Scientific Reports,, 04 August 2025
Pulmonary fibrosis (PF) is a progressive, irreversible disease with current treatment options being limited and not entirely effective. Specifically, idiopathic pulmonary fibrosis (IPF), the most common type of interstitial lung disease, has a prognosis worse than many types of cancer, with a median survival time of only 3–5 years. Pirfenidone (PFD) is conditionally recommended for IPF treatment, but its efficacy as a monotherapy is limited due to the high effective doses required and numerous adverse effects. The urgent need for improved and effective treatments for patients with pulmonary fibrosis is critically important.
A recent study published in Scientific Reports offers significant hope, demonstrating that a combined therapy of PFD and human umbilical cord-derived mesenchymal stem cells (UC-MSCs) can reverse bleomycin-induced pulmonary fibrosis.
UC-MSCs: A Promising Therapy UC-MSCs are widely used in preclinical studies on pulmonary regenerative medicine due to their broad availability, safe collection process, lack of ethical restrictions, and low immunogenicity. Although previous studies have compared the efficacy of PFD or nintedanib with MSCs from various sources (bone marrow, adipose tissue, or umbilical cord) in treating bleomycin-induced fibrosis models, research on the combination of traditional anti-fibrotic drugs with MSCs remains limited.
This study utilized a bleomycin-induced pulmonary fibrosis mouse model (C57BL/6 mice) to evaluate the therapeutic efficacy of PFD, UC-MSCs, and their combination. Mice were divided into nine groups, including control, model, PFD, various doses of UC-MSCs (0.5 × 10^6, 1.0 × 10^6, and 2.0 × 10^6 cells per animal), and PFD combined with these UC-MSCs doses. PFD was administered intraperitoneally twice daily from day 4 to 21, while UC-MSCs were injected via the tail vein on day 4.
The study results showed significant improvements:
- Improved Lung Function: Both the high-dose UC-MSCs alone group and the PFD combined with high-dose UC-MSCs group achieved significant improvements in pulmonary function in IPF mice. Parameters such as Te, Penh, FVC, PIF, Cdyn, and TV showed marked recovery, approaching those of the control group with no statistically significant difference.
- Reduced Inflammation and Collagen Deposition:
- Levels of inflammatory factors like TGF-β1, INF-γ, and IL-6 in serum, bronchoalveolar lavage fluid (BALF), and lung tissues were significantly decreased in the treated groups compared to the model group.
- The total number of inflammatory cells (total cells, neutrophils, lymphocytes, and macrophages) in BALF also significantly decreased after treatment.
- Hydroxyproline (HYP) levels, a surrogate marker for collagen content, in lung tissues were significantly reduced in the treated groups, indicating a slowdown in collagen deposition and fibrosis.
- Reversed Histopathological Damage and Fibrosis Markers:
- Histopathological examination (H&E staining) revealed reduced inflammatory cell infiltration and improved lung structure in treated groups.
- Masson trichrome staining showed a significant reduction in blue-stained collagen and fibrotic areas.
- Fibrosis markers such as α-SMA and Collagen I, along with p-SMAD 2/3 (an indicator of the TGF-β/SMAD pathway), were significantly reduced.
- Notably, the PFD + high-dose UC-MSCs group showed the most reduction in p-SMAD 2/3 levels and stronger inhibition of pro-fibrotic gene expression.
- Reduced PFD Side Effects: The study also observed that combining with UC-MSCs somewhat mitigated the gastrointestinal adverse reactions caused by PFD in mice, which could enhance the tolerance and compliance of IPF patients with PFD therapy in a clinical setting.
In the pathogenesis of IPF, persistent inflammatory responses stimulate excessive fibroblast proliferation, ultimately leading to fibrosis. The TGF-β pathway plays a pivotal role in the initiation and maintenance of fibrosis. PFD not only exhibits anti-inflammatory and antioxidant effects but also inhibits fibrosis by suppressing the TGF-β pathway, thereby reducing collagen synthesis. UC-MSCs, when combined with PFD, may enhance the anti-fibrotic efficacy because PFD can partially inhibit UC-MSCs’ secretion of pro-fibrotic factors like TGF-β, making the combination treatment more effective than UC-MSCs alone.
This study demonstrated that treatment with UC-MSCs alone or in combination with PFD had superior therapeutic effects in restoring lung function and alleviating inflammatory infiltration compared to PFD treatment alone in the bleomycin-induced pulmonary fibrosis model. The combination of PFD and UC-MSCs showed a more pronounced inhibitory effect on pro-fibrotic genes and also suppressed the activation of the TGF-β/SMAD pathway, partially reversing the progression of fibrosis. These findings offer a promising new perspective for the future clinical treatment of pulmonary fibrosis.
However, this study primarily focused on the early stages of fibrosis. Further research is needed to explore the therapeutic efficacy of this combined therapy in chronic fibrosis stages of IPF models, as well as to investigate the underlying mechanisms of this combination treatment in more depth.
References
Xu, J., Abudureheman, Z., Gong, H., Zhong, X., Xue, L., Zou, X., & Li, L. (2025). Pirfenidone combined with UC-MSCs reversed bleomycin-induced pulmonary fibrosis. Scientific Reports, 15(1), 28339.
Source: Scientific Reports,
Link: https://www.nature.com/articles/s41598-025-14286-4#citeas
