Idiopathic Pulmonary Fibrosis Lung Research Articles

Integrated multiomic analysis identifies TRIP13 as a mediator of alveolar epithelial type II cell dysfunction in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a lethal progressive lung disease urgently needing new therapies. Current treatments only delay disease progression, leaving lung transplant as the sole remaining option. Recent studies support a model whereby IPF arises because alveolar epithelial type II (AT2) cells, which normally mediate distal lung regeneration, acquire airway and/or mesenchymal characteristics, preventing proper repair. Mechanisms driving this abnormal differentiation remain unclear. We performed integrated transcriptomic and epigenomic analysis of purified AT2 cells which revealed genome-wide alterations in IPF lungs. The most prominent epigenetic alteration was activation of an enhancer in thyroid receptor interactor 13 (TRIP13), although TRIP13 was not the most significantly transcriptionally upregulated gene. TRIP13 is broadly implicated in epithelial-mesenchymal plasticity. In cultured human AT2 cells and lung slices, small molecule TRIP13 inhibitor DCZ0415 prevented acquisition of the mesenchymal gene signature characteristic of IPF, suggesting TRIP13 inhibition as a potential therapeutic approach to fibrotic disease.

YAP Alleviates Pulmonary Fibrosis Through Promoting Alveolar Regeneration via Modulating the Stemness of Alveolar Type 2 Cells.

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with no cure except transplantation. Abnormal alveolar epithelial regeneration is a key driver of IPF development. The function of Yes1 Associated Transcriptional Regulator (YAP) in alveolar regeneration and IPF pathogenesis remains elusive. Here, we first revealed the activation of YAP in alveolar epithelium 2 cells (AEC2s) from human IPF lungs and fibrotic mouse lungs. Notably, conditional deletion of YAP in mouse AEC2s exacerbated bleomycin-induced pulmonary fibrosis. Intriguingly, we showed in both conditional knockout mice and alveolar organoids that YAP deficiency impaired AEC2 proliferation and differentiation into alveolar epithelium 1 cells (AEC1s). Mechanistically, YAP regulated expression levels of genes associated with cell cycle progression and AEC1 differentiation. Furthermore, overexpression of YAP in vitro promoted cell proliferation. These results indicate the critical role of YAP in alveolar regeneration and IPF pathogenesis. Our findings provide new insights into the regulation of alveolar regeneration and IPF pathogenesis, paving the road for developing novel treatment strategies.

Nerandomilast Improves Bleomycin-Induced Systemic Sclerosis-Associated Interstitial Lung Disease in Mice by Regulating the TGF-β1 Pathway.

Systemic sclerosis (SSc) is a rare connective tissue disease with a heterogeneous clinical course. Interstitial lung disease (ILD) is a common complication of SSc and a major contributor to SSc-related deaths. Besides nintedanib and tocilizumab, there are currently no clinically approved drugs for SSc-ILD, highlighting the urgent need for new treatment strategies. Previous studies have shown that cyclic adenosine monophosphate (cAMP) plays a crucial role in the pathogenesis of SSc and lung fibrosis. Phosphodiesterases (PDEs) are enzymes that specifically hydrolyze cAMP, making PDE inhibitors promising candidates for SSc-ILD treatment. Nerandomilast, a preferential phosphodiesterase 4B (PDE4B) inhibitor currently undergoing phase III clinical trials for idiopathic pulmonary fibrosis and progressive fibrosing interstitial lung diseases (PF-ILD), has good preference for PDE4B but lacks studies for SSc-ILD. Our research demonstrates that nerandomilast effectively inhibits skin and lung fibrosis in a bleomycin-induced mouse model of SSc-ILD. For lung fibrosis, we found that nerandomilast could improve bleomycin-induced SSc-ILD through inhibiting PDE4B and the TGF-β1-Smads/non-Smads signaling pathways, which provides a theoretical basis for potential therapeutic drug development for SSc-ILD.

Revisiting the role of MicroRNAs in the pathogenesis of idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a prevalent chronic pulmonary fibrosis disease characterized by alveolar epithelial cell damage, fibroblast proliferation and activation, excessive extracellular matrix deposition, and abnormal epithelial-mesenchymal transition (EMT), resulting in tissue remodeling and irreversible structural distortion. The mortality rate of IPF is very high, with a median survival time of 2-3years after diagnosis. The exact cause of IPF remains unknown, but increasing evidence supports the central role of epigenetic changes, particularly microRNA (miRNA), in IPF. Approximately 10% of miRNAs in IPF lung tissue exhibit differential expression compared to normal lung tissue. Diverse miRNA phenotypes exert either a pro-fibrotic or anti-fibrotic influence on the progression of IPF. In the context of IPF, epigenetic factors such as DNA methylation and long non-coding RNAs (lncRNAs) regulate differentially expressed miRNAs, which in turn modulate various signaling pathways implicated in this process, including transforming growth factor-β1 (TGF-β1)/Smad, mitogen-activated protein kinase (MAPK), and phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT) pathways. Therefore, this review presents the epidemiology of IPF, discusses the multifaceted regulatory roles of miRNAs in IPF, and explores the impact of miRNAs on IPF through various pathways, particularly the TGF-β1/Smad pathway and its constituent structures. Consequently, we investigate the potential for targeting miRNAs as a treatment for IPF, thereby contributing to advancements in IPF research.

The soluble factor milieu in idiopathic pulmonary fibrosis dysregulates epithelial differentiation.

In idiopathic pulmonary fibrosis (IPF), epithelial abnormalities are present including bronchiolization and alveolar cell dysfunction. We hypothesized that the IPF microenvironment disrupts normal epithelial growth and differentiation. We mimicked the soluble factors within an IPF microenvironment using an IPF cocktail (IPFc), composed of nine factors which are increased in IPF lungs (CCL2, IL-1β, IL-4, IL-8, IL-13, IL-33, TGF-β, TNFα, and TSLP). Using IPFc, we asked whether the soluble factor milieu in IPF affects epithelial growth and differentiation and how IPFc compares to TGF-β alone. Epithelial growth and differentiation were studied using mouse lung organoids (primary Epcam+ epithelial cells co-cultured with CCL206 fibroblasts). Organoids exposed to IPFc and TGF-β were re-sorted into epithelial and fibroblast fractions and subjected to RNA sequencing. IPFc did not affect the number of organoids formed. However, pro-surfactant protein C expression was decreased. On these parameters, TGF-β alone had similar effects. However, RNA sequencing of re-sorted organoids revealed that IPFc and TGF-β had distinct effects on both epithelial cells and fibroblasts. IPFc upregulated goblet cell markers, whereas these were inhibited by TGF-β. Although both IPFc and TGF-β increased extracellular matrix gene expression, only TGF-β increased myofibroblast markers. VEGF-C and Wnt signaling were among the most differentially regulated signaling pathways by IPFc versus TGF-β. Interestingly, Wnt pathway activation rescued Sftpc downregulation induced by IPFc. In conclusion, IPFc alters epithelial differentiation in a way that is distinct from TGF-β. Alterations in Wnt signaling contribute to these effects. IPFc may be a more comprehensive representation of the soluble factor microenvironment in IPF.

Delineating, Imaging, and Assessing Pulmonary Fibrosis Remodeling via Collagen Hybridization.

Idiopathic pulmonary fibrosis (IPF) is a progressive, life-threatening disease with no early detection, few treatments, and dismal outcomes. Although collagen overdeposition is a hallmark of lung fibrosis, current research mostly focuses on the cellular aspect, leaving collagen, particularly its dynamic remodeling (i.e., degradation and turnover), largely unexplored. Here, using a collagen hybridizing peptide (CHP) that specifically binds unfolded collagen chains, we reveal vast collagen denaturation in human IPF lungs and delineate the spatiotemporal progression of collagen denaturation three-dimensionally within fibrotic lungs in mice. Transcriptomic analyses support that lung collagen denaturation is strongly associated with up-regulated collagen catabolism in mice and patients. We thus show that CHP probing differentiates remodeling responses to antifibrotics and highlights the resolution of established fibrosis by agents up-regulating collagen catabolism. We further develop a radioactive CHP that detects fibrosis in vivo in mice as early as 7 days postlung-injury (Ashcroft score: 2-3) by positron emission tomography (PET) imaging and ex vivo in clinical lung specimens. These findings establish collagen denaturation as a promising marker of fibrotic remodeling for the investigation, diagnosis, and therapeutic development of pulmonary fibrosis.

Identification of FGFR4 as a regulator of myofibroblast differentiation in pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease with limited therapeutic options. Fibroblast growth factor receptor-4 (FGFR4) is a known receptor for several paracrine fibroblast growth factors (FGFs). FGFR4 is also the main receptor for FGF19, an endocrine FGF that was demonstrated by our group to have antifibrotic properties in the lung. We aimed to determine whether FGFR4 could modulate pulmonary fibrogenesis. We assessed FGFR4 mRNA and protein levels in IPF and control lungs. In vitro, we determined the effect of transforming growth factor-β (TGF-β), endothelin-1, and platelet-derived growth factor (PDGF) on FGFR4 expression in human lung fibroblasts. We determined the effect of FGFR4 inhibition, using a specific pharmacological inhibitor (FGF401), or genetic deletion in murine embryonic fibroblasts (MEFs) on TGF-β-induced myofibroblastic differentiation. In vivo, we evaluated the development of bleomycin-induced lung fibrosis in Fgfr4-deficient (Fgfr4-/-) mice compared with wild-type littermates (WT) and after FGF401 treatment in WT mice compared with a control group receiving the solvent only. FGFR4 was decreased in IPF lungs, as compared with control lungs, at mRNA and protein levels. In vitro, FGFR4 was downregulated after treatment with TGF-β, endothelin-1, and PDGF. In vitro, FGFR4 inhibition by FGF401 prevented TGF-β1-induced collagen and ACTA2 increase in lung fibroblasts. Similar results were observed in Fgfr4-/- MEFs. In vivo, FGFR4 genetic deficiency or FGFR4 pharmacological inhibition did not modulate bleomycin-induced pulmonary fibrosis. Our data suggest that FGFR4 exerts profibrotic properties by enhancing TGF-β signaling in vitro. However, the inhibition of FGFR4 is not sufficient to prevent the development of pulmonary fibrosis in vivo.NEW & NOTEWORTHY FGFR4 has been reported to have antifibrotic effects in the liver. We aimed to determine the involvement of FGFR4 during IPF. Our data suggest that FGFR4 exerts profibrotic properties by enhancing TGF-β signaling in vitro. However, the inhibition of FGFR4 is not sufficient to prevent the development of pulmonary fibrosis in vivo. To our knowledge, this is the first study to assess the profibrotic action of FGFR4 during pulmonary fibrosis.

Identification of immune patterns in idiopathic pulmonary fibrosis patients driven by PLA2G7-positive macrophages using an integrated machine learning survival framework

Patients with advanced idiopathic pulmonary fibrosis (IPF), a complex and incurable lung disease with an elusive pathology, are nearly exclusive candidates for lung transplantation. Improved identification of patient subtypes can enhance early diagnosis and intervention, ultimately leading to better prognostic outcomes for patients. The goal of this study is to identify new immune patterns and biomarkers in patients. Immune subtypes in IPF patients were identified using single-sample gene set enrichment analysis, and immune subtype-related genes were explored using the weighted correlation network analysis algorithm. A machine learning integration framework was used to establish the optimal prognostic model, known as the immune-related risk score (IRS). Single-cell sequencing was conducted to investigate the major role of macrophage-derived PLA2G7 in the immune microenvironment. We assessed the stability of celecoxib in targeting PLA2G7 through molecular docking and surface plasmon resonance. IPF patients present two distinct immune subtypes, one characterized by immune activation and inflammation, and the other by immune suppression. IRS can predict the immune status and prognosis of IPF patients. Furthermore, multi-cohort analysis and single-cell sequencing analysis demonstrated the diagnostic and prognostic value of PLA2G7 derived from macrophages and its role in shaping the inflammatory immune microenvironment in IPF patients. Celecoxib could effectively and stably bind with PLA2G7. PLA2G7, as identified through IRS, demonstrates marked stability in diagnosing and predicting the prognosis of IPF patients as well as predicting their immune status. It can serve as a novel biomarker for IPF patients.

CSP7 Protects Alveolar Epithelial Cells by Targeting p53-Fibrinolytic Pathways During Lung Injuries.

Impaired alveolar epithelial regeneration in patients with idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD) is attributed to telomere dysfunction in type II alveolar epithelial cells (A2Cs). Genetic susceptibility, aging, and toxicant exposures, including tobacco smoke (TS), contribute to telomere dysfunction in A2Cs. Here we investigated whether improvement of telomere function plays a role in CSP7-mediated protection of A2Cs against ongoing senescence and apoptosis during bleomycin (BLM)-induced pulmonary fibrosis (PF) as well as alveolar injury caused by chronic TS exposure. We found a significant telomere shortening in A2Cs isolated from IPF and COPD lungs in line with other studies. These cells showed increased p53 in addition to its post-translational modification with induction of activated caspase-3 and β-galactosidase, suggesting a p53-mediated loss of A2C renewal. Further, we found increased expression of SIAH-1, a p53-inducible E3 ubiquitin ligase known to down-regulate telomere repeats binding factor 2 (TRF2). Consistent with the loss of TRF2 and upregulation of TRF1, telomerase reverse transcriptase (TERT) was downregulated in A2Cs. A2Cs from fibrotic lungs of mice either repeatedly instilled with BLM or isolated from chronic TS exposure-induced lung injury model showed reduced telomere length along with induction of p53, PAI-1, SIAH1 and TRF1 as well as loss of TRF2 and TERT, which were reversed in wild-type mice after treatment with CSP7. Interestingly, PAI-1-/- mice, or those lacking microRNA-34a expression in A2Cs, resisted telomere dysfunction, while uPA-/- mice failed to respond to CSP7 treatment, suggesting p53-microRNA-34a feed-forward induction and p53-uPA pathway contributes to telomere dysfunction.

The transcriptome of CD14 + CD163 - HLA-DR low monocytes predicts mortality in Idiopathic Pulmonary Fibrosis.

The association between immune-cell-specific transcriptomic profiles and Idiopathic Pulmonary Fibrosis (IPF) mortality is unknown. To determine immune-cell-specific transcriptomic profiles associated with IPF mortality. We profiled peripheral blood mononuclear cells (PBMC) in 18 participants [University of South Florida: IPF, COVID-19, post-COVID-19 Interstitial Lung Disease (Post-COVID-19 ILD), controls] by single-cell RNA sequencing (scRNA-seq) and identified 16 immune-cell-specific transcriptomic profiles. The Scoring Algorithm of Molecular Subphenotypes (SAMS) was used to calculate Up-scores based on these 16 gene profiles. Their association with outcomes was investigated in peripheral blood, Bronchoalveolar Lavage (BAL) and lung tissue of N=416 IPF patients from six cohorts. Findings were validated in an independent IPF, PBMC scRNA-seq dataset (N=38). Cox-regression models demonstrated that 230 genes from CD14 + CD163 - HLA-DR low circulating monocytes predicted IPF mortality [Pittsburgh (p=0.02), Chicago (p=0.003)]. PBMC proportions of CD14 + CD163 - HLA-DR low monocytes were higher in progressive versus stable IPF (Yale, 0.13±0.05 versus 0.09±0.05, p=0.034). Receiving operating characteristic identified a 230 gene, Up-score >41.84 (Pittsburgh) predictive of mortality in Chicago (HR: 6.58, 95%CI: 2.15-20.13, p=0.001) and in pooled analysis of BAL cohorts (HR: 2.20, 95%CI: 1.44-3.37, p=0.0003). High-risk patients had decreased expression of the T-cell co-stimulatory genes CD28 , ICOS , ITK and LCK (Pittsburgh and Chicago, p<0.01). 230 gene-up-scores negatively correlated with Forced Vital Capacity (FVC) in IPF lung tissues (LGRC, rho=-0.2, p=0.02). Results were replicated using a subset of 13 genes from the 230-gene signature (pooled PBMC cohorts - HR: 5.34, 95%CI: 2.83-10.06, p<0.0001). The transcriptome of CD14 + CD163 - HLA-DR low monocytes is associated with increased IPF mortality.

Anti-Heat Shock Protein 70 Autoantibodies from Patients with Idiopathic Pulmonary Fibrosis Epigenetically Enhance Lung Fibroblast Apoptosis Resistance and Bcl-2 Expression.

IgG autoantibodies to heat shock protein 70 (HSP70) are found in many immune-mediated clinical syndromes, and their presence among patients with idiopathic pulmonary fibrosis (IPF) portends especially poor outcomes. However, pathological effects of IPF anti-HSP70 have not been studied extensively. IPF lung fibroblasts are apoptosis resistant, and this dysregulation contributes to the accumulation of fibroblasts that characterizes the disease. During stress, HSP70 protein is exported extracellularly, where it binds to cognate cell surface receptors that mediate a variety of functional effects, including apoptosis inhibition. We hypothesized anti-HSP70 could engage HSP70-receptor complexes on fibroblasts that alter their apoptosis susceptibility. We found HSP70 is ubiquitously expressed on primary human lung fibroblasts. Treatment with anti-HSP70 isolated from patients with IPF with acute exacerbations increased Bcl-2 expression in human lung fibroblasts and reduced their susceptibility to staurosporine-induced apoptosis. Chromatin immunoprecipitation assays showed Bcl-2 gene promoter regions are enriched with the active histone mark H4 lysine 16 acetylation, and this was increased in the autoantibody-treated fibroblasts. When H4 lysine 16 acetylation was decreased by knocking down its acetyltransferase, MOF (males absent on the first), the anti-HSP70 treatments failed to upregulate Bcl-2. This study describes a heretofore unknown, to our knowledge, pathogenic consequence of autoimmunity in which autoantibodies affect the epigenetic regulation of fibroblast apoptosis. In addition to IPF, this autoimmune process could also have relevance in other immunological syndromes characterized by anti-HSP70 autoimmunity. These findings lend credence to the importance of autoimmunity in IPF and illustrate pathways that could be targeted in innovative therapies for this morbid, medically refractory lung disease.

Toll-like Receptor 9 Inhibition Mitigates Fibroproliferative Responses in Translational Models of Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease for which current treatment options only slow clinical progression. Previously, we identified a subset of patients with IPF with an accelerated disease course associated with fibroblast expression of Toll-Like Receptor 9 (TLR9) mediated by interactions with its ligand mitochondrial DNA (mtDNA). We aimed to show that TLR9 activation induces fibroproliferative responses that are abrogated by its antagonism by using two commercially-available indirect inhibitors and a proprietary, selective direct small molecule inhibitor. We employed two independent cohorts of patients with IPF, multiple in vitro fibroblast cell culture platforms, an in vivo mouse model, and an ex vivo human precision cut lung slices system to investigate the clinical and biologic significance of TLR9 in this disease. In two independent IPF cohorts, plasma mtDNA activates TLR9 in a manner associated with the expression of MCP-1, IL-6, TNFα, and IP-10 and worsened transplant-free survival. Our cell culture platform showed that TLR9 mediates fibroblast activation via TGFβ1 and stiff substrates, and that its antagonism, particularly direct inhibition, ameliorates this process, including production of these TLR9 associated pharmacodynamic endpoints. We further demonstrated that direct TLR9 inhibition mitigates these fibroproliferative responses in our in vivo and ex vivo models of pulmonary fibrosis. In this novel study, we found that direct TLR9 inhibition mitigates fibroproliferative responses in preclinical models of pulmonary fibrosis. Our work demonstrates the therapeutic potential of direct TLR9 antagonism in IPF and related fibrotic lung diseases.

Fibroblast-derived extracellular vesicles contain SFRP1 and mediate pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a lethal chronic lung disease characterized by aberrant intercellular communication, extracellular matrix deposition, and destruction of functional lung tissue. While extracellular vesicles (EVs) accumulate in the IPF lung, their cargo and biological effects remain unclear. We interrogated the proteome of EV and non-EV fractions during pulmonary fibrosis and characterized their contribution to fibrosis. EVs accumulated 14 days after bleomycin challenge, correlating with decreased lung function and initiated fibrogenesis in healthy precision-cut lung slices. Label-free proteomics of bronchoalveolar lavage fluid EVs (BALF-EVs) collected from mice challenged with bleomycin or control identified 107 proteins enriched in fibrotic vesicles. Multiomic analysis revealed fibroblasts as a major cellular source of BALF-EV cargo, which was enriched in secreted frizzled related protein 1 (SFRP1). Sfrp1 deficiency inhibited the activity of fibroblast-derived EVs to potentiate lung fibrosis in vivo. SFRP1 led to increased transitional cell markers, such as keratin 8, and WNT/β-catenin signaling in primary alveolar type 2 cells. SFRP1 was expressed within the IPF lung and localized at the surface of EVs from patient-derived fibroblasts and BALF. Our work reveals altered EV protein cargo in fibrotic EVs promoting fibrogenesis and identifies fibroblast-derived vesicular SFRP1 as a fibrotic mediator and potential therapeutic target for IPF.

Spatial transcriptomic characterization of pathologic niches in IPF.

Despite advancements in antifibrotic therapy, idiopathic pulmonary fibrosis (IPF) remains a medical condition with unmet needs. Single-cell RNA sequencing (scRNA-seq) has enhanced our understanding of IPF but lacks the cellular tissue context and gene expression localization that spatial transcriptomics provides. To bridge this gap, we profiled IPF and control patient lung tissue using spatial transcriptomics, integrating the data with an IPF scRNA-seq atlas. We identified three disease-associated niches with unique cellular compositions and localizations. These include a fibrotic niche, consisting of myofibroblasts and aberrant basaloid cells, located around airways and adjacent to an airway macrophage niche in the lumen, containing SPP1+ macrophages. In addition, we identified an immune niche, characterized by distinct lymphoid cell foci in fibrotic tissue, surrounded by remodeled endothelial vessels. This spatial characterization of IPF niches will facilitate the identification of drug targets that disrupt disease-driving niches and aid in the development of disease relevant in vitro models.

Sustained amphiregulin expression in intermediate alveolar stem cells drives progressive fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal fibrotic disease. Recent studies have highlighted the persistence of an intermediate state of alveolar stem cells in IPF lungs. In this study, we discovered a close correlation between the distribution pattern of intermediate alveolar stem cells and the progression of fibrotic changes. We showed that amphiregulin (AREG) expression is significantly elevated in intermediate alveolar stem cells of mouse fibrotic lungs and IPF patients. High levels of serum AREG correlate significantly with profound deteriorations in lung function in IPF patients. We demonstrated that AREG in alveolar stem cells is both required and sufficient for activating EGFR in fibroblasts, thereby driving lung fibrosis. Moreover, pharmacological inhibition of AREG using a neutralizing antibody effectively blocked the initiation and progression of lung fibrosis in mice. Our study underscores the therapeutic potential of anti-AREG antibodies in attenuating IPF progression, offering a promising strategy for treating fibrotic diseases.

Macrophage-fibroblast crosstalk drives Arg1-dependent lung fibrosis via ornithine loading.

Monocyte-derived macrophages recruited to injured tissues induce a maladaptive fibrotic response characterized by excessive production of collagen by local fibroblasts. Macrophages initiate this programming via paracrine factors, but it is unknown whether reciprocal responses from fibroblasts enhance profibrotic polarization of macrophages. We identify macrophage-fibroblast crosstalk necessary for injury-associated fibrosis, in which macrophages induced interleukin 6 ( IL-6 ) expression in fibroblasts via purinergic receptor P2rx4 signaling, and IL-6, in turn, induced arginase 1 ( Arg1 ) expression in macrophages. Arg1 contributed to fibrotic responses by metabolizing arginine to ornithine, which fibroblasts used as a substrate to synthesize proline, a uniquely abundant constituent of collagen. Imaging of idiopathic pulmonary fibrosis (IPF) lung samples confirmed expression of ARG1 in myeloid cells, and arginase inhibition suppressed collagen expression in cultured precision-cut IPF lung slices. Taken together, we define a circuit between macrophages and fibroblasts that facilitates cross-feeding metabolism necessary for injury-associated fibrosis.

Immune disease dialogue of chemokine-based cell communications as revealed by single-cell RNA sequencing meta-analysis.

Immune-mediated diseases are characterized by aberrant immune responses, posing significant challenges to global health. In both inflammatory and autoimmune diseases, dysregulated immune reactions mediated by tissue-residing immune and non-immune cells precipitate chronic inflammation and tissue damage that is amplified by peripheral immune cell extravasation into the tissue. Chemokine receptors are pivotal in orchestrating immune cell migration, yet deciphering the signaling code across cell types, diseases and tissues remains an open challenge. To delineate disease-specific cell-cell communications involved in immune cell migration, we conducted a meta-analysis of publicly available single-cell RNA sequencing (scRNA-seq) data across diverse immune diseases and tissues. Our comprehensive analysis spanned multiple immune disorders affecting major organs: atopic dermatitis and psoriasis (skin), chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis (lung), ulcerative colitis (colon), IgA nephropathy and lupus nephritis (kidney). By interrogating ligand-receptor (L-R) interactions, alterations in cell proportions, and differential gene expression, we unveiled intricate disease-specific and common immune cell chemoattraction and extravasation patterns. Our findings delineate disease-specific L-R networks and shed light on shared immune responses across tissues and diseases. Insights gleaned from this analysis hold promise for the development of targeted therapeutics aimed at modulating immune cell migration to mitigate inflammation and tissue damage. This nuanced understanding of immune cell dynamics at the single-cell resolution opens avenues for precision medicine in immune disease management.

The dorsal muscle group area at the T12 vertebral level as a risk factor for tolerability of nintedanib in patients with idiopathic pulmonary fibrosis or other progressive fibrosing interstitial lung diseases.

39 patients with IPF or other progressive fibrosing ILDs who started nintedanib at a regular dose (300 mg/day) were enrolled. We compared the characteristics between patients who stopped nintedanib at a regular dose before 6 months and/or continue to take nintedanib at a low dose (150 mg/day) and patients who were still taking nintedanib at a regular dose over 6 months. This study retrospectively investigated clinical parameters including T12DMA index (T12DMA/height2) to evaluate whether these parameters might serve as risk factor for the tolerability of nintedanib in patients with IPF and other progressive fibrosing ILDs. Discontinuation or dose reductions of nintedanib due to adverse events were observed in 14 (35.8%) patients. A multiple logistic regression model showed T12DMA index to be the only significant risk factor for predicting for the early termination of nintedanib (odd rate, 0.549; 95% confidence interval, 0.327-0.922; P = .023). This study revealed that T12DMA index was a risk factor for the early termination of nintedanib. The initial dose of nintedanib adjusted to the differences in skeletal muscle mass and careful management of adverse events may contribute to the longer nintedanib treatment, which would lead to a better clinical outcome.

Single-cell RNA sequencing reveals special basal cells and fibroblasts in idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is the most predominant type of idiopathic interstitial pneumonia and has an increasing incidence, poor prognosis, and unclear pathogenesis. In order to investigate the molecular mechanisms underlying IPF further, we performed single-cell RNA sequencing analysis on three healthy controls and five IPF lung tissue samples. The results revealed a significant shift in epithelial cells (ECs) phenotypes in IPF, which may be attributed to the differentiation of alveolar type 2 cells to basal cells. In addition, several previously unrecognized basal cell subtypes were preliminarily identified, including extracellular matrix basal cells, which were increased in the IPF group. We identified a special population of fibroblasts that highly expressed extracellular matrix-related genes, POSTN, CTHRC1, COL3A1, COL5A2, and COL12A1. We propose that the close interaction between ECs and fibroblasts through ligand–receptor pairs may have a critical function in IPF development. Collectively, these outcomes provide innovative perspectives on the complexity and diversity of basal cells and fibroblasts in IPF and contribute to the understanding of possible mechanisms in pathological lung fibrosis.

Mapping spatially resolved transcriptomes in human and mouse pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with poor prognosis and limited treatment options. Efforts to identify effective treatments are thwarted by limited understanding of IPF pathogenesis and poor translatability of available preclinical models. Here we generated spatially resolved transcriptome maps of human IPF (n = 4) and bleomycin-induced mouse pulmonary fibrosis (n = 6) to address these limitations. We uncovered distinct fibrotic niches in the IPF lung, characterized by aberrant alveolar epithelial cells in a microenvironment dominated by transforming growth factor beta signaling alongside predicted regulators, such as TP53 and APOE. We also identified a clear divergence between the arrested alveolar regeneration in the IPF fibrotic niches and the active tissue repair in the acutely fibrotic mouse lung. Our study offers in-depth insights into the IPF transcriptional landscape and proposes alveolar regeneration as a promising therapeutic strategy for IPF.