A small molecule, orally active, α4β1/α4β7 dual antagonist reduces leukocyte infiltration and airway hyper‐responsiveness in an experimental model of allergic asthma in Brown Norway rats

Cortijo, Julio; Sanz, María-Jesús; Iranzo, A; Montesinos, José Luis González; Nabah, Yafa Naim Abu; Alfón, José; Gómez, Luis Alberto; Morcillo, Esteban J.

doi:10.1038/sj.bjp.0706658

Cited by 31 publications

(15 citation statements)

References 62 publications

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“…IL-4 and other T H 2 cytokines also increase T cell infiltration in Helicobacter pylori-induced gastric mucosa-associated lymphoid tissue lymphomas, and this lymphoma growth is T H 2 cytokine-dependent [34,35]. IL-4 stimulates leukocyte rolling, adhesion, and emigration in a rat asthma model [36].…”

Section: Discussionmentioning

confidence: 99%

Differential polarization of alveolar macrophages and bone marrow-derived monocytes following chemically and pathogen-induced chronic lung inflammation

Redente

Higgins

Dwyer‐Nield

et al. 2010

Journal of Leukocyte Biology

105

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Alveolar macrophages and BDMCs undergo sequential biochemical changes during the chronic inflammatory response to chemically induced lung carcinogenesis in mice. Herein, we examine two chronic lung inflammation models-repeated exposure to BHT and infection with Mycobacterium tuberculosis-to establish whether similar macrophage phenotype changes occur in non-neoplastic pulmonary disease. Exposure to BHT or M. tuberculosis results in pulmonary inflammation characterized by an influx of macrophages, followed by systemic effects on the BM and other organs. In both models, pulmonary IFN-gamma and IL-4 production coincided with altered polarization of alveolar macrophages. Soon after BHT administration or M. tuberculosis infection, IFN-gamma content in BALF increased, and BAL macrophages became classically (M1) polarized, as characterized by increased expression of iNOS. As inflammation progressed in both models, the amount of BALF IFN-gamma content and BAL macrophage iNOS expression decreased, and BALF IL-4 content and macrophage arginase I expression rose, indicating alternative/M2 polarization. Macrophages present in M. tuberculosis-induced granulomas remained M1-polarized, implying that these two pulmonary macrophage populations, alveolar and granuloma-associated, are exposed to different activating cytokines. BDMCs from BHT-treated mice displayed polarization profiles similar to alveolar macrophages, but BDMCs in M. tuberculosis-infected mice did not become polarized. Thus, only alveolar macrophages in these two models of chronic lung disease exhibit a similar progression of polarization changes; polarization of BDMCs was specific to BHT-induced pulmonary inflammation, and polarization of granuloma macrophages was specific to the M. tuberculosis infection.

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Section: Discussionmentioning

confidence: 99%

Differential polarization of alveolar macrophages and bone marrow-derived monocytes following chemically and pathogen-induced chronic lung inflammation

Redente

Higgins

Dwyer‐Nield

et al. 2010

Journal of Leukocyte Biology

105

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“…α4β1 (very late antigen 4, VLA-4) is expressed on all circulating leukocytes, except neutrophils, and binds to vascular cell adhesion molecule-1 (VCAM-1) (Cortijo et al, 2006). α4 integrins and their binding sites, therefore, are attractive therapeutic targets in inflammatory airways diseases, such as asthma and chronic bronchitis.…”

Section: Discussionmentioning

confidence: 99%

“…A dual α1 integrin small molecule antagonist decreases airways hyperresponsiveness and the recruitment of leukocytes into the airway of Brown Norway rats exposed to aerosolized antigen (Cortijo et al, 2006). The administration of a small molecule α4β1 antagonist reduced airways hyperresponsiveness to inhaled carbachol and airway inflammatory cell infiltration in sheep exposed to Ascaris antigen (Abraham et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

An α4β1 integrin antagonist decreases airway inflammation in ovalbumin-exposed mice

Kenyon

Liu

O'Roark

et al. 2009

European Journal of Pharmacology

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Inhibition of the α4 subunit of both the α4β1 and α4β7 integrins has shown promise in decreasing airway inflammation and airway hyperresponsiveness in various animal models. We hypothesized that a novel, high-affinity α4β1 antagonist (LLP2A) would decrease the migration of eosinophils to the lung and ameliorate the airway hyperresponsiveness in a mouse model of ovalbumin-induced airway inflammation. To test this hypothesis, we administered LLP2A, or scrambled LLP2A (a negative control), prior to exposure of sensitized BALB/c mice to ovalbumin aerosol. We can partially prevent, or reverse, the airway inflammatory response, but not airways hyperresponsiveness, by treatment of mice with LLP2A, a synthetic peptidomimetic α4β1 antagonist LLP2A. Specifically engineered, PEGylated (PEG) formulations of this antagonist further reduce the airway inflammatory response to ovalbumin lbumin, presumably by improving the circulating half-life of the drug.

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“…306 For instance, Chan et al . developed a NP system that targets vascular antigens exposed in cardiovascular-related diseases such as angioplasty-injured vasculature (Fig.…”

Section: Targeting Ligandsmentioning

confidence: 99%

Targeted polymeric therapeutic nanoparticles: design, development and clinical translation

et al. 2012

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Polymeric materials have been used in a range of pharmaceutical and biotechnology products for more than 40 years. These materials have evolved from their earlier use as biodegradable products such as resorbable sutures, orthopaedic implants, macroscale and microscale drug delivery systems such as microparticles and wafers used as controlled drug release depots, to multifunctional nanoparticles (NPs) capable of targeting, and controlled release of therapeutic and diagnostic agents. These newer generations of targeted and controlled release polymeric NPs are now engineered to navigate the complex in vivo environment, and incorporate functionalities for achieving target specificity, control of drug concentration and exposure kinetics at the tissue, cell, and subcellular levels. Indeed this optimization of drug pharmacology as aided by careful design of multifunctional NPs can lead to improved drug safety and efficacy, and may be complimentary to drug enhancements that are traditionally achieved by medicinal chemistry. In this regard, polymeric NPs have the potential to result in a highly differentiated new class of therapeutics, distinct from the original active drugs used in their composition, and distinct from first generation NPs that largely facilitated drug formulation. A greater flexibility in the design of drug molecules themselves may also be facilitated following their incorporation into NPs, as drug properties (solubility, metabolism, plasma binding, biodistribution, target tissue accumulation) will no longer be constrained to the same extent by drug chemical composition, but also become in-part the function of the physicochemical properties of the NP. The combination of optimally designed drugs with optimally engineered polymeric NPs opens up the possibility of improved clinical outcomes that may not be achievable with the administration of drugs in their conventional form. In this critical review, we aim to provide insights into the design and development of targeted polymeric NPs and to highlight the challenges associated with the engineering of this novel class of therapeutics, including considerations of NP design optimization, development and biophysicochemical properties. Additionally, we highlight some recent examples from the literature, which demonstrate current trends and novel concepts in both the design and utility of targeted polymeric NPs (444 references).

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A small molecule, orally active, α₄β₁/α₄β₇ dual antagonist reduces leukocyte infiltration and airway hyper‐responsiveness in an experimental model of allergic asthma in Brown Norway rats

Cited by 31 publications

References 62 publications

Differential polarization of alveolar macrophages and bone marrow-derived monocytes following chemically and pathogen-induced chronic lung inflammation

Differential polarization of alveolar macrophages and bone marrow-derived monocytes following chemically and pathogen-induced chronic lung inflammation

An α4β1 integrin antagonist decreases airway inflammation in ovalbumin-exposed mice

Targeted polymeric therapeutic nanoparticles: design, development and clinical translation

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