Airway inflammation evaluated in a human nasal lipopolysaccharide challenge model by investigating the effect of a <scp>CXCR</scp>2 inhibitor

Virtala, Robert; Ekman, A-K; Jansson, Linda; Westin, Ulla; Cardell, Lars-Olaf

doi:10.1111/j.1365-2222.2011.03921.x

Cited by 43 publications

(31 citation statements)

References 37 publications

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“…AZD8309 was firstly produced and used in a phase I clinical trials for COPD and rheumatoid arthritis. AZD8309 was well tolerated in a study investigating the efficacy of the drug in the inhibition of LPSinduced neutrophil recruitment in the upper airways of healthy subjects [71]. A novel version of the compound AZD5069 was used in a phase I and II studies for COPD and asthma (clinicaltrial.gov number: NCT01233232).…”

Section: Small Moleculesmentioning

confidence: 99%

The CXCR1/2 Pathway: Involvement in Diabetes Pathophysiology and Potential Target for T1D Interventions

2015

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Although numerous chemokine/chemokine receptor pathways have been described to be implicated in the pathogenesis of type 1 diabetes (T1D), the CXCR1/2 axis has recently been proved to be crucial for leucocyte recruitment involved in insulitis and β cell damage. Multiple strategies blocking the CXCR1/2 pathway are available such as neutralizing antibodies, small molecules and peptide-derived inhibitors. They were firstly and widely used in cancer thanks to their anti-tumorigenic activity and only recently they were tested as a new interventional approach for T1D. As well, CXCR1/2 inhibition has been demonstrated to prevent inflammation- and autoimmunity-mediated damage of the pancreatic islets through inhibiting the migration of CXCR1/2-expressing cells. Among them, neutrophils, macrophages, and, although to a smaller extent, lymphoid cells are the main CXCR1/2-expressing cells. These results supported the active role of the innate immunity in the autoimmune process and opened new interventional approaches for the management of T1D.

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Section: Small Moleculesmentioning

confidence: 99%

The CXCR1/2 Pathway: Involvement in Diabetes Pathophysiology and Potential Target for T1D Interventions

2015

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“…Two selective CXCR2 antagonists, SCH-527123 (61) or SB-656933 (84), caused significant attenuation of ozone-induced airway neutrophilia in healthy subjects. Treatment with AZD-8309, a potent small molecule reversible CXCR2 antagonist, led to reduction of inflammation and airway neutrophilia in healthy volunteers challenged with LPS, an inducer of acute neutrophilic response in the airways (86,164). In patients with severe asthma, treatment with another selective CXCR2 antagonist, SCH-527123, resulted in reduction of sputum neutrophils accompanied by moderate improvement in asthma features (114).…”

Section: Chemokine Receptors In Chronic Lung Diseasesmentioning

confidence: 99%

Chemokine receptors and their therapeutic opportunities in diseased lung: Far beyond leukocyte trafficking

Tománková

Kriegová

Liu

2015

American Journal of Physiology-Lung Cellular and Molecular Phys

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Chemokine receptors and their chemokine ligands, key mediators of inflammatory and immune cell trafficking, are involved in the regulation of both physiological and pathological processes in the lung. The discovery that chemokine receptors/chemokines, typically expressed by inflammatory and immune cells, are also expressed in structural lung tissue cells suggests their role in mediating the restoration of lung tissue structure and functions. Thus, chemokine receptors/chemokines contribute not only to inflammatory and immune responses in the lung but also play a critical role in the regulation of lung tissue repair, regeneration, and remodeling. This review aims to summarize current state-of-the-art on chemokine receptors and their ligands in lung diseases such as chronic obstructive pulmonary disease, asthma/allergy, pulmonary fibrosis, acute lung injury, and lung infection. Furthermore, the therapeutic opportunities of chemokine receptors in aforementioned lung diseases are discussed. The review also aims to delineate the potential contribution of chemokine receptors to the processes leading to repair/regeneration of the lung tissue.

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“…These are in different stages of drug development and have been shown to have an effect on neutrophil recruitment to the lung in clinical studies (Holz et al, 2010;Lazaar et al, 2011;Virtala et al, 2012;Pavord et al, 2013). In addition, the effect of inhibiting neutrophil recruitment has been shown for clinical biomarkers and endpoints indicative of disease efficacy as investigated in cystic fibrosis, severe asthma, and COPD (Nair et al, 2012;Moss et al, 2013;Rennard et al, 2015).…”

Section: Abbreviations: Az10397767 (R)mentioning

confidence: 99%

Pharmacological Characterization of AZD5069, a Slowly Reversible CXC Chemokine Receptor 2 Antagonist

Nicholls

Wiley

Dainty

et al. 2015

J Pharmacol Exp Ther

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In normal physiologic responses to injury and infection, inflammatory cells enter tissue and sites of inflammation through a chemotactic process regulated by several families of proteins, including inflammatory chemokines, a family of small inducible cytokines. In neutrophils, chemokines chemokine (CXC motif) ligand 1 (CXCL1) and CXCL8 are potent chemoattractants and activate G protein-coupled receptors CXC chemokine receptor 1 (CXCR1) and CXCR2. Several small-molecule antagonists of CXCR2 have been developed to inhibit the inflammatory responses mediated by this receptor. Here, we present the data describing the pharmacology of 3S)-3,4-dihydroxybutan-2-yloxy)pyrimidin-4-yl)azetidine-1-sulfonamide], a novel antagonist of CXCR2. AZD5069 was shown to inhibit binding of radiolabeled CXCL8 to human CXCR2 with a pIC 50 value of 9.1. Furthermore, AZD5069 inhibited neutrophil chemotaxis, with a pA 2 of approximately 9.6, and adhesion molecule expression, with a pA 2 of 6.9, in response to CXCL1. AZD5069 was a slowly reversible antagonist of CXCR2 with effects of time and temperature evident on the pharmacology and binding kinetics. With short incubation times, AZD5069 appeared to have an antagonist profile with insurmountable antagonism of calcium response curves. This behavior was also observed in vivo in an acute lipopolysaccharide-induced lung inflammation model. Altogether, the data presented here show that AZD5069 represents a novel, potent, and selective CXCR2 antagonist with potential as a therapeutic agent in inflammatory conditions.

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Airway inflammation evaluated in a human nasal lipopolysaccharide challenge model by investigating the effect of a CXCR2 inhibitor

Cited by 43 publications

References 37 publications

The CXCR1/2 Pathway: Involvement in Diabetes Pathophysiology and Potential Target for T1D Interventions

The CXCR1/2 Pathway: Involvement in Diabetes Pathophysiology and Potential Target for T1D Interventions

Chemokine receptors and their therapeutic opportunities in diseased lung: Far beyond leukocyte trafficking

Pharmacological Characterization of AZD5069, a Slowly Reversible CXC Chemokine Receptor 2 Antagonist

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