Treatment Of Pulmonary Fibrosis Research Articles

Design and Synthesis of Novel Ultralong-Acting Peptides as EDP-EBP Interaction Inhibitors for Pulmonary Fibrosis Treatment.

The increased remodeling of the extracellular matrix (ECM) in pulmonary fibrosis (PF) generates bioactive ECM fragments called matricryptins, which include elastin-derived peptides (EDPs). The interaction between EDPs and their receptors, including elastin-binding protein (EBP), plays a crucial role in exacerbating fibrosis. Here, we present LXJ-02 for the first time, a novel ultralong-acting inhibitor that disrupts the EDPs/EBP peptide-protein interaction, promoting macrophages to secrete matrix metalloproteinase-12 (MMP-12), and showing great promise as a stable peptide. MMP-12 has traditionally been implicated in promoting inflammation and fibrosis in various acute and chronic diseases. However, we reveal a novel role of LXJ-02 that activates the macrophage-MMP-12 axis to increase MMP-12 expression and degrade ECM components like elastin. This leads to the preventing of PF while also improving EDP-EBP interaction. LXJ-02 effectively reverses PF in mouse models with minimal side effects, holding great promise as an excellent therapeutic agent for lung fibrosis.

Tacrolimus alleviates pulmonary fibrosis progression through inhibiting the activation and interaction of ILC2 and monocytes

Idiopathic pulmonary fibrosis (IPF) is a heterogeneous group of lung diseases with different etiologies and characterized by progressive fibrosis. This disease usually causes pulmonary structural remodeling and decreased pulmonary function. The median survival of IPF patients is 2–5 years. Predominantly accumulation of type II innate immune cells accelerates fibrosis progression by secreting multiple pro-fibrotic cytokines. Group 2 innate lymphoid cells (ILC2) and monocytes/macrophages play key roles in innate immunity and aggravate the formation of pro-fibrotic environment. As a potent immunosuppressant, tacrolimus has shown efficacy in alleviating the progression of pulmonary fibrosis. In this study, we found that tacrolimus is capable of suppressing ILC2 activation, monocyte differentiation and the interaction of these two cells. This effect further reduced activation of monocyte-derived macrophages (Mo-M), thus resulting in a decline of myofibroblast activation and collagen deposition. The combination of tacrolimus and nintedanib was more effective than either drug alone. This study will reveal the specific process of tacrolimus alleviating pulmonary fibrosis by regulating type II immunity, and explore the potential feasibility of tacrolimus combined with nintedanib in the treatment of pulmonary fibrosis. This project will provide new ideas for clinical optimization of anti-pulmonary fibrosis drug strategies.

Inhalable FN-binding liposomes or liposome-exosome hybrid bionic vesicles encapsulated microparticles for enhanced pulmonary fibrosis therapy

Pulmonary fibrosis (PF) is a chronic, progressive and irreversible interstitial lung disease that seriously threatens human life and health. Our previous study demonstrated the unique superiority of traditional Chinese medicine cryptotanshinone (CTS) combined with sustained pulmonary drug delivery for treating PF. In this study, we aimed to enhance the selectivity, targeting efficiency and sustained-release capability based on this delivery system. To this end, we developed and evaluated CTS-loaded modified liposomes-chitosan (CS) microspheres SM(CT-lipo) and liposome-exosome hybrid bionic vesicles-CS microspheres SM(LE). The prepared nano-in-micro particles system integrates the advantages of the carriers and complements each other. SM(CT-lipo) and SM(LE) achieved lung myofibroblast-specific targeting through CREKA peptide binding specifically to fibronectin (FN) and the homing effect of exosomes on parent cells, respectively, facilitating efficient delivery of anti-fibrosis drugs to lung lesions. Furthermore, compared with daily administration of conventional microspheres SM(NC) and positive control drug pirfenidone (PFD), inhaled administration of SM(CT-lipo) and SM(LE) every two days still attained similar efficacy, exhibiting excellent sustained drug release ability. In summary, our findings suggest that the developed SM(CT-lipo) and SM(LE) delivery strategies could achieve more accurate, efficient and safe therapy, providing novel insights into the treatment of chronic PF.

A WNT mimetic with broad spectrum FZD-specificity decreases fibrosis and improves function in a pulmonary damage model

BackgroundWnt/β-catenin signaling is critical for lung development and AT2 stem cell maintenance in adults, but excessive pathway activation has been associated with pulmonary fibrosis, both in animal models and human diseases such as idiopathic pulmonary fibrosis (IPF). IPF is a detrimental interstitial lung disease, and although two approved drugs limit functional decline, transplantation is the only treatment that extends survival, highlighting the need for regenerative therapies.MethodsUsing our antibody-based platform of Wnt/β-catenin modulators, we investigated the ability of a pathway antagonist and pathway activators to reduce pulmonary fibrosis in the acute bleomycin model, and we tested the ability of a WNT mimetic to affect alveolar organoid cultures.ResultsA WNT mimetic agonist with broad FZD-binding specificity (FZD1,2,5,7,8) potently expanded alveolar organoids. Upon therapeutic dosing, a broad FZD-binding specific Wnt mimetic decreased pulmonary inflammation and fibrosis and increased lung function in the bleomycin model, and it impacted multiple lung cell types in vivo.ConclusionsOur results highlight the unexpected capacity of a WNT mimetic to effect tissue repair after lung damage and support the continued development of Wnt/β-catenin pathway modulation for the treatment of pulmonary fibrosis.

Advances in the Study of Non-Coding RNA in the Signaling Pathway of Pulmonary Fibrosis.

Pulmonary fibrosis is a group of chronic, progressive, and irreversible interstitial lung diseases, which are common to most end-stage lung diseases and are one of the most difficult diseases of the respiratory system. In recent years, due to the frequent occurrence of air pollution and smog, the incidence of pulmonary fibrosis in China has increased year by year, the morbidity and mortality rates of pulmonary fibrosis have gradually increased and the age of the disease tends to be younger. However, the pathogenesis of pulmonary fibrosis is not yet fully understood and is needed to further explore new drug targets. Studies have shown that non-coding RNAs play an important role in regulating the process of pulmonary fibrosis, non-coding RNAs and their specifically expressed can promote or inhibit the process. Here, we review the role of some in the regulation of pulmonary fibrosis signaling pathways and provide new ideas for the clinical diagnosis and treatment of pulmonary fibrosis.

Geneticin ameliorates pulmonary fibrosis by attenuating the TGF-β/Smad via modulating AMPK/SIRT1 signaling

AimIdiopathic pulmonary fibrosis (IPF) is a chronic, progressive condition with unknown aetiology that causes the lung parenchyma to scar incessantly, lowering the quality of life and hastening death. In this investigation, we studied the anti-fibrotic activity of Geneticin (a derivative of gentamycin) using in vitro and in vivo models. Main methodsThe TGF-β-mediated differentiation model was adopted to investigate (fibrotic marker's levels/expression) the anti-fibrotic activity of geneticin (GNC) in in-vitro scenarios (Ll29 and DHLF cells). In vivo, the bleomycin (BLM)-induced pulmonary fibrosis model was employed by administering BLM intratracheally. Post 14 days of BLM administration, animals were treated with geneticin (6.25, 12.5, and 25 mg·kg−1) for another 14 days, and their therapeutic effect was investigated using a spectrum of techniques. Key findingsRTqPCR and western-blot results revealed that geneticin treatment significantly attenuated the TGF-β mediated fibrotic cascade of markers in both in-vitro and in-vivo models. Further, the BLM-induced pulmonary fibrosis model revealed, that geneticin dose-dependently reduced the BLM-induced inflammatory cell infiltrations, and thickness of the alveoli walls, improved the structural distortion of the lung, and aided in improving the survival rate of the rats. Picrosirus and Masson's trichrome staining indicated that geneticin therapy reduced collagen deposition and, as a result, lung functional characteristics were improved as assessed by flexivent. Mechanistic studies have shown that geneticin reduced fibrosis by attenuating the TGF-β/Smad through modulating the AMPK/SIRT1 signaling. SignificanceThese findings suggest that geneticin may be a promising therapeutic agent for the treatment of pulmonary fibrosis in clinical settings.

Tanshinone IIA positively regulates the Keap1-Nrf2 system to alleviate pulmonary fibrosis via the sestrin2-sqstm1 signaling axis-mediated autophagy

BackgroundActivation of myofibroblasts, linked to oxidative stress, emerges as a pivotal role in the progression of pulmonary fibrosis (PF). Our prior research has underscored the therapeutic promise of tanshinone IIA (Tan-IIA) in mitigating PF by enhancing nuclear factor-erythroid 2-related factor 2 (Nrf2) activity. Nevertheless, the molecular basis through which Tan-IIA influences Nrf2 activity has yet to be fully elucidated. MethodsThe influence of Tan-IIA on PF was assessed in vivo and in vitro models. Inhibitors, overexpression plasmids, and small interfering RNA (siRNA) were utilized to probe the underlying mechanism of action in vitro. ResultsWe demonstrate that Tan-IIA effectively activates the kelch-like ECH-associated protein 1 (Keap1)-Nrf2 antioxidant pathway, which in turn inhibits myofibroblast activation and ameliorates PF. Notably, the stability and nucleo-cytoplasmic shuttling of Nrf2 is shown to be dependent on augmented autophagic flux, which is in alignment with the observation that Tan-IIA induces autophagy. Inhibition of autophagy, conversely, fosters the activation of extracellular matrix (ECM)-producing myofibroblasts. Further, Tan-IIA initiates an autophagy program through the sestrin 2 (Sesn2)-sequestosome 1 (Sqstm1) signaling axis, crucial for protecting Nrf2 from Keap1-mediated degradation. Meanwhile, these findings were corroborated in a murine model of PF. ConclusionCollectively, we observed for the first time that the Sqstm1-Sesn2 axis-mediated autophagic degradation of Keap1 effectively prevents myofibroblast activation and reduces the synthesis of ECM. This autophagy‐dependent degradation of Keap1 can be initiated by the Tan-IIA treatment, which solidifies its potential as an Nrf2-modulating agent for PF treatment.

Ferroptosis Mediates Pulmonary Fibrosis: Implications for the Effect of Astragalus and Panax notoginseng Decoction.

To investigate the mechanism through which Astragalus and Panax notoginseng decoction (APD) facilitates the treatment of ferroptosis-mediated pulmonary fibrosis. First, the electromedical measurement systems were used to measure respiratory function in mice; the lungs were then collected for histological staining. Potential pharmacologic targets were predicted via network pharmacology. Finally, tests including immunohistochemistry, reverse transcription-quantitative polymerase chain reaction, and western blotting were used to evaluate the relative expression levels of collagen, transforming growth factor β, α-smooth muscle actin, hydroxyproline, and ferroptosis-related genes (GPX4, SLC7A11, ACSL4, and PTGS2) and candidates involved in the mediation of pathways associated with ferroptosis (Hif-1α and EGFR). APD prevented the occurrence of restrictive ventilation dysfunction induced by ferroptosis. Extracellular matrix and collagen fiber deposition were significantly reduced when the APD group compared with the model group; furthermore, ferroptosis was attenuated, expression of PTGS2 and ACSL4 increased, and expression of GPX4 and SLC7A11 decreased. In the APD group, the candidates related to the mediation of ferroptosis (Hif-1α and EGFR) decreased compared with the model group. Discussion and Conclusions. APD may ameliorate restrictive ventilatory dysfunction through the inhibition of ferroptosis. This was achieved through the attenuation of collagen deposition and inflammatory recruitment in pulmonary fibrosis. The underlying mechanisms might involve Hif-1α and EGFR.

Study on miRNA expression and regulatory network of Amygdalus mongolica oil and amygdalin in the treatment of pulmonary fibrosis

IntroductionAmygdalus mongolica (Maxim.) Ricker is a traditional Chinese medicine known for its ability to relieve cough and expectorate phlegm and is commonly used to treat dry throat, dry cough, and bronchitis. A. mongolica oil and amygdalin were the active components isolated from the seed kernel seeds of A. mongolica. The main objective of this study was to investigate the effects of A. mongolica oil and amygdalin on bleomycin-induced pulmonary fibrosis (PF) in rats by integrating pharmacodynamic, transcriptomics, and bioinformatics, to determine the changes of miRNAs in both against PF, and to explore the underlying mechanisms. MethodsA rat model of PF was induced by administering bleomycin through the trachea. The rats were randomized into several groups: a control group (CON), an untreated model group (MOD), an active control group treated with pirfenidone (PFD), and groups receiving different doses of A. mongolica oil (5 g/kg [OIL-L], 10 g/kg [OIL-M], and 15 g/kg [OIL-H]), or amygdalin (20 mg/kg [AMY-L], 40 mg/kg [AMY-M], and 80 mg/kg [AMY-H]). After 28 days, samples were collected for subsequent pharmacodynamic and transcriptomic analyses. ResultsThe results demonstrated that A. mongolica oil and amygdalin effectively reduced the abnormally elevated levels of IL-1β, IL-6, HA, LN and COL-IV in PF rats and alleviated bleomycin-induced pulmonary fibrotic changes. Furthermore, compared to the MOD group, the expression levels of 27 miRNAs were up-regulated and 23 miRNAs were down-regulated in the OIL 10 g/kg group. Among the up-regulated miRNAs, two novel differentially expressed miRNAs (DE-miRNAs) were identified. In the AMY 20 mg/kg group, 12 miRNAs were up-regulated and 10 were down-regulated when compared to the MOD group. These DE-miRNAs were found to be enriched in pathways such as the PI3K-Akt signalling pathway, MAPK signalling pathway, and calcium signalling pathway. The microRNAs miR-301b-3p, miR-667-5p, miR-363-3p, and miR-540-3p may be associated with both the anti-PF mechanism of A. mongolica oil and the anti-PF mechanism of amygdalin. DiscussionNumerous studies have demonstrated the significance of various pathways, including PI3K-Akt, MAPK, and calcium signalling pathways, in the mechanism of PF and the development of anti-PF medications. Meanwhile, multiple miRNAs, including miR-301b-3p, miR-667-5p, miR-363-3p, and miR-540-3p, have been found to be associated with lung disease and fibrosis. ConclusionsThe present experiments confirmed the effectiveness of A. mongolica oil and amygdalin in reducing inflammation and fibrosis in bleomycin-induced PF rats, with particularly favorable outcomes observed in the A. mongolica oil 10 g/kg versus amygdalin 20 mg/kg. Meanwhile, miRNAs miR-301b-3p, miR-667-5p, miR-363-3p and miR-540-3p were found to be potentially associated with both A. mongolica oil and amygdalin anti-PF mechanisms. Based on our findings, we suggest that these miRNAs might play key roles in the anti-PF mechanism of A. mongolica. The individual miRNAs require further investigation.

Inhaled nintedanib nanoparticles for enhanced efficacy in idiopathic pulmonary fibrosis (IPF) treatment – Evidence in disease-relevant in-vitro models

Idiopathic pulmonary fibrosis (IPF) is a fatal and progressive interstitial lung disease with a high mortality rate due to limited prognosis. According to the National Institutes of Health (NIH), approximately 100,000 people in the United States suffer from IPF, and around 50% likelihood of dying within 2–3 years. Currently, nintedanib (Nint) is one of the only 2 FDA-approved drugs for the treatment of IPF, with anti-fibrotic and anti-inflammatory activities. However, Nint oral capsules have some undesirable limitations such as low bioavailability and high dose requirement for sufficient therapeutic efficacy, leading to various side effects associated with oral delivery. To address these shortcomings and enhance the therapeutic potential, Nint was loaded into PLGA nanoparticles (Nint NPs) for localized pulmonary delivery. In-vitro cell culture studies indicated that nano-sized particles (179 ± 3 nm) of Nint NPs enhanced cellular uptake in airway epithelial cells and normal human lung fibroblasts, while readily avoiding macrophage phagocytosis. Transforming growth factor-beta (TGF-β) (10 ng/mL) was selected to establish IPF in cells, which resulted in proliferation and rapid wound healing, whereas Nint NPs showed superior ability in inhibiting these pathological phenomena compared to free Nint. Upon further evaluation of pathological mechanisms of IPF, Nint NPs remarkably attenuated epithelial-to-mesenchymal transition (EMT) by elevating epithelial marker E-cadherin level and reducing extracellular matrix (ECM) deposition by evidence of reduced collagen production and fibroblast-to-myofibroblast differentiation marker, α-SMA. Nint NPs also decreased expression of inflammatory cytokine IL-17A and indicated autophagy as a separate anti-fibrotic mechanism. Finally, Nint NPs proved their superior efficacy in a novel IPF cell model using diseased lung ECM substrates. Hence, inhalation therapy of Nint NPs is a promising alternative tool for oral capsules in IPF therapy.

Exosomes from senescent epithelial cells activate pulmonary fibroblasts via the miR-217-5p/Sirt1 axis in paraquat-induced pulmonary fibrosis

BackgroundParaquat (PQ) is a widely used and highly toxic herbicide that poses a significant risk to human health. The main consequence of PQ poisoning is pulmonary fibrosis, which can result in respiratory failure and potentially death. Our research aims to uncover a crucial mechanism in which PQ poisoning induces senescence in epithelial cells, ultimately regulating the activation of pulmonary fibroblasts through the exosomal pathway.MethodsCellular senescence was determined by immunohistochemistry and SA-β-Gal staining. The expression of miRNAs was measured by qPCR. Pulmonary fibroblasts treated with specific siRNA of SIRT1 or LV-SIRT1 were used to analysis senescent exosomes-mediated fibroblasts activation. Luciferase reporter assay and western blot were performed to elucidated the underlying molecular mechanisms. The effects of miR-217-5p antagomir on pulmonary fibrosis were assessed in PQ-poisoned mice models.ResultsImpairing the secretion of exosomes effectively mitigates the harmful effects of senescent epithelial cells on pulmonary fibroblasts, offering protection against PQ-induced pulmonary fibrosis in mice. Additionally, we have identified a remarkable elevation of miR-217-5p expression in the exosomes of PQ-treated epithelial cells, which specifically contributes to fibroblasts activation via targeted inhibition of SIRT1, a protein involved in cellular stress response. Remarkably, suppression of miR-217-5p effectively impaired senescent epithelial cells-induced fibroblasts activation. Further investigation has revealed that miR-217-5p attenuated SIRT1 expression and subsequently resulted in enhanced acetylation of β-catenin and Wnt signaling activation.ConclusionThese findings highlight a potential strategy for the treatment of pulmonary fibrosis induced by PQ poisoning. Disrupting the communication between senescent epithelial cells and pulmonary fibroblasts, particularly by targeting the miR-217-5p/SIRT1/β-catenin axis, may be able to alleviate the effects of PQ poisoning on the lungs.

MAP kinase phosphatase-1 inhibition of p38α within lung myofibroblasts is essential for spontaneous fibrosis resolution.

Fibrosis following tissue injury is distinguished from normal repair by the accumulation of pathogenic and apoptosis-resistant myofibroblasts (MFs), which arise primarily by differentiation from resident fibroblasts. Endogenous molecular brakes that promote MF dedifferentiation and clearance during spontaneous resolution of experimental lung fibrosis may provide insights that could inform and improve treatment of progressive pulmonary fibrosis in patients. Mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP1) influences cellular phenotype and fate through precise and timely regulation of MAPK activity within various cell types and tissues, yet its role in lung fibroblasts and pulmonary fibrosis has not been explored. Utilizing gain- and loss-of-function studies, we found that MKP1 promoted lung MF dedifferentiation and restored their sensitivity to apoptosis - effects determined to be mainly dependent upon its dephosphorylation of p38α MAPK (p38α). Fibroblast-specific deletion of MKP1 following peak bleomycin-induced lung fibrosis largely abrogated its subsequent spontaneous resolution. Such resolution was restored by treating these transgenic mice with the p38α inhibitor VX-702. We conclude that MKP1 is a critical antifibrotic brake whose inhibition of pathogenic p38α in lung fibroblasts is necessary for fibrosis resolution following lung injury.

Toll-Like Receptor 9 Aggravates Pulmonary Fibrosis by Promoting NLRP3-Mediated Pyroptosis of Alveolar Epithelial Cells.

The apoptosis-prone property of alveolar epithelial cells plays a crucial role in pulmonary fibrosis(PF), but the role of pyroptosis in it is still unclear. Toll-like receptor 9(TLR9) has been reported to play a vital role in the pathogenesis of many diseases. However, the effect of TLR9 on alveolar epithelial cells in PF has not been fully elucidated. Gene expression microarray related to Idiopathic pulmonary fibrosis(IPF) was obtained from the Gene Expression Omnibus(GEO) database. In the mouse model of bleomycin-induced PF, adeno-associated virus(AAV6) was used to interfere with TLR9 to construct TLR9 knockdown mice to study the role of TLR9 in PF, and the specific mechanism was studied by intratracheal instillation of NLR family pyrin domain containing 3(NLRP3) activator. In vitro experiments were performed using A549 cells. Bleomycin-induced pyroptosis in the lung tissue of PF mice increased, and TLR9 protein levels also increased, especially in alveolar epithelial cells. The levels of fibrosis and pyroptosis in lung tissue of TLR9 knockdown mice were improved. We found that TLR9 can bind to the NLRP3, thereby increasing the activation of the NLRP3/caspase-1 inflammasome pathway. When we use the NLRP3 activator, the levels of fibrosis and pyroptosis in lung tissue of TLR9 knockout mice can be counteracted. Pyroptosis of alveolar epithelial cells plays a vital role in PF, and TLR9 can promote NLRP3-mediated pyroptosis of alveolar epithelial cells to aggravate the progression of PF and may become a feasible target for the prevention and treatment of PF.

Steroidal saponins and homoisoflavonoids from the fibrous roots of ophiopogon japonicus and their anti-pulmonary fibrosis activities

The chemical investigation of the fibrous roots of Ophiopogon japonicus afforded two new steroidal saponins, named ophiojaponin F (1) and ophiojaponin G (2), together with twelve known steroidal saponins (3–14) and ten known homoisoflavonoids (15–24). The structures of the isolated compounds were established unambiguously via spectroscopic analyses (NMR and HR-ESI-MS). Ophiojaponin F (1) is a 23-hydroxylated spirostanol saponin, and this type of steroidal saponin rarely been reported in liriopogons. All isolates were evaluated for their anti-pulmonary fibrosis activities on TGF-β1-actived NIH3T3 cells for the first time. Among them, compounds 3, 4, 11–13, 15–19, 21 and 24 showed potential anti-pulmonary fibrosis effects with IC50 values ranging from 3.61 ± 0.86 μM to 21.33 ± 1.82 μM, and the main component ophiopogonin D (4) displayed the best activity with an IC50 value of 3.61 ± 0.86 μM. Thus, ophiopogonin D may be a potent candidate for the treatment of pulmonary fibrosis.

LncRNA-mediated ceRNA network reveals the mechanism of action of Saorilao-4 decoction against pulmonary fibrosis.

Introduction: Pulmonary fibrosis (PF), a type of interstitial pneumonia with complex etiology and high mortality, is characterized by progressive scarring of the alveolar interstitium and myofibroblastic lesions. In this study, we screened for potential biomarkers in PF and clarified the role of the lncRNA-miRNA-mRNA ceRNA network in the inhibitory effect of SRL-4 on PF. Methods: Healthy male SPF SD rats were randomly divided into three groups, namely, CON, MOD, and SRL-4. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed to determine the biological functions of the target genes. A visualized lncRNA-miRNA-mRNA ceRNA network was constructed using Cytoscape, while key genes in the network were identified using the cytoNCA plugin. Results: Seventy-four differentially expressed lncRNAs and 118 differentially expressed mRNAs were identified. Gene Ontology analysis revealed that the target genes were mainly enriched in the cell membrane and in response to organic substances, while Kyoto Encyclopedia of Genes and Genomes analysis showed that the target genes were mainly enriched in the AMPK, PPAR, and cAMP signaling pathways. We elucidated a ceRNA axis, namely, Plcd3-OT1/rno-miR-150-3p/Fkbp5, with potential implications in PF. Key genes, such as AABR07051308.1-201, F2rl2-OT1, and LINC3337, may be important targets for the treatment of PF, while the AMPK, PPAR, and cAMP signaling pathways are potential key targets and important pathways through which SRL-4 mitigates PF. Conclusion: Our findings suggest that SRL-4 improves PF by regulating the lncRNA-miRNA-mRNA network.

Circular RNA MKLN1 promotes epithelial-mesenchymal transition in pulmonary fibrosis by regulating the miR-26a/b-5p/CDK8 axis in human alveolar epithelial cells and mice models.

Pulmonary fibrosis involves destruction of the lung parenchyma and extracellular matrix deposition. Effective treatments for pulmonary fibrosis are lacking and its pathogenesis is still unclear. Studies have found that epithelial-mesenchymal transition (EMT) of alveolar epithelial cells (AECs) plays an important role in progression of pulmonary fibrosis. Thus, an in-depth exploration of its mechanism might identify new therapeutic targets. In this study, we revealed that a novel circular RNA, MKLN1 (circMKLN1), was significantly elevated in two pulmonary fibrosis models (intraperitoneally with PQ, 50mg/kg for 7days, and intratracheally with BLM, 5mg/kg for 28days). Additionally, circMKLN1 was positively correlated with the severity of pulmonary fibrosis. Inhibition of circMKLN1 expression significantly reduced collagen deposition and inhibited EMT in AECs. EMT was aggravated after circMKLN1 overexpression in AECs. MiR-26a-5p/miR-26b-5p (miR-26a/b), the targets of circMKLN1, were confirmed by luciferase reporter assays. CircMKLN1 inhibition elevated miR-26a/b expression. Significantly decreased expression of CDK8 (one of the miR-26a/b targets) was observed after inhibition of circMKLN1. EMT was exacerbated again, and CDK8 expression was significantly increased after circMKLN1 inhibition and cotransfection of miR-26a/b inhibitors in AECs. Our research indicated that circMKLN1 promoted CDK8 expression through sponge adsorption of miR-26a/b, which regulates EMT and pulmonary fibrosis. This study provides a theoretical basis for finding new targets or biomarkers in pulmonary fibrosis.

Integrated analysis of ceRNA-miRNA changes in paraquat-induced pulmonary epithelial-mesenchymal transition via high-throughput sequencing.

Recent studies have shown that epithelial-mesenchymal transition (EMT) plays an important role in paraquat (PQ)-induced tissue fibrosis, which is the main cause of death in patients with PQ poisoning. However, no effective treatment for pulmonary interstitial fibrosis caused by PQ poisoning exists. It is of great significance for us to find new therapeutic targets through bioinformatics in PQ-induced EMT. We conducted transcriptome sequencing to determine the expression profiles of 1210 messenger RNAs (mRNAs), 558 long noncoding RNAs, 28 microRNAs (miRNAs), including 18 known-miRNAs, 10 novel-miRNAsand 154 circular RNAs in the PQ-exposed EMT group mice. Using gene ontology and Kyoto Encyclopaedia of Genes and Genomes analyses, we identified the pathways associated with signal transduction, cancers, endocrine systemsand immune systems were involved in PQ-induced EMT. Furthermore, we constructedlong noncoding RNA-miRNA-mRNA interrelated networks and found that upregulated genes included Il22ra2, Mdm4, Slc35e2and Angptl4, and downregulated genes included RGS2, Gabpb2, Acvr1, Prkd3, Sp100, Tlr12, Syt15and Camk2d. Thirteen new potential competitive endogenous RNA targets were also identified for further treatment of PQ-induced pulmonary tissue fibrosis. Through further study of the pathway and networks, we may identify new molecular targets in PQ-induced pulmonary EMT.

Spatially resolved metabolomics visualizes heterogeneous distribution of metabolites in lung tissue and the anti-pulmonary fibrosis effect of Prismatomeris connate extract

Pulmonary fibrosis (PF) is a chronic progressive end-stage lung disease. However, the mechanisms underlying the progression of this disease remain elusive. Presently, clinically employed drugs are scarce for the treatment of pulmonary fibrosis. Hence, there is an urgent need for developing novel drugs to address such diseases. properties. Our study found for the first time that a natural source of Prismatomeris connate ethyl acetate extract (HG-2) had a significant anti-pulmonary fibrosis effect by inhibiting the expression of the transforming growth factor beta 1/suppressor of mothers against decapentaplegic (TGF-β1/Smad) pathway. Network pharmacological analysis suggested that HG-2 had effects on tyrosine kinase phosphorylation, cellular response to reactive oxygen species, and extracellular matrix disassembly. Moreover, mass spectrometry imaging (MSI) was used to visualize the heterogeneous distribution of endogenous metabolites in lung tissue and reveal the anti-pulmonary fibrosis metabolic mechanism of HG-2, which was related to arginine synthesis, alanine, aspartic acid and glutamate metabolism, the down-regulation of arachidonic acid metabolism, and the up-regulation of glycerophospholipid metabolism. In conclusion, we elaborated on the relationship between metabolite distribution and the progression of PF, constructed the regulatory metabolic network of HG-2, and discovered the multi-target therapeutic effect of HG-2, which might be conducive to the development of new drugs for PF.

Curcumin as a promising treatment for pulmonary fibrosis: Mechanism and therapeutic potential

IntroductionPulmonary fibrosis (PF) is characterized by excessive proliferation of alveolar epithelial cells and fibroblasts, abnormal deposition of fibrous connective tissue, altered alveolar structure, impaired lung function, and increased airway resistance. Curcumin has been studied as an inhibitor of pulmonary fibrosis. MethodsThis study investigated curcumin's inhibitory effect and mechanism on bleomycin (BLM) -induced pulmonary fibrosis in mice. Curcumin was administered to the mice to assess its therapeutic potential. The mice were weighed every two days, and the respiratory function of the mice was measured on day 7, 14, and 21. After 21 days, the mice's lung tissue was examined for hydroxyproline (HYP), malondialdehyde (MDA), superoxide dismutase (SOD) levels, as well as relevant protein expression. ResultsThe administration of curcumin significantly alleviated respiratory dysfunction and improved the quality of life of mice with pulmonary fibrosis. It led to an increase in the expression of oxidative stress-related proteins Nuclear factor erythroid 2-related factor 2 (Nrf2) and Heme Oxygenase-1 (HO-1), while reducing apoptosis-related factors. Pathological examination revealed a notable reduction in lung tissue fibrosis. ConclusionsCurcumin demonstrated promising therapeutic effects in mice with BLM-induced pulmonary fibrosis. The activation of the Akt pathway, upregulating the expression of Nrf2 and HO-1, contributed to curcumin's antioxidant effects and its potential for treating pulmonary fibrosis in mice.

Use of Race-Specific Equations in Pulmonary Function Tests Impedes Potential Eligibility for Care and Treatment of Pulmonary Fibrosis.

The use of race-specific reference values to evaluate pulmonary function has long been embedded into clinical practice; however, there is a growing consensus that this practice may be inappropriate and that use of race-neutral equations should be adopted to improve access to healthcare. To evaluate if using race-neutral equations to assess percent predicted forced vital capacity (FVC%pred) impacts eligibility for clinical trials, antifibrotic therapy and referral for lung transplantation in Black, Hispanic/Latino, and White patients with interstitial lung disease (ILD) Methods: FVC%pred values for patients from the Pulmonary Fibrosis Foundation Patient Registry were calculated using race-specific (Hankinson 1999), race-agnostic (Global Lung Function Initiative [GLI]-2012), and race-neutral (GLI-2022 or GLI-Global) equations. Eligibility for ILD clinical trials (FVC%pred >45% and <90%), antifibrotic therapy (FVC%pred >55% and <82%), and lung transplantation referral (FVC%pred <70%) using GLI-2022 and GLI-2012 were compared with that of Hankinson 1999. Baseline characteristics were available for 1882 patients (Black, n=104; Hispanic/Latino, n=103; White, n=1675), and outcomes were evaluated in 1531 patients with FVC%pred within ±90 days of Registry enrollment (Black, n=78; Hispanic/Latino, n=72; White, n=1381). Black patients were younger at consent and more likely to be female than Hispanic/Latino or White patients. Compared with GLI-2022, Hankinson's 1999 criteria misclassified 22% of Black patients, 14% of Hispanic/Latino patients, and 12% of White patients for ILD clinical trial eligibility; misclassified 21% of Black patients, 17% of Hispanic/Latino patients, and 19% of White patients for antifibrotic therapy eligibility; and misclassified 6% of Black patients, 14% of Hispanic/Latino patients, and 12% of White patients for lung transplantation referral. Similar trends were observed when comparing GLI-2012 with Hankinson 1999. Misclassification of patients for critical interventions is highly prevalent when using Hankinson's 1999 criteria and highlights the need to consider adopting the race-neutral GLI-2022 for enhanced accuracy and more equitable representation in pulmonary healthcare. Our results make a compelling case for re-evaluating the use of race as a physiological variable and emphasize the pressing need for continuous innovation to ensure equal and optimal care for all patients, regardless of their race or ethnicity. NCT02758808 Primary source of funding: This analysis was sponsored by F. Hoffmann-La Roche, Ltd./Genentech, Inc.