related NSAID that promotes L-selectin shedding in neutrophils in vitro [10] and in vivo [11], was shown to interfere with the ability of neutrophils to accumulate at inflammatory foci [11]. At the doses used in that study, N-phenylanthranilic acid did not block COX and did not show any additive anti-inflammatory effect to treatment with Mel-14, a functional blocking monoclonal antibody against murine L-selectin [11].…”

Section: L-selectin-based Effects Of Nsaidsmentioning

confidence: 99%

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NSAIDs: Learning new tricks from old drugs

Dı́az-González

Sánchez-Madrid

2015

Eur J Immunol

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Nonsteroidal anti-inflammatory drugs (NSAIDs) comprise a heterogeneous group of pharmacological agents used for the symptomatic treatment of fever, pain, and inflammation. Although the main mechanism of action of NSAIDs consists of inhibiting prostaglandin synthesis by blocking the enzyme cyclooxygenase (COX), clinical, and experimental data strongly indicate the existence of additional mechanisms. Some of the COX-independent effects are related to the ability of NSAIDs to penetrate biological membranes and disrupt important molecular interactions necessary for a wide array of cellular functions, including cell adhesion. These effects, in particular those that interfere with L-selectin function in neutrophils during the inflammatory response, may contribute to the antiinflammatory properties that NSAIDs exert in vivo. Recent contributions in this field have shown that the anti-L-selectin effect of NSAIDs is related to the NADPH-oxidasedependent generation of superoxide anion at the plasma membrane. These findings might represent a novel approach for developing new and effective anti-inflammatory compounds with a better safety profile than the currently available NSAIDs.Keywords: L-selectin r Non-steroidal anti-inflammatory drugs r NADPH oxidase IntroductionNonsteroidal anti-inflammatory drugs (NSAIDs) are a heterogeneous group of therapeutic agents widely used for the symptomatic treatment of rheumatic disorders. Since the early seventies of last century, it has been widely accepted that the main mechanism of action of these compounds, which is also responsible for the main side effect of gastric mucosal damage, is inhibition of cyclooxygenase (COX), a key enzyme in prostaglandin synthesis [1]. Prostaglandins are group of hormone-like lipid compounds with a wide variety of strong physiological effects, including regulation of inflammation, pain sensitization, and platelet aggregation, among many others. However, a growing body of evidence suggests that NSAIDs have additional anti-inflammatory properties (reviewed in [2]). Some of these effects appear to be related to the ability of NSAIDs to penetrate biological membranes, as evaluated in vitro using membrane mimetic models, cell cultures, Correspondence: Prof. Federico Díaz-González e-mail: federico.diaz.gonzalez@gmail.com and molecular dynamic simulation systems [3,4], where they disrupt normal signaling events and modify important processes necessary for cellular function, including cell adhesion [5,6].The ability of NSAIDs to interfere with either cell adhesion, for example, by cleavage of epithelial cell adhesion molecule protein on tumor cells [6], or with leukocyte adhesion pathways essential for the inflammatory response, such as causing L-selectin shedding on neutrophil [5], has been described. Interestingly, this antiadhesive effect of NSAIDs has also been shown to influence platelet adhesion, and it has been suggested that coagulation, hemostasis, and thrombus formation could be modulated by these compounds independently of the release of proinflammat...

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Section: Inhibition Of Cell Adhesion By Nsaidsmentioning

confidence: 99%

Section: L-selectin-based Effects Of Nsaidsmentioning

confidence: 99%

NSAIDs: Learning new tricks from old drugs

Dı́az-González

Sánchez-Madrid

2015

Eur J Immunol

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“…This phenomenon was accompanied by leukocyte CD44 and b2 integrin cleavage but, and as expected, did not affect RBC adhesion molecule expression. Although cleavage of adhesion molecules from leukocyte and cytokine‐activated ECs has been described to occur by anti‐inflammatory drug‐related compounds (48, 49), in our system, SS leukocyte and SSRBC separation from the endothelium may implicate MEK/ERK1/2 signaling in regulating cleavage of endothelial E‐selectin, P‐selectin, and avb3, and leukocyte b2 and CD44, when these proteins are engaged in firm cell‐cell binding. Also, this may hinder SSRBCs and SS leukocytes from readhering to ECs and SSRBC‐leukocyte from interacting.…”

Section: Discussionmentioning

confidence: 71%

MEK1/2 inhibitors reverse acute vascular occlusion in mouse models of sickle cell disease

et al. 2015

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In sickle cell disease (SCD), treatment of recurrent vasoocclusive episodes, leading to pain crises and organ damage, is still a therapeutic challenge. Vasoocclusion is caused primarily by adherence of homozygous for hemoglobin S (SS) red blood cells (SSRBCs) and leukocytes to the endothelium. We tested the therapeutic benefits of MEK1/2 inhibitors in reversing vasoocclusion in nude and humanized SCD mouse models of acute vasoocclusive episodes using intravital microscopy. Administration of 0.2, 0.3, 1, or 2 mg/kg MEK1/2 inhibitor to TNF-α-pretreated nude mice before human SSRBC infusion inhibited SSRBC adhesion in inflamed vessels, prevented the progression of vasoocclusion, and reduced SSRBC organ sequestration. By use of a more clinically relevant protocol, 0.3 or 1 mg/kg MEK1/2 inhibitor given to TNF-α-pretreated nude mice after human SSRBC infusion and onset of vasoocclusion reversed SSRBC adhesion and vasoocclusion and restored blood flow. In SCD mice, 0.025, 0.05, or 0.1 mg/kg MEK1/2 inhibitor also reversed leukocyte and erythrocyte adhesion after the inflammatory trigger of vasoocclusion and improved microcirculatory blood flow. Cell adhesion was reversed by shedding of endothelial E-selectin, P-selectin, and αvβ3 integrin, and leukocyte CD44 and β2 integrin. Thus, MEK1/2 inhibitors, by targeting the adhesive function of SSRBCs and leukocytes, could represent a valuable therapeutic intervention for acute sickle cell vasoocclusive crises.

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“…Of note, NSAIDs were found to modulate intracellular ATP content and, most interestingly, cause the shedding of cell adhesion molecules such as L ‐selectin in vitro . In this issue of the European Journal of Immunology , Herrera‐Garcia et al report that the indomethacin‐related NSAID N ‐phenylanthranilic acid ( N ‐Ph) causes L ‐selectin shedding from neutrophils in vivo . In addition, N ‐Ph treatment reduced neutrophil recruitment in the zymosan‐induced “air pouch” model in a dose‐dependent manner while having no effect on prostaglandin synthesis, as measured by TxB 2 release from platelets .…”

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confidence: 99%

L‐selectin shedding by NSAIDs: Old friends in new dresses

Zarbock

Rossaint

2013

Eur J Immunol

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The recruitment of leukocytes to sites of inflammation requires the highly organized interplay of cell adhesion molecules on both leukocytes and inflamed endothelial cells, and disrupting the interaction of these molecules may compromise efficient recruitment of immune cells. Non-steroidal anti-inflammatory drugs inhibit inflammatory responses by several mechanisms including inhibition of prostaglandin synthesis and decreasing the expression of cell surface adhesion molecules. A report by Herrera-Garcia et al. [Eur. J. Immunol. 2013. 43: 55-64] in this issue of the European Journal of Immunology shows that the non-steroidal anti-inflammatory drug N-phenylanthranilic acid (N-Ph) causes L-selectin to be shed from the leukocyte plasma membrane and that this process in turn causes a decrease in leukocyte recruitment during inflammation in vivo. This finding may lead to novel approaches using N-Ph in the control of inflammatory processes as discussed in this Commentary.

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In vivo modulation of the inflammatory response by nonsteroidal antiinflammatory drug‐related compounds that trigger L‐selectin shedding

Cited by 14 publications

References 45 publications

NSAIDs: Learning new tricks from old drugs

NSAIDs: Learning new tricks from old drugs

MEK1/2 inhibitors reverse acute vascular occlusion in mouse models of sickle cell disease

L‐selectin shedding by NSAIDs: Old friends in new dresses

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