Pulmonary Fibrosis Model Research Articles

Identification of potential mechanisms of Schisandrin B in the treatment of idiopathic pulmonary fibrosis by integrating network pharmacology and experimental validation.

Idiopathic pulmonary fibrosis (IPF) is a worsening fibrotic condition characterized by a short survival rate and limited treatment options. This study evaluates the potential anti-fibrotic properties of Schisandrin B (Sch B) through network pharmacology and experimental validation. A mouse model of bleomycin-induced pulmonary fibrosis was established, and the modeled mice were treated with Sch B at three doses (20 mg/kg/day, 40 mg/kg/day, and 80 mg/kg/day). A fibrotic model was developed in NIH/3T3 cells by treating them with TGF-β (10 ng/mL) and administering Sch B at various concentrations (10, 20, and 40 µM). The results revealed that Sch B treatment delayed the development of bleomycin-induced pulmonary fibrosis and substantially decreased the transcription levels of collagen I and α-SMA in TGF-β-induced fibroblasts. Core targets were screened with protein-protein interaction network analysis, molecular complex detection (MCODE), and CytoHubba plugin. The application of Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, and molecular docking highlighted the significance of the HIF-1α signaling pathway in the potential mechanism of Sch B in IPF therapy. Western blot, PCR, and immunofluorescence were performed to validate the effects of Sch B on HIF-1α. In vivo and in vitro, Sch B administration reduced HIF-1α expression. These outcomes provide valuable insights into the potential mechanism by which Sch B delays IPF development, with HIF-1α potentially serving as a key target. However, further investigation is warranted to assess the safety and efficacy of Sch B in clinical settings.

Development and Evaluation of ABI-171, a New Fluoro-Catechin Derivative, for the Treatment of Idiopathic Pulmonary Fibrosis.

The persistent challenge of idiopathic pulmonary fibrosis (IPF), characterized by disease progression and high mortality, underscores the urgent need for innovative therapeutic strategies. We have developed a novel small molecule-catechin derivative ABI-171-selectively targeting dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) and proviral integration site for Moloney murine leukemia virus 1 (PIM1) kinases, crucial in the pathogenesis of fibrotic processes. We employed the Bleomycin-induced (intratracheal) mouse model of pulmonary fibrosis (PF) to evaluate the therapeutic efficacy of ABI-171. Mice with induced PF were treated QD with ABI-171, either prophylactically or therapeutically, using oral and intranasal routes. Pirfenidone (100 mg/kg, TID) and Epigallocatechin gallate (EGCG, 100 mg/kg, QD), a natural catechin currently in a Phase 1 clinical trial, were used as reference compounds. ABI-171, administered prophylactically, led to a significant reduction in hydroxyproline levels and fibrotic tissue formation compared to the control group. Treatment with ABI-171 improved body weight, indicating mitigation of disease-related weight loss. Additionally, ABI-171 demonstrated anti-inflammatory activity, reducing lymphocyte and neutrophil infiltration. In the therapeutic setting, ABI-171, administered 7 days post-induction, reduced mortality rates (p = 0.04) compared with the bleomycin and EGCG control groups. ABI-171 also ameliorated the severity of lung injuries assessed by improved Masson's trichrome scores when administered both orally and intranasally. ABI-171 significantly decreases bleomycin-induced PF and improves survival in mice, showcasing promising therapeutic potential beyond current medications like pirfenidone and EGCG for patients with IPF. Based on these results, further studies with ABI-171 are ongoing in preclinical studies.

ACSL1 improves pulmonary fibrosis by reducing mitochondrial damage and activating PINK1/Parkin mediated mitophagy

Pulmonary fibrosis is a chronic interstitial lung disease with no curative therapeutic treatment, leading to significant mortality. The aims of this study were to investigate the regulatory mechanisms of mitophagy in the progression of pulmonary fibrosis. Through bioinformatics analysis, we identified the downregulation of long-chain fatty acyl-CoA synthetase 1 (ACSL1) as being associated with the severity of pulmonary fibrosis. A pulmonary fibrosis model was established through bleomycin (BLM) exposure both in vivo and in vitro. Mitoquinone (MitoQ) pretreatment significantly decreased redox damage, stabilized mitochondrial membrane potential (MMP), improved mitochondrial dynamics, and activated PINK1/Parkin-mediated mitophagy, thereby alleviating pulmonary fibrosis. In vitro, overexpression of ACSL1 mitigated mitochondrial damage and restored PINK1/Parkin-mediated mitophagy under BLM exposure. In contrast, ACSL1 inhibition exacerbated pulmonary fibrosis, and these adverse effects could not be reversed by MitoQ treatment. Taken together, our study reveals a novel mechanism underlying the pathogenesis of pulmonary fibrosis and suggests a potential therapeutic target for its treatment.

Personalized in silico model for radiation-induced pulmonary fibrosis.

Radiation-induced pulmonary fibrosis (RIPF) is a severe late-stage complication of radiotherapy (RT) to the chest area, typically used in lung cancer treatment. This condition is characterized by the gradual and irreversible replacement of healthy lung tissue with fibrous scar tissue, leading to decreased lung function, reduced oxygen exchange and critical respiratory deficiencies. Currently, predicting and managing lung fibrosis post-RT remains challenging, with limited preventive and treatment options. Accurate prediction of fibrosis onset and progression is therefore clinically crucial. We present a personalized in silico model for pulmonary fibrosis that encompasses tumour regression, fibrosis development and lung tissue remodelling post-radiation. Our continuum-based model was developed using data from 12 RT-treated lung cancer patients and integrates computed tomography (CT) and dosimetry data to simulate the spatio-temporal evolution of fibrosis. We demonstrate the ability of the in silico model to capture the extent of fibrosis in the entire cohort with a less than 1% deviation from clinical observations, in addition to providing quantitative metrics of spatial similarity. These findings underscore the potential of the model to improve treatment planning and risk assessment, paving the way for more personalized and effective management of RIPF.

Compression-induced apoptosis of fibroblasts and myofibroblasts in an in vitro model of pulmonary fibrosis by alginate/gelatin scaffold

Pulmonary fibrosis leads to increased mortality but is poorly understood. Fibrotic progression is associated with abnormal wound repair and an increase in myofibroblast cell populations. Here we investigate how the myofibroblast population is impacted by unique compression-induced apoptosis derived from mechanical strain characteristic of asthma. Using a mechanical device, both static and dynamic mechanical strains were applied to alginate/gelatin/CaCl2 scaffolds containing fibroblasts and myofibroblasts. As cell groups were stimulated with 30 % static strain for 12 h, fibroblast and myofibroblast cell groups showed increased cell apoptosis by 5.55 % and 19.56 %, respectively, compared to control groups. Additionally, myofibroblasts exhibited higher susceptibility to apoptosis induction than did fibroblasts. Comparing dynamic and static loading modes, dynamic loading resulted in a higher apoptosis rate of fibroblast and myofibroblast cells, indicating its potential to induce apoptosis effectively. These findings suggest that mechanical stimulation can be considered a promising approach to induce apoptosis in myofibroblasts, thus offering the potential for future approaches to treating pulmonary fibrosis. Moreover, mechanical loads can be designed for other diseases, selectively reducing or increasing apoptosis in either hard or soft cell groups, based on specific application needs.

Hemin attenuates bleomycin-induced lung fibrosis in mice by regulating the TGF-β1/MAPK and AMPK/SIRT1/PGC-1α/HO-1/NF-κB pathways.

The objective of this study was to investigate the protective effect and potential mechanism of action of hemin on bleomycin-induced pulmonary fibrosis in mice. Male C57BL/6 mice were randomly divided into control, bleomycin and bleomycin + hemin groups. Mice in the bleomycin and bleomycin + hemin groups were injected intratracheally with bleomycin to establish the pulmonary fibrosis model. The bleomycin + hemin group mice were injected intraperitoneally with hemin starting 7 days before modeling until the end of Day 21 after modeling. Pathological changes in lung tissue were assessed by HE and Masson staining. Malondialdehyde (MDA), superoxide dismutase (SOD) and catalase (CAT) levels were determined in lung tissue. Immunohistochemistry was performed to assess the expression of α-SMA and collagen I. The serum levels of IL-6 and TNF-α were measured via ELISA. Western blotting was used to determine the expression of TGF-β1, SIRT1, PGC-1α and HO-1 and the phosphorylation levels of p38, ERK1/2, JNK, AMPK and NF-κB p65 in lung tissue. Hemin significantly reduced lung indices, increased terminal body weight. It also significantly increased SOD and CAT activities; decreased MDA, IL-6 and TNF-α levels; reduced the levels of α-SMA and collagen I-positive cells; upregulated SIRT1, PGC-1α and HO-1 expression; promoted AMPK phosphorylation; and downregulated TGF-β1 expression and p38, ERK1/2, JNK and NF-κB p65 phosphorylation. Hemin might attenuate oxidative damage and inflammatory responses and reduces extracellular matrix deposition by regulating the expression and phosphorylation of proteins associated with the TGF-β1/MAPK and AMPK/SIRT1/PGC-1α/HO-1/NF-κB pathways, thereby alleviating bleomycin-induced pulmonary fibrosis.

Yohimbine treatment improves pulmonary fibrosis by attenuating the inflammation and oxidative stress via modulating the MAPK pathway

Idiopathic pulmonary fibrosis (IPF) is a devastating interstitial lung disorder characterized by the accumulation of extracellular matrix and collagen, resulting in significant parenchymal scarring and respiratory failure that leads to mortality. Yohimbine (YBH) is an α-2 adrenergic receptor antagonist with anti-oxidant and anti-inflammatory properties. In the current study, we aimed to investigate the anti-inflammatory, anti-oxidant and anti-fibrotic activity of YBH against LPS/TGF-β-induced differentiation in BEAS-2B/LL29 cells and bleomycin (BLMN) induced pulmonary fibrosis model in rats. Network pharmacology, gene expression, Western-blot analysis, immune-cytochemistry/immunohistochemistry, lung function and histology techniques were used to assess the fibrotic marker expression/levels in cells or rat lung tissues. YBH treatment significantly attenuated the LPS-induced pro-inflammatory (identified through a network-pharmacology approach) and oxidative stress markers expression in lung epithelial cells. TGF-β stimulation significantly elevated the fibrotic cascade of markers and treatment with YBH attenuated these markers’ expression/levels. Intra-tracheal administration of BLMN caused a significant elevation of various inflammatory/oxidative stress and fibrotic markers expression in lung tissues and treatment with YBH significantly mitigated the same. Ashcroft score analysis revealed that BLMN exhibited severe distortion of the lungs, elevation of thickness of the alveolar walls and accumulation of collagen in tissues, further treatment with YBH significantly suppressed these events and improved the lung architecture. Lung functional parameters demonstrated that BLMN-induced stiffness and resistance were reduced considerably upon YBH treatment and restored lung function dose-dependently. Overall, this study reveals that YBH treatment significantly attenuated the BLMN-induced fibrosis by regulating the MAPK pathway and provided insightful information for progressing towards translational outcomes.

Mesenchymal stem/stromal cells alleviate early-stage pulmonary fibrosis in a uPAR-dependent manner.

Pulmonary fibrosis, a debilitating lung disorder characterised by excessive fibrous tissue accumulation in lung parenchyma, compromises respiratory function leading to a life-threatening respiratory failure. While its origins are multifaceted and poorly understood, the urokinase system, including urokinase-type plasminogen activator (uPA) and its receptor (uPAR), plays a significant role in regulating fibrotic response, extracellular matrix remodelling, and tissue repair. Mesenchymal stem/stromal cells (MSCs) hold promise in regenerative medicine for treating pulmonary fibrosis. Our study aimed to investigate the potential of MSCs to inhibit pulmonary fibrosis as well as the contribution of uPAR expression to this effect. We found that intravenous MSC administration significantly reduced lung fibrosis in the bleomycin-induced pulmonary fibrosis model in mice as revealed by MRI and histological evaluations. Notably, administering the MSCs isolated from adipose tissue of uPAR knockout mice (Plaur-/- MSCs) attenuated lung fibrosis to a lesser extent as compared to WT MSCs. Collagen deposition, a hallmark of fibrosis, was markedly reduced in lungs treated with WT MSCs versus Plaur-/- MSCs. Along with that, endogenous uPA levels were affected differently; after Plaur-/- MSCs were administered, the uPA content was specifically decreased within the blood vessels. Our findings support the potential of MSC treatment in attenuating pulmonary fibrosis. We provide evidence that the observed anti-fibrotic effect depends on uPAR expression in MSCs, suggesting that uPAR might counteract the uPA accumulation in lungs.

A novel Non-rodent animal model of hydrochloric acid-induced acute and chronic lung injury

Hydrochloric acid is one of the most prevalent and hazardous chemicals. Accidental spills occur in industrial plants or during transportation. Exposure to HCl can induce severe health impairment, including acute and chronic pulmonary diseases. We have previously described the molecular, structural, and functional aspects of the development of chronic lung injury and pulmonary fibrosis caused by intratracheal instillation of HCl in mice. Although mouse models of human disease have many advantages, rodents are evolutionary far from human and exhibit significant anatomical and physiological differences. Genetic and anatomic similarities between rabbits and humans are significantly higher. Rabbit models of HCl-induced lung injury have been used sparsely to evaluate acute lung injury. In this study, for the first time, we utilized rabbits as a model of HCl-induced pulmonary fibrosis and chronic lung injury. We present molecular, histological, and functional evidence that demonstrate the utility of using this model for studying new pharmaceutics against pulmonary fibrosis.

Protective effects of Silibinin and cinnamic acid against paraquat-induced lung toxicity in rats: impact on oxidative stress, PI3K/AKT pathway, and miR-193a signaling.

Levels of reactive oxygen species (ROS) are the primary determinants of pulmonary fibrosis. It was discovered that antioxidants can ameliorate pulmonary fibrosis caused by prolonged paraquat (PQ) exposure. However, research on the precise mechanisms by which antioxidants influence the signaling pathways implicated in pulmonary fibrosis induced by paraquat is still insufficient. This research utilized a rat model of pulmonary fibrosis induced by PQ to examine the impacts of Silibinin (Sil) and cinnamic acid (CA) on pulmonary fibrosis, with a specific focus on pro-fibrotic signaling pathways and ROS-related autophagy. Lung injury induced by paraquat was demonstrated to be associated with oxidative stress and inflammation of the lungs, downregulated (miR-193a), and upregulated PI3K/AKT/mTOR signaling lung tissues. Expression levels of miR-193a were determined with quantitative real-time PCR, protein level of protein kinase B (Akt), and phosphoinositide 3-Kinase (PI3K) which were determined by western blot analysis. Hydroxyproline levels (HYP) and transforming growth factor-β1 (TGF-β1) were measured by ELISA, malondialdehyde (MDA), total antioxidant capacity (TAC), glutathione peroxidase (GSH), and catalase and were measured in lung tissue homogenates colorimetrically using spectrophotometer. Long-term exposure to paraquat resulted in decreased PI3K/AKT signaling, decreased cell autophagy, increased oxidative stress, and increased pulmonary fibrosis formation. Silibinin and cinnamic acid also decreased oxidative stress by increasing autophagy and miR-193a expression, which in turn decreased pulmonary fibrosis. These effects were associated by low TGF-β1. Silibinin and cinnamic acid inhibited PQ-induced PI3K/AKT by stimulating miR-193-a expression, thus attenuating PQ-induced pulmonary fibrosis.

Polyphyllin VI Ameliorates Pulmonary Fibrosis by Suppressing the MAPK/ERK and PI3K/AKT Signaling Pathways via Upregulating DUSP6.

Pulmonary fibrosis (PF) is a lethal disease caused by inordinate repair of damaged lungs, for which limited strategies are available. Polyphyllin VI (PPVI), extracted and isolated from Paris polyphylla Smith var. chinensis (Franch.) Hara, has been regarded as an important traditional Chinese herbal medicine for the treatment of respiratory system diseases. This study evaluated effects of PPVI on PF and its underlying mechanism. Experimental procedure For evaluating the anti-PF effect of PPVI, we established an in vivo PF mouse model via intratracheal infusion of bleomycin (BLM) in mice and an in vitro PF model induced by TGF-β1 in NIH/3T3, HPF and A549, respectively. Subsequently, the mechanism of PPVI effects was further explored using RNA sequencing (RNA-Seq). The in vivo and in vitro results demonstrated that PPVI significantly inhibited inflammation, oxidative damage, and epithelial-mesenchymal transition. Furthermore, RNA sequencing indicated that PPVI ameliorated PF by modulating inflammation and oxidative stress responses. Furthermore, dual specificity phosphatase 6 (DUSP6), was the shared and most significant differentially expressed gene associated with inflammation and oxidative stress response after PPVI treatment. Mechanistically, silencing DUSP6 can eliminate the suppressive impact on PPVI for the activation of fibroblast and the phosphorylation of ERK and AKT. Summarily, our findings revealed the potential of PPVI in mitigating PF via upregulating DUSP6 and highlighted the regulatory function of DUSP6 in the pathogenesis of PF.

Optimized administration of human embryonic stem cell-derived immunity-and-matrix regulatory cells for mouse lung injury and fibrosis

BackgroundLung injury and pulmonary fibrosis (PF), frequently arising as sequelae of severe and acute lung disease, currently face a dearth of effective therapeutic potions. Mesenchymal stem cells (MSCs) with immunomodulatory and tissue repair functions have immense potential to treat lung injury and PF. However, the optimal route of administration, timing, and frequency of dosing remain elusive. Human embryonic stem cell-derived immunity-and-matrix-regulatory cells (IMRCs) have shown therapeutic potential for lung injury and PF.MethodsTo ascertain the optimal therapeutic regimen for IMRCs in PF, we conducted an experimental study. Utilizing a mouse model of PF induced by bleomycin (BLM), IMRCs were administered via either a single or double intravenous (IV) or intratracheal (IT) injection on the first and seventh days post-BLM induction.ResultsOur findings revealed that IV infusion of IMRCs surpassed IT infusion in enhancing survival rates, facilitating body weight recovery, and optimizing Ashcroft and Szapiel scores among the model mice. Notably, IV administration exhibited a more profound ability to mitigate lung inflammation and fibrosis. Moreover, earlier and more frequent administrations of IMRCs were found to be advantageous in enhancing their therapeutic effects. Specifically, early administration with two IV infusions significantly improved body weight, lung organ coefficient, pulmonary ventilation and diffusion functions, and PF. This was accompanied by an increase in alveolar type I and II epithelial cells and a suppression of macrophage infiltration via CD24.ConclusionCollectively, these results suggested that IMRCs infusion ameliorated lung injury by promoting lung regeneration and inhibiting macrophage infiltration in a route, time, and frequency-dependent manner.

Albendazole ameliorates aerobic glycolysis in myofibroblasts to reverse pulmonary fibrosis

BackgroundIdiopathic pulmonary fibrosis (IPF) is a chronic and lethal lung disorder for which effective treatments remain limited. Recent investigations revealed a potential link between altered glucose metabolism and the activation of fibroblasts, the key cells responsible for generating and depositing extracellular matrix proteins within the lung interstitium during IPF development.MethodIn this study, we aimed to investigate the potential therapeutic impact of albendazole on fibroblast to myofibroblast transition in IPF. We assess albendazole’s effectiveness in attenuating the activation of fibroblasts. We focused on elucidating the mechanism underlying albendazole's impact on TGF-β1-induced aerobic glycolysis in both lung tissues and fibroblasts obtained from patients with IPF and other lung fibrosis types. Furthermore, the antifibrotic effects of oral administration of albendazole were investigated in mouse models of pulmonary fibrosis induced by BLM or SiO2. Human precision-cut lung slices were employed to evaluate the impact of albendazole following TGF-β1 stimulation.ResultIn this work, we demonstrated that albendazole, a first-line broad-spectrum anthelmintic drug, effectively attenuated fibroblast to myofibroblast transition through alleviating TGF-β1-induced aerobic glycolysis dependent on the LRRN3/PFKFB3 signaling pathway. Additionally, LRRN3 expression was downregulated in both lung tissues and fibroblasts from patients with IPF and other types of lung fibrosis. Importantly, the levels of LRRN3 correlated with the progression of the disease. Notably, oral administration of albendazole exerted potent antifibrotic effects in mouse models of pulmonary fibrosis induced by BLM or SiO2, and in human precision-cut lung slices after TGF-β1 stimulation, as evidenced by improvements in lung morphology, reduced myofibroblast formation, and downregulation of α-SMA, collagen type 1 and Fibronectin expression in the lungs.ConclusionOur study implies that albendazole can act as a potent agonist of LRRN3 during fibroblast to myofibroblast differentiation and its oral administration shows potential as a viable therapeutic approach for managing IPF.

Cromolyn sodium and masitinib combination inhibits fibroblast-myofibroblast transition and exerts additive cell-protective and antioxidant effects on a bleomycin-induced invitro fibrosis model.

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal fibrotic lung disease. While recent studies have suggested the potential efficacy of tyrosine kinase inhibitors in managing IPF, masitinib, a clinically used tyrosine kinase inhibitor, has not yet been investigated for its efficacy in fibrotic lung diseases. In a previous study on an invitro neurodegenerative model, we demonstrated the synergistic antitoxic and antioxidant effects of masitinib combined with cromolyn sodium, an FDA-approved mast cell stabilizer. This study aims to investigate the anti-fibrotic and antioxidant effects of the masitinib-cromolyn sodium combination in an invitro model of pulmonary fibrosis. Fibroblast cell cultures treated with bleomycin and/or hydrogen peroxide (H2O2) were subjected to masitinib and/or cromolyn sodium, followed by assessments of cell viability, morphological and apoptotic nuclear changes, triple-immunofluorescence labeling, and total oxidant/antioxidant capacities, besides ratio of Bax and Bcl-2 mRNA expressions as an indication of apoptosis. The combined treatment of masitinib and cromolyn sodium effectively prevented the fibroblast myofibroblast transition, a hallmark of fibrosis, and significantly reduced bleomycin / H2O2-induced apoptosis and oxidative stress. This study is the first to demonstrate the additive anti-fibrotic, cell-protective, and antioxidant effects of the masitinib-cromolyn sodium combination in an invitro fibrosis model, suggesting its potential as an innovative therapeutic approach for pulmonary fibrosis. Combination therapy may be more advantageous in that both drugs could be administered in lower doses, exerting less side effects, and at the same time providing diverse mechanisms of action simultaneously.

TLR2–EGR1 signaling axis modulates TGFβ1-induced differentiation of fibroblasts into myofibroblasts in pulmonary fibrosis

Pulmonary fibrosis is a progressive lung condition characterized by the excessive activation of myofibroblasts. Transforming growth factor beta 1 (TGFβ1) plays a crucial role in the differentiation of fibroblasts into myofibroblasts. In addition, toll-like receptor 2 (TLR2), known for its role in immune responses, contributes to pulmonary fibrosis by promoting myofibroblast differentiation. However, the interplay between TGFβ1 and TLR2 signaling pathways in myofibroblast differentiation has remained elusive. In the present study, we investigated the involvement of TLR2 in TGFβ1-induced fibroblast differentiation into myofibroblasts using IMR-90 human pulmonary fibroblasts as a model cell line. We found that TLR2 activation induced myofibroblast differentiation by enhancing the expression of early growth response 1 (EGR1) via the mitogen-activated protein kinase (MAPK) signaling pathway. Elevated EGR1 levels were detected in the lung tissues of a bleomycin (BLM)-induced mouse model of pulmonary fibrosis. Moreover, the administration of tomaralimab, an antagonistic anti-TLR2 antibody, reduced the EGR1 expression and collagen deposition. Altogether, targeting the TLR2–EGR1 pathway could be a promising therapeutic approach for pulmonary fibrosis by blocking TGFβ1-induced myofibroblast differentiation.

Rutaecarpine, Isolated from Evodia rutaecarpa, Inhibits Epithelial-Mesenchymal Transition and Cellular Senescence in a Mouse Model of Pulmonary Fibrosis

Rutaecarpine, Isolated from Evodia rutaecarpa, Inhibits Epithelial-Mesenchymal Transition and Cellular Senescence in a Mouse Model of Pulmonary Fibrosis

Lung-Targeting Perylenediimide Nanocomposites for Efficient Therapy of Idiopathic Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis, an idiopathic interstitial lung disease with high mortality, remains challenging to treat due to the lack of clinically approved lung-targeting drugs. Herein, we present PDIC-DPC, a perylenediimide derivative that exhibits superior lung-selective enrichment. PDIC-DPC forms nanocomposites with plasma proteins, including fibrinogen beta chain and vitronectin, which bind to pulmonary endothelial receptors for lung-specific accumulation. Moreover, PDIC-DPC significantly suppresses transforming growth factor beta1 and activates adenosine monophosphate-activated protein kinase. As a result, compared to existing therapeutic drugs, PDIC-DPC achieves superior therapeutic outcomes, evidenced by the lowest Ashcroft score, significantly improved pulmonary function, and an extended survival rate in a bleomycin-induced pulmonary fibrosis model. This study elucidates the lung-selective enrichment of assembled prodrug from biological perspectives and affords a platform enabling therapeutic efficiency on idiopathic pulmonary fibrosis.

Toll-like Receptor 9 in Preclinical Models of Idiopathic Pulmonary Fibrosis.

Toll-like Receptor 9 in Preclinical Models of Idiopathic Pulmonary Fibrosis.

Human decidual mesenchymal stem cells obtained from early pregnancy attenuate bleomycin-induced lung fibrosis by inhibiting inflammation and apoptosis

BackgroundDecidual mesenchymal stem cells (DMSCs) are easily obtained and exhibit strong anti-inflammatory and anti-apoptotic effects. Compared with bone marrow mesenchymal stem cells (BMSCs), their role in cell transplantation after idiopathic pulmonary fibrosis remains unclear. We investigated whether the transplantation of BMSCs and DMSCs could alleviate pulmonary inflammation and fibrosis in a bleomycin-induced mouse model of pulmonary fibrosis. MethodsBMSCs and DMSCs were derived from healthy donors. The anti-inflammatory and anti-apoptotic effects on both cell types were evaluated in vitro. The function of DMSCs in MLE-12 cells and mouse lung fibroblasts was examined using additional transwell coculture experiments in vitro. Twenty-one days after MSC transplantation, we examined the inflammatory factors in the serum and bronchoalveolar lavage fluid, collagen content, pathology, fibrotic area, lung function, and micro-computed tomography of the lung tissue. ResultsDMSCs exhibited better anti-inflammatory and anti-apoptotic effects than BMSCs on MLE-12 cells in vitro. In addition, DMSCs inhibited tumor growth factor β-dependent epithelial-mesenchymal transition in MLE-12 cells and attenuated mouse lung fibroblasts fibrosis. Furthermore, transplantation of DMSCs in the mouse idiopathic pulmonary fibrosis model significantly attenuated pulmonary inflammation and lung fibrosis compared with BMSCs transplantation. ConclusionsDMSCs exhibited better efficacy in improving pulmonary inflammation and lung fibrosis than BMSCs. Thus, DMSCs are a potential therapeutic target for pulmonary fibrosis.

Tanshinone IIA Loaded Inhaled Polymer Nanoparticles Alleviate Established Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a fatal respiratory disease characterized by chronic, progressive scarring of the lung parenchyma, leading to an irreversible decline in lung function. Apart from supportive care, there is currently no specific treatment available to reverse the disease. Based on the fact that tanshinone IIA (TAN) had an effect on protecting against TGF-β1-induced fibrosis through the inhibition of Smad and non-Smad signal pathways to avoid myofibroblasts activation, this study reported the development of the inhalable tanshinone IIA-loaded chitosan-oligosaccharides-coated poly(lactic-co-glycolic acid) (PLGA) nanoparticles (CPN@TAN) for enhancing the pulmonary delivery of tanshinone IIA to treat pulmonary fibrosis. The CPN@TAN with a size of 206.5 nm exhibited excellent in vitro aerosol delivery characteristics, featuring a mass median aerodynamic diameter (MMAD) of 3.967 ± 0.025 μm and a fine particle fraction (FPF) of 70.516 ± 0.929%. Moreover, the nanoparticles showed good stability during atomization and enhanced the mucosal penetration capabilities. The results of confocal spectroscopy confirmed the potential of the nanoparticles as carriers that facilitated the uptake of drugs by NIH3T3, A549, and MH-S cells. Additionally, the nanoparticles demonstrated good in vitro biocompatibility. In a mouse model of bleomycin-induced pulmonary fibrosis, noninvasive inhalation of aerosol CPN@TAN greatly suppressed collagen formation and facilitated re-epithelialization of the destroyed alveolar epithelium without causing systemic toxicity compared with intravenous administration. Consequently, our noninvasive inhalation drug delivery technology based on polymers may represent a promising paradigm and open the door to overcoming the difficulties associated with managing pulmonary fibrosis.