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Cationic CaMKII Inhibiting Nanoparticles Prevent Allergic Asthma.

ABSTRACT: Asthma is a common lung disease affecting over 300 million people worldwide and is associated with increased reactive oxygen species, eosinophilic airway inflammation, bronchoconstriction, and mucus production. Targeting of novel therapeutic agents to the lungs of patients with asthma may improve efficacy of treatments and minimize side effects. We previously demonstrated that Ca2+/calmodulin-dependent protein kinase (CaMKII) is expressed and activated in the bronchial epithelium of asthmatic patients. CaMKII inhibition in murine models of allergic asthma reduces key disease phenotypes, providing the rationale for targeted CaMKII inhibition as a potential therapeutic approach for asthma. Herein we developed a novel cationic nanoparticle (NP)-based system for delivery of the potent and specific CaMKII inhibitor peptide, CaMKIIN, to airways.1 CaMKIIN-loaded NPs abrogated the severity of allergic asthma in a murine model. These findings provide the basis for development of innovative, site-specific drug delivery therapies, particularly for treatment of pulmonary diseases such as asthma.

SUBMITTER: Morris AS

PROVIDER: S-EPMC5800301 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Cationic CaMKII Inhibiting Nanoparticles Prevent Allergic Asthma.

Morris Angie S AS Sebag Sara C SC Paschke John D JD Wongrakpanich Amaraporn A Ebeid Kareem K Anderson Mark E ME Grumbach Isabella M IM Salem Aliasger K AK

Molecular pharmaceutics 20170509 6

Asthma is a common lung disease affecting over 300 million people worldwide and is associated with increased reactive oxygen species, eosinophilic airway inflammation, bronchoconstriction, and mucus production. Targeting of novel therapeutic agents to the lungs of patients with asthma may improve efficacy of treatments and minimize side effects. We previously demonstrated that Ca<sup>2+</sup>/calmodulin-dependent protein kinase (CaMKII) is expressed and activated in the bronchial epithelium of a ...[more]

PMID: 28460526

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Project description:BackgroundAngiotensin (Ang)-(1-7) can reduce airway inflammation and airway remodeling in allergic asthma. Autophagy-related 5 (ATG5) has attracted wide attentions in asthma. However, the effects of Ang-(1-7) on ATG5-mediated autophagy in allergic asthma are unclear.MethodsIn this study, human bronchial epithelial cell (BEAS-2B) and human bronchial smooth muscle cell (HBSMC) were treated with different dose of Ang-(1-7) to observe changes of cell viability. Changes of ATG5 protein expression were measured in 10 ng/mL of interleukin (IL)-13-treated cells. Transfection of ATG5 small interference RNA (siRNA) or ATG5 cDNA in cells was used to analyze the effects of ATG5 on secretion of cytokines in the IL-13-treated cells. The effects of Ang-(1-7) were compared to the effects of ATG5 siRNA transfection or ATG5 cDNA transfection in the IL-13-treated cells. In wild-type (WT) mice and ATG5 knockout (ATG5-/-) mice, ovalbumin (OVA)-induced airway inflammation, fibrosis and autophagy were observed. In the OVA-induced WT mice, Ang-(1-7) treatment was performed to observe its effects on airway inflammation, fibrosis and autophagy.ResultsThe results showed that ATG5 protein level was decreased with Ang-(1-7) dose administration in the IL-13-treated BEAS-2B and IL13-treated HBSMC. Ang-(1-7) played similar results to ATG5 siRNA that it suppressed the secretion of IL-25 and IL-13 in the IL-13-treated BEAS-2B cells, and inhibited the expression of transforming growth factor (TGF)-β1 and α-smooth muscle actin (α-SMA) protein in the IL-13-treated HBSMC cells. ATG5 cDNA treatment significantly increased the secretion of IL-25 and IL-13 and expression of TGF-β1 and α-SMA protein in IL-13-treated cells. Ang-(1-7) treatment suppressed the effects of ATG5 cDNA in the IL-13-treated cells. In OVA-induced WT mice, Ang-(1-7) treatment suppressed airway inflammation, remodeling and autophagy. ATG5 knockout also suppressed the airway inflammation, remodeling and autophagy.ConclusionsAng-(1-7) treatment suppressed airway inflammation and remodeling in allergic asthma through inhibiting ATG5, providing an underlying mechanism of Ang-(1-7) for allergic asthma treatment.

Project description:Titanium dioxide nanoparticles (TiO2NPs) are widely used in industrial and medicinal fields and in various consumer products, and their increasing use has led to an increase in the number of toxicity studies; however, studies investigating the underlying toxicity mechanism have been rare. In this study, we evaluated potential toxic effects of TiO2NPs exposure on lungs as well as the development of asthma through the ovalbumin (OVA)-induced mouse model of asthma. Furthermore, we also investigated the associated toxic mechanism. TiO2NPs caused pulmonary toxicity by exacerbating the inflammatory response, indicated by an increase in the number and level of inflammatory cells and mediators, respectively. OVA-induced asthma exposed mice to TiO2NPs led to significant increases in inflammatory mediators, cytokines, and airway hyperresponsiveness compared with those in non-exposed asthmatic mice. This was also accompanied by increased inflammatory cell infiltration and mucus production in the lung tissues. Additionally, TiO2NPs decreased the expression of B-cell lymphoma 2 (Bcl2) and the expressions of thioredoxin-interacting protein (TXNIP), phospho-apoptosis signal-regulating kinase 1, Bcl2-associated X, and cleaved-caspase 3 were escalated in the lungs of asthmatic mice compared with those in non-exposed asthmatic mice. These responses were consistent with in vitro results obtained using human airway epithelial cells. TiO2NPs treated cells exhibited an increase in the mRNA and protein expression of interleukin (IL)-1β, IL-6, and tumor necrosis factor-α with an elevation of TXNIP signaling compared to non-treated cells. Moreover, pathophysiological changes induced by TiO2NP treatment were significantly decreased by TXNIP knockdown in airway epithelial cells. Overall, TiO2NP exposure induced toxicological changes in the respiratory tract and exacerbated the development of asthma via activation of the TXNIP-apoptosis pathway. These results provide insights into the underlying mechanism of TiO2NP-mediated respiratory toxicity.

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Cationic CaMKII Inhibiting Nanoparticles Prevent Allergic Asthma.

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Cationic CaMKII Inhibiting Nanoparticles Prevent Allergic Asthma.

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