Oral Lovastatin Attenuates Airway Inflammation and Mucus Secretion in Ovalbumin-Induced Murine Model of Asthma

Liou, Chian-Jiun; Cheng, Po Jen; Huang, Wen‐Chung; Chan, Chiu‐Po; Chen, Mengchun; Kuo, Ming‐Ling; Shen, Jiann-Jong

doi:10.4168/aair.2014.6.6.548

Cited by 40 publications

(28 citation statements)

References 36 publications

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“…The binding of activated platelets to eosinophils by P‐selectin occur in both non‐severe and severe asthma and this complex may affect the activation of eosinophil . Adhesion molecules are known to mediate migration of intravascular immune cells to surrounding tissues during inflammatory responses . In this study, we found the increased expression of VCAM and ICAM in lung tissue homogenates obtained from OVA‐sensitized and ‐challenged mice, which were not inhibited by clopidogrel treatment.…”

Section: Discussionmentioning

confidence: 61%

P2Y12 antagonist attenuates eosinophilic inflammation and airway hyperresponsiveness in a mouse model of asthma

Suh

Trinh

Liu

et al. 2015

J Cellular Molecular Medi

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Leukotriene E4 (LTE4) that plays a key role in airway inflammation is expressed on platelets and eosinophils. We investigated whether blocking of the P2Y12 receptor can suppress eosinophilic inflammation in a mouse model of asthma because platelets and eosinophils share this receptor to be activated. BALB/c mice were sensitized by intraperitoneal injection of ovalbumin (OVA), followed by OVA nebulization. On each challenge day, clopidogrel, a P2Y12 antagonist was administered 30 min. before each challenge. Forty‐eight hours after the last OVA challenge, mice were assessed for airway hyperresponsiveness (AHR), cell composition and cytokine levels, including chemokine ligand 5 (CCL5), in bronchoalveolar lavage (BAL) fluid. EOL cells were treated with LTE4, with or without clopidogrel treatment, and intracellular and extracellular eosinophil cationic protein (ECP) expressions were measured to find the inhibiting function of P2Y12 antagonist on eosinophilic activation. The levels of P2Y12 expression were increased markedly in the lung homogenates of OVA‐sensitized and ‐challenged mice after platelet depletion. Administration of clopidogrel decreased AHR and the number of airway inflammatory cells, including eosinophils, in BAL fluid following OVA challenge. These results were associated with decreased levels of Th2 cytokines and CCL5. Histological examination showed that inflammatory cells as well as mucus‐containing goblet cells were reduced in clopidogrel‐administered mice compared to vehicle‐treated mice. Clopidogrel inhibited extracellular ECP secretion after LTE4 stimulation in EOL‐1 cells. Clopidogrel could prevent development of AHR and airway inflammation in a mouse model of asthma. P2Y12 can be a novel therapeutic target to the suppression of eosinophils in asthma.

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Section: Discussionmentioning

confidence: 61%

P2Y12 antagonist attenuates eosinophilic inflammation and airway hyperresponsiveness in a mouse model of asthma

Suh

Trinh

Liu

et al. 2015

J Cellular Molecular Medi

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“…We used human bronchial ECs instead of mouse bronchial ECs as previous literatures [25–27], because previous reports showed that approximately 99 % of mouse genes have a homologue in the human genome [28], and bioinformatic analysis and human curation of 60,770 full-length mouse cDNA clones showed similarity (70–85 % identity) to known human-disease genes [29]. …”

Section: Discussionmentioning

confidence: 99%

Administration of JTE013 abrogates experimental asthma by regulating proinflammatory cytokine production from bronchial epithelial cells

et al. 2016

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BackgroundSphingosine-1-phosphate (S1P) is a bioactive phospholipid that acts as a signal transducer by binding to S1P receptors (S1PR) 1 to 5. The S1P/S1PRs pathway has been associated with remodeling and allergic inflammation in asthma, but the expression pattern of S1PR and its effects on non-immune cells have not been completely clarified. The aim of this study was to examine the contribution of the signaling of S1P and S1PRs expressed in airway epithelial cells (ECs) to asthma responses in mice.MethodsBronchial asthma was experimentally induced in BALB/c mice by ovalbumin (OVA) sensitization followed by an OVA inhalation challenge. The effects of S1PR antagonists on the development of asthma were analyzed 24 h after the OVA challenge.ResultsImmunohistological analysis revealed S1PR1-3 expression on mouse airway ECs. Quantitative real-time polymerase chain reaction demonstrated that S1P greatly stimulated the induction of CCL3 and TIMP2 mRNA in human airway ECs, i.e., BEAS-2B cells, in a dose-dependent manner. Pretreatment with the S1PR2 antagonist JTE013 inhibited the CCL3 gene expression in BEAS-2B cells. Immunohistological analysis also showed that the expression level of CCL3 was attenuated by JTE013 in asthmatic mice. Furthermore, JTE013 as well as anti-CCL3 antibody attenuated allergic responses. Intratracheal administration of JTE013 also attenuated eosinophilic reactions in bronchoalveolar lavage fluids. S1P induced transcription factor NFκB activation, while JTE013 greatly reduced the NFκB activation.ConclusionsJTE013 attenuated allergic airway reactions by regulating CCL3 production from bronchial ECs. The intratracheal administration of JTE013 may be a promising therapeutic strategy for bronchial asthma.Electronic supplementary materialThe online version of this article (doi:10.1186/s12931-016-0465-x) contains supplementary material, which is available to authorized users.

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“…(2) Attenuating airway remodelling by regulating cellular architecture and function and reducing airway epithelial changes. Studies have shown that statin treatment could reduce contractile and proliferative properties of airway smooth muscle cells during airway hyperresponsiveness [94,95], regulate MMP expressions [96,97], and decrease MUC gene expression leading to decreased mucin production and suppression of goblet cell hyperplasia [98][99][100][101][102][103][104].…”

Section: Potential Role Of Statins In the Treatment Of Respiratory DImentioning

confidence: 99%

Repurposing of statins via inhalation to treat lung inflammatory conditions

Bradbury

Traini

Ammit

et al. 2018

Advanced Drug Delivery Reviews

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Despite many therapeutic advancements over the past decade, the continued rise in chronic inflammatory lung diseases incidence has driven the need to identify and develop new therapeutic strategies, with superior efficacy to treat these diseases. Statins are one class of drug that could potentially be repurposed as an alternative treatment for chronic lung diseases. They are currently used to treat hypercholesterolemia by inhibiting the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, that catalyses the rate limiting step in the mevalonate biosynthesis pathway, a key intermediate in cholesterol metabolism. Recent research has identified statins to have other protective pleiotropic properties including anti-inflammatory, anti-oxidant, muco-inhibitory effects that may be beneficial for the treatment of chronic inflammatory lung diseases. However, clinical studies have yielded conflicting results. This review will summarise some of the current evidences for statins pleiotropic effects that could be applied for the treatment of chronic inflammatory lung diseases, their mechanisms of actions, and the potential to repurpose statins as an inhaled therapy, including a detailed discussion on their different physical-chemical properties and how these characteristics could ultimately affect treatment efficacies. The repurposing of statins from conventional anti-cholesterol oral therapy to inhaled anti-inflammatory formulation is promising, as it provides direct delivery to the airways, reduced risk of side effects, increased bioavailability and tailored physical-chemical properties for enhanced efficacy.

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Oral Lovastatin Attenuates Airway Inflammation and Mucus Secretion in Ovalbumin-Induced Murine Model of Asthma

Cited by 40 publications

References 36 publications

P2Y12 antagonist attenuates eosinophilic inflammation and airway hyperresponsiveness in a mouse model of asthma

P2Y12 antagonist attenuates eosinophilic inflammation and airway hyperresponsiveness in a mouse model of asthma

Administration of JTE013 abrogates experimental asthma by regulating proinflammatory cytokine production from bronchial epithelial cells

Repurposing of statins via inhalation to treat lung inflammatory conditions

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