Nebulization of risedronate alleviates airway obstruction and inflammation of chronic obstructive pulmonary diseases via suppressing prenylation-dependent RAS/ERK/NF-κB and RhoA/ROCK1/MLCP signaling
Abstract Background Chronic obstructive pulmonary disease (COPD) is a progressive disorder that causes airway obstruction and lung inflammation. The first-line treatment of COPD is the bronchodilators of β2-agonists and antimuscarinic drugs, which can help control the airway obstruction, but the lon...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2022-12-01
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| Series: | Respiratory Research |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12931-022-02274-5 |
| _version_ | 1828083301194137600 |
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| author | Di Liu Wen Xu Yuan Tang Jingxue Cao Ran Chen Dingwei Wu Hongpeng Chen Bo Su Jinfu Xu |
| author_facet | Di Liu Wen Xu Yuan Tang Jingxue Cao Ran Chen Dingwei Wu Hongpeng Chen Bo Su Jinfu Xu |
| author_sort | Di Liu |
| collection | DOAJ |
| description | Abstract Background Chronic obstructive pulmonary disease (COPD) is a progressive disorder that causes airway obstruction and lung inflammation. The first-line treatment of COPD is the bronchodilators of β2-agonists and antimuscarinic drugs, which can help control the airway obstruction, but the long-term use might render the drug tolerance. Bisphosphonates are widely used in osteoclast-mediated bone diseases treatment for decades. For drug repurposing, can delivery of a third generation of nitrogen-containing bisphosphonate, risedronate (RIS) ameliorate the progression of COPD? Methods COPD rats or mice models have been established through cigarette-smoking and elastase injection, and then the animals are received RIS treatment via nebulization. Lung deposition of RIS was primarily assessed by high-performance liquid chromatography (HPLC). The respiratory parameters of airway obstruction in COPD rats and mice were documented using plethysmography method and resistance-compliance system. Results High lung deposition and bioavailability of RIS was monitored with 88.8% of RIS input dose. We found that RIS could rescue the lung function decline of airspace enlargement and mean linear intercept in the COPD lung. RIS could curb the airway obstruction by suppressing 60% of the respiratory resistance and elevating the airway’s dynamic compliance, tidal volume and mid-expiratory flow. As an inhibitor of farnesyl diphosphate synthase (FDPS), RIS suppresses FDPS-mediated RAS and RhoA prenylation to obstruct its membrane localization in airway smooth muscle cells (ASMCs), leading to the inhibition of downstream ERK-MLCK and ROCK1-MLCP pathway to cause ASMCs relaxation. Additionally, RIS nebulization impeded pro-inflammatory cell accumulation, particularly macrophages infiltration in alveolar parenchyma. The NF-κB, tumor necrosis factor-alpha, IL-1β, IL-8, and IL-6 declined in microphages following RIS nebulization. Surprisingly, nebulization of RIS could overcome the tolerance of β2-agonists in COPD-rats by increasing the expression of β2 receptors. Conclusions Nebulization of RIS could alleviate airway obstruction and lung inflammation in COPD, providing a novel strategy for treating COPD patients, even those with β2-agonists tolerance. |
| first_indexed | 2024-04-11T04:05:45Z |
| format | Article |
| id | doaj.art-e3ff3b7119ec43c09042eb5e59f1f19d |
| institution | Directory Open Access Journal |
| issn | 1465-993X |
| language | English |
| last_indexed | 2024-04-11T04:05:45Z |
| publishDate | 2022-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Respiratory Research |
| spelling | doaj.art-e3ff3b7119ec43c09042eb5e59f1f19d2023-01-01T12:25:37ZengBMCRespiratory Research1465-993X2022-12-0123111410.1186/s12931-022-02274-5Nebulization of risedronate alleviates airway obstruction and inflammation of chronic obstructive pulmonary diseases via suppressing prenylation-dependent RAS/ERK/NF-κB and RhoA/ROCK1/MLCP signalingDi Liu0Wen Xu1Yuan Tang2Jingxue Cao3Ran Chen4Dingwei Wu5Hongpeng Chen6Bo Su7Jinfu Xu8Central Laboratory, Shanghai Pulmonary Hospital, School of Medicine, Tongji UniversityDepartment of Respiratory and Critical Care Medicine, Shanghai Pulmonary Hospital, School of Medicine, Tongji UniversityCentral Laboratory, Shanghai Pulmonary Hospital, School of Medicine, Tongji UniversityCentral Laboratory, Shanghai Pulmonary Hospital, School of Medicine, Tongji UniversityCentral Laboratory, Shanghai Pulmonary Hospital, School of Medicine, Tongji UniversityZhejiang Xianju Pharmaceutical Co., LtdZhejiang Xianju Pharmaceutical Co., LtdCentral Laboratory, Shanghai Pulmonary Hospital, School of Medicine, Tongji UniversityDepartment of Respiratory and Critical Care Medicine, Shanghai Pulmonary Hospital, School of Medicine, Tongji UniversityAbstract Background Chronic obstructive pulmonary disease (COPD) is a progressive disorder that causes airway obstruction and lung inflammation. The first-line treatment of COPD is the bronchodilators of β2-agonists and antimuscarinic drugs, which can help control the airway obstruction, but the long-term use might render the drug tolerance. Bisphosphonates are widely used in osteoclast-mediated bone diseases treatment for decades. For drug repurposing, can delivery of a third generation of nitrogen-containing bisphosphonate, risedronate (RIS) ameliorate the progression of COPD? Methods COPD rats or mice models have been established through cigarette-smoking and elastase injection, and then the animals are received RIS treatment via nebulization. Lung deposition of RIS was primarily assessed by high-performance liquid chromatography (HPLC). The respiratory parameters of airway obstruction in COPD rats and mice were documented using plethysmography method and resistance-compliance system. Results High lung deposition and bioavailability of RIS was monitored with 88.8% of RIS input dose. We found that RIS could rescue the lung function decline of airspace enlargement and mean linear intercept in the COPD lung. RIS could curb the airway obstruction by suppressing 60% of the respiratory resistance and elevating the airway’s dynamic compliance, tidal volume and mid-expiratory flow. As an inhibitor of farnesyl diphosphate synthase (FDPS), RIS suppresses FDPS-mediated RAS and RhoA prenylation to obstruct its membrane localization in airway smooth muscle cells (ASMCs), leading to the inhibition of downstream ERK-MLCK and ROCK1-MLCP pathway to cause ASMCs relaxation. Additionally, RIS nebulization impeded pro-inflammatory cell accumulation, particularly macrophages infiltration in alveolar parenchyma. The NF-κB, tumor necrosis factor-alpha, IL-1β, IL-8, and IL-6 declined in microphages following RIS nebulization. Surprisingly, nebulization of RIS could overcome the tolerance of β2-agonists in COPD-rats by increasing the expression of β2 receptors. Conclusions Nebulization of RIS could alleviate airway obstruction and lung inflammation in COPD, providing a novel strategy for treating COPD patients, even those with β2-agonists tolerance.https://doi.org/10.1186/s12931-022-02274-5Pulmonary diseaseChronic obstructiveRisedronic acidInflammationAnimal models |
| spellingShingle | Di Liu Wen Xu Yuan Tang Jingxue Cao Ran Chen Dingwei Wu Hongpeng Chen Bo Su Jinfu Xu Nebulization of risedronate alleviates airway obstruction and inflammation of chronic obstructive pulmonary diseases via suppressing prenylation-dependent RAS/ERK/NF-κB and RhoA/ROCK1/MLCP signaling Respiratory Research Pulmonary disease Chronic obstructive Risedronic acid Inflammation Animal models |
| title | Nebulization of risedronate alleviates airway obstruction and inflammation of chronic obstructive pulmonary diseases via suppressing prenylation-dependent RAS/ERK/NF-κB and RhoA/ROCK1/MLCP signaling |
| title_full | Nebulization of risedronate alleviates airway obstruction and inflammation of chronic obstructive pulmonary diseases via suppressing prenylation-dependent RAS/ERK/NF-κB and RhoA/ROCK1/MLCP signaling |
| title_fullStr | Nebulization of risedronate alleviates airway obstruction and inflammation of chronic obstructive pulmonary diseases via suppressing prenylation-dependent RAS/ERK/NF-κB and RhoA/ROCK1/MLCP signaling |
| title_full_unstemmed | Nebulization of risedronate alleviates airway obstruction and inflammation of chronic obstructive pulmonary diseases via suppressing prenylation-dependent RAS/ERK/NF-κB and RhoA/ROCK1/MLCP signaling |
| title_short | Nebulization of risedronate alleviates airway obstruction and inflammation of chronic obstructive pulmonary diseases via suppressing prenylation-dependent RAS/ERK/NF-κB and RhoA/ROCK1/MLCP signaling |
| title_sort | nebulization of risedronate alleviates airway obstruction and inflammation of chronic obstructive pulmonary diseases via suppressing prenylation dependent ras erk nf κb and rhoa rock1 mlcp signaling |
| topic | Pulmonary disease Chronic obstructive Risedronic acid Inflammation Animal models |
| url | https://doi.org/10.1186/s12931-022-02274-5 |
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