Efficient pulmonary fibrosis therapy via regulating macrophage polarization using respirable cryptotanshinone-loaded
Xiuhua Wang1, Wei Wan1, Jiguo Zhang2
1National-Local Joint Engineering Laboratory of Druggability and New Drugs Evaluation, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Guangdong Province Engineering Laboratoty for Druggability and New Drug Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
Abstract:
Lung inflammation and fibrogenesis are the two main characteristics during the development of pulmonary fibrosis (PF), which are particularly associated with pulmonary macrophages. In this context, whether cryptotanshinone (CTS) could alleviate PF through regulating macrophage polarization were preliminarily demonstrated in vitro. Then the time course of PF and its relationship with macrophage polarization was determined in BLM-induced mice based on cytokine levels in bronchoalveolar lavage fluid (BALF), lung histopathology, flow cytometric analysis, mRNA and protein expression. CTS was loaded into macrophage-targeted and responsively released mannose-modified liposomes (Man-lipo), and the liposomes were then embedded into mannitol microparticles (M-MPs) using spray drying to achieve efficient pulmonary delivery. Afterwards, how CTS regulates macrophage polarization in vivo during different time courses of PF was probed. Furthermore, the molecular mechanisms of CTS against PF by regulating macrophage polarization were elucidated in vivo and in vitro. The full-course therapy group could achieve comparable therapeutic effects compared with the positive control drug PFD group. CTS can alleviate PF through regulating macrophage polarization, mainly by inhibiting NLRP3/TGF-β1 pathway during the inflammation course and modulating MMP-9/TIMP-1 balance during the fibrosis development course, providing new insights into chronic PF treatment.
Insights
Cryptotanshinone (CTS) alleviates pulmonary fibrosis (PF) by regulating macrophage polarization. This study elucidates CTS
Area of Science:
- Pulmonary Medicine
- Immunology
- Pharmacology
Background:
- Pulmonary fibrosis (PF) is characterized by lung inflammation and fibrogenesis, processes linked to pulmonary macrophages.
- Macrophage polarization plays a critical role in the development and progression of PF.
- Cryptotanshinone (CTS) has shown preliminary in vitro potential in alleviating PF by modulating macrophage polarization.
Purpose of the Study:
- To investigate the therapeutic effects of cryptotanshinone (CTS) on pulmonary fibrosis (PF) in vivo.
- To determine how CTS regulates macrophage polarization during different stages of PF.
- To elucidate the molecular mechanisms underlying CTS's anti-fibrotic effects mediated by macrophage polarization.
Main Methods:
- Established a bleomycin (BLM)-induced mouse model of PF to study disease progression and macrophage polarization.
- Utilized cytokine analysis, histopathology, flow cytometry, and gene/protein expression to assess PF and macrophage status.
- Developed mannose-modified liposomes (Man-lipo) embedded in mannitol microparticles (M-MPs) for efficient pulmonary delivery of CTS.
Main Results:
- CTS treatment, particularly with full-course therapy, demonstrated therapeutic effects comparable to the positive control drug pirfenidone (PFD).
- CTS effectively alleviated PF by modulating macrophage polarization, inhibiting the NLRP3/TGF-β1 pathway during inflammation.
- CTS regulated the MMP-9/TIMP-1 balance during fibrosis development, contributing to its anti-fibrotic action.
Conclusions:
- Cryptotanshinone (CTS) exhibits significant therapeutic potential for chronic pulmonary fibrosis (PF) by targeting macrophage polarization.
- CTS acts by inhibiting the NLRP3/TGF-β1 pathway during the inflammatory phase and balancing MMP-9/TIMP-1 during fibrogenesis.
- This study provides novel insights into the mechanisms of CTS in treating PF, highlighting its role in macrophage-driven pathways.
