Chloroquine Attenuates Asthma Development by Restoring Airway Smooth Muscle Cell Phenotype Via the ROS-AKT Pathway
Switching of airway smooth muscle (ASM) cell phenotype from differentiated-contractile to dedifferentiated-proliferative/synthetic state often occurs in asthmatic subjects with airway dysfunction. Evidence has been provided that chloroquine (an agonist of bitter taste receptors) presented benefits t...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2022-06-01
|
| Series: | Frontiers in Pharmacology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2022.916508/full |
| _version_ | 1811232273804034048 |
|---|---|
| author | Yan Ren Yan Ren Xiuhua Zhong Hongyu Wang Zhongqi Chen Yanan Liu Yanan Liu Xiaoning Zeng Yuan Ma |
| author_facet | Yan Ren Yan Ren Xiuhua Zhong Hongyu Wang Zhongqi Chen Yanan Liu Yanan Liu Xiaoning Zeng Yuan Ma |
| author_sort | Yan Ren |
| collection | DOAJ |
| description | Switching of airway smooth muscle (ASM) cell phenotype from differentiated-contractile to dedifferentiated-proliferative/synthetic state often occurs in asthmatic subjects with airway dysfunction. Evidence has been provided that chloroquine (an agonist of bitter taste receptors) presented benefits to ASM cell function implicated in asthma. However, the underlying mechanism is unclear. House dust mite (HDM)-sensitized mice were administered with chloroquine or dexamethasone before challenge. BALF and lung tissue were obtained for cell counting, histological analysis or ELISA. Primary cultured ASM cells were stimulated with transforming growth factor (TGF)-β1 or H2O2. Cells and supernatant were collected for the detection of ASM phenotype, ROS level, and proinflammatory cytokine production. In HDM-sensitized mice, chloroquine attenuated airway hyperresponsiveness (AHR), inflammation and remodeling with an inhibition of immunoglobulin E, IL-4/-13, and TGF-β1 in BALF. ASM cell proliferation (PCNA), hypertrophy (α-SMA), and parasecretion (MMP-9 and MMP-13) were strongly suppressed by chloroquine, hinting the rebalance of the heterogeneous ASM populations in asthmatic airway. Our data in vitro indicated that chloroquine markedly restrained maladaptive alteration in ASM phenotype in concert with a remission of ROS. Using H2O2 and PI3K inhibitor (LY294002), we found that the inhibition of oxidative stress level and ROS-AKT signal by chloroquine may serve as a potential mechanism that dedicates to the restoration of the phenotypic imbalance in ASM cells. Overall, the present findings suggested that chloroquine improves asthmatic airway function by controlling ASM cell phenotype shift, sketching a novel profile of chloroquine as a new therapeutic candidate for airway remodeling. |
| first_indexed | 2024-04-12T11:00:37Z |
| format | Article |
| id | doaj.art-d2f46315f7e746c68eb7ad8711126772 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-04-12T11:00:37Z |
| publishDate | 2022-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-d2f46315f7e746c68eb7ad87111267722022-12-22T03:35:59ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122022-06-011310.3389/fphar.2022.916508916508Chloroquine Attenuates Asthma Development by Restoring Airway Smooth Muscle Cell Phenotype Via the ROS-AKT PathwayYan Ren0Yan Ren1Xiuhua Zhong2Hongyu Wang3Zhongqi Chen4Yanan Liu5Yanan Liu6Xiaoning Zeng7Yuan Ma8Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, ChinaDepartment of Medical Genetics, Nanjing University School of Medicine, Nanjing, ChinaDepartment of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, ChinaDepartment of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, ChinaDepartment of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, ChinaDepartment of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, ChinaDepartment of Respiratory and Critical Care Medicine, Affiliated Hospital of Xuzhou Medical University, Xuzhou, ChinaDepartment of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, ChinaDepartment of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, ChinaSwitching of airway smooth muscle (ASM) cell phenotype from differentiated-contractile to dedifferentiated-proliferative/synthetic state often occurs in asthmatic subjects with airway dysfunction. Evidence has been provided that chloroquine (an agonist of bitter taste receptors) presented benefits to ASM cell function implicated in asthma. However, the underlying mechanism is unclear. House dust mite (HDM)-sensitized mice were administered with chloroquine or dexamethasone before challenge. BALF and lung tissue were obtained for cell counting, histological analysis or ELISA. Primary cultured ASM cells were stimulated with transforming growth factor (TGF)-β1 or H2O2. Cells and supernatant were collected for the detection of ASM phenotype, ROS level, and proinflammatory cytokine production. In HDM-sensitized mice, chloroquine attenuated airway hyperresponsiveness (AHR), inflammation and remodeling with an inhibition of immunoglobulin E, IL-4/-13, and TGF-β1 in BALF. ASM cell proliferation (PCNA), hypertrophy (α-SMA), and parasecretion (MMP-9 and MMP-13) were strongly suppressed by chloroquine, hinting the rebalance of the heterogeneous ASM populations in asthmatic airway. Our data in vitro indicated that chloroquine markedly restrained maladaptive alteration in ASM phenotype in concert with a remission of ROS. Using H2O2 and PI3K inhibitor (LY294002), we found that the inhibition of oxidative stress level and ROS-AKT signal by chloroquine may serve as a potential mechanism that dedicates to the restoration of the phenotypic imbalance in ASM cells. Overall, the present findings suggested that chloroquine improves asthmatic airway function by controlling ASM cell phenotype shift, sketching a novel profile of chloroquine as a new therapeutic candidate for airway remodeling.https://www.frontiersin.org/articles/10.3389/fphar.2022.916508/fullchloroquineairway smooth muscle (ASM) cellsbitter taste receptors (TAS2Rs)TGF-β1asthma |
| spellingShingle | Yan Ren Yan Ren Xiuhua Zhong Hongyu Wang Zhongqi Chen Yanan Liu Yanan Liu Xiaoning Zeng Yuan Ma Chloroquine Attenuates Asthma Development by Restoring Airway Smooth Muscle Cell Phenotype Via the ROS-AKT Pathway Frontiers in Pharmacology chloroquine airway smooth muscle (ASM) cells bitter taste receptors (TAS2Rs) TGF-β1 asthma |
| title | Chloroquine Attenuates Asthma Development by Restoring Airway Smooth Muscle Cell Phenotype Via the ROS-AKT Pathway |
| title_full | Chloroquine Attenuates Asthma Development by Restoring Airway Smooth Muscle Cell Phenotype Via the ROS-AKT Pathway |
| title_fullStr | Chloroquine Attenuates Asthma Development by Restoring Airway Smooth Muscle Cell Phenotype Via the ROS-AKT Pathway |
| title_full_unstemmed | Chloroquine Attenuates Asthma Development by Restoring Airway Smooth Muscle Cell Phenotype Via the ROS-AKT Pathway |
| title_short | Chloroquine Attenuates Asthma Development by Restoring Airway Smooth Muscle Cell Phenotype Via the ROS-AKT Pathway |
| title_sort | chloroquine attenuates asthma development by restoring airway smooth muscle cell phenotype via the ros akt pathway |
| topic | chloroquine airway smooth muscle (ASM) cells bitter taste receptors (TAS2Rs) TGF-β1 asthma |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2022.916508/full |
| work_keys_str_mv | AT yanren chloroquineattenuatesasthmadevelopmentbyrestoringairwaysmoothmusclecellphenotypeviatherosaktpathway AT yanren chloroquineattenuatesasthmadevelopmentbyrestoringairwaysmoothmusclecellphenotypeviatherosaktpathway AT xiuhuazhong chloroquineattenuatesasthmadevelopmentbyrestoringairwaysmoothmusclecellphenotypeviatherosaktpathway AT hongyuwang chloroquineattenuatesasthmadevelopmentbyrestoringairwaysmoothmusclecellphenotypeviatherosaktpathway AT zhongqichen chloroquineattenuatesasthmadevelopmentbyrestoringairwaysmoothmusclecellphenotypeviatherosaktpathway AT yananliu chloroquineattenuatesasthmadevelopmentbyrestoringairwaysmoothmusclecellphenotypeviatherosaktpathway AT yananliu chloroquineattenuatesasthmadevelopmentbyrestoringairwaysmoothmusclecellphenotypeviatherosaktpathway AT xiaoningzeng chloroquineattenuatesasthmadevelopmentbyrestoringairwaysmoothmusclecellphenotypeviatherosaktpathway AT yuanma chloroquineattenuatesasthmadevelopmentbyrestoringairwaysmoothmusclecellphenotypeviatherosaktpathway |