FLT3 signaling inhibition abrogates opioid tolerance and hyperalgesia while preserving analgesia.

Navigating the duality of opioids' potent analgesia and side effects, including tolerance and hyperalgesia, is a significant challenge in chronic pain management, often prompting hazardous dose escalation to maintain analgesic effects. The peripheral mu-opioid receptor (MOR) is known to mediate these contradictory effects. Here, we show that the fms-like tyrosine kinase receptor 3 (FLT3) in peripheral somatosensory neurons drives morphine tolerance and hyperalgesia in a male rodent model.

Randomized double-blind placebo-controlled cosmetic trial of a topical first-in-class Neutraligand targeting the chemokine TARC/CCL17 in mild-to-moderate atopic dermatitis.

Background: Atopic dermatitis has a marked economic impact and affects the quality of life. A cosmetic compound with an innovative strategy is proposed here as a small chemical neutraligand, GPN279 (previously identified as a theophylline derivative), that binds and potently neutralizes the TARC/CCL17 chemokine, activating the Th2 cell-expressed CCR4 receptor.

Objective: Our objective was to evaluate the safety and activity of topically applied GPN279 in mild-to-moderate atopic dermatitis patients in a randomized, double-blind, placebo-controlled, parallel group trial.

[Production of innervated bronchial epithelium from a blood sample].

Asthma is a frequent respiratory disease, with severe asthma occurring in 3 to 5% of cases. Chronic inflammation of the bronchial epithelium is essential to its pathophysiology. When activated by the bronchial environment, the peripheral sensory nervous system contributes to inflammation of the airways.

Antagonizing the CX3CR1 Receptor Markedly Reduces Development of Cardiac Hypertrophy After Transverse Aortic Constriction in Mice.

Left-ventricular hypertrophy, characterized by cardiomyocyte hypertrophy, interstitial cell proliferation, and immune cell infiltration, is a high risk factor for heart failure and death. Chemokines interacting with G protein-coupled chemokine receptors probably play a role in left-ventricular hypertrophy development by promoting recruitment of activated leukocytes and modulating left-ventricular remodeling. Using the minimally invasive model of transverse aortic constriction in mice, we demonstrated that a variety of chemokine and chemokine receptor messenger Ribonucleic Acid are overexpressed in the early and late phase of hypertrophy progression.

A Selective Neutraligand for CXCL12/SDF-1α With Beneficial Regulatory Functions in MRL/Lpr Lupus Prone Mice.

Dysregulation of CXCL12/SDF-1-CXCR4/CD184 signaling is associated with inflammatory diseases and notably with systemic lupus erythematosus. Issued from the lead molecule chalcone-4, the first neutraligand of the CXCL12 chemokine, LIT-927 was recently described as a potent analogue with improved solubility and stability. We aimed to investigate the capacity of LIT-927 to correct immune alterations in lupus-prone MRL/lpr mice and to explore the mechanism of action implemented by this small molecule in this model.

An optimized derivative of an endogenous CXCR4 antagonist prevents atopic dermatitis and airway inflammation.

Aberrant CXCR4/CXCL12 signaling is involved in many pathophysiological processes such as cancer and inflammatory diseases. A natural fragment of serum albumin, named EPI-X4, has previously been identified as endogenous peptide antagonist and inverse agonist of CXCR4 and is a promising compound for the development of improved analogues for the therapy of CXCR4-associated diseases. To generate optimized EPI-X4 derivatives we here performed molecular docking analysis to identify key interaction motifs of EPI-X4/CXCR4.

An Autophagy Modulator Peptide Prevents Lung Function Decrease and Corrects Established Inflammation in Murine Models of Airway Allergy.

The involvement of autophagy and its dysfunction in asthma is still poorly documented. By using a murine model of chronic house dust mite (HDM)-induced airway inflammation, we tested the expression of several autophagy markers in the lung and spleen of asthma-like animals. Compared to control mice, in HDM-sensitized and challenged mice, the expression of sequestosome-1/p62, a multifunctional adaptor protein that plays an important role in the autophagy machinery, was raised in the splenocytes.

Overexpression of the MSK1 Kinase in Patients With Chronic Lung Allograft Dysfunction and Its Confirmed Role in a Murine Model.

Background: Chronic lung allograft dysfunction (CLAD) and its obstructive form, the obliterative bronchiolitis (OB), are the main long-term complications related to high mortality rate postlung transplantation. CLAD treatment lacks a significant success in survival. Here, we investigated a new strategy through inhibition of the proinflammatory mitogen- and stress-activated kinase 1 (MSK1) kinase.

Eosinophils in Asthma Models to House Dust Mite for Drug Development.

Murine models of asthma are developed to better understand the mechanisms of asthma including eosinophil recruitment in the airways with the aim of evaluating new therapeutic strategies. They are intended to model the typical features of human disease, in particular airway inflammation, hyperresponsiveness (AHR), and remodeling. The phenotype of inflammatory cells recovered from the bronchoalveolar lavage fluid (BAL) is studied with innovative flow cytometry techniques while airway obstruction is measured using the forced oscillation technique, and airway responsiveness approached by barometric plethysmography in awake and unconstrained animals.

Design, Synthesis and Biological Evaluation of Arylpyridin-2-yl Guanidine Derivatives and Cyclic Mimetics as Novel MSK1 Inhibitors. An Application in an Asthma Model.

Mitogen- and Stress-Activated Kinase 1 (MSK1) is a nuclear kinase, taking part in the activation pathway of the pro-inflammatory transcription factor NF-kB and is demonstrating a therapeutic target potential in inflammatory diseases such as asthma, psoriasis and atherosclerosis. To date, few MSK1 inhibitors were reported. In order to identify new MSK1 inhibitors, a screening of a library of low molecular weight compounds was performed, and the results highlighted the 6-phenylpyridin-2-yl guanidine (compound , IC~18 µM) as a starting hit for structure-activity relationship study.

Activation of Resolution Pathways to Prevent and Fight Chronic Inflammation: Lessons From Asthma and Inflammatory Bowel Disease.

Formerly considered as a passive process, the resolution of acute inflammation is now recognized as an active host response, with a cascade of coordinated cellular and molecular events that promotes termination of the inflammatory response and initiates tissue repair and healing. In a state of immune fitness, the resolution of inflammation is contained in time and space enabling the restoration of tissue homeostasis. There is increasing evidence that poor and/or inappropriate resolution of inflammation participates in the pathogenesis of chronic inflammatory diseases, extending in time the actions of pro-inflammatory mechanisms, and responsible in the long run for excessive tissue damage and pathology.

Neutralization of CXCL12 attenuates established pulmonary hypertension in rats.

Aims: The progressive accumulation of cells in pulmonary vascular walls is a key pathological feature of pulmonary arterial hypertension (PAH) that results in narrowing of the vessel lumen, but treatments targeting this mechanism are lacking. The C-X-C motif chemokine 12 (CXCL12) appears to be crucial in these processes. We investigated the activity of two CXCL12 neutraligands on experimental pulmonary hypertension (PH), using two complementary animal models.

Discovery of a Locally and Orally Active CXCL12 Neutraligand (LIT-927) with Anti-inflammatory Effect in a Murine Model of Allergic Airway Hypereosinophilia.

We previously reported Chalcone-4 (1) that binds the chemokine CXCL12, not its cognate receptors CXCR4 or CXCR7, and neutralizes its biological activity. However, this neutraligand suffers from limitations such as poor chemical stability, solubility, and oral activity. Herein, we report on the discovery of pyrimidinone 57 (LIT-927), a novel neutraligand of CXCL12 which displays a higher solubility than 1 and is no longer a Michael acceptor.

Optimising experimental research in respiratory diseases: an ERS statement.

Experimental models are critical for the understanding of lung health and disease and are indispensable for drug development. However, the pathogenetic and clinical relevance of the models is often unclear. Further, the use of animals in biomedical research is controversial from an ethical perspective.

A bifunctional-biased mu-opioid agonist-neuropeptide FF receptor antagonist as analgesic with improved acute and chronic side effects.

Opioid analgesics, such as morphine, oxycodone, and fentanyl, are the cornerstones for treating moderate to severe pain. However, on chronic administration, their efficiency is limited by prominent side effects such as analgesic tolerance and dependence liability. Neuropeptide FF (NPFF) and its receptors (NPFF1R and NPFF2R) are recognized as an important pronociceptive system involved in opioid-induced hyperalgesia and analgesic tolerance.

Decreased Migration of Dendritic Cells into the Jugular-Nodose Ganglia by the CXCL12 Neutraligand Chalcone 4 in Ovalbumin-Sensitized Asthmatic Mice.

Objective: The chemokine CXCL12 interacting with the CXC receptor 4 (CXCR4) has been reported to play a role in the development and progression of bronchial asthma, but its mechanism of action is still unknown. The objective of this study was to assess the effect of the CXCL12 neutraligand chalcone 4 on the migration of dendritic cells (DCs) in a murine model of allergic airway inflammation.

Methods: A 21-day ovalbumin (OVA)-induced allergic-airway TH2 inflammation model in BALB/c mice was used.

Phenylpyridine-2-ylguanidines and rigid mimetics as novel inhibitors of TNFα overproduction: Beneficial action in models of neuropathic pain and of acute lung inflammation.

4-phenylpyridin-2-yl-guanidine (5b): a new inhibitor of the overproduction of pro-inflammatory cytokines (TNFα and Il1β) was identified from a high-throughput screening of a chemical library on human peripheral blood mononuclear cells (PBMCs) after LPS stimulation. Derivatives, homologues and rigid mimetics of 5b were designed and synthesized, and their cytotoxicity and ability to inhibit TNFα overproduction were evaluated. Among them, compound 5b and its mimetic 12 (2-aminodihydroquinazoline) showed similar inhibitory activities, and were evaluated in vivo in models of lung inflammation and neuropathic pain in mice.

Towards targeting resolution pathways of airway inflammation in asthma.

Asthma is a chronic disorder characterized by persistent inflammation of the airways with mucosal infiltration of eosinophils, T lymphocytes, and mast cells, and release of proinflammatory cytokines and lipid mediators. The natural resolution of airway inflammation is now recognized as an active host response, with highly coordinated cellular events under the control of endogenous pro-resolving mediators that enable the restoration of tissue homeostasis. Lead members of proresolving mediators are enzymatically derived from essential polyunsaturated fatty acids, including arachidonic acid-derived lipoxins, eicosapentaenoic acid-derived E-series resolvins, and docosahexaenoic acid-derived D-series resolvins, protectins, and maresins.

Technique of Minimally Invasive Transverse Aortic Constriction in Mice for Induction of Left Ventricular Hypertrophy.

Transverse aortic constriction (TAC) in mice is one of the most commonly used surgical techniques for experimental investigation of pressure overload-induced left ventricular hypertrophy (LVH) and its progression to heart failure. In the majority of the reported investigations, this procedure is performed with intubation and ventilation of the animal which renders it demanding and time-consuming and adds to the surgical burden to the animal. The aim of this protocol is to describe a simplified technique of minimally invasive TAC without intubation and ventilation of mice.

A Fast, Easy, and Customizable Eight-Color Flow Cytometric Method for Analysis of the Cellular Content of Bronchoalveolar Lavage Fluid in the Mouse.

The cell composition of bronchoalveolar lavage fluid (BAL) is an important indicator of airway inflammation. It is commonly determined by cytocentrifuging leukocytes on slides, then staining, identifying, and counting them as eosinophils, neutrophils, macrophages, or lymphocytes according to morphological criteria under light microscopy, where it is not always easy to distinguish macrophages from lymphocytes. We describe here a one-step, easy-to-use, and easy-to-customize 8-color flow cytometric method for performing differential cell count and comparing it to morphological counts on stained cytospins.