Loss of ZNF451 mediates fibroblast activation and promotes lung fibrosis.

BACKGROUND: No effective therapies for pulmonary fibrosis (PF) exist because of the unclear molecular pathogenesis and the lack of effective therapeutic targets. Zinc finger protein 451 (ZNF451), a transcriptional regulator, plays crucial roles in the pathogenesis of several diseases. However, its expression pattern and function in PF remain unknown. This study was designed to investigate the role of ZNF451 in the pathogenesis of lung fibrosis. METHODS: GEO dataset analysis, RT‒PCR, and immunoblot assays were used to examine the expression of ZNF451 in PF; ZNF451 knockout mice and ZNF451-overexpressing lentivirus were used to determine the importance of ZNF451 in PF progression; and migration assays, immunofluorescence staining, and RNA-seq analysis were used for mechanistic studies. RESULTS: ZNF451 is downregulated and negatively associated with disease severity in PF. Compared with wild-type (WT) mice, ZNF451 knockout mice exhibited much more serious PF changes. However, ZNF451 overexpression protects mice from BLM-induced pulmonary fibrosis. Mechanistically, ZNF451 downregulation triggers fibroblast activation by increasing the expression of PDGFB and subsequently activating PI3K/Akt signaling. CONCLUSION: These findings uncover a critical role of ZNF451 in PF progression and introduce a novel regulatory mechanism of ZNF451 in fibroblast activation. Our study suggests that ZNF451 serves as a potential therapeutic target for PF and that strategies aimed at increasing ZNF451 expression may be promising therapeutic approaches for PF.

Acute Exacerbation of Idiopathic Pulmonary Fibrosis With Concurrent Cardiac Amyloidosis: A Technetium Pyrophosphate Study.

Amyloidosis presents a diagnostic challenge, particularly when concomitant with severe conditions like acute exacerbations of idiopathic pulmonary fibrosis (IPF). In this report, we detail the case of a 73-year-old patient with acute exacerbation of IPF and simultaneous emergence of cardiac amyloidosis. The patient's clinical journey began with persistent exertional dyspnea, progressing to hypoxemia on admission. Chest CT scans showed extensive ground-glass opacities, consolidations, and pre-existing honeycombing-like cysts and reticular shadows, accompanied by a right-sided pleural effusion. The therapeutic strategy for acute exacerbation of IPF encompassed methylprednisolone pulse therapy, tacrolimus, and nintedanib, augmented with intravenous immunoglobulin and recombinant thrombomodulin. Concurrently, heart failure with preserved ejection fraction was managed with a pharmacological trio: empagliflozin, diuretics, and eplerenone. A hypertrophied heart and low limb voltage prompted an investigation for cardiac amyloidosis, which 99mTechnetium pyrophosphate (99mTc-PYP) scintigraphy confirmed, yielding a probable diagnosis. Following steroid tapering, the patient was discharged home. This case prompted an investigation into the potential role of amyloidosis in pulmonary pathology. Our retrospective review of 10 patients, including four with cardiac amyloidosis, who underwent 99mTc-PYP scintigraphy, revealed a nonsignificant yet notable trend of increased pulmonary accumulation in cardiac amyloidosis cases (median (interquartile range): 5.4×104 (5.3-13.1×104) vs. 3.6×104 (2.4-5.1×104), p=0.0667). Notably, the pulmonary counts in this patient exceeded the negative cohort's mean values, hinting at a possible contribution of amyloid deposition to pulmonary pathology. This study, pioneering in evaluating lung field accumulation of 99mTc-PYP in cardiac amyloidosis, may provide novel insights into the influence of amyloidosis on pulmonary conditions.

Role of transient receptor potential ankyrin 1 in idiopathic pulmonary fibrosis: modulation of M2 macrophage polarization.

Idiopathic pulmonary fibrosis (IPF) poses significant challenges due to limited treatment options despite its complex pathogenesis involving cellular and molecular mechanisms. This study investigated the role of transient receptor potential ankyrin 1 (TRPA1) channels in regulating M2 macrophage polarization in IPF progression, potentially offering novel therapeutic targets. Using a bleomycin-induced pulmonary fibrosis model in C57BL/6J mice, we assessed the therapeutic potential of the TRPA1 inhibitor HC-030031. TRPA1 upregulation was observed in fibrotic lungs, correlating with worsened lung function and reduced survival. TRPA1 inhibition mitigated fibrosis severity, evidenced by decreased collagen deposition and restored lung tissue stiffness. Furthermore, TRPA1 blockade reversed aberrant M2 macrophage polarization induced by bleomycin, associated with reduced Smad2 phosphorylation in the TGF-ß1-Smad2 pathway. In vitro studies with THP-1 cells treated with bleomycin and HC-030031 corroborated these findings, highlighting TRPA1's involvement in fibrotic modulation and macrophage polarization control. Overall, targeting TRPA1 channels presents promising therapeutic potential in managing pulmonary fibrosis by reducing pro-fibrotic marker expression, inhibiting M2 macrophage polarization, and diminishing collagen deposition. This study sheds light on a novel avenue for therapeutic intervention in IPF, addressing a critical need in the management of this challenging disease.

Potential application of mesenchymal stromal cells as a new therapeutic approach in acute respiratory distress syndrome and pulmonary fibrosis.

While the COVID-19 outbreak and its complications are still under investigation, post-inflammatory pulmonary fibrosis (PF) has already been described as a long-term sequela of acute respiratory distress syndrome (ARDS) secondary to SARS-CoV2 infection. However, therapeutical strategies for patients with ARDS and PF are still limited and do not significantly extend lifespan. So far, lung transplantation remains the only definitive treatment for end-stage PF. Over the last years, numerous preclinical and clinical studies have shown that allogeneic mesenchymal stromal cells (MSCs) might represent a promising therapeutical approach in several lung disorders, and their potential for ARDS treatment and PF prevention has been investigated during the COVID-19 pandemic. From April 2020 to April 2022, we treated six adult patients with moderate COVID-19-related ARDS in a late proliferative stage with up to two same-dose infusions of third-party allogeneic bone marrow-derived MSCs (BM-MSCs), administered intravenously 15 days apart. No major adverse events were registered. Four patients completed the treatment and reached ICU discharge, while two received only one dose of MSCs due to multiorgan dysfunction syndrome (MODS) and subsequent death. All four survivors showed improved gas exchanges (PaO2/FiO2 ratio > 200), contrary to the others. Furthermore, LDH trends after MSCs significantly differed between survivors and the deceased. Although further investigations and shared protocols are still needed, the safety of MSC therapy has been recurrently shown, and its potential in treating ARDS and preventing PF might represent a new therapeutic strategy.

Bibliometric analysis of the pirfenidone and nintedanib in interstitial lung diseases.

Background: At the beginning of 21st century, reclassification of fibrosing interstitial lung diseases (ILD) scored academic concerning, and then propelled development. Decade before, pifenidone and nintedanib were approved for idiopathic pulmonary fibrosis, but no more drugs are yet available. To evaluate the development traits of pirfenidone and nintedanib in fibrosing ILD, including the influential country, institution, authors, keywords, and the major problems or the priorities of the field emerge and evolve, bibliometric analysis was used to summarize and draw scientific knowledge maps. Methods: We confined the words to "pirfenidone", "nintedanib", "pulmonary fibrosis", and "lung disease, interstitial". Publications were retrieved from the Web of Science Core Collection on February 24, 2024 with the search strategies. Citespace and VOSviewer were adopted for bibliometric analysis. Results: For the knowledge map of pirfenidone, a total of 4359 authors from 279 institutions in 58 countries/regions contributed to 538 studies. The United States and Italy are way ahead. Genentech Inc and the University of Turin are the institutions with the strongest influence. AM J RESP CRIT CARE is the maximized influential periodical. Raghu G was the most frequently co-cited scholar. keywords cluster demonstrated that vital capacity, safety, outcome, effectiveness, acute exacerbation, pathway, cell, collagen were the hotspots. The burst timeline of hotspots and references revealed academic transitions of pirfenidone-related studies. About the knowledge map of nintedanib, 3297 authors from 238 institutions in 47 countries/regions published 374 studies. Japan, the United States, and Italy are the most productive countries. Boehringer Ingelheim is the overriding productive institution. New ENGL J MED have important roles in reporting milestones of nintedanib. Richeldi L carried numerous capital publications to support the anti-fibrotic effect of nintedanib. From the network of co-occurrence keywords, idiopathic pulmonary fibrosis, efficacy, and safety were the hotspots. Nintedanib for systemic sclerosis-related ILD and progressive pulmonary fibrosis is the hotspot with sharp evolution recently. Conclusions: We summarized and showed developmental alterations of pirfenidone and nintedanib in fibrosing ILD through bibliographic index-based analysis. Our findings showed just dozen years sharp development period of pirfenidone and nintedanib in ILD, and identifies potential partners for interested researchers. The burst of hotspots demonstrated the evolvement of research priorities and major problems, and we observed the transition of keywords from experimental terms like mouse, bleomycin, cell, pathway, collagen, gene expression, to clinical terms including efficacy, safety, survival, acute exacerbation, and progressive pulmonary fibrosis. In the future, exploration about disparity models of drug administration, differences between early and later initiate anti-fibrotic therapy, both short-term and long-term efficacy of pirfenidone and nintedanib in fibrosing ILD, specifically in connective disease associate ILD would be emphatically concerned by pulmonologists.

Lipid Deficiency Contributes to Impaired Alveolar Progenitor Cell Function in Aging and Idiopathic Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is an aging-associated interstitial lung disease resulting from repeated epithelial injury and inadequate epithelial repair. Alveolar type II cells (AEC2) are progenitor cells that maintain epithelial homeostasis and repair the lung after injury. In the current study, we assessed lipid metabolism in AEC2s from human lungs of IPF patients and healthy donors, as well as AEC2s from bleomycin-injured young and old mice. Through single cell RNA sequencing (scRNA-seq), we observed that lipid metabolism-related genes were downregulated in IPF AEC2s and bleomycin-injured mouse AEC2s. Aging aggravated this decrease and hindered recovery of lipid metabolism gene expression in AEC2s after bleomycin injury. Pathway analyses revealed down-regulation of genes related to lipid biosynthesis and fatty acid -oxidation in AEC2s from IPF lungs and bleomycin-injured, aged mouse lungs compared to the respective controls. We confirmed decreased cellular lipid content in AEC2s from IPF lungs and bleomycin-injured, aged mouse lungs using immunofluorescence staining and flow cytometry. We further show that lipid metabolism was associated with AEC2 progenitor function. Lipid supplementation and peroxisome proliferator activated receptor gamma (PPARγ) activation promoted progenitor renewal capacity of both human and mouse AEC2s in 3D organoid cultures. Lipid supplementation also increased AEC2 proliferation and expression of SFTPC in AEC2s. In summary, we identified a lipid metabolism deficiency in AEC2s from lungs of patients with IPF and bleomycin-injured aged mice. Restoration of lipid metabolism homeostasis in AEC2s might promote AEC2 progenitor function and offer new opportunities for therapeutic approaches to IPF. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Downregulation of HMGCS2 mediated AECIIs lipid metabolic alteration promotes pulmonary fibrosis by activating fibroblasts.

BACKGROUND: Abnormal lipid metabolism has recently been reported as a crucial signature of idiopathic pulmonary fibrosis (IPF). However, the origin and biological function of the lipid and possible mechanisms of increased lipid content in the pathogenesis of IPF remains undetermined. METHODS: Oil-red staining and immunofluorescence analysis were used to detect lipid accumulation in mouse lung fibrosis frozen sections, Bleomycin-treated human type II alveolar epithelial cells (AECIIs) and lung fibroblast. Untargeted Lipid omics analysis was applied to investigate differential lipid species and identified LysoPC was utilized to treat human lung fibroblasts and mice. Microarray and single-cell RNA expression data sets identified lipid metabolism-related differentially expressed genes. Gain of function experiment was used to study the function of 3-hydroxy-3-methylglutaryl-Coa Synthase 2 (HMGCS2) in regulating AECIIs lipid metabolism. Mice with AECII-HMGCS2 high were established by intratracheally delivering HBAAV2/6-SFTPC- HMGCS2 adeno-associated virus. Western blot, Co-immunoprecipitation, immunofluorescence, site-directed mutation and flow cytometry were utilized to investigate the mechanisms of HMGCS2-mediated lipid metabolism in AECIIs. RESULTS: Injured AECIIs were the primary source of accumulated lipids in response to Bleomycin stimulation. LysoPCs released by injured AECIIs could activate lung fibroblasts, thus promoting the progression of pulmonary fibrosis. Mechanistically, HMGCS2 was decreased explicitly in AECIIs and ectopic expression of HMGCS2 in AECIIs using the AAV system significantly alleviated experimental mouse lung fibrosis progression via modulating lipid degradation in AECIIs through promoting CPT1A and CPT2 expression by interacting with PPARα. CONCLUSIONS: These data unveiled a novel etiological mechanism of HMGCS2-mediated AECII lipid metabolism in the genesis and development of pulmonary fibrosis and provided a novel target for clinical intervention.

Mendelian randomisation highlights type 1 diabetes as a causal determinant of idiopathic pulmonary fibrosis.

BACKGROUND: It is unclear whether type 1 diabetes (T1D) causes idiopathic pulmonary fibrosis (IPF), despite observational research linking the two conditions. Therefore, our study aimed to examine the causal link between T1D and the likelihood of IPF by employing the Mendelian randomization (MR) technique of two-sample Mendelian randomization. METHODS: Using data from two genome-wide association studies (GWAS) with European ancestry, we performed a two-sample MR analysis. These studies involved 18,856 individuals (6,683 cases and 12,173 controls) for T1D and 198,014 individuals (10,028 cases and 196,986 controls) for IPF. We utilized inverse-variance weighted (IVW) analysis as our main approach to determine the association between the risk of IPF and T1D. To evaluate multidirectionality, the MR-Egger regression test was utilized, whereas heterogeneity was assessed using Cochran's Q test. Additionally, a leave-one-out analysis was performed to assess the reliability of the results. RESULTS: 38 SNPs linked to T1D were employed as instrumental variables (IVs). Multiple MR methods yielded consistent results, and the MR analysis reveals a significant and positive causal impact of T1D on IPF (MR-IVW, odds ratio [OR] = 1.128, 95% confidence interval [CI] 1.034-1.230; P = 0.006). The limitations of the study include the lack of data from non-European groups and the inability to rule out the possibility of small links. Larger MR experiments are necessary to investigate minute impacts. CONCLUSIONS: The results of this study provide evidence that T1D contributes to the onset and advancement of IPF. This finding may provide important insights into the cause of IPF and possible treatments in the future.

COVID-19 Chest Manifestation on CT Scan and Associated Risk Factors for Developing Pulmonary Fibrosis.

PURPOSE: This retrospective study describes the imaging findings on chest computed tomography (CT) scans of coronavirus disease 2019 (COVID-19) patients as well as the prevalence of pulmonary fibrosis and the potential risk factors for the disease. METHODS: One of the major COVID-19 centers in the western province of Saudi Arabia, the King Abdullah Medical Complex in Jeddah, was the site of this study. All adult COVID-19 patients who got a CT chest scan between January 2020 and April 2022 were included in the trial. The imaging findings and pulmonary severity scores (PSS) were obtained from the patients' CT chest. Patients were divided into two groups according to the evidence of fibrotic-like lung changes; clinical and radiological data between the two groups were subsequently compared. Data from the patients' electronic records was collected. RESULTS: The average patient age was 56.4 years, and most (73.5%) patients were men. Two-thirds of the patients had comorbidities (69.1%). CT scans revealed that diffuse lung infiltration is reported in 61% of cases, followed by lower lobes in 19.9%. Ground glass opacity (94.1%), consolidation (76.5%), septal thickening, and/or reticulation (24.4%) were the main chest findings during the initial CT scan. Fibrotic-like lung changes were developed in 9.6% of patients. Patients known to have a positive history of hypertension (p-value = 0.031) and coronary artery disease (CAD) (p-value = 0.011) were found to be significantly more likely to develop lung fibrosis. The patients' pneumonia severity score was significantly higher among the lung fibrotic patients (p-value = 0.026). Also, patients who were diagnosed with pulmonary fibrosis stayed longer in the hospital (p-value 0.001). Sex and age did not correlate significantly with risk of lung fibrosis. CONCLUSION: Pulmonary fibrosis was observed in 9.6% of COVID-19 patients. A close follow-up of patients with severe pneumonia, prolonged hospitalization, and pre-existing CAD and hypertension was necessary, as pulmonary fibrosis was more likely to occur as a result of these factors. There is a need for a thorough, long-term investigation with a large sample size.

A Case of Tension Pneumomediastinum Treated With Mediastinal Drainage Using a Semi-flexible Fiberscope via a Subxiphoid Approach.

Tension pneumomediastinum with hemodynamic failure is a rare but life-threatening condition. Rapid decompression of the mediastinum by drainage is essential to save the patient's life. This report presents a case of tension pneumomediastinum that developed during conservative management of a pneumomediastinum associated with idiopathic pulmonary fibrosis. Endoscopically guided mediastinal drainage was successfully performed in the emergency situation of tension pneumomediastinum. Using the semi-flexible fiberscope inserted through a subxiphoid approach, the drainage catheter was easily and safely placed at the appropriate site in the mediastinum. Good mediastinal decompression was achieved, and the patient was out of this critical condition.

Exploring therapeutic targets for molecular therapy of idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis is a chronic and progressive interstitial lung disease with a poor prognosis. Idiopathic pulmonary fibrosis is characterized by repeated alveolar epithelial damage leading to abnormal repair. The intercellular microenvironment is disturbed, leading to continuous activation of fibroblasts and myofibroblasts, deposition of extracellular matrix, and ultimately fibrosis. Moreover, pulmonary fibrosis was also found as a COVID-19 complication. Currently, two drugs, pirfenidone and nintedanib, are approved for clinical therapy worldwide. However, they can merely slow the disease's progression rather than rescue it. These two drugs have other limitations, such as lack of efficacy, adverse effects, and poor pharmacokinetics. Consequently, a growing number of molecular therapies have been actively developed. Treatment options for IPF are becoming increasingly available. This article reviews the research platform, including cell and animal models involved in molecular therapy studies of idiopathic pulmonary fibrosis as well as the promising therapeutic targets and their development progress during clinical trials. The former includes patient case/control studies, cell models, and animal models. The latter includes transforming growth factor-beta, vascular endothelial growth factor, platelet-derived growth factor, fibroblast growth factor, lysophosphatidic acid, interleukin-13, Rho-associated coiled-coil forming protein kinase family, and Janus kinases/signal transducers and activators of transcription pathway. We mainly focused on the therapeutic targets that have not only entered clinical trials but were publicly published with their clinical outcomes. Moreover, this work provides an outlook on some promising targets for further validation of their possibilities to cure the disease.

Smoking and idiopathic pulmonary fibrosis: A meta-analysis.

INTRODUCTION: In this study, we aimed to systematically explore the relationship between smoking and idiopathic pulmonary fibrosis (IPF). METHODS: The PubMed, Web of Science and Embase databases were searched to systematically identify eligible studies. The Newcastle‒Ottawa Quality Assessment Scale (NOS) was used to evaluate the quality of the selected studies. The pooled odds ratio (OR) and survival hazard ratio (HR) were calculated with a random effects model using Stata 16.0 software. RESULTS: Thirty studies were enrolled. All of the included studies were considered to have intermediate or high quality. Nine studies were suitable for meta-analysis of ORs, and twenty-one studies were suitable for meta-analysis of survival HR. The pooled analysis revealed a significant difference in the risk of IPF between the smoking group and the never smoking group (OR 1.71, 95% CI 1.27-2.30, P < 0.001), indicating that smoking is a risk factor for IPF. When analyzing pooled survival HRs, never smoking was compared to former smoking or current smoking. Former smoking was shown to be a poor prognostic factor for IPF (HR 1.43, 95% CI 1.18-1.74, P < 0.001), but current smoking was not a significant factor. CONCLUSIONS: Our results indicated that smoking is a risk factor for IPF patients. IMPLICATIONS: In this study, we mainly concluded that smoking is a risk factor for IPF and that former smoking is a poor prognostic factor for IPF. To our knowledge, this is the first meta-analysis report focusing on the association between smoking per se and IPF. Through our current study, we hope to further raise awareness of the relationship between smoking and IPF.

A Machine Learning System to Indicate Diagnosis of Idiopathic Pulmonary Fibrosis Non-Invasively in Challenging Cases.

Radiologic usual interstitial pneumonia (UIP) patterns and concordant clinical characteristics define a diagnosis of idiopathic pulmonary fibrosis (IPF). However, limited expert access and high inter-clinician variability challenge early and pre-invasive diagnostic sensitivity and differentiation of IPF from other interstitial lung diseases (ILDs). We investigated a machine learning-driven software system, Fibresolve, to indicate IPF diagnosis in a heterogeneous group of 300 patients with interstitial lung disease work-up in a retrospective analysis of previously and prospectively collected registry data from two US clinical sites. Fibresolve analyzed cases at the initial pre-invasive assessment. An Expert Clinical Panel (ECP) and three panels of clinicians with varying experience analyzed the cases for comparison. Ground Truth was defined by separate multi-disciplinary discussion (MDD) with the benefit of surgical pathology results and follow-up. Fibresolve met both pre-specified co-primary endpoints of sensitivity superior to ECP and significantly greater specificity (p = 0.0007) than the non-inferior boundary of 80.0%. In the key subgroup of cases with thin-slice CT and atypical UIP patterns (n = 124), Fibresolve's diagnostic yield was 53.1% [CI: 41.3-64.9] (versus 0% pre-invasive clinician diagnostic yield in this group), and its specificity was 85.9% [CI: 76.7-92.6%]. Overall, Fibresolve was found to increase the sensitivity and diagnostic yield for IPF among cases of patients undergoing ILD work-up. These results demonstrate that in combination with standard clinical assessment, Fibresolve may serve as an adjunct in the diagnosis of IPF in a pre-invasive setting.

lncRNA-mRNA Co-Expression and Regulation Analysis in Lung Fibroblasts from Idiopathic Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease marked by abnormal accumulation of extracellular matrix (ECM) due to dysregulated expression of various RNAs in pulmonary fibroblasts. This study utilized RNA-seq data meta-analysis to explore the regulatory network of hub long non-coding RNAs (lncRNAs) and messenger RNAs (mRNAs) in IPF fibroblasts. The meta-analysis unveiled 584 differentially expressed mRNAs (DEmRNA) and 75 differentially expressed lncRNAs (DElncRNA) in lung fibroblasts from IPF. Among these, BCL6, EFNB1, EPHB2, FOXO1, FOXO3, GNAI1, IRF4, PIK3R1, and RXRA were identified as hub mRNAs, while AC008708.1, AC091806.1, AL442071.1, FAM111A-DT, and LINC01989 were designated as hub lncRNAs. Functional characterization revealed involvement in TGF-ß, PI3K, FOXO, and MAPK signaling pathways. Additionally, this study identified regulatory interactions between sequences of hub mRNAs and lncRNAs. In summary, the findings suggest that AC008708.1, AC091806.1, FAM111A-DT, LINC01989, and AL442071.1 lncRNAs can regulate BCL6, EFNB1, EPHB2, FOXO1, FOXO3, GNAI1, IRF4, PIK3R1, and RXRA mRNAs in fibroblasts bearing IPF and contribute to fibrosis by modulating crucial signaling pathways such as FoxO signaling, chemical carcinogenesis, longevity regulatory pathways, non-small cell lung cancer, and AMPK signaling pathways.

Adipose-derived stromal vascular fraction cells to treat long-term pulmonary sequelae of coronavirus disease 2019: 12-month follow-up.

BACKGROUND AIMS: Long coronavirus disease (COVID) is estimated to occur in up to 20% of patients with coronavirus disease 2019 (COVID-19) infections, with many having persistent pulmonary symptoms. Mesenchymal stromal cells (MSCs) have been shown to have powerful immunomodulatory and anti-fibrotic properties. Autologous adipose-derived (AD) stromal vascular fraction (SVF) contains MSC and other healing cell components and can be obtained by small-volume lipoaspiration and administered on the same day. This study was designed to study the safety of AD SVF infused intravenously to treat the pulmonary symptoms of long COVID. METHODS: Five subjects with persistent cough and dyspnea after hospitalization and subsequent discharge for COVID-19 pneumonia were treated with 40 million intravenous autologous AD SVF cells and followed for 12 months, to include with pulmonary function tests and computed tomography scans of the lung. RESULTS: SVF infusion was safe, with no significant adverse events related to the infusion out to 12 months. Four subjects had improvements in pulmonary symptoms, pulmonary function tests, and computed tomography scans, with some improvement noted as soon as 1 month after SVF treatment. CONCLUSIONS: It is not possible to distinguish between naturally occurring improvement or improvement caused by SVF treatment in this small, uncontrolled study. However, the results support further study of autologous AD SVF as a treatment for long COVID.

IL20Rb aggravates pulmonary fibrosis through enhancing bone marrow derived profibrotic macrophage activation.

Idiopathic pulmonary fibrosis (IPF) is one of the most fatal chronic interstitial lung diseases with unknown pathogenesis, current treatments cannot truly reverse the progression of the disease. Pulmonary macrophages, especially bone marrow derived pro-fibrotic macrophages, secrete multiple kinds of profibrotic mediators (SPP1, CD206, CD163, IL-10, CCL18…), thus further promote myofibroblast activation and fibrosis procession. IL20Rb is a cell-surface receptor that belongs to IL-20 family. The role of IL20Rb in macrophage activation and pulmonary fibrosis remains unclear. In this study, we established a bleomycin-induced pulmonary fibrosis model, used IL4/13-inducing THP1 cells to induce profibrotic macrophage (M2-like phenotype) polarization models. We found that IL20Rb is upregulated in the progression of pulmonary fibrosis, and its absence can alleviate the progression of pulmonary fibrosis. In addition, we demonstrated that IL20Rb promote the activation of bone marrow derived profibrotic macrophages by regulating the Jak2/Stat3 and Pi3k/Akt signaling pathways. In terms of therapeutic strategy, we used IL20Rb neutralizing antibodies for animal administration, which was found to alleviate the progression of IPF. Our results suggest that IL20Rb plays a profibrotic role by promoting profibrotic macrophage polarization, and IL20Rb may become a potential therapeutic target for IPF. Neutralizing antibodies against IL20Rb may become a potential drug for the clinical treatment of IPF.

Prognostic implication of 1-year decline in diffusing capacity in newly diagnosed idiopathic pulmonary fibrosis.

The progression of idiopathic pulmonary fibrosis (IPF) is assessed through serial monitoring of forced vital capacity (FVC). Currently, data regarding the clinical significance of longitudinal changes in diffusing capacity for carbon monoxide (DLCO) is lacking. We investigated the prognostic implications of a 1-year decline in DLCO in 319 patients newly diagnosed with IPF at a tertiary hospital between January 2010 and December 2020. Changes in FVC and DLCO over the first year after the initial diagnosis were reviewed; a decline in FVC ≥ 5% and DLCO ≥ 10% predicted were considered significant changes. During the first year after diagnosis, a significant decline in FVC and DLCO was observed in 101 (31.7%) and 64 (20.1%) patients, respectively. Multivariable analysis showed that a 1-year decline in FVC ≥ 5% predicted (aHR 2.74, 95% CI 1.88-4.00) and 1-year decline in DLCO ≥ 10% predicted (aHR 2.31, 95% CI 1.47-3.62) were independently associated with a higher risk of subsequent mortality. The prognostic impact of a decline in DLCO remained significant regardless of changes in FVC, presence of emphysema, or radiographic indications of pulmonary hypertension. Therefore, serial monitoring of DLCO should be recommended because it may offer additional prognostic information compared with monitoring of FVC alone.

Defining the mechanism of galectin-3-mediated TGF-ß1 activation and its role in lung fibrosis.

Integrin-mediated activation of the pro-fibrotic mediator transforming growth factor-ß1 (TGF-ß1), plays a critical role in idiopathic pulmonary fibrosis (IPF) pathogenesis. Galectin-3 is believed to contribute to the pathological wound healing seen in IPF, although its mechanism of action is not precisely defined. We hypothesised that galectin-3 potentiates TGF-ß1 activation and/or signaling in the lung to promote fibrogenesis. We show that galectin-3 induces TGF-ß1 activation in human lung fibroblasts (HLFs) and specifically that extracellular galectin-3 promotes oleoyl-L-α-lysophosphatidic acid sodium salt (LPA)-induced integrin-mediated TGF-ß1 activation. Surface plasmon resonance (SPR) analysis confirmed that galectin-3 binds to αv integrins, αvß1, αvß5 and αvß6 and to the TGFßRII subunit in a glycosylation-dependent manner. This binding is heterogeneous and not a 1:1 binding stoichiometry. Binding interactions were blocked by small molecule inhibitors of galectin-3 which target the carbohydrate recognition domain. Galectin-3 binding to ß1 integrin was validated in vitro by co-immunoprecipitation in HLFs. Proximity ligation assays indicated galectin-3 and ß1 integrin colocalize closely (≤40 nm) on the cell surface, that colocalization is increased by TGF-ß1 treatment and blocked by galectin-3 inhibitors. In the absence of TGF-ß1 stimulation, colocalization was detectable only in HLFs from IPF patients suggesting the proteins are inherently more closely associated in the disease state. Galectin-3 inhibitor treatment of precision cut lung slices from IPF patients reduced Col1a1, TIMP1 and HA secretion to a similar degree as TGF-ß type I receptor inhibitor. These data suggest galectin-3 promotes TGF-ß1 signaling and may induce fibrogenesis by interacting directly with components of the TGF-ß1 signaling cascade.

Prevalence and prognostic meaning of interstitial lung abnormalities in remote CT scans of patients with interstitial lung disease treated with antifibrotic therapy.

OBJECTIVES: To describe the prevalence and characteristics of interstitial lung abnormalities (ILA) in CT scans performed prior to the initiation of antifibrotics in a series of patients with interstitial lung disease (ILD), and to identify characteristics apparent on early CT scans that could help to predict outcomes. METHODS: We conducted a retrospective observational study. The original cohort consisted of 101 patients diagnosed with ILD and treated with antifibrotics in a tertiary hospital. Patients were included if they had a thoracic CT scan performed at least one year before initiation of therapy. They were classified radiologically in three groups: without ILA, with radiological ILA and extensive abnormalities. ILA were classified as subpleural fibrotic, subpleural non-fibrotic and non-subpleural. The initial scan and the latest CT scan performed before treatment were read for assessing progression. The relationship between CT findings of fibrosis and the radiological progression rate and mortality were analyzed. RESULTS: We included 50 patients. Only 1 (2%) had a normal CT scan, 25 (50%) had extensive alterations and 24 (48%) had radiological criteria for ILA, a median of 98.2 months before initiation of antifibrotics, of them 18 (75%) had a subpleural fibrotic pattern. Significant bronchiectasis and obvious honeycombing in the lower zones were associated with shorter survival (p = 0.04). Obvious honeycombing in the lower zones was also significantly (p < 0.05) associated with a faster progression rate. CONCLUSIONS: Fibrotic ILAs are frequent in remote scans of patients with clinically relevant ILD, long before they require antifibrotics. Findings of traction bronchiectasis and honeycombing in the earliest scans, even in asymptomatic patients, are related to mortality and progression later on.

The multifaceted role of macrophage mitophagy in SiO2-induced pulmonary fibrosis: A brief review.

Prolonged exposure to environments with high concentrations of crystalline silica (CS) can lead to silicosis. Macrophages play a crucial role in the pathogenesis of silicosis. In the process of silicosis, silica (SiO2) invades alveolar macrophages (AMs) and induces mitophagy which usually exists in three states: normal, excessive, and/or deficiency. Different mitophagy states lead to corresponding toxic responses, including successful macrophage repair, injury, necrosis, apoptosis, and even pulmonary fibrosis. This is a complex process accompanied by various cytokines. Unfortunately, the details have not been fully systematically summarized. Therefore, it is necessary to elucidate the role of macrophage mitophagy in SiO2-induced pulmonary fibrosis by systematic analysis on the literature reports. In this review, we first summarized the current data on the macrophage mitophagy in the development of SiO2-induced pulmonary fibrosis. Then, we introduce the molecular mechanism on how SiO2-induced mitophagy causes pulmonary fibrosis. Finally, we focus on introducing new therapies based on newly developed mitophagy-inducing strategies. We conclude that macrophage mitophagy plays a multifaceted role in the progression of SiO2-induced pulmonary fibrosis, and reprogramming the macrophage mitophagy state accordingly may be a potential means of preventing and treating pulmonary fibrosis.