DF2755A, a novel non-competitive allosteric inhibitor of CXCR1/2, reduces inflammatory and post-operative pain

Lopes, Alexandre H.; Brandolini, Laura; Aramini, Andrea; Bianchini, Gianluca; Silva, Rangel L.; Zaperlon, Ana C.; Verri, Waldiceu A.; Alves‐Filho, José C.; Cunha, Fernando Q.; Teixeira, Mauro Martins; Allegretti, Marcello; Cunha, Thiago M.

doi:10.1016/j.phrs.2015.11.005

Cited by 27 publications

(41 citation statements)

References 46 publications

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“…Because CXCR1/2 drives neutrophil influx in experimental models and neutrophils may contribute to the pathogenesis of certain inflammatory diseases, several CXCR1/2 antagonists, including DF2162, have been developed ( 33 ). These antagonists are effective at blocking chemokine-driven neutrophil influx in various models of inflammation and some are undergoing clinical evaluation in humans ( 34 , 35 ). Here, we have used the CXCR1/2 antagonist DF2162 because of its suitable pharmacokinetic profile and effectiveness in murine models of neutrophilic inflammation ( 14 , 16 ).…”

Section: Discussionmentioning

confidence: 99%

CXCR1/2 Antagonism Is Protective during Influenza and Post-Influenza Pneumococcal Infection

et al. 2017

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RationaleInfluenza A infections are a leading cause of morbidity and mortality worldwide especially when associated with secondary pneumococcal infections. Inflammation is important to control pathogen proliferation but may also cause tissue injury and death. CXCR1/2 are chemokine receptors relevant for the recruitment of neutrophils. We investigated the role of CXCR1/2 during influenza, pneumococcal, and post-influenza pneumococcal infections.MethodsMice were infected with influenza A virus (IAV) or Streptococcus pneumoniae and then treated daily with the CXCR1/2 antagonist DF2162. To study secondary pneumococcal infection, mice were infected with a sublethal inoculum of IAV then infected with S. pneumoniae 14 days later. DF2162 was given in a therapeutic schedule from days 3 to 6 after influenza infection. Lethality, weight loss, inflammation, virus/bacteria counts, and lung injury were assessed.ResultsCXCL1 and CXCL2 were produced at high levels during IAV infection. DF2162 treatment decreased morbidity and this was associated with decreased infiltration of neutrophils in the lungs and reduced pulmonary damage and viral titers. During S. pneumoniae infection, DF2162 treatment decreased neutrophil recruitment, pulmonary damage, and lethality rates, without affecting bacteria burden. Therapeutic treatment with DF2162 during sublethal IAV infection reduced the morbidity associated with virus infection and also decreased the magnitude of inflammation, lung damage, and number of bacteria in the blood of mice subsequently infected with S. pneumoniae.ConclusionModulation of the inflammatory response by blocking CXCR1/2 improves disease outcome during respiratory influenza and pneumococcal infections, without compromising the ability of the murine host to deal with infection. Altogether, inhibition of CXCR1/2 may be a valid therapeutic strategy for treating lung infections caused by these pathogens, especially controlling secondary bacterial infection after influenza.

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Section: Discussionmentioning

confidence: 99%

CXCR1/2 Antagonism Is Protective during Influenza and Post-Influenza Pneumococcal Infection

et al. 2017

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“…It is a member of the G-protein-coupled receptor family, binding with high affinity to IL8 and mediating chemotaxis. With such a central role in the inflammatory response, CXCR1 has been targeted for the development of pain-relieving drugs (56, 57). Similar to the gene OAS2, CXCR1 was clearly upregulated in patient N5 at the 5-week time point with an increase in expression of nearly fivefold, again indicating that the inflammatory response in this patient can be detected by these genes.…”

Section: Discussionmentioning

confidence: 99%

Radiotherapy-Associated Long-term Modification of Expression of the Inflammatory Biomarker Genes ARG1, BCL2L1, and MYC

et al. 2017

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Ionizing radiation (IR) exposure of cells in vitro and in vivo triggers a complex cellular response among which modifications of gene expression have been consistently reported. Nevertheless, little is currently known about the transcriptionally responsive genes which play a role in the inflammation response. In order to improve our understanding of such transcriptional response to radiation in vivo, we simultaneously monitored the expression of 249 genes associated with the inflammation response over the course of the radiotherapy treatment in blood of patients treated for endometrial or head and neck cancer. We have identified genes whose transcriptional expression is either upregulated (ARG1, BCL2L1) or downregulated (MYC) several fold in vivo. These modifications were consistently detected across patients and further confirmed by quantitative real-time polymerase chain reaction (QRT-PCR); they were specifically significant toward the end of the radiotherapy treatment, 5 weeks following the first radiation fraction and more pronounced in endometrial patients (respectively, 2.9, 4.1, and 1.8 times). Importantly, in an attempt to correlate expression levels with normal tissue reaction to IR, we also identified three other genes CD40, OAS2, and CXCR1 whose expression level fluctuations during radiotherapy were more pronounced in patients developing late normal tissue responses to curative radiotherapy after the end of the radiotherapy treatment. Overall, we identified inflammation-associated genes which are promising biomarkers of IR exposure and susceptibility to radiation-induced toxicity.

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“…Furthermore, these flogistic Cg subtypes are extensively used to induce inflammation in several experimental animal models especially to study novel anti-inflammatory and analgesic drugs [8][9][10][11]. For instance, Cg injected into the rodents hindpaw causes a classical innate immune response characterized by paw oedema, neutrophil migration and pain [12,13].…”

Section: Introductionmentioning

confidence: 99%

Molecular basis of carrageenan-induced cytokines production in macrophages

et al. 2020

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Background Low molecular weight carrageenan (Cg) is a seaweed-derived sulfated polysaccharide widely used as inflammatory stimulus in preclinical studies. However, the molecular mechanisms of Cg-induced inflammation are not fully elucidated. The present study aimed to investigate the molecular basis involved in Cg-induced macrophages activation and cytokines production. Methods Primary culture of mouse peritoneal macrophages were stimulated with Kappa Cg. The supernatant and cell lysate were used for ELISA, western blotting, immunofluorescence. Cg-induced mouse colitis was also developed. Results Here we show that Cg activates peritoneal macrophages to produce pro-inflammatory cytokines such as TNF and IL-1β. While Cg-induced TNF production/secretion depends on TLR4/MyD88 signaling, the production of pro-IL-1β relies on TLR4/TRIF/SYK/reactive oxygen species (ROS) signaling pathway. The maturation of pro-IL1β into IL-1β is dependent on canonical NLRP3 inflammasome activation via Pannexin-1/P2X7/K+ efflux signaling. In vivo, Cg-induced colitis was reduced in mice in the absence of NLRP3 inflammasome components. Conclusions In conclusion, we unravel a critical role of the NLRP3 inflammasome in Cg-induced pro-inflammatory cytokines production and colitis, which is an important discovery on the pro-inflammatory properties of this sulfated polysaccharide for pre-clinical studies. Graphical Abstract Carrageenan (Cg) is one the most used flogistic stimulus in preclinical studies. Nevertheless, the molecular basis of Cg-induced inflammation is not totally elucidated. Herein, Lopes et al. unraveled the molecular basis for Cg-induced macrophages production of biological active IL-1β. The Cg-stimulated macrophages produces pro-IL-1β depends on TLR4/TRIF/Syk/ROS, whereas its processing into mature IL-1β is dependent on the canonical NLRP3 inflammasome.

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DF2755A, a novel non-competitive allosteric inhibitor of CXCR1/2, reduces inflammatory and post-operative pain

Cited by 27 publications

References 46 publications

CXCR1/2 Antagonism Is Protective during Influenza and Post-Influenza Pneumococcal Infection

CXCR1/2 Antagonism Is Protective during Influenza and Post-Influenza Pneumococcal Infection

Radiotherapy-Associated Long-term Modification of Expression of the Inflammatory Biomarker Genes ARG1, BCL2L1, and MYC

Molecular basis of carrageenan-induced cytokines production in macrophages

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