Abstract
Background: Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease with limited treatment options. It also leads to progressive respiratory failure, which subsequently affects the heart functionality, a pathological heart-lung interaction increasingly noticed and defined as pulmonary-heart disease (PHD). Traditional Chinese medicine (TCM) theory for treating “phlegm-stasis cementation syndrome” may suggest a possibility of treating PHD complication with Chinese medicine prescriptions previously used for cardiovascular diseases.Methods: Here, we evaluate the efficacies of two compound Chinese medicine prescriptions, Danlou prescription (DLP) and Danhong prescription (DHP), which share a common herbal component, Salvia miltiorrhiza (Danshen), on pulmonary fibrosis. Severity grades of Bleomycin (BLM)-induced pulmonary fibrosis were assessed by micro-Computerized Tomography (μCT) in accordance with the clinical evaluation standard. Lung pathological changes and collagen deposition were investigated by histopathology. Myofibroblast differentiation was assessed by immunohistochemistry of α-SMA and TGF-β receptor type II expression in situ. Network pharmacology analysis of the drug-target interaction in IPF progression for DLP or DHP was performed using Ingenuity® Pathways Analysis (IPA) system.Results: We show that a non-invasive μCT effectively monitor and quantify BLM-induced pulmonary fibrosis and its treatment efficacy by Chinese medicine prescription in rodents. In addition, although both containing Salvia miltiorrhiza, DLP but not DHP mitigates BLM-induced lung fibrosis by inhibiting the TGF-β signaling-activated myofibroblast differentiation and α-SMA expression in a mouse model. Core analysis by IPA revealed that DLP ingredients regulated not only pulmonary fibrosis related inflammatory genes but also genes associated with myofibroblast activation and collagen deposition.Conclusion: This study suggests that a clinically efficacious cardiovascular Chinese herbal medicine (DLP) can be successfully repurposed to treat a lung disease in pulmonary fibrosis guided by TCM theory. Our comparative study between DLP and DHP demonstrated a critical requirement of suppressing both pro-inflammatory and pro-fibrotic pathways for the treatment of pulmonary fibrosis, supporting that a multi-component prescription capable of “removing both phlegm and blood stasis” will better achieve co-protection of heart and lung in PHD.
Highlights
Idiopathic pulmonary fibrosis (IPF) is a chronic and life-threatening disease characterized by a progressive decline in lung function (Gross and Hunninghake, 2001)
We presented the morphology of fibrosis tissue by μCT scanning (Choi et al, 2014), together with histopathological assay and immunohistochemistry assay, in order to test DLP and DHP therapy effects, laying a solid foundation for developing cardiovascular and IPF combination therapy based on traditional Chinese medicine (TCM) prescription compatibility theory
We quantified the degree of pulmonary fibrosis before and after drug-administration using a scale adapted from clinical practice (Lee et al, 2008; Figure 2)
Summary
Idiopathic pulmonary fibrosis (IPF) is a chronic and life-threatening disease characterized by a progressive decline in lung function (Gross and Hunninghake, 2001). It is associated with an extremely poor prognosis and limited curative therapies (Raghu et al, 2011; Richeldi et al, 2017), causing the median survival time of patient from diagnosis to 2–4 years and very high lethality (Bjoraker et al, 1998; Ley et al, 2011; Richeldi et al, 2017). It leads to progressive respiratory failure, which subsequently affects the heart functionality, a pathological heart-lung interaction increasingly noticed and defined as pulmonary-heart disease (PHD). Traditional Chinese medicine (TCM) theory for treating “phlegm-stasis cementation syndrome” may suggest a possibility of treating PHD complication with Chinese medicine prescriptions previously used for cardiovascular diseases
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