Treatment Of Pulmonary Fibrosis Research Articles

Design, synthesis, and biological evaluation of novel discoidin domain receptor inhibitors for the treatment of lung adenocarcinoma and pulmonary fibrosis

Discoidin domain receptors (DDR) play crucial roles in cell proliferation and differentiation. When DDRs are overexpressed, it has been associated with various diseases such as cancers, fibrotic disorders, and inflammation. This study aimed to expand on previous research by using a structure-based drug design approach to develop a series of new indole-urea derivatives as potent inhibitors of DDR1. Through biochemical analyses, it was found that these compounds effectively inhibited DDR1/2, with compound 7s demonstrating the highest activity against A549 cells (IC50 value of 1.84 μM) while maintaining selectivity for other kinases. In vivo studies showed that compound 7s exhibited stronger antitumor activity compared to dasatinib, without causing significant weight loss at a dose of 30 mg/kg. Further investigation revealed that compound 7s hindered the migration of A549 cells by targeting the ERK, Akt1, and EMT pathways. Additionally, cellular experiments demonstrated that compound 7s suppressed the activation of fibroblasts induced by TGF-β1. In vivo experiments confirmed that compound 7s, at a dose of 30 mg/kg, effectively inhibited DDR1 activation, resulting in a reduction of lung injury and fibrosis induced by bleomycin. Overall, these findings highlight the potential of these novel DDR1 inhibitors as promising therapeutic candidates for the treatment of DDR-related diseases.

Perspectives on Post-COVID-19 Pulmonary Fibrosis Treatment.

Pulmonary fibrosis, a critical outcome of chronic inflammatory diseases, has gained prominence in the context of post-coronavirus (post-COVID-19) complications. This review delves into the multifaceted landscape of post-COVID-19 pulmonary fibrosis, elucidating the intricate molecular mechanisms underlying its pathogenesis and highlighting promising therapeutic avenues. Examining the aftermath of severe acute respiratory syndrome-2 (SARS-CoV-2) infection, the review reveals key signaling pathways implicated in the fibrotic cascade. Drawing parallels with previous coronavirus outbreaks enhances our understanding of the distinctive features of post-COVID-19 fibrosis. Antifibrotic drugs, like pirfenidone and nintedanib, take center stage; their mechanisms of action and potential applications in post-COVID-19 cases are thoroughly explored. Beyond the established treatments, this review investigates emerging therapeutic modalities, including anti-interleukin agents, immunosuppressants, and experimental compounds, like buloxybutide, saracatinib, sirolimus, and resveratrol. Emphasizing the critical importance of early intervention, this review highlights the dynamic nature of post-COVID-19 pulmonary fibrosis research. In conclusion, the synthesis of current knowledge offers a foundation for advancing our approaches to the prevention and treatment of these consequential sequelae of COVID-19.

Efficient pulmonary fibrosis therapy via regulating macrophage polarization using respirable cryptotanshinone-loaded liposomal microparticles

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.

Pulmonary Fibrosis Stakeholder Summit: A Joint NHLBI, Three Lakes Foundation, and Pulmonary Fibrosis Foundation Workshop Report.

Despite progress in elucidation of disease mechanisms, identification of risk factors, biomarker discovery, and the approval of two medications to slow lung function decline in idiopathic pulmonary fibrosis and one medication to slow lung function decline in progressive pulmonary fibrosis, pulmonary fibrosis remains a disease with a high morbidity and mortality. In recognition of the need to catalyze ongoing advances and collaboration in the field of pulmonary fibrosis, the NHLBI, the Three Lakes Foundation, and the Pulmonary Fibrosis Foundation hosted the Pulmonary Fibrosis Stakeholder Summit on November 8-9, 2022. This workshop was held virtually and was organized into three topic areas: 1) novel models and research tools to better study pulmonary fibrosis and uncover new therapies, 2) early disease risk factors and methods to improve diagnosis, and 3) innovative approaches toward clinical trial design for pulmonary fibrosis. In this workshop report, we summarize the content of the presentations and discussions, enumerating research opportunities for advancing our understanding of the pathogenesis, treatment, and outcomes of pulmonary fibrosis.

CircZNF609 regulates pulmonary fibrosis via miR-145-5p/KLF4 axis and its translation function

BackgroundPulmonary fibrosis is a growing clinical problem that develops as a result of abnormal wound healing, leading to breathlessness, pulmonary dysfunction and ultimately death. However, therapeutic options for pulmonary fibrosis are limited because the underlying pathogenesis remains incompletely understood. Circular RNAs, as key regulators in various diseases, remain poorly understood in pulmonary fibrosis induced by silica.MethodsWe performed studies with fibroblast cell lines and silica-induced mouse pulmonary fibrosis models. The expression of circZNF609, miR-145-5p, and KLF4 was determined by quantitative real-time polymerase chain reaction (qRT-PCR) analysis. RNA immunoprecipitation (RIP) assays and m6A RNA immunoprecipitation assays (MeRIP), Western blotting, immunofluorescence assays, and CCK8 were performed to investigate the role of the circZNF609/miR-145-5p/KLF4 axis and circZNF609-encoded peptides in fibroblast activation.ResultsOur data showed that circZNF609 was downregulated in activated fibroblasts and silica-induced fibrotic mouse lung tissues. Overexpression of circZNF609 could inhibit fibroblast activation induced by transforming growth factor-β1 (TGF-β1). Mechanically, we revealed that circZNF609 regulates pulmonary fibrosis via miR-145-5p/KLF4 axis and circZNF609-encoded peptides. Furthermore, circZNF609 was highly methylated and its expression was controlled by N6-methyladenosine (m6A) modification. Lastly, in vivo studies revealed that overexpression of circZNF609 attenuates silica-induced lung fibrosis in mice.ConclusionsOur data indicate that circZNF609 is a critical regulator of fibroblast activation and silica-induced lung fibrosis. The circZNF609 and its derived peptides may represent novel promising targets for the treatment of pulmonary fibrosis.

Curcumin ameliorates pulmonary fibrosis progression by inhibiting the fibrotic process of lung fibroblasts.

The objective of this study was to analyze the effect of curcumin (Cur) on pulmonary fibrosis (PF), so as to provide new clinical evidence for future PF treatment. To achieve these goals, the researchers set up bought human lung fibroblasts MRC-5 as a control group without treatment, a model group for PF cell modeling, and an intervention group for Cur intervention after PF modeling. Cell proliferation capacity and cellular TGF-β1, α-SMA, Collagen I, Collagen III, Bax, N-cadherin and E-cadherin protein expression were determined. The results show that markedly enhanced cell proliferation capacity and TGF-β1, α-SMA, Collagen I and Collagen III protein levels were observed in the model group, while the cell activity and fibrosis degree in the intervention group were significantly decreased compared with the model group (P<0.05). In addition, the intervention group exhibited lower N-cadherin and Bax with higher E-cadherin than the model group (P<0.05). In addition, the team found that the inflammatory response and oxidative stress were also more significantly improved in the intervention group (P<0.05). These experimental results tell us that Cur can ameliorate the fibrotic process of PF by inhibiting the activity of MRC-5.

Spatial targeting of fibrosis-promoting macrophages with nanoscale metal-organic frameworks for idiopathic pulmonary fibrosis therapy

Targeted delivery of therapeutic drugs to fibrosis-promoting macrophages (FPMs) holds promise as a challenging yet effective approach for the treatment of idiopathic pulmonary fibrosis (IPF). Here, nanocarriers composed of Mn-curcumin metal-organic frameworks (MOFs) were utilized to deliver the immune inhibitor BLZ-945 to the lungs, with the goal of depleting fibrosis-promoting macrophages (FPMs) from fibrotic lung tissues. FPM targeting was achieved by functionalizing the nanocarrier surface with an M2-like FPM binding peptide (M2pep). As a result, significant therapeutic benefits were observed through the successful depletion of approximately 80 % of the M2-like macrophages (FPMs) in a bleomycin-induced fibrosis mouse model treated with the designed M2-like FPM-targeting nanoparticle (referred to as M2NP-BLZ@Mn-Cur).Importantly, the released Mn2+ and curcumin after the degradation of M2NP-BLZ@Mn-Cur accumulated in the fibrotic lung tissue, which can alleviate inflammation and oxidative stress reactions, thereby further improving IPF therapy. This study presents a novel strategy with promising prospects for molecular-targeted fibrosis therapy. Statement of significanceMetal−organic frameworks (MOFs)- based nanocarriers equipped with both fibrosis-promoting macrophage (FPM)-specific targeting ability and therapeutic drugs are appealing for pulmonary fibrosis treatment. Here, we prepared M2pep (an M2-like FPM binding peptide)-modified and BLZ945 (a small molecule inhibitor of CSF1/CSF-1R axis)-loaded Mn-curcumin MOF nanoparticles (M2NP-BLZ@Mn-Cur) for pulmonary fibrosis therapy. The functionalized M2NP-BLZ@Mn-Cur nanoparticles can be preferentially taken up by FPMs, resulting in their depletion from fibrotic lung tissues. In addition, Mn2+and curcumin released from the nanocarriers have anti-inflammation and immune regulation effects, which further enhance the antifibrotic effect of the nanoparticles.

Design, synthesis and evaluation of novel UDCA-aminopyrimidine hybrids as ATX inhibitors for the treatment of hepatic and pulmonary fibrosis

To discover novel anti-fibrotic agents, a series of UDCA-aminopyrimidine hybrids were designed and synthesized as potent ATX inhibitors by molecular hybridization strategy. The ATX inhibitory activities of all synthesized compounds were evaluated using the LPC choline release assay. The preliminary structure-activity relationship was concluded. Among them, 12a and 12h exhibited the strongest ATX inhibitory activities with IC50 values of 7.62 ± 0.62 and 7.51 ± 0.72 nM respectively, which were 9-fold more effective than the positive control drug GLPG-1690. Molecular docking studies revealed that 12a and 12h occupied the hydrophobic pocket and tunnel of the ATX binding site. The cytotoxicity assay of 12a and 12h revealed that they had no obvious toxicity at concentrations up to 80 μM, therefore their anti-hepatic fibrosis and anti-pulmonary fibrosis activities were further investigated. The results suggested that 12a and 12h significantly decreased the gene and protein expression of α-SMA, COL1A1 and FN in both TGF-β1-induced HSC-LX2 and CCC-HPF-1 cells. In addition, 12a and 12h significantly inhibited cells migration in both TGF-β1-induced HSC-LX2 and CCC-HPF-1 cells. Preliminary mechanistic studies indicated that 12a and 12h exerted anti-hepatic fibrosis and anti-pulmonary fibrosis effects by inhibiting the TGF-β/Smad signaling pathway. Overall, our findings suggested that 12a and 12h might be two promising anti-fibrotic agents, or might serve as two new lead compounds for the further development of anti-fibrotic agents.

Pulmonary fibrosis: from pathogenesis to clinical decision-making.

Pulmonary fibrosis (PF) encompasses a spectrum of chronic lung diseases that progressively impact the interstitium, resulting in compromised gas exchange, breathlessness, diminished quality of life (QoL), and ultimately respiratory failure and mortality. Various diseases can cause PF, with their underlying causes primarily affecting the lung interstitium, leading to their referral as interstitial lung diseases (ILDs). The current understanding is that PF arises from abnormal wound healing processes triggered by various factors specific to each disease, leading to excessive inflammation and fibrosis. While significant progress has been made in understanding the molecular mechanisms of PF, its pathogenesis remains elusive. This review provides an in-depth exploration of the latest insights into PF pathophysiology, diagnosis, treatment, and future perspectives.

Identification and Biological Evaluation of a Potent and Selective JAK1 Inhibitor for the Treatment of Pulmonary Fibrosis.

Janus kinase 1 (JAK1) plays a pivotal role in regulating inflammation and fibrosis via the JAK/STAT signaling pathway, making it a promising target for associated diseases. In this study, we explored the modification of an N-methyl 1H-pyrrolo[2,3-b]pyridine-5-carboxylate core, leading to the identification of 4-(((2S,4S)-1-(4-trifluoromethyl)-2-methylpiperidin-4-yl)amino)-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (36b) as a highly potent and selective JAK1 inhibitor. Compound 36b exhibited an impressive IC50 value of 0.044 nM for JAK1 and demonstrated remarkable selectivity of 382-fold, 210-fold, and 1325-fold specificity over JAK2, JAK3, and TYK2, respectively. The kinase panel assays further confirmed its specificity, and cell-based experiments established its efficacy in inhibiting JAK1-STAT phosphorylation in human L-132 or SK-MES-1 cells. Pharmacokinetic studies revealed that compound 36b boasts an oral bioavailability exceeding 36%. In a bleomycin-induced fibrosis mouse model, compound 36b significantly reduced STAT3 phosphorylation, resulting in improvement in body weight and reduced collagen deposition, all achieved without significant side effects.

METTL3-mediated m6A RNA methylation induces the differentiation of lung resident mesenchymal stem cells into myofibroblasts via the miR-21/PTEN pathway

BackgroundThe accumulation of myofibroblasts is the key pathological feature of pulmonary fibrosis (PF). Aberrant differentiation of lung-resident mesenchymal stem cells (LR-MSCs) has been identified as a critical source of myofibroblasts, but the molecular mechanisms underlying this process remain largely unknown. In recent years, N6-methyladenosine (m6A) RNA modification has been implicated in fibrosis development across diverse organs; however, its specific role in promoting the differentiation of LR-MSCs into myofibroblasts in PF is not well defined.MethodsIn this study, we examined the levels of m6A RNA methylation and the expression of its regulatory enzymes in both TGF-β1-treated LR-MSCs and fibrotic mouse lung tissues. The downstream target genes of m6A and their related pathways were identified according to a literature review, bioinformatic analysis and experimental verification. We also assessed the expression levels of myofibroblast markers in treated LR-MSCs and confirmed the involvement of the above-described pathway in the aberrant differentiation direction of LR-MSCs under TGF-β1 stimulation by overexpressing or knocking down key genes within the pathway.ResultsOur results revealed that METTL3-mediated m6A RNA methylation was significantly upregulated in both TGF-β1-treated LR-MSCs and fibrotic mouse lung tissues. This process directly led to the aberrant differentiation of LR-MSCs into myofibroblasts by targeting the miR-21/PTEN pathway. Moreover, inhibition of METTL3 or miR-21 and overexpression of PTEN could rescue this abnormal differentiation.ConclusionOur study demonstrated that m6A RNA methylation induced aberrant LR-MSC differentiation into myofibroblasts via the METTL3/miR-21/PTEN signaling pathway. We indicated a novel mechanism to promote PF progression. Targeting METTL3-mediated m6A RNA methylation and its downstream targets may present innovative therapeutic approaches for the prevention and treatment of PF.

Exploring the mechanism of Gentiana rigescens Franch. in the treatment of pulmonary fibrosis based on network pharmacology

Pulmonary fibrosis (PF) is a severe chronic interstitial lung disease with high mortality, and there is currently a lack of definite and effective treatment methods. Studies have found that gentiopicroside, a secoiridoid glycoside compound derived from plants of the Gentiana genus, can significantly improve pulmonary inflammation and fibrosis lesions in mice with pulmonary fibrosis. However, the mechanism of its anti-fibrotic effect is unclear. Therefore, in this study, we employed network pharmacology's virtual computer technology to investigate the potential mechanism underlying the anti-pulmonary fibrosis effect of Gentianae Radix et Rhizome (Longdan in Chinese, GRR). Our findings offer valuable theoretical insights and serve as a guiding reference for future experimental investigations. A total of 10 active compounds and 920 drug-target proteins were identified from the TCMSP database. The compound-target-pathway-disease network showed that GRR could potentially treat PF by regulating the MDM2, ERBB2 and VEGFA, signaling pathways through its key targets, including AKT1, TNF, and MAPK1. The protein‒protein interaction network revealed that these targets had strong interactions with each other, indicating a potential synergistic effect of GRR in treating PF. The GO and KEGG enrichment analyses further supported the potential anti-pulmonary fibrosis mechanisms of GRR, including regulating the inflammatory response, ECM-receptor interaction, and TGF-beta signaling pathways. Our study provides a systematic analysis of the potential anti-pulmonary fibrosis mechanisms of GRR based on network pharmacology. These findings could contribute to the development of novel treatments for PF and provide a basis for further experimental studies.

The Role of Nintedanib in the Treatment of Progressive Pulmonary Fibrosis of Autoimmune-Related Interstitial Lung Disease

Interstitial lung disease (ILD), which is characterized by pulmonary fibrosis, is a diverse group of disorders. Nintedanib, an antifibrotic drug, is known to attenuate disease progression in ILD with progressive fibrosis, but its efficacy in autoimmune-disease-related ILD remains uncertain. We conducted a comprehensive search for relevant randomized controlled trials, systematic reviews and meta-analyses included in PubMed, ScienceDirect and Scopus databases as of 23 June 2022 and manually reviewed reference lists. Among the 689 titles and abstracts screened, 24 studies were considered, with 4 randomized controlled trials included in our review. Nintedanib, administered at 150 mg twice daily for 52 weeks, consistently slowed forced vital capacity decline. Enhanced efficacy was observed when combining nintedanib with immunomodulators, and the most common adverse effect was diarrhea. In conclusion, our study suggests that nintedanib is a safe option for mitigating the progression of autoimmune-disease-related ILD, providing valuable insights into its potential therapeutic role in this context.

Linking NLRP3 inflammasome and pulmonary fibrosis: mechanistic insights and promising therapeutic avenues.

Pulmonary fibrosis is a devastating disorder distinguished by redundant inflammation and matrix accumulation in the lung interstitium. The early inflammatory cascade coupled with recurring tissue injury orchestrates a set of events marked by perturbed matrix hemostasis, deposition of matrix proteins, and remodeling in lung tissue. Numerous investigations have corroborated a direct correlation between the NLR family pyrin domain-containing 3 (NLRP3) activation and the development of pulmonary fibrosis. Dysregulated activation of NLRP3 within the pulmonary microenvironment exacerbates inflammation and may incite fibrogenic responses. Nevertheless, the precise mechanisms through which the NLRP3 inflammasome elicits pro-fibrogenic responses remain inadequately defined. Contemporary findings suggest that the pro-fibrotic consequences stemming from NLRP3 signaling primarily hinge on the action of interleukin-1β (IL-1β). IL-1β instigates IL-1 receptor signaling, potentiating the activity of transforming growth factor-beta (TGF-β). This signaling cascade, in turn, exerts influence over various transcription factors, including SNAIL, TWIST, and zinc finger E-box-binding homeobox 1 (ZEB 1/2), which collectively foster myofibroblast activation and consequent lung fibrosis. Here, we have connected the dots to illustrate how the NLRP3 inflammasome orchestrates a multitude of signaling events, including the activation of transcription factors that facilitate myofibroblast activation and subsequent lung remodeling. In addition, we have highlighted the prominent role played by various cells in the formation of myofibroblasts, the primary culprit in lung fibrosis. We alsoprovided a concise overview of various compounds that hold the potential to impede NLRP3 inflammasome signaling, thus offering a promising avenue for the treatment of pulmonary fibrosis.

A case of successful treatment of diffuse post-coronavirus pulmonary fibrosis with pirfenidone

IntroductionAccumulated evidence suggests that pulmonary fibrosis is a common complication of COVID-19. Fibrotic post-coronavirus lung changes are similar to the changes found in patients with idiopathic pulmonary fibrosis.AimThe paper describes the outcomes of pirfenidone usage in treatment of patients with post-coronavirus pulmonary fibrosis.Case studyThe paper presents a case study about a 51-year-old male patient, who had diffuse post-coronavirus pulmonary fibrosis with significant impairment of external respiratory function. The patient had experienced severe COVID-19 bilateral polysegmental pneumonia. In the 3rd week of the disease, multislice computed tomography detected signs of fibrosis that affected 80% of lung tissue. It was decided to start antifibrotic treatment with pirfenidone, which is usually used to treat idiopathic pulmonary fibrosis.Results and discussionPirfenidone was prescribed for 3 months according to the conventional scheme in combination with methylprednisolone. This therapy resulted in significant decrease of fibrosis scope , normalization of respiratory function and improvement of patient's quality of life. A key feature of the presented clinical case is a significant positive effect of pirfenidone in treating coronavirus-associated pulmonary fibrosis, which affected 80% of lung tissue of the patient.ConclusionsPost-coronavirus pulmonary fibrosis is characterized by the severe oxygen insufficiency and requires a constant oxygen support. The treatment that included pirfenidone in combination with steroids has demonstrated convincing positive effect. It reduces post-coronavirus pulmonary fibrosis and improves lung function.

Cellular Senescence: A Troy Horse in Pulmonary Fibrosis.

Pulmonary fibrosis (PF) is a chronic interstitial lung disease characterized by myofibroblast abnormal activation and extracellular matrix deposition. However, the pathogenesis of PF remains unclear, and treatment options are limited. Epidemiological studies have shown that the average age of PF patients is estimated to be over 65 years, and the incidence of the disease increases with age. Therefore, PF is considered an age-related disease. A preliminary study on PF patients demonstrated that the combination therapy of the anti-senescence drugs dasatinib and quercetin improved physical functional indicators. Given the global aging population and the role of cellular senescence in tissue and organ aging, understanding the impact of cellular senescence on PF is of growing interest. This article systematically summarizes the causes and signaling pathways of cellular senescence in PF. It also objectively analyzes the impact of senescence in AECs and fibroblasts on PF development. Furthermore, potential intervention methods targeting cellular senescence in PF treatment are discussed. This review not only provides a strong theoretical foundation for understanding and manipulating cellular senescence, developing new therapies to improve age-related diseases, and extending a healthy lifespan but also offers hope for reversing the toxicity caused by the massive accumulation of senescence cells in humans.

OGG1 promoted lung fibrosis by activating fibroblasts via interacting with Snail1

One of abundant DNA lesions induced by reactive oxygen species is 8-oxoguanine (8-oxoG), which compromises genetic instability. 8-oxoG is recognized by the DNA repair protein 8-oxoguanine DNA glycosylase-1 (OGG1) that not only participates in base excision repair but also involves in transcriptional regulation.OGG1 has an important role inIdiopathic Pulmonary Fibrosis (IPF) processing and targeting fibroblasts is a major strategy for the treatment of pulmonary fibrosis, but whether OGG1 activate fibroblast is not clear. In this study, we show that OGG1 expression level is increased at the fibroblast activation stage in mouse lungs induced by bleomycin (BLM) treatment. OGG1 promoted the expression level of fibroblast activation markers (CTGF, fibronectin, and collagen 1) in a pro-fibrotic gene transcriptional regulation pathway via interacting with Snail1, which dependent on 8-oxoG recognition. Global inhibition of OGG1 at the middle stage of lung fibrosis also relieved BLM-induced lung fibrosis in mice. Our results suggest that OGG1 is a target for inhibiting fibroblast activation and a potential therapeutic target for IPF.

The compound artemisinin-hydroxychloroquine ameliorates bleomycin-induced pulmonary fibrosis in rats by inhibiting TGF-β1/Smad2/3 signaling pathway

Pulmonary fibrosis (PF) is a lethal disease characterized by a progressive decline in lung function. Currently, lung transplantation remains the only available treatment for PF. However, both artemisinin (ART) and hydroxychloroquine (HCQ) possess potential antifibrotic properties. This study aimed to investigate the effects and mechanisms of a compound known as Artemisinin-Hydroxychloroquine (AH) in treating PF, specifically by targeting the TGF-β1/Smad2/3 pathway. To do this, we utilized an animal model of PF induced by a single tracheal drip of bleomycin (BLM) in Sprague-Dawley (SD) rats. The PF animal models were administered various doses of AH, and the efficacy and safety of AH were evaluated through pulmonary function testing, blood routine tests, serum biochemistry tests, organ index measurements, and pathological examinations. Additionally, Elisa, western blotting, and qPCR techniques were employed to explore the potential molecular mechanisms of AH in treating PF. Our findings reveal that AH effectively and safely alleviate PF by inhibiting BLM-induced specific inflammation, reducing extracellular matrix (ECM) deposition, and interfering with the TGF-β1/Smad2/3 signaling pathway. Notably, the windfall for this study is that the inhibition of ECM may initiate self-healing in the BLM-induced PF animal model. In conclusion, AH shows promise as a potential therapeutic drug for PF, as it inhibits disease progression through the TGF-β1/Smad2/3 signaling pathway.

TrxR/Trx inhibitor butaselen ameliorates pulmonary fibrosis by suppressing NF-κB/TGF-β1/Smads signaling

Pulmonary fibrosis is highly lethal with limited treatments. Butaselen (BS) is an inhibitor of thioredoxin reductase (TrxR)/thioredoxin (Trx) with anti-tumor activity. However, its impact on pulmonary fibrosis and the involved mechanisms remain unclear. Here, we demonstrate that BS is a potential drug for the treatment of pulmonary fibrosis. Specifically, BS can inhibit pulmonary fibrosis both in vitro and in vivo, with comparable efficacy and enhanced safety when compared with pirfenidone. BS and dexamethasone display a synergistic effect in inhibiting pulmonary fibrosis both in vitro and in vivo. Mechanistic studies reveal that BS can inhibit the TrxR activity during pulmonary fibrosis. RNA-sequencing analysis identifies that genes of ECM-related signaling pathways are notably affected by BS. BS can not only inhibit the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and reduce pulmonary fibrosis-related inflammation, but also reduce NF-κB-activated transcriptional expression of transforming growth factor-β1 (TGF-β1), which leads to the inactivation of Smad2/Smad3 and decrease of collagen formation and fibrosis. Moreover, the knockdown of Trx1 with siRNA can also inhibit NF-κB/TGF-β1/Smads signaling. In conclusion, the TrxR/Trx inhibitor butaselen can suppress pulmonary fibrosis by inhibiting NF-κB/TGF-β1/Smads signaling.

The main bioactive compound of Panax notoginseng, notoginsenoside R1, alleviates pulmonary fibrosis via MBD2/SHIP and STAT3 pathway

Notoginsenoside R1 is known as the main bioactive compound of the traditional Chinese medicine and functional food, Panax notoginseng. Network pharmacology prediction indicated that notoginsenoside R1 might be effective in the treatment of pulmonary fibrosis. This study investigated the effectiveness and pharmacological mechanism of notoginsenoside R1 on attenuating pulmonary fibrosis in mice. The results showed that notoginsenoside R1 alleviated the inflammatory response in the lung by down-regulating the polarization of M1 macrophages via the SOCS3/STAT3 pathway. Meanwhile, notoginsenoside R1 promoted the transcription of SH2 domain containing inositol 5′-phosphatase (SHIP) by down-regulating methyl-CpG binding domain 2 (MBD2) expression, thus attenuated PI3K/AKT-mediated polarization of M2 macrophages, and finally regulated the TGF-β1/Smad3 signaling pathway in order to attenuate pulmonary fibrosis. This study presented some possible mechanism of notoginsenoside R1 in the treatment of pulmonary fibrosis, suggesting that P. notoginseng may be served as potential medicined diet in preventing and treating such diseases.