Phytomedicine. 2022 Dec 13;109:154604. doi: 10.1016/j.phymed.2022.154604. Online ahead of print.

ABSTRACT

BACKGROUND: Jinshui Huanxian formula (JHF) ameliorates idiopathic pulmonary fibrosis patients. Active compounds, including icariin, isoliquiritigenin, nobiletin, peimine, and paeoniflorin, deriving from JHF were combined as effective-component compatibility ECC of JHF II (ECC-JHF II), which is an effective therapeutic strategy for pulmonary fibrosis (PF) induced by bleomycin (BLM) in rats.

PURPOSE: This study aimed to explore the underlying mechanism of ECC-JHF II on pulmonary fibrosis.

METHODS: A model of PF in rats was established through intratracheal instillation of BLM. Pulmonary function, pathological changes, and collagen deposition were examined. The gene and protein expressions in fibroblast activation were detected by quantitative real-time PCR and western blotting respectively.

RESULTS: ECC-JHF II significantly improved BLM-induced PF in rats, manifested as decreased collagen deposition, reduced pathological damage and improved pulmonary function. Furthermore, ECC-JHF II inhibited fibroblast activation by reducing the expression of α-smooth muscle actin (α-SMA) and fibronectin. We analyzed the targets of ECC-JHF II and differentially expressed genes (DEGs) of fibroblast activation induced by transforming growth factor-β1 (TGF-β1) and found that ECC-JHF II might regulate fibroblast activation by EGFR, PI3K-Akt or mTOR signaling pathway. In vitro experiments, we also found that ECC-JHF II suppressed the mTOR pathway, such as downregulating the phosphorylation levels of p70S6K in fibroblast activation induced by TGF-β1. After activating mTOR signaling, the inhibition of ECC-JHF II on fibroblast activation was blocked. These results suggested that ECC-JHF II potently ameliorated pulmonary fibrosis in rats and effectively suppressed fibroblast activation by interfering with mTOR signaling.

CONCLUSION: We combined transcriptomics with the network analysis to predict the mechanism underlying ECC-JHF II suppression of fibroblast activation. In summary, ECC-JHF II improved BLM-induced pulmonary fibrosis, which might be associated with the suppression of fibroblast activation by inhibiting the mTOR signaling.

PMID:36610143 | DOI:10.1016/j.phymed.2022.154604

Immunol Lett. 2023 Jan 3:S0165-2478(23)00002-0. doi: 10.1016/j.imlet.2023.01.002. Online ahead of print.

ABSTRACT

Interstitial lung disease comprises numerous clinical entities posing significant challenges towards a prompt and accurate diagnosis. Amongst the contributing factors are intricate pathophysiological mechanisms, an overlap between conditions, and interobserver disagreement. We developed a model for patient clustering offering an additional approach to such complex clinical cases. The model is based on surface phenotyping of over 40 markers on immune cells isolated from bronchoalveolar lavage in combination with clinical data. Based on the marker expression pattern we constructed an individual immune cell profile, then merged these to create a global profile encompassing various pathologies. The contribution of each participant to the global profile was assessed through dimensionality reduction tools and the ensuing similarity between samples was calculated. Our model enables two approaches. First, assessing the immune cell population landscape similarity between patients within a diagnostic group allows rapid identification of divergent profiles, which is particularly helpful for cases with uncertain diagnoses. Second, sample clustering is based exclusively on the calculated similarity of the immune cell profiles, thereby removing physician bias and relying on cellular nearest neighbors.

PMID:36608905 | DOI:10.1016/j.imlet.2023.01.002

Tissue Cell. 2022 Dec 27;81:102005. doi: 10.1016/j.tice.2022.102005. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a common chronic and progressive lung disease. Fibulin-2 (FBLN2) is upregulated in patients with IPF; however, its exact role in IPF remains unclear. The present study aimed to investigate the role and the regulatory mechanism of FBLN2 in TGF-β1-induced fibrogenesis using human lung fibroblast-derived MRC-5 cells. Cell transfection was performed to regulate FBLN2 expression. Reverse transcription-quantitative PCR and western blot analyses were performed to detect the expression levels of FBLN2 and vitronectin (VTN). Cell viability and migration were determined via the Cell Counting Kit-8 and wound healing assays, respectively. Immunofluorescence was performed to detect α-smooth muscle actin (α-SMA)-positive cells. The STRING database was used to predict the interaction between FBLN2 and VTN, which was verified via the protein immunoprecipitation assay. The results demonstrated that inhibition of FBLN2 notably inhibited TGF-β1-induced proliferation and migration, as well as downregulating the protein expression levels of MMP2 and MMP9 in MRC-5 cells. In addition, inhibition of FBLN2 suppressed the expression levels of α-SMA, collagen type 1 α1 and fibronectin. FBLN2 was demonstrated to bind to VTN and negatively regulate its expression. Furthermore, overexpression of VTN partly abolished the inhibitory effects of FBLN2 knockdown on TGF-β1-induced proliferation, migration and fibrosis, as well as the activity of focal adhesion kinase (FAK) signaling. Taken together, the results of the present study suggest that FBLN2 knockdown can attenuate TGF-β1-induced fibrosis in MRC-5 cells by downregulating VTN expression via FAK signaling. Thus, FBLN2 may be a potential therapeutic target for IPF treatment.

PMID:36608640 | DOI:10.1016/j.tice.2022.102005

Gene. 2023 Jan 2:147142. doi: 10.1016/j.gene.2022.147142. Online ahead of print.

ABSTRACT

Mesenchymal cells in the lung are crucial during development, but also contribute to the pathogenesis of fibrotic disorders, including idiopathic pulmonary fibrosis (IPF), the most common and deadly form of fibrotic interstitial lung diseases. Originally thought to behave as supporting cells for the lung epithelium and endothelium with a singular function of producing basement membrane, mesenchymal cells encompass a variety of cell types, including resident fibroblasts, lipofibroblasts, myofibroblasts, smooth muscle cells, and pericytes, which all occupy different anatomic locations and exhibit diverse homeostatic functions in the lung. During injury, each of these subtypes demonstrate remarkable plasticity and undergo varying capacity to proliferate and differentiate into activated myofibroblasts. Therefore, these cells secrete high levels of extracellular matrix (ECM) proteins and inflammatory cytokines, which contribute to tissue repair, or in pathologic situations, scarring and fibrosis. Whereas epithelial damage is considered the initial trigger that leads to lung injury, lung mesenchymal cells are recognized as the ultimate effector of fibrosis and attempts to better understand the different functions and actions of each mesenchymal cell subtype will lead to a better understanding of why fibrosis develops and how to better target it for future therapy. This review summarizes current findings related to various lung mesenchymal cells as well as signaling pathways, and their contribution to the pathogenesis of pulmonary fibrosis.

PMID:36603696 | DOI:10.1016/j.gene.2022.147142

Am J Respir Crit Care Med. 2023 Jan 5. doi: 10.1164/rccm.202206-1139LE. Online ahead of print.

NO ABSTRACT

PMID:36603154 | DOI:10.1164/rccm.202206-1139LE

Am J Respir Crit Care Med. 2023 Jan 5. doi: 10.1164/rccm.202207-1331OC. Online ahead of print.

ABSTRACT

RATIONALE: Idiopathic pulmonary fibrosis is a rare, irreversible, and progressive disease of the lungs. Common genetic variants, in addition to non-genetic factors, have been consistently associated with IPF. Rare variants identified by candidate gene, family-based, and exome studies have also been reported to associate with IPF. However, the extent to which rare variants genome-wide may contribute to the risk of IPF remains unknown.

OBJECTIVES: We used whole-genome sequencing to investigate the role of rare variants, genome-wide, on IPF risk.

METHODS: As part of the Trans-Omics for Precision Medicine Program, we sequenced 2,180 cases of IPF. Association testing focused on the aggregated effect of rare variants (minor allele frequency ≤0.01) within genes or regions. We also identified individual variants that are influential within genes and estimated the heritability of IPF based on rare and common variants.

MEASUREMENTS AND MAIN RESULTS: Rare variants in both TERT and RTEL1 were significantly associated with IPF. A single rare variant in each of the TERT and RTEL1 genes was found to consistently influence the aggregated test statistics. There was no significant evidence of association with other previously reported rare variants. The SNP-heritability of IPF was estimated to be 32% (s.e. 3%).

CONCLUSIONS: Rare variants within the TERT and RTEL1 genes and well-established common variants have the largest contribution to IPF risk overall. Efforts in risk profiling or development of therapies for IPF that focus on TERT, RTEL1, common variants, and environmental risk factors are likely to have the largest impact on this complex disease.

PMID:36602845 | DOI:10.1164/rccm.202207-1331OC

Front Mol Biosci. 2022 Dec 19;9:1056121. doi: 10.3389/fmolb.2022.1056121. eCollection 2022.

ABSTRACT

Introduction: Early diagnosis of interstitial lung disease (ILD) associated with rheumatoid arthritis (RA) constitutes a challenge for the clinicians. Pulmonary vasculopathy is relevant in the development of interstitial lung disease. Accordingly, we aimed to explore the role of vascular cell adhesion molecule-1 (VCAM-1), monocyte chemoattractant protein-1 (MCP-1) and asymmetric dimethylarginine (ADMA), key molecules in the vasculopathy, as potential biomarkers of pulmonary fibrosis in RA-ILD+. Methods: We included 21 RA-ILD+ patients and two comparative groups: 25 RA-ILD- patients and 21 idiopathic pulmonary fibrosis (IPF) patients. Serum levels of the molecules were determined by ELISA, and mRNA expression was quantified by qPCR. Results: VCAM-1, MCP-1 and ADMA serum levels were increased in RA-ILD+ patients in relation to RA-ILD- and IPF patients. Additionally, RA-ILD+ patients exhibited increased CCL2 (gene encoding MCP-1) and decreased PRMT1 (gene related to ADMA synthesis) mRNA expression in relation to RA-ILD- patients. A lower expression of VCAM1, CCL2, and PRMT1 was observed in RA-ILD+ patients when compared with those with IPF. Furthermore, MCP-1 serum levels and PRMT1 mRNA expression were positively correlated with RA duration, and ADMA serum levels were positively associated with C-reactive protein in RA-ILD+ patients. Conclusion: Our study suggests that VCAM-1, MCP-1 and ADMA could be considered as useful biomarkers to identify ILD in RA patients, as well as to discriminate RA-ILD+ from IPF, contributing to the early diagnosis of RA-ILD+.

PMID:36601584 | PMC:PMC9806218 | DOI:10.3389/fmolb.2022.1056121

Front Immunol. 2022 Dec 19;13:1010345. doi: 10.3389/fimmu.2022.1010345. eCollection 2022.

ABSTRACT

BACKGROUND: The role of inflammation in the formation of idiopathic pulmonary fibrosis (IPF) has gained a lot of attention recently. However, the involvement of genes related to inflammation and immune exchange environment status in the prognosis of IPF remains to be further clarified. The objective of this research is to establish a new model for the prediction of the overall survival (OS) rate of inflammation-related IPF.

METHODS: Gene Expression Omnibus (GEO) was employed to obtain the three expression microarrays of IPF, including two from alveolar lavage fluid cells and one from peripheral blood mononuclear cells. To construct the risk assessment model of inflammation-linked genes, least absolute shrinkage and selection operator (lasso), univariate cox and multivariate stepwise regression, and random forest method were used. The proportion of immune cell infiltration was evaluated by single sample Gene Set Enrichment Analysis (ssGSEA) algorithm.

RESULTS: The value of genes linked with inflammation in the prognosis of IPF was analyzed, and a four-genes risk model was constructed, including tpbg, Myc, ffar2, and CCL2. It was highlighted by Kaplan Meier (K-M) survival analysis that patients with high-risk scores had worse overall survival time in all training and validation sets, and univariate and multivariate analysis highlighted that it has the potential to act as an independent risk indicator for poor prognosis. ROC analysis showed that the prediction efficiency of 1-, 3-, and 5-year OS time in the training set reached 0.784, 0.835, and 0.921, respectively. Immune infiltration analysis showed that Myeloid-Derived Suppressor Cells (MDSC), macrophages, regulatory T cells, cd4+ t cells, neutrophils, and dendritic cells were more infiltrated in the high-risk group than in the low-risk group.

CONCLUSION: Inflammation-related genes can be well used to evaluate the IPF prognosis and impart a new idea for the treatment and follow-up management of IPF patients.

PMID:36601116 | PMC:PMC9806212 | DOI:10.3389/fimmu.2022.1010345

Thorax. 2023 Jan;78(1):85-87. doi: 10.1136/thoraxjnl-2022-218772. Epub 2022 Sep 7.

ABSTRACT

Lymphangioleiomyomatosis (LAM) is a rare lung disease of women, causing cystic remodelling of the lung and progressive respiratory failure. The cellular composition, microenvironment and cellular interactions within the LAM lesion remain unclear. To facilitate data sharing and collaborative LAM research, we performed an integrative analysis of single-cell data compiled from lung, uterus and kidney of patients with LAM from three research centres and developed an LAM Cell Atlas (LCA) Web-Portal. The LCA offers a variety of interactive options for investigators to search, visualise and reanalyse comprehensive single-cell multiomics data sets to reveal dysregulated genetic programmes at transcriptomic, epigenomic and cell-cell connectome levels.

PMID:36599466 | DOI:10.1136/thoraxjnl-2022-218772

In Vivo. 2023 Jan-Feb;37(1):310-319. doi: 10.21873/invivo.13081.

ABSTRACT

BACKGROUND/AIM: Lung transplantation is a life-saving procedure for patients with end-stage lung diseases. T-Cell receptor excision circle (TREC) is circular DNA produced during T-cell receptor gene rearrangement in the thymus and indicates naive T-cell migration from the thymus. Therefore, its levels represent thymic T-cell output. Post-transplant lymphocyte kinetics correlate with graft tolerance. The aim of this study was to investigate T-lymphocyte kinetics in the early recovery period after lung transplantation. For this purpose, copy numbers of TREC were determined in patients with a lung transplant. In addition, TREC copy numbers were evaluated according to age, diagnosis and the forced expiratory volume in 1 second (FEV1) of lung transplant patients.

MATERIALS AND METHODS: Peripheral blood samples were taken from patients aged 23 to 59 years who underwent lung transplantation at the Thoracic Surgery Clinic, Kartal-Koşuyolu High Specialization Educational and Research Hospital. This study included peripheral blood samples from 11 lung transplant patients (comprising four with chronic obstructive pulmonary disease, three with idiopathic pulmonary fibrosis, one with cystic fibrosis, one with silicosis and two with bronchiectasis; three females in total). Samples were taken at three different timepoints: Before transplant, and 24 hours and 7 days post transplant. TREC copy numbers were analyzed with real time reverse transcriptase-polymerase chain reaction.

RESULTS: Post-transplant TREC numbers and density values were higher compared to pre-transplant values, although these differences were statistically insignificant. TREC copy numbers were found to be significantly higher in patients younger than 45 years compared to patients older than 45 years. At 24 hours after the transplant, the average TREC copy number/peripheral blood mononuclear cells of the cases with an FEV1 value of or below 50% was found to be statistically significantly higher than that of cases with an FEV1 value above 50% (p=0.046). There was no statistically significant difference in TREC copy numbers between male and female patients or by diagnostic group.

CONCLUSION: TREC copy numbers can be evaluated as a prognostic marker for lung transplantation. There is a need for multicenter studies with more patients.

PMID:36593057 | DOI:10.21873/invivo.13081

Int J Biochem Cell Biol. 2022 Dec 30:106361. doi: 10.1016/j.biocel.2022.106361. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis is a progressive lung disease of unknown etiology characterized by distorted distal lung architecture, inflammation, and fibrosis. Several lung cell types, including alveolar epithelial cells and fibroblasts, have been implicated in the development and progression of fibrosis. However, the pathogenesis of idiopathic pulmonary fibrosis is still incompletely understood. The latest research has found that dysregulation of lipid metabolism plays an important role in idiopathic pulmonary fibrosis. The changes in the synthesis and activity of fatty acids, cholesterol and other lipids seriously affect the regenerative function of alveolar epithelial cells and promote the transformation of fibroblasts into myofibroblasts. Mitochondrial function is the key to regulating the metabolic needs of a variety of cells, including alveolar epithelial cells. Sirtuins located in mitochondria are essential to maintain mitochondrial function and cellular metabolic homeostasis. Sirtuins can maintain normal lipid metabolism by regulating respiratory enzyme activity, resisting oxidative stress, and protecting mitochondrial function. In this review, we aimed to discuss the difference between normal and idiopathic pulmonary fibrosis lungs in terms of lipid metabolism. Additionally, we highlight recent breakthroughs on the effect of abnormal lipid metabolism on idiopathic pulmonary fibrosis, including the effects of sirtuins. Idiopathic pulmonary fibrosis has its high mortality and limited therapeutic options; therefore, we believe that this review will help to develop a new therapeutic direction from the aspect of lipid metabolism in idiopathic pulmonary fibrosis.

PMID:36592687 | DOI:10.1016/j.biocel.2022.106361

Respir Med Case Rep. 2022 Dec 23;41:101802. doi: 10.1016/j.rmcr.2022.101802. eCollection 2023.

ABSTRACT

Understanding of pulmonary mechanics is essential to understanding mechanical ventilation. Typically, clinicians are mindful of peak and plateau pressures displayed on the ventilator and lung compliance, which is decreased in lung disease such as idiopathic pulmonary fibrosis (IPF). Decreased lung compliance leads to elevated peak and plateau pressures. We present a patient with IPF undergoing mechanical ventilation after cardiac arrest. Despite low lung compliance, he had normal peak and plateau pressures due to the presence of flail chest and increased chest wall compliance. This case highlights the role chest wall compliance plays in total respiratory system compliance and pulmonary mechanics.

PMID:36590250 | PMC:PMC9800186 | DOI:10.1016/j.rmcr.2022.101802

Int J Inflam. 2022 Dec 22;2022:7179766. doi: 10.1155/2022/7179766. eCollection 2022.

ABSTRACT

OBJECTIVE: Pulmonary toxicity induced by CCl4, a model of idiopathic pulmonary fibrosis (IPF), leads to tissue remodeling and inflammation. Human umbilical cord mesenchymal cell-conditioned medium (hMSC-CM) is a potent anti-inflammatory, antioxidative, and antifibrotic agent.

METHODS: Forty male Wistar rats were assigned to the control (C), olive oil control (C.O) (hMSC-CM), control (C.Ms), fibrosis (fb), and fibrosis with hMSC-CM (f.Ms) treatment groups. The groups C, C.O, and C.Ms received PBS (200 µl), olive oil (1 ml/kg), and hMSC-CM (100 μg protein/kg), respectively. The fibrosis group was administered with only CCl4 (1 ml/kg). The last group, f.Ms was treated with CCl4 (1 ml/kg) and 100 μg protein/kg IV hMSC-CM. While the treatment with olive oil and CCl4 was performed for 2 days/week from the first week for 12 weeks, the treatment with PBS and hMSC-CM was carried out 2 days/week from week 4th to week 12th. The effect of the UC-MSC culture medium treatment on the lung was evaluated by assessing lysyl oxidase (LOX), tumor necrosis factor-alpha (TNF-α), and transforming growth factor-β1 (TGF-β1) genes, and proteins expression by real-time RCR and western blotting, respectively.

RESULTS: Lysyl oxidase (LOX), tumor necrosis factor-alpha (TNF-α), transforming growth factor-b1 (TGF-β1), malondialdehyde (MDA), and oxidative stress levels were markedly higher in the fibrosis group than in the control groups (p ≤ 0.001). Additionally, glutathione (GSH) in the fibrosis group was markedly lower than those in the control groups (p ≤ 0.001). Fibrosis in the UC-MSC treatment group had milder histopathological injuries than in the fibrosis group.

CONCLUSION: hMSC-MSC as a strong anti-inflammatory, antioxidative, and antifibrotic decreases the level of oxidative stress, proinflammatory cytokines, and MDA causing a restoring effect against CCl4-induced pulmonary fibrosis.

PMID:36588784 | PMC:PMC9800074 | DOI:10.1155/2022/7179766

Front Pharmacol. 2022 Dec 16;13:1117317. doi: 10.3389/fphar.2022.1117317. eCollection 2022.

ABSTRACT

[This corrects the article DOI: 10.3389/fphar.2022.993567.].

PMID:36588674 | PMC:PMC9802109 | DOI:10.3389/fphar.2022.1117317

Ther Adv Respir Dis. 2023 Jan-Dec;17:17534666231165912. doi: 10.1177/17534666231165912.

ABSTRACT

BACKGROUND: It is unclear whether continuing anti-fibrotic therapy until the time of lung transplant increases the risk of complications in patients with idiopathic pulmonary fibrosis.

OBJECTIVES: To investigate whether the time between discontinuation of anti-fibrotic therapy and lung transplant in patients with idiopathic pulmonary fibrosis affects the risk of complications.

METHODS: We assessed intra-operative and post-transplant complications among patients with idiopathic pulmonary fibrosis who underwent lung transplant and had been treated with nintedanib or pirfenidone continuously for ⩾ 90 days at listing. Patients were grouped according to whether they had a shorter (⩽ 5 medication half-lives) or longer (> 5 medication half-lives) time between discontinuation of anti-fibrotic medication and transplant. Five half-lives corresponded to 2 days for nintedanib and 1 day for pirfenidone.

RESULTS: Among patients taking nintedanib (n = 107) or pirfenidone (n = 190), 211 (71.0%) had discontinued anti-fibrotic therapy ⩽ 5 medication half-lives before transplant. Anastomotic and sternal dehiscence occurred only in this group (anastomotic: 11 patients [5.2%], p = 0.031 vs patients with longer time between discontinuation of anti-fibrotic medication and transplant; sternal: 12 patients [5.7%], p = 0.024). No differences were observed in surgical wound dehiscence, length of hospital stay, or survival to discharge between groups with a shorter versus longer time between discontinuation of anti-fibrotic therapy and transplant.

CONCLUSION: Anastomotic and sternal dehiscence only occurred in patients with idiopathic pulmonary fibrosis who discontinued anti-fibrotic therapy < 5 medication half-lives before transplant. The frequency of other intra-operative and post-transplant complications did not appear to differ depending on when anti-fibrotic therapy was discontinued.

REGISTRATION: clinicaltrials.gov NCT04316780: https://clinicaltrials.gov/ct2/show/NCT04316780.

PMID:37073794 | DOI:10.1177/17534666231165912

Cesk Patol. 2023 Spring;59(1):10-17.

ABSTRACT

Histopathological pattern of progressive pulmonary fibrosis could be seen in many different fibrotic lung interstitial diseases. Exact diagnosis is crucial for precise therapy, moreover, different diseases have different prognosis. The most important disorders in this group are idiopatic pulmonary fibrosis and fibrotic hypersensitivity pneumonitis, and their separation is crucial because of totally different treatment of the patients. The aim of this review is to sum up the most important characteristics of usual interstitial pneumonia, histopathological pattern of idiopatic pulmonary fibrosis, and fibrotic hypersensitivity pneumonitis and provide a practical work-up for precise diagnostics of these diseases in the frame of effectively cooperating multidisciplinary team.

PMID:37072274

2023 Mar 18. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan–.

ABSTRACT

Pulmonary hypertension (PH) is defined as a resting mean pulmonary arterial pressure (mPAP) of more than 20 mmHg. Pulmonary hypertension is a complex, heterogeneous disease with multiple etiologies, subtypes, and various methods were used to classify the disease. WHO has categorized pulmonary hypertension into five broad clinical groups based on the underlying etiologies, similarities in pathophysiology, and treatment approach.

WHO group 1 is generally referred to as pulmonary arterial hypertension (PAH). WHO group 2 PH is caused by left heart disease. WHO group 3 is PH related to lung disease and/or hypoxia. WHO group 4 is PH due to pulmonary artery obstructions such as chronic thromboembolic pulmonary hypertension (CTEPH). WHO group 5 PH has unclear and/or multifactorial mechanisms.

Pulmonary veno-occlusive disease (PVOD) is a rare subtype of PAH characterized by progressive obstruction of small pulmonary veins leading to elevated pulmonary arterial pressure and right-sided heart failure. Although PVOD was first described in 1934, the understanding of the disease remains poor.

The clinical features are very non-specific and can resemble congestive heart failure, idiopathic pulmonary arterial hypertension (IPAH), and restrictive lung diseases such as pulmonary fibrosis. The gold standard for diagnosis is a biopsy, which is risky and not advisable in pulmonary hypertension due to a high risk of procedure-related complications such as life-threatening bleeding.

No medical therapy is supported by evidence, and the only curative option is lung transplantation. The prognosis is poor, and life expectancy is two years after symptom onset. This review aims to educate clinicians on this rare, less emphasized, and poorly understood disease.

PMID:36256776 | Bookshelf:NBK585129

Pharmacol Res. 2022 Dec 28:106636. doi: 10.1016/j.phrs.2022.106636. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive disease with high mortality and limited therapeutic options. The immune checkpoint PD1/PD-L1 axis is related to the pathogenesis of pulmonary fibrosis, and upregulated expression levels of PD-L1 have been demonstrated in IPF patients. However, the mechanism of PD-L1 in pulmonary fibrosis is not fully understood. Here, we demonstrated upregulated expression of PD-L1 in fibrotic lung tissues and sera of IPF patients. Bleomycin (BLM) treatment induced PD-L1 upregulation, EMT (Epithelial-Mesenchymal Transition) and fibrosis-like morphology changes in human pulmonary alveolar epithelial cells (HPAEpiCs). Silencing PD-L1 attenuated BLM-induced EMT and fibrosis-like morphology changes in HPAEpiCs. In addition, we identified that PD-L1 directly binds to vimentin and inhibits vimentin ubiquitination, thereby increasing vimentin levels in HPAEpiCs. Silencing of vimentin inhibited BLM- and PD-L1-induced fibrosis in HPAEpiCs. The correlation between PD-L1 and EMT or vimentin expression was further confirmed in clinical samples and animal models. Finally, we used BLM- and paraquat-induced pulmonary fibrosis animal models to confirm the anti-pulmonary fibrosis effects of PD-L1 silencing. Taken together, our findings suggest that upregulated PD-L1 stimulates EMT of alveolar epithelial cells by increasing vimentin levels by inhibiting vimentin ubiquitination, thereby contributing to pulmonary fibrosis.

PMID:36586643 | DOI:10.1016/j.phrs.2022.106636

Eur Respir J. 2022 Dec 30:2200604. doi: 10.1183/13993003.00604-2022. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic disease characterized by aberrant fibroblast/myofibroblast accumulation and excessive collagen matrix deposition in the alveolar areas of lungs. As the first approved IPF medication, pirfenidone (PFD) significantly decelerates lung function decline while its underlying anti-fibrotic mechanism remains elusive. In this study, using transcriptomic and immunofluorescence analyses of primary human IPF tissues, we showed that myocardin related transcription factor (MRTF) signaling is activated in myofibroblasts accumulated in IPF lungs. Furthermore, we showed that PFD inhibits MRTF activation in primary human lung fibroblasts at the clinically achievable concentrations (half-maximal inhibitory concentration (IC50)=50-150 µM, maximal inhibition>90%, maximal concentration of PFD in patients<100 µM). Mechanistically, PFD appears to exert its inhibitory effects by promoting the interaction between MRTF and actin indirectly. Finally, PFD-treated IPF lungs exhibit significantly less MRTF activation in FF areas than naïve IPF lungs. Our results suggest MRTF signaling as a direct target for PFD and implicate that some of the anti-fibrotic effects of PFD may be due to MRTF inhibition in lung fibroblasts.

PMID:36585256 | DOI:10.1183/13993003.00604-2022

J Ethnopharmacol. 2022 Dec 27:116071. doi: 10.1016/j.jep.2022.116071. Online ahead of print.

ABSTRACT

ETHNOPHARMACOLOGICAL RELEVANCE: Idiopathic pulmonary fibrosis (IPF), characterized by excessive collagen deposition, is a progressive and typically fatal lung disease without effective therapeutic methods. Tanreqing injection (TRQ), a Traditional Chinese Patent Medicine, has been widely used to treat inflammatory respiratory diseases clinically.

AIM OF THE STUDY: The present work aims to elucidate the therapeutic effects and the possible mechanism of TRQ against pulmonary fibrosis.

METHODS: The pulmonary fibrosis murine model were constructed by the intratracheal injection of bleomycin (BLM). 7 days later, TRQ-L (2.6 ml/kg) and TRQ-H (5.2 ml/kg) were administered via intraperitoneal injection respectively for 21 days. The efficacy and underlying molecular mechanism of TRQ were investigated.

RESULTS: Here, we showed that TRQ significantly inhibited BLM-induced lung edema and pulmonary function. TRQ markedly reduced BLM-promoted inflammatory cell infiltration in BALF and inflammatory cytokines release (TNF-α, IL-6, and IL-1β) in serum and lung tissues. Meanwhile, TRQ also alleviated BLM-induced collagen synthesis and deposition. Simultaneously, TRQ attenuated BLM-induced pulmonary fibrosis through regulating the expression of fibrotic hallmarks, manifested by down-regulated α-SMA and up-regulated E-cadherin. Moreover, we found that TRQ significantly prevented STING, p-P65, BIP, p-PERK, p-eIF2α, and ATF4 expression in lung fibrosis mice.

CONCLUSIONS: Taken together, our results indicated that TRQ positively affects inflammatory responses and lung fibrosis by regulating STING-mediated endoplasmic reticulum stress (ERS) signal pathway.

PMID:36584920 | DOI:10.1016/j.jep.2022.116071