Cortisol regulates neonatal lung development via Smoothened
Abstract Background Neonatal respiratory distress syndrome (NRDS), one of the main causes of neonatal death, is clinically characterized by progressive dyspnea and cyanosis 1 to 2 h after birth. Corticosteroids are commonly used to prevent NRDS in clinical. However, the protective mechanism of the c...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2025-01-01
|
| Series: | Respiratory Research |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12931-025-03104-0 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832594516606976000 |
|---|---|
| author | Shanshan Lu Yifei Chen Jiawen Song Liangliang Ren Jun Du Donglai Shen Jiayin Peng Yao Yin Xia Li Yuqing Wang Yan Gao Siman Han Yichang Jia Yun Zhao Yizheng Wang |
| author_facet | Shanshan Lu Yifei Chen Jiawen Song Liangliang Ren Jun Du Donglai Shen Jiayin Peng Yao Yin Xia Li Yuqing Wang Yan Gao Siman Han Yichang Jia Yun Zhao Yizheng Wang |
| author_sort | Shanshan Lu |
| collection | DOAJ |
| description | Abstract Background Neonatal respiratory distress syndrome (NRDS), one of the main causes of neonatal death, is clinically characterized by progressive dyspnea and cyanosis 1 to 2 h after birth. Corticosteroids are commonly used to prevent NRDS in clinical. However, the protective mechanism of the corticosteroids remains largely unclear. Methods In this study, the simulation of the molecular docking by Autodock, in vitro binding experiments, and Sonic Hedgehog (SHH) pathway examination in cells were performed to study the directly binding of cortisol to Smoothened (SMO). To explore the effect of cortisol action on the SHH pathway on neonatal lung development, we generated a genetic mouse, in which leucine 116 (L112 in human) of SMO was mutated to alanine 116 (L116A, Smo a/a ) by the CRISPR-Cas9, based on sequence differences between human and mice. Then, we performed morphological analysis, single-cell RNA sequencing (scRNA-seq) on lung tissue and fluorescence in situ hybridization (FISH). Results In this study, we reported that cortisol, the endogenous glucocorticoid, inhibited the sonic hedgehog (Shh)/SMO-mediated proliferation of lung fibroblasts to maintain the normal lung development. Specifically, cortisol competed with cholesterol for binding to the cysteine-rich domain (CRD) in SMO to inhibit the activation of Shh/SMO signaling, a critical signaling known for cell proliferation. Cortisol did not inhibit the activation of SMO when L112 in its CRD was mutated to A112. Moreover, Smo a/a (L116A) mice exhibited the immature lungs in which over-proliferation of interstitial fibroblasts and reduction in the surfactant protein were evident. Conclusion Together, these results suggested that cortisol regulated cholesterol stimulation of SMO by competitively binding to the CRD to regulate neonatal lung maturation in mice. |
| format | Article |
| id | doaj-art-e071a7959b2f4b639efd44fa9db59c39 |
| institution | Kabale University |
| issn | 1465-993X |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Respiratory Research |
| spelling | doaj-art-e071a7959b2f4b639efd44fa9db59c392025-01-19T12:36:35ZengBMCRespiratory Research1465-993X2025-01-0126111710.1186/s12931-025-03104-0Cortisol regulates neonatal lung development via SmoothenedShanshan Lu0Yifei Chen1Jiawen Song2Liangliang Ren3Jun Du4Donglai Shen5Jiayin Peng6Yao Yin7Xia Li8Yuqing Wang9Yan Gao10Siman Han11Yichang Jia12Yun Zhao13Yizheng Wang14The Brain Science Center, Beijing Institute of Basic Medical SciencesThe Brain Science Center, Beijing Institute of Basic Medical SciencesState Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of SciencesThe Brain Science Center, Beijing Institute of Basic Medical SciencesThe Brain Science Center, Beijing Institute of Basic Medical SciencesThe Brain Science Center, Beijing Institute of Basic Medical SciencesState Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of SciencesThe Brain Science Center, Beijing Institute of Basic Medical SciencesThe Brain Science Center, Beijing Institute of Basic Medical SciencesThe Brain Science Center, Beijing Institute of Basic Medical SciencesThe Brain Science Center, Beijing Institute of Basic Medical SciencesThe Brain Science Center, Beijing Institute of Basic Medical SciencesTsinghua-Peking Joint Center for Life Sciences, School of Medicine, Medical Science Building, Tsinghua UniversityState Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of SciencesNational Clinical Research Center for Aging and Medicine, State Key Laboratory of Medical Neurobiology, Huashan Hospital, Fudan UniversityAbstract Background Neonatal respiratory distress syndrome (NRDS), one of the main causes of neonatal death, is clinically characterized by progressive dyspnea and cyanosis 1 to 2 h after birth. Corticosteroids are commonly used to prevent NRDS in clinical. However, the protective mechanism of the corticosteroids remains largely unclear. Methods In this study, the simulation of the molecular docking by Autodock, in vitro binding experiments, and Sonic Hedgehog (SHH) pathway examination in cells were performed to study the directly binding of cortisol to Smoothened (SMO). To explore the effect of cortisol action on the SHH pathway on neonatal lung development, we generated a genetic mouse, in which leucine 116 (L112 in human) of SMO was mutated to alanine 116 (L116A, Smo a/a ) by the CRISPR-Cas9, based on sequence differences between human and mice. Then, we performed morphological analysis, single-cell RNA sequencing (scRNA-seq) on lung tissue and fluorescence in situ hybridization (FISH). Results In this study, we reported that cortisol, the endogenous glucocorticoid, inhibited the sonic hedgehog (Shh)/SMO-mediated proliferation of lung fibroblasts to maintain the normal lung development. Specifically, cortisol competed with cholesterol for binding to the cysteine-rich domain (CRD) in SMO to inhibit the activation of Shh/SMO signaling, a critical signaling known for cell proliferation. Cortisol did not inhibit the activation of SMO when L112 in its CRD was mutated to A112. Moreover, Smo a/a (L116A) mice exhibited the immature lungs in which over-proliferation of interstitial fibroblasts and reduction in the surfactant protein were evident. Conclusion Together, these results suggested that cortisol regulated cholesterol stimulation of SMO by competitively binding to the CRD to regulate neonatal lung maturation in mice.https://doi.org/10.1186/s12931-025-03104-0Neonatal respiratory distress syndromeLung developmentCortisolSHH pathway |
| spellingShingle | Shanshan Lu Yifei Chen Jiawen Song Liangliang Ren Jun Du Donglai Shen Jiayin Peng Yao Yin Xia Li Yuqing Wang Yan Gao Siman Han Yichang Jia Yun Zhao Yizheng Wang Cortisol regulates neonatal lung development via Smoothened Respiratory Research Neonatal respiratory distress syndrome Lung development Cortisol SHH pathway |
| title | Cortisol regulates neonatal lung development via Smoothened |
| title_full | Cortisol regulates neonatal lung development via Smoothened |
| title_fullStr | Cortisol regulates neonatal lung development via Smoothened |
| title_full_unstemmed | Cortisol regulates neonatal lung development via Smoothened |
| title_short | Cortisol regulates neonatal lung development via Smoothened |
| title_sort | cortisol regulates neonatal lung development via smoothened |
| topic | Neonatal respiratory distress syndrome Lung development Cortisol SHH pathway |
| url | https://doi.org/10.1186/s12931-025-03104-0 |
| work_keys_str_mv | AT shanshanlu cortisolregulatesneonatallungdevelopmentviasmoothened AT yifeichen cortisolregulatesneonatallungdevelopmentviasmoothened AT jiawensong cortisolregulatesneonatallungdevelopmentviasmoothened AT liangliangren cortisolregulatesneonatallungdevelopmentviasmoothened AT jundu cortisolregulatesneonatallungdevelopmentviasmoothened AT donglaishen cortisolregulatesneonatallungdevelopmentviasmoothened AT jiayinpeng cortisolregulatesneonatallungdevelopmentviasmoothened AT yaoyin cortisolregulatesneonatallungdevelopmentviasmoothened AT xiali cortisolregulatesneonatallungdevelopmentviasmoothened AT yuqingwang cortisolregulatesneonatallungdevelopmentviasmoothened AT yangao cortisolregulatesneonatallungdevelopmentviasmoothened AT simanhan cortisolregulatesneonatallungdevelopmentviasmoothened AT yichangjia cortisolregulatesneonatallungdevelopmentviasmoothened AT yunzhao cortisolregulatesneonatallungdevelopmentviasmoothened AT yizhengwang cortisolregulatesneonatallungdevelopmentviasmoothened |