Idiopathic pulmonary fibrosis (IPF) is a chronic and lethal interstitial lung disease (ILD) of unknown origin, characterized by limited treatment efficacy and a fibroproliferative nature. It is marked by excessive extracellular matrix deposition in the pulmonary parenchyma, leading to progressive lung volume decline and impaired gas exchange. The chemokine system, a network of proteins involved in cellular communication with diverse biological functions, plays a crucial role in various respiratory diseases. Chemokine receptors trigger the activation, proliferation, and migration of lung-resident cells, including pneumocytes, endothelial cells, alveolar macrophages, and fibroblasts. Around 50 chemokines can potentially interact with 20 receptors, expressed by both leukocytes and non-leukocytes such as tissue parenchyma cells, contributing to processes such as leukocyte mobilization from the bone marrow, recirculation through lymphoid organs, and tissue influx during inflammation or immune response. This narrative review explores the complexity of the chemokine system in the context of IPF and the bleomycin-induced lung fibrosis mouse model. The goal is to identify specific chemokines and receptors as potential therapeutic targets. Recent progress in understanding the role of the chemokine system during IPF, using experimental models and molecular diagnosis, underscores the complex nature of this system in the context of the disease. Despite advances in experimental models and molecular diagnostics, discovering an effective therapy for IPF remains a significant challenge in both medicine and pharmacology. This work delves into microarray results from lung samples of IPF patients and murine samples at different stages of bleomycin-induced pulmonary fibrosis. By discussing common pathways identified in both IPF and the experimental model, we aim to shed light on potential targets for therapeutic intervention. Dysregulation caused by abnormal chemokine levels observed in IPF lungs may activate multiple targets, suggesting that chemokine signaling plays a central role in maintaining or perpetuating lung fibrogenesis. The highlighted chemokine axes (CCL8-CCR2, CCL19/CCL21-CCR7, CXCL9-CXCR3, CCL3/CCL4/CCL5-CCR5, and CCL20-CCR6) present promising opportunities for advancing IPF treatment research and uncovering new pharmacological targets within the chemokine system.

Immune signalling is a crucial component in the progression of fibrosis. However, approaches for the safety assessment of potentially profibrotic substances, that provide information on mechanistic immune responses, are underdeveloped. This study aimed to develop a novel framework for assessing the immunotoxicity of fibrotic compounds. We exposed macrophages in vitro to multiple sublethal concentrations of the profibrotic agent bleomycin, over multiple timepoints, and generated RNA sequencing data. Using a toxicogenomic approach, we performed dose-dependent analysis to discover genes dysregulated by bleomycin exposure in a dose-responsive manner. A subset of immune genes displayed a sustained dose-dependent and differential expression response to profibrotic challenge. An immunoassay revealed cytokines and proteinases responding to bleomycin exposure that closely correlated to transcriptomic alterations, underscoring the integration between transcriptional immune response and external immune signalling activity. This study not only increases our understanding of the immunological mechanisms of fibrosis, but also offers an innovative framework for the toxicological evaluation of substances with potential fibrogenic effects on macrophage signalling. Our work brings a new immunotoxicogenomic direction for hazard assessment of fibrotic compounds, through the implementation of a time and resource efficient in vitro methodology.

Rationale: Fibrotic hypersensitivity pneumonitis (FHP) is a debilitating interstitial lung disease driven by incompletely understood immune mechanisms. Objectives: To elucidate immune aberrations in FHP in single-cell resolution. Methods: Single-cell 5' RNA sequencing was conducted on peripheral blood mononuclear cells and BAL cells obtained from 45 patients with FHP, 63 patients with idiopathic pulmonary fibrosis (IPF), 4 patients with nonfibrotic hypersensitivity pneumonitis, and 36 healthy control subjects in the United States and Mexico. Analyses included differential gene expression (Seurat), TF (transcription factor) activity imputation (DoRothEA-VIPER), and trajectory analyses (Monocle3 and Velocyto-scVelo-CellRank). Measurements and Main Results: Overall, 501,534 peripheral blood mononuclear cells from 110 patients and control subjects and 88,336 BAL cells from 19 patients were profiled. Compared with control samples, FHP has elevated classical monocytes (adjusted-P = 2.5 × 10-3) and is enriched in CCL3hi/CCL4hi and S100Ahi classical monocytes (adjusted-P < 2.2 × 10-16). Trajectory analyses demonstrate that S100Ahi classical monocytes differentiate into SPP1hi lung macrophages associated with fibrosis. Compared with both control subjects and IPF, cells from patients with FHP are significantly enriched in GZMhi cytotoxic T cells. These cells exhibit TF activities indicative of TGFβ and TNFα and NFκB pathways. These results are publicly available at http://ildimmunecellatlas.com. Conclusions: Single-cell transcriptomics of patients with FHP uncovered novel immune perturbations, including previously undescribed increases in GZMhi cytotoxic CD4+ and CD8+ T cells-reflecting this disease's unique inflammatory T cell-driven nature-as well as increased S100Ahi and CCL3hi/CCL4hi classical monocytes also observed in IPF. Both cell populations may guide the development of new biomarkers and therapeutic interventions.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrotic interstitial pneumonia, which is the commonest type of idiopathic interstitial pneumonia in the clinic. For most patients, the course of the disease is slow and prolonged, but a percentage of them develop an acute respiratory worsening during the disease, known as an acute exacerbation of IPF (AE-IPF). The updated guidelines define AE-IPF as an acute worsening of dyspnea in an IPF patient within 1 month and exclude other conditions such as left heart failure and pulmonary embolism. However, the prevention and treatment of AE-IPF are still unclear. Based on the high mortality rate caused by AE, in this article, we will focus on the latest research advances in AE-IPF treatment strategies and provide a comprehensive review of its pathogenesis, risk factors, clinical features, and diagnosis.

This study searched for relevant literature published from 2018 to 2023 in the PubMed database. The search terms used were as follows: "Acute exacerbation", "Idiopathic pulmonary fibrosis", "Biomarker", "Pathogenesis", "Treatment", "HRCT", "Antifibrotic", "Infection", "Immunosuppressant", "Autoantibody", "Oxygen therapy", "Hemoperfusion", "Inflammation".

The review found that corticosteroids are still the primary treatment strategy at present, although there is some controversy regarding the dosing and tapering of corticosteroids. However, corticosteroids combined with intravenous cyclophosphamide have been shown to be detrimental to the prognosis of patients with AE-IPF. Given its deadly high mortality rate, early intervention is crucial. Pirfenidone and nintedanib have been proven to reduce incidence of AE. Meanwhile, in the future, the lung microbiome may also be a break-through.

This study reviewed the pathogenesis and risk factors of AE-IPF and updated the current and potential treatment strategies regarding AE-IPF. The pathogenesis of AE-IPF is not exact, multiple mechanisms may be involved simultaneously. Corticosteroids remain the mainstream treatment modality in the medical treatment of AE-IFP. Many other treatment modalities have been proposed in succession, but no clear conclusions can be drawn about the effectiveness and safety of these interventions.

Idiopathic pulmonary fibrosis (IPF) is a lung disease that worsens over time, causing fibrosis in the lungs and ultimately resulting in respiratory failure and a high risk of death. Macrophages play a crucial role in the immune system, showing flexibility by transforming into either pro-inflammatory (M1) or anti-inflammatory (M2) macrophages when exposed to different stimuli, ultimately impacting the development of IPF. Recent research has indicated that the polarization of macrophages is crucial in the onset and progression of IPF. M1 macrophages secrete inflammatory cytokines and agents causing early lung damage and fibrosis, while M2 macrophages support tissue healing and fibrosis by releasing anti-inflammatory cytokines. Developing novel treatments for IPF relies on a thorough comprehension of the processes involved in macrophage polarization in IPF. The review outlines the regulation of macrophage polarization and its impact on the development of IPF, with the goal of investigating the possible therapeutic benefits of macrophage polarization in the advancement of IPF.

Fibrotic interstitial lung diseases (fILDs) have poor survival rates and lack effective therapies. Despite evidence for immune mechanisms in lung fibrosis, immunotherapies have been unsuccessful for major types of fILD. Here, we review immunological mechanisms in lung fibrosis that have the potential to impact clinical practice. We first examine innate immunity, which is broadly involved across fILD subtypes. We illustrate how innate immunity in fILD involves a complex interplay of multiple cell subpopulations and molecular pathways. We then review the growing evidence for adaptive immunity in lung fibrosis to provoke a re-examination of its role in clinical fILD. We close with future directions to address key knowledge gaps in fILD pathobiology: (1) longitudinal studies emphasizing early-stage clinical disease, (2) immune mechanisms of acute exacerbations, and (3) next-generation immunophenotyping integrating spatial, genetic, and single-cell approaches. Advances in these areas are essential for the future of precision medicine and immunotherapy in fILD.

While idiopathic interstitial pneumonia (IIP) centering on idiopathic pulmonary fibrosis (IPF) is the most prevalent interstitial lung disease (ILD), especially in the older adult population, connective tissue disease (CTD)-related ILD is the second most prevalent ILD. The pathogenesis of IPF is primarily fibrosis, whereas that of other ILDs, particularly CTD-ILD, is mainly inflammation. Therefore, a precise diagnosis is crucial for selecting appropriate treatments, such as antifibrotic or immunosuppressive agents. In addition, some patients with IIP have CTD-related features, such as arthritis and skin eruption, but do not meet the criteria for any CTD, this is referred to as interstitial pneumonia with autoimmune features (IPAF). IPAF is closely associated with idiopathic nonspecific interstitial pneumonia (iNSIP) and cryptogenic organizing pneumonia (COP). Furthermore, patients with iNSIP or those with NSIP with OP overlap frequently develop polymyositis/dermatomyositis after the diagnosis of IIP. Acute exacerbation of ILD, the most common cause of death, occurs more frequently in patients with IPF than in those with other ILDs. Although acute exacerbation of CTD-ILD occurs at a low rate of incidence, patients with rheumatoid arthritis, microscopic polyangiitis, or systemic sclerosis experience more acute exacerbation of CTD-ILD than those with other CTD. In this review, the features of each IIP, focusing on CTD-related signatures, are summarized, and the pathogenesis and appropriate treatments to improve the prognoses of patients with various ILDs are discussed.

Patients with pulmonary fibrosis (PF) often experience exacerbations of their disease, characterised by a rapid, severe deterioration in lung function that is associated with high mortality. Whilst the pathobiology of such exacerbations is poorly understood, virus infection is a trigger. The present study investigated virus-induced injury responses of alveolar and bronchial epithelial cells (AECs and BECs, respectively) from patients with PF and age-matched controls (Ctrls). Air-liquid interface (ALI) cultures of AECs, comprising type I and II pneumocytes or BECs were inoculated with influenza A virus (H1N1) at 0.1 multiplicity of infection (MOI). Levels of interleukin-6 (IL-6), IL-36γ and IL-1β were elevated in cultures of AECs from PF patients (PF-AECs, n = 8-11), being markedly higher than Ctrl-AECs (n = 5-6), 48 h post inoculation (pi) (P<0.05); despite no difference in H1N1 RNA copy numbers 24 h pi. Furthermore, the virus-induced inflammatory responses of PF-AECs were greater than BECs (from either PF patients or controls), even though viral loads in the BECs were overall 2- to 3-fold higher than AECs. Baseline levels of the senescence and DNA damage markers, nuclear p21, p16 and H2AXγ were also significantly higher in PF-AECs than Ctrl-AECs and further elevated post-infection. Senescence induction using etoposide augmented virus-induced injuries in AECs (but not viral load), whereas selected senotherapeutics (rapamycin and mitoTEMPO) were protective. The present study provides evidence that senescence increases the susceptibility of AECs from PF patients to severe virus-induced injury and suggests targeting senescence may provide an alternative option to prevent or treat the exacerbations that worsen the underlying disease.

Idiopathic pulmonary fibrosis (IPF) is a fatal and irreversible disease with few effective treatments. Alveolar macrophages (AMs) are involved in the development of IPF from the initial stages due to direct exposure to air and respond to external oxidative damage (a major inducement of pulmonary fibrosis). Oxidative stress in AMs plays an indispensable role in promoting fibrosis development. The oligopeptide histidine transporter SLC15A3, mainly expressed on the lysosomal membrane of macrophages and highly expressed in the lung, has proved to be involved in innate immune and antiviral signaling pathways. In this study, we demonstrated that during bleomycin (BLM)- or radiation-induced pulmonary fibrosis, the recruitment of macrophages induced an increase of SLC15A3 in the lung, and the deficiency of SLC15A3 protected mice from pulmonary fibrosis and maintained the homeostasis of the pulmonary microenvironment. Mechanistically, deficiency of SLC15A3 resisted oxidative stress in macrophages, and SLC15A3 interacted with the scaffold protein p62 to regulate its expression and phosphorylation activation, thereby regulating p62-nuclear factor erythroid 2-related factor 2 (NRF2) antioxidant stress pathway protein, which is related to the production of reactive oxygen species (ROS). Overall, our data provided a novel mechanism for targeting SLC15A3 to regulate oxidative stress in macrophages, supporting the therapeutic potential of inhibiting or silencing SLC15A3 for the precautions and treatment of pulmonary fibrosis.

Pulmonary fibrosis (PF) is a terminal change of a lung disease that is marked by damage to alveolar epithelial cells, abnormal proliferative transformation of fibroblasts, excessive deposition of extracellular matrix (ECM), and concomitant inflammatory damage. Its characteristics include short median survival, high mortality rate, and limited treatment effectiveness. More in-depth studies on the mechanisms of PF are needed to provide better treatment options. The idea of the gut-lung axis has emerged as a result of comprehensive investigations into the microbiome, metabolome, and immune system. This theory is based on the material basis of microorganisms and their metabolites, while the gut-lung circulatory system and the shared mucosal immune system act as the connectors that facilitate the interplay between the gastrointestinal and respiratory systems. The emergence of a new view of the gut-lung axis is complementary and cross-cutting to the study of the mechanisms involved in PF and provides new ideas for its treatment. This article reviews the mechanisms involved in PF, the gut-lung axis theory, and the correlation between the two. Exploring the gut-lung axis mechanism and treatments related to PF from the perspectives of microorganisms, microbial metabolites, and the immune system. The study of the gut-lung axis and PF is still in its early stages. This review systematically summarizes the mechanisms of PF related to the gut-lung axis, providing ideas for subsequent research and treatment of related mechanisms.

Idiopathic pulmonary fibrosis (IPF) is a progressive and irreversible condition characterized by the deposition of extracellular matrix resulting from repetitive damage to the alveolar epithelium. These injuries, along with dysregulated wound repair and fibroblast dysfunction, lead to continuous tissue remodeling and fibrosis, eventually resulting in end-stage pulmonary fibrosis. Currently, there is no specific pharmacological treatment available for IPF. The role of inflammation in the development of IPF is still a topic of debate, and it is sometimes considered incidental to fibrosis. Over the past decade, macrophages have emerged as significant contributors to the pathogenesis of fibrosis. M1 macrophages are responsible for wound healing following alveolar epithelial injury, while M2 macrophages are involved in resolving wound repair and terminating the inflammatory response in the lungs. Various studies provide evidence that M2-like macrophages contribute to the abnormal fibrogenesis. In recent years, there has been growing interest in understanding macrophage polarization and its role in the development of pulmonary fibrosis. Histone deacetylase 6 (HDAC6), a member of the HDAC family with two functional deacetylase structural domains and a ubiquitin-binding zinc finger structural domain (ZnF-BUZ), plays a crucial role in pulmonary fibrosis. This article explores the role of HDAC6 in pulmonary fibrosis and evaluates its potential as a treatment approach for IPF.

PubMed, Cochrane Library, China National Knowledge Infrastructure (CNKI), Wanfang, China Biomedical Literature Service System (CBMdisc) and Web of Science were searched to obtain researches, published in English and Chinese, until July 2023. The search was performed using specific keywords such as Histone deacetylase 6, HDAC6, Idiopathic pulmonary fibrosis, IPF, fibrosis.

HDAC6 has diverse effects on physiological processes, including the NLRP3 inflammasome, epithelial-mesenchymal transition, the TGFβ-PI3K-AKT pathway, macrophage polarization and TGF-β-Smad signaling pathway, due to its unique structure. HDAC6 has been found to enhance the inflammatory response and fibrosis of lung tissues, contributing to the development of IPF.

In the future, HDAC6 inhibitors are expected to play a crucial role in the treatment of fibrotic disorders and should be studied further deserves to pursue in future research.

The purpose of this work was to use integrated bioinformatics analysis to screen for pyroptosis-related genes (PRGs) and possible immunological phenotypes linked to the development and course of IPF. Transcriptome sequencing datasets GSE70866, GSE47460 and GSE150910 were obtained from GEO database. From the GSE70866 database, 34 PRGs with differential expression were found in IPF as compared to healthy controls. In addition, a diagnostic model containing 4 genes PRGs (CAMP, MKI67, TCEA3 and USP24) was constructed based on LASSO logistic regression. The diagnostic model showed good predictive ability to differentiate between IPF and healthy, with ROC-AUC ranging from 0.910 to 0.997 in GSE70866 and GSE150910 datasets. Moreover, based on a combined cohort of the Freiburg and the Siena cohorts from GSE70866 dataset, we identified ten PRGs that might predict prognosis for IPF. We constructed a prognostic model that included eight PRGs (CLEC5A, TREM2, MMP1, IRF2, SEZ6L2, ADORA3, NOS2, USP24) by LASSO Cox regression and validated it in the Leuven cohort. The risk model divided IPF patients from the combined cohort into high-risk and low-risk subgroups. There were significant differences between the two subgroups in terms of IPF survival and GAP stage. There is a close correlation between leukocyte migration, plasma membrane junction, and poor prognosis in a high-risk subgroup. Furthermore, a high-risk score was associated with more plasma cells, activated NK cells, monocytes, and activated mast cells. Additionally, we identified HDAC inhibitors in the cMAP database that might be therapeutic for IPF. To summarize, pyroptosis and its underlying immunological features are to blame for the onset and progression of IPF. PRG-based predictive models and drugs may offer new treatment options for IPF.

The ILD-GAP scoring system is known to be useful in predicting prognosis in patients with interstitial lung disease (ILD). An elevated monocyte count was associated with increased risks of IPF poor prognosis. We examined whether the ILD-GAP scoring system combined with the monocyte ratio (ILD-GAPM) is superior to the conventional ILD-GAP model in predicting ILD prognosis.

In patients with ILD treated between April 2013 and April 2017, we were retrospectively assessed the relationships between baseline clinical parameters, including age, sex, Charlson Comorbidity Index score (CCIS), ILD diagnosis, blood biomarkers, pulmonary function test results, and disease outcomes. In ILD patients were included idiopathic pulmonary fibrosis (IPF), idiopathic nonspecific interstitial pneumonia (iNSIP), collagen vascular disease-related interstitial pneumonia (CVD-IP), chronic hypersensitivity pneumonitis (CHP), and unclassifiable ILD (UC-ILD). We also assessed the ability to predict prognosis was compared between the ILD-GAP and ILD-GAPM models.

A total of 179 patients (mean age, 73 years) were assessed. All of them were taken pulmonary function test, including percentage predicted diffusion capacity for carbon monoxide. ILD patients included 56 IPF cases, 112 iNSIP and CVD-IP cases, 6 CHP cases and 5 UC-ILD cases. ILD-GAPM provided a greater area under the receiver-operating characteristic curve (0.747) than ILD-GAP (0.710) for predicting 3-year ILD-related events. Furthermore, the log-rank test showed that the Kaplan-Meier curves in ILD-GAPM were significantly different by stage (P = 0.015), but not by stage in ILD-GAP (P = 0.074).

The ILD-GAPM model may be a more accurate predictor of prognosis for ILD patients than the ILD-GAP model.

This meta-analysis aimed to examine the prognosis of patients with acute exacerbation of interstitial lung disease (AE-ILD) treated with lung transplantation compared to those with stable interstitial lung disease (ILD).

We conducted a detailed search in PubMed, Embase, Web of Science, and the Cochrane Library, with the primary outcomes being overall survival (OS), acute cellular rejection (ACR), primary graft dysfunction (PGD), and length of stay (LOS).

Five cohort studies were included in this meta-analysis, with 183 patients enrolled in the AE-ILD group and 337 patients in the stable-ILD group. The results showed that in regard to perioperative outcomes, the AE-ILD group did not differ from the stable-ILD group in the incidence of ACR (relative risks [RR] = 0.34, p = 0.44) and the incidence of PGD Ⅲ (RR = 0.53, p = 0.43), but had a longer LOS (mean difference = 9.15, p = 0.02). Regarding prognosis, the two also did not differ in 90-day OS (RR = 0.97, p = 0.59), 1-year OS (RR = 1.05, p = 0.66), and 3-year OS (RR = 0.91, p = 0.76).

Our study concluded that the efficacy of lung transplantation in patients with AE-ILD is not inferior to that of patients with stable ILD. Lung transplantation is one of the potential treatments for patients with AE-ILD.

Macrophages are key regulators of tissue repair and fibrosis. Following injury, macrophages undergo marked phenotypic and functional changes to play crucial roles throughout the phases of tissue repair. Idiopathic Pulmonary Fibrosis, which is the most common fibrosing lung disease, has been described as an aberrant reparative response to repetitive alveolar epithelial injury in a genetically susceptible aging individual. The marked destruction of the lung architecture results from the excessive secretion of extracellular matrix by activated fibroblasts and myofibroblasts. Accumulating evidence suggests that macrophages have a pivotal regulatory role in pulmonary fibrosis. The origins and characteristics of macrophages in the lung and their role in regulating lung homeostasis, repair, and fibrosis are reviewed herein. We discuss recent studies that have employed single-cell RNA-sequencing to improve the identification and characterization of macrophage populations in the context of homeostatic and fibrotic conditions. We also discuss the current understanding of the macrophage-mediated mechanisms underlying the initiation and progression of pulmonary fibrosis, with a focus on the phenotypic and functional changes that aging macrophages acquire and how these changes ultimately contribute to age-related chronic lung diseases.

Serum heme oxygenase (HO)-1 level has been reported as a clinically reliable diagnostic biomarker for acute exacerbation of interstitial lung disease (ILD); however, its utility for predicting mortality among these patients is unclear. Serum HO-1 levels of patients newly diagnosed with acute exacerbation of ILD were measured at the time of initiating steroid pulse therapy. The relationship between serum HO-1 and various other serum biomarkers, change in HRCT findings, and disease prognosis at 12 weeks after diagnosis of acute exacerbation was evaluated in 51 patients, of whom 17 (33%) had idiopathic pulmonary fibrosis (IPF). Serum HO-1 was higher in patients with acute exacerbation of IPF than in patients with acute exacerbation of other ILDs. Serum HO-1 levels were higher in patients who died within these 12 weeks than in survivors. Among age, sex, comorbidities, IPF diagnosis, HRCT findings, and blood biomarkers, serum HO-1 was a primary predictor of 12-week mortality. In 41 patients who underwent repeat HRCT, serum HO-1 was higher in patients with honeycomb progression than in those without. Serum HO-1 measurement could be useful for evaluating disease mortality and morbidity of patients with acute exacerbation of ILDs.

Acute exacerbation of interstitial lung disease (AE-ILD) significantly impacts prognosis, leading to high mortality rates. Although lung transplantation is a life-saving treatment for selected patients with ILD, its outcomes in those presenting with AE-ILD have yielded conflicting results compared with those with stable ILD. This study aims to investigate the impact of pre-existing AE on the prognosis of ILD patients who underwent lung transplantation.

We conducted a single-center retrospective study by reviewing the medical records of 108 patients who underwent lung transplantation for predisposing ILD at Asan Medical Center, Seoul, South Korea, between 2008 and 2022. The primary objective was to compare the survival of patients with AE-ILD at the time of transplantation with those without AE-ILD.

Among the 108 patients, 52 (48.1%) experienced AE-ILD at the time of lung transplantation, and 81 (75.0%) required pre-transplant mechanical ventilation. Although the type of ILD (IPF vs. non-IPF ILD) did not affect clinical outcomes after transplantation, AE-ILD was associated with worse survival outcomes. The survival probabilities at 90 days, 1 year, and 3 years post-transplant for patients with AE-ILD were 86.5%, 73.1%, and 60.1%, respectively, while those for patients without AE-ILD were higher, at 92.9%, 83.9%, and 79.6% (p = 0.032). In the multivariable analysis, pre-existing AE was an independent prognostic factor for mortality in ILD patients who underwent lung transplantation.

Although lung transplantation remains an effective treatment option for ILD patients with pre-existing AE, careful consideration is needed, especially in patients requiring pre-transplant mechanical respiratory support.

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

Epidemiological evidence indicates that exposure to particulate matter is linked to the development of idiopathic pulmonary fibrosis (IPF) and increases the incidence of acute exacerbations of IPF. In addition to accelerating the rate of lung function decline, exposure to fine particulate matter (particulate matter smaller than 2.5 μm [PM2.5]) is a risk factor for increased mortality in subjects with IPF. In this article, we show that exposure to PM2.5 mediates monocyte recruitment and fibrotic progression in mice with established fibrosis. In mice with established fibrosis, bronchoalveolar lavage cells showed monocyte/macrophage heterogeneity after exposure to PM2.5. These cells had a significant inflammatory and anti-inflammatory signature. The mixed heterogeneity of cells contributed to the proinflammatory and anti-inflammatory response. Although monocyte-derived macrophages were recruited to the lung in bleomycin-injured mice treated with PM2.5, recruitment of monocytes expressing Ly6Chi to the lung promoted progression of fibrosis, reduced lung aeration on computed tomography, and impacted lung compliance. Ly6Chi monocytes isolated from PM2.5-exposed fibrotic mice showed enhanced expression of proinflammatory markers compared with fibrotic mice exposed to vehicle. Moreover, IPF bronchoalveolar lavage cells treated ex vivo with PM2.5 showed an exaggerated inflammatory response. Targeting Ly6Chi monocyte recruitment inhibited fibrotic progression in mice. Moreover, the adoptive transfer of Ly6Chi monocytes exacerbated established fibrosis. These observations suggest that enhanced recruitment of Ly6Chi monocytes with a proinflammatory phenotype mediates acute exacerbations of pulmonary fibrosis, and targeting these cells may provide a potential novel therapeutic target to protect against acute exacerbations of IPF.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive scarring interstitial lung disease with an unknown cause. Some patients may experience acute exacerbations (AE), which result in severe lung damage visible on imaging or through examination of tissue samples, often leading to high mortality rates. However, the etiology and pathogenesis of AE-IPF remain unclear. AE-IPF patients exhibit diffuse lung damage, apoptosis of type II alveolar epithelial cells, and an excessive inflammatory response. Establishing a reliable animal model of AE is critical for investigating the pathogenesis. Recent studies have reported a variety of animal models for AE-IPF, each with its own advantages and disadvantages. These models are usually established in mice with bleomycin-induced pulmonary fibrosis, using viruses, bacteria, small peptides, or specific drugs. In this review, we present an overview of different AE models, hoping to provide a useful resource for exploring the mechanisms and targeted therapies for AE-IPF.

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease whereby excessive deposition of extracellular matrix proteins (ECM) ultimately leads to respiratory failure. While there have been advances in pharmacotherapies for pulmonary fibrosis, IPF remains an incurable and irreversible disease. There remains an unmet clinical need for treatments that reverse fibrosis, or at the very least have a more tolerable side effect profile than currently available treatments. Transforming growth factor β1(TGFβ1) is considered the main driver of fibrosis in IPF. However, as our understanding of the role of the pulmonary renin-angiotensin system (PRAS) in the pathogenesis of IPF increases, it is becoming clear that targeting angiotensin receptors represents a potential novel treatment strategy for IPF - in particular, via activation of the anti-fibrotic angiotensin type 2 receptor (AT2R). This review describes the current understanding of the pathophysiology of IPF and the mediators implicated in its pathogenesis; focusing on TGFβ1, angiotensin II and related peptides in the PRAS and their contribution to fibrotic processes in the lung. Preclinical and clinical assessment of currently available AT2R agonists and the development of novel, highly selective ligands for this receptor will also be described, with a focus on compound 21, currently in clinical trials for IPF. Collectively, this review provides evidence of the potential of AT2R as a novel therapeutic target for IPF.

Fibrosis of the lung can occur in idiopathic pulmonary fibrosis, collagen vascular diseases, and hypersensitivity pneumonitis, among other diseases. Transforming growth factor (TGF)-β, vascular epithelial growth factor, fibroblast growth factor, and platelet-derived growth factor contribute to the pathophysiology of fibrosis. TGF-β and other cytokines, including interleukin (IL)-1β, IL-6, and IL-23, activate type-17 immunity, which is involved in pulmonary fibrosis. The components of type-17 immunity include type-17 helper T cells, γδT cells, IL-17A-producing CD8-positive T cells, invariant NKT cells, and group 3 innate lymphoid cells. IL-17A, the main cytokine of type-17 immunity, is able to induce the epithelial-mesenchymal transition in epithelial cells via a production of TGF-β, directly stimulate fibroblasts and fibrocytes, and inhibit autophagy, which otherwise protects against pulmonary fibrosis. IL-23 induces type-17 immunity and plays an important role in the acute exacerbation of pulmonary fibrosis. Clinical studies have also linked type-17 immunity to the pathogenesis of pulmonary fibrosis. Consequently, targeting type-17 immunity may serve as a new therapeutic strategy to prevent the development or exacerbation of pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive devastating lung disease with substantial morbidity. It is associated with cough, dyspnea and impaired quality of life. If left untreated, IPF has a median survival of 3 years. IPF affects ∼3 million people worldwide, with increasing incidence in older patients. The current concept of pathogenesis is that pulmonary fibrosis results from repetitive injury to the lung epithelium, with fibroblast accumulation, myofibroblast activation, and deposition of matrix. These injuries, in combination with innate and adaptive immune responses, dysregulated wound repair and fibroblast dysfunction, lead to recurring tissue remodeling and self-perpetuating fibrosis as seen in IPF. The diagnostic approach includes the exclusion of other interstitial lung diseases or underlying conditions and depends on a multidisciplinary team-based discussion combining radiological and clinical features and well as in some cases histology. In the last decade, considerable progress has been made in the understanding of IPF clinical management, with the availability of two drugs, pirfenidone and nintedanib, that decrease pulmonary lung function decline. However, current IPF therapies only slow disease progression and prognosis remains poor. Fortunately, there are multiple clinical trials ongoing with potential new therapies targeting different disease pathways. This review provides an overview of IPF epidemiology, current insights in pathophysiology, diagnostic and therapeutic management approaches. Finally, a detailed description of current and evolving therapeutic approaches is also provided.

Single-cell RNA sequencing (scRNA-seq) technology has enabled assessment of transcriptome-wide changes at single-cell resolution. Due to the heterogeneity in environmental exposure and genetic background across subjects, subject effect contributes to the major source of variation in scRNA-seq data with multiple subjects, which severely confounds cell type specific differential expression (DE) analysis. Moreover, dropout events are prevalent in scRNA-seq data, leading to excessive number of zeroes in the data, which further aggravates the challenge in DE analysis.

We developed iDESC to detect cell type specific DE genes between two groups of subjects in scRNA-seq data. iDESC uses a zero-inflated negative binomial mixed model to consider both subject effect and dropouts. The prevalence of dropout events (dropout rate) was demonstrated to be dependent on gene expression level, which is modeled by pooling information across genes. Subject effect is modeled as a random effect in the log-mean of the negative binomial component. We evaluated and compared the performance of iDESC with eleven existing DE analysis methods. Using simulated data, we demonstrated that iDESC had well-controlled type I error and higher power compared to the existing methods. Applications of those methods with well-controlled type I error to three real scRNA-seq datasets from the same tissue and disease showed that the results of iDESC achieved the best consistency between datasets and the best disease relevance.

iDESC was able to achieve more accurate and robust DE analysis results by separating subject effect from disease effect with consideration of dropouts to identify DE genes, suggesting the importance of considering subject effect and dropouts in the DE analysis of scRNA-seq data with multiple subjects.

Epithelial-to-mesenchymal transition (EMT) is a reversible process, in which epithelial cells lose their epithelial traits and acquire a mesenchymal phenotype. This transformation has been described in different lung diseases, such as lung cancer, interstitial lung diseases, asthma, chronic obstructive pulmonary disease and other muco-obstructive lung diseases, such as cystic fibrosis and non-cystic fibrosis bronchiectasis. The exaggerated chronic inflammation typical of these pulmonary diseases can induce molecular reprogramming with subsequent self-sustaining aberrant and excessive profibrotic tissue repair. Over time this process leads to structural changes with progressive organ dysfunction and lung function impairment. Although having common signalling pathways, specific triggers and regulation mechanisms might be present in each disease. This review aims to describe the various mechanisms associated with fibrotic changes and airway remodelling involved in chronic airway diseases. Having better knowledge of the mechanisms underlying the EMT process may help us to identify specific targets and thus lead to the development of novel therapeutic strategies to prevent or limit the onset of irreversible structural changes.

Several markers have been identified to increase the risk for acute exacerbation of interstitial lung disease (AE-ILD) or mortality related to AE-ILD. However, less is known about the risk predictors of ILD patients who have survived AE. The aim of the study was to characterise AE-ILD survivors and investigate prognostic factors in this subpopulation.

All AE-ILD patients (n = 95) who had been discharged alive from two hospitals located in Northern Finland were selected from a population of 128 AE-ILD patients. Clinical data related to the hospital treatment and six-month follow-up visit were collected retrospectively from medical records.

Fifty-three patients with idiopathic pulmonary fibrosis (IPF) and 42 patients with other ILD were identified. Two thirds of the patients had been treated without invasive or non-invasive ventilation support. The clinical features of six-month survivors (n = 65) and non-survivors (n = 30) did not differ in terms of medical treatment or oxygen requirements. Of the patients, 82.5% used corticosteroids at the six-month follow-up visit. Fifty-two patients experienced at least one non-elective respiratory re-hospitalisation before the six-month follow-up visit. In a univariate model, IPF diagnosis, high age and a non-elective respiratory re-hospitalisation increased the risk of death, although re-hospitalisation was the only independent risk factor in a multivariate model. In six-month survivors, there was no statistically significant decrease in pulmonary function test results (PFT) examined at the follow-up visit compared with earlier PFT examined near the time of AE-ILD.

The AE-ILD survivors were a heterogeneous group of patients both clinically and in terms of their outcome. A non-elective respiratory re-hospitalisation was identified as a marker of poor prognosis among AE-ILD survivors.

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease characterized by progressive lung fibrogenesis and histological features of usual interstitial pneumonia. IPF has a poor prognosis and presents a spectrum of disease courses ranging from slow evolving disease to rapid deterioration; thus, a differential diagnosis remains challenging. Several biomarkers have been identified to achieve a differential diagnosis; however, comprehensive reviews are lacking. This review summarizes over 100 biomarkers which can be divided into six categories according to their functions: differentially expressed biomarkers in the IPF compared to healthy controls; biomarkers distinguishing IPF from other types of interstitial lung disease; biomarkers differentiating acute exacerbation of IPF from stable disease; biomarkers predicting disease progression; biomarkers related to disease severity; and biomarkers related to treatment. Specimen used for the diagnosis of IPF included serum, bronchoalveolar lavage fluid, lung tissue, and sputum. IPF-specific biomarkers are of great clinical value for the differential diagnosis of IPF. Currently, the physiological measurements used to evaluate the occurrence of acute exacerbation, disease progression, and disease severity have limitations. Combining physiological measurements with biomarkers may increase the accuracy and sensitivity of diagnosis and disease evaluation of IPF. Most biomarkers described in this review are not routinely used in clinical practice. Future large-scale multicenter studies are required to design and validate suitable biomarker panels that have diagnostic utility for IPF.

Cigarette smoke (CS) poses a significant risk factor for respiratory, vascular, and organ diseases owing to its high content of harmful chemicals and reactive oxygen species (ROS). These substances are known to induce oxidative stress, inflammation, apoptosis, and senescence due to their exposure to environmental pollutants and the presence of oxidative enzymes. The lung is particularly susceptible to oxidative stress. Persistent oxidative stress caused by chronic exposure to CS can lead to respiratory diseases such as chronic obstructive pulmonary disease (COPD), pulmonary fibrosis (PF), and lung cancer. Avoiding exposure to environmental pollutants, like cigarette smoke and air pollution, can help mitigate oxidative stress. A comprehensive understanding of oxidative stress and its impact on the lungs requires future research. This includes identifying strategies for preventing and treating lung diseases as well as investigating the underlying mechanisms behind oxidative stress. Thus, this review aims to investigate the cellular processes induced by CS, specifically inflammation, apoptosis, senescence, and their associated biomarkers. Furthermore, this review will delve into the alveolar response provoked by CS, emphasizing the roles of potential therapeutic target markers and strategies in inflammation and oxidative stress.

This study was conducted to establish a rat model of acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) using the combination of bleomycin (BLM) and lipopolysaccharides (LPS).

Twenty-four male Sprague Dawley rats were allocated into two equal groups: the sham or the bleomycin and lipopolysaccharides-induced AE-IPF group (BLM-LPS). On Day 7, BLM intratracheally and LPS intraperitoneally were both used to administer AE-IPF. The BLM-LPS group and its respective sham group were terminated on Days 8, 14, or 21. Samples of bronchoalveolar lavage fluid (BALF) and lungs were taken and investigated for cell count and histopathology.

On Day 8, histological analysis revealed inflammatory cell infiltration with edema and hyaline membrane, and the BALF differential cell count revealed high neutrophil counts. By having a higher collagen density area and Ashcroft modified score than the sham group on Day 14, the BLM-LPS group displayed significantly lower oxygen saturation, alveolar air area, and a fibrotic appearance. However, there was a spontaneous resolution in inflammation and fibrotic appearance on Day 21 after the BLM administration.

By combining BLM and LPS, it was possible to create a successful rat model of AE-IPF. The present model showed the peak exacerbation on Day 8 and the fibrotic peak on Day 14, which gradually improved. The optimal time for the new AE-IPF therapeutic intervention was determined to be between Days 8 and 14.

A better capacity to identify patients with idiopathic pulmonary fibrosis (IPF) at risk of acute exacerbation (AEIPF) might improve outcomes and reduce healthcare costs.

We critically appraised the available evidence of the differences in clinical, respiratory, and biochemical parameters between AEIPF and IPF patients with stable disease (SIPF) by conducting a systematic review and meta-analysis.

PubMed, Web of Science and Scopus were reviewed up until August 1, 2022, for studies reporting differences in clinical, respiratory, and biochemical parameters (including investigational biomarkers) between AEIPF and SIPF patients. The Joanna Briggs Institute Critical Appraisal Checklist was used to assess the risk of bias.

Twenty-nine cross-sectional studies published between 2010 and 2022 were identified (all with a low risk of bias). Of the 32 meta-analysed parameters, significant differences were observed between groups, assessed through standard mean differences or relative ratios, with age, forced vital capacity, vital capacity, carbon monoxide diffusion capacity, total lung capacity, oxygen partial pressure, alveolar-arterial oxygen gradient, P/F ratio, 6 min walk test distance, C-reactive protein, lactate dehydrogenase, white blood cell count, albumin, Krebs von den Lungen 6, surfactant protein D, high mobility group box 1 protein, and interleukin-1β, 6, and 8.

We identified significant differences between AEIPF and SIPF patients in age and specific parameters of respiratory function, inflammation, and epithelial lung damage. Prospective studies are warranted to determine the capacity of these parameters to predict AEIPF more accurately (PROSPERO registration number: CRD42022356640).

Acute respiratory distress syndrome (ARDS) has a fibroproliferative phase that may be followed by pulmonary fibrosis. This has been described in patients with COVID-19 pneumonia, but the underlying mechanisms have not been completely defined. We hypothesized that protein mediators of tissue remodeling and monocyte chemotaxis are elevated in the plasma and endotracheal aspirates of critically ill patients with COVID-19 who subsequently develop radiographic fibrosis. We enrolled COVID-19 patients admitted to the ICU who had hypoxemic respiratory failure, were hospitalized and alive for at least 10 days, and had chest imaging done during hospitalization ( n = 119). Plasma was collected within 24h of ICU admission and at 7d. In mechanically ventilated patients, endotracheal aspirates (ETA) were collected at 24h and 48-96h. Protein concentrations were measured by immunoassay. We tested for associations between protein concentrations and radiographic evidence of fibrosis using logistic regression adjusting for age, sex, and APACHE score. We identified 39 patients (33%) with features of fibrosis. Within 24h of ICU admission, plasma proteins related to tissue remodeling (MMP-9, Amphiregulin) and monocyte chemotaxis (CCL-2/MCP-1, CCL-13/MCP-4) were associated with the subsequent development of fibrosis whereas markers of inflammation (IL-6, TNF-α) were not. After 1 week, plasma MMP-9 increased in patients without fibrosis. In ETAs, only CCL-2/MCP-1 was associated with fibrosis at the later timepoint. This cohort study identifies proteins of tissue remodeling and monocyte recruitment that may identify early fibrotic remodeling following COVID-19. Measuring changes in these proteins over time may allow for early detection of fibrosis in patients with COVID-19.

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease that has no cure. Although mesenchymal stem cells (MSCs) have been reported to ameliorate lung inflammation and fibrosis in mouse models, their mechanisms of action remain unknown. Therefore, we aimed to determine the changes in various immune cells, especially macrophages and monocytes, involved in the effects of MSC treatment on pulmonary fibrosis.

We collected and analyzed explanted lung tissues and blood from patients with IPF who underwent lung transplantation. After establishing a pulmonary fibrosis model via the intratracheal administration of bleomycin (BLM) to 8-week-old mice, MSCs derived from human umbilical cords were administered intravenously or intratracheally on day 10 and the lungs were immunologically analyzed on days 14 and 21. Flow cytometry was performed to analyze the immune cell characteristics, and gene expression levels were examined using quantitative reverse transcription-polymerase chain reaction.

In the histological analysis of explanted human lung tissues, the terminally fibrotic areas contained a larger number of macrophages and monocytes than the early fibrotic areas of the lungs. When human monocyte-derived macrophages (MoMs) were stimulated with interleukin-13 in vitro, the expression of type 2 macrophage (M2) markers was more prominent in MoMs from the classical monocyte subset than in those from intermediate or non-classical monocyte subsets, and MSCs suppressed M2 marker expression independent of MoM subsets. In the mouse model, the increased number of inflammatory cells in the bronchoalveolar lavage fluid and the degree of lung fibrosis observed in BLM-treated mice were significantly reduced by MSC treatment, which tended to be more prominent with intravenous administration than intratracheal administration. Both M1 and M2 MoMs were upregulated in BLM-treated mice. The M2c subset of M2 MoMs was significantly reduced by MSC treatment. Among M2 MoMs, M2 MoMs derived from Ly6C⁺ monocytes were most effectively regulated by the intravenous administration, not intratracheal administration, of MSCs.

Inflammatory classical monocytes may play a role in lung fibrosis in human IPF and BLM-induced pulmonary fibrosis. Intravenous rather than intratracheal administration of MSCs may ameliorate pulmonary fibrosis by inhibiting monocyte differentiation into M2 macrophages.

Idiopathic pulmonary fibrosis (IPF), characterized by progressive worsening of dyspnea and irreversible decline in lung function, is a chronic and progressive respiratory disease with a poor prognosis. Chronic or repeated lung injury results in inflammation and an excessive injury-repairing response that drives the development of IPF. A number of studies have shown that the development and progression of IPF are associated with dysregulated expression of several chemokines and chemokine receptors, several of which have been used as predictors of IPF outcome. Chemokines of the CC family play significant roles in exacerbating IPF progression by immune cell attraction or fibroblast activation. Modulating levels of detrimental CC chemokines and interrupting the corresponding transduction axis by neutralizing antibodies or antagonists are potential treatment options for IPF. Here, we review the roles of different CC chemokines in the pathogenesis of IPF, and their potential use as biomarkers or therapeutic targets.

The aim was to evaluate the determinants of acute exacerbation (AE) and death in new cases of idiopathic pulmonary fibrosis (IPF) using administrative databases in the Marche Region. Adults at their first prescription of antifibrotics or hospitalization with a diagnosis of IPF occurring in 2014-2019 were considered as new cases. Multiple Cox regression was used to estimate the risk of AE and of all-cause mortality adjusted by demographic and clinical characteristics, stratifying patients according to antifibrotic treatment. Overall, 676 new cases of IPF were identified and 276 deaths and 248 AE events occurred. In never-treated patients, the risk of AE was higher in patients with poor health conditions at diagnosis; the risk of death was higher in males, in patients aged ≥75 and in those with poor health conditions at baseline. The increasing number of AEs increased the risk of death in treated and never-treated patients. Within the limits of an observational study based on secondary data, the combined use of healthcare administrative databases allows the accurate analysis of progression and survival of IPF from the beginning of the antifibrotic therapy era, suggesting that timely and early diagnosis is critical to prescribing the most suitable treatment to increase survival and maintain a healthy life expectancy.

Interstitial lung disease is an overarching term for a wide range of disorders characterized by inflammation and/or fibrosis in the lungs. Most prevalent forms, among others, include idiopathic pulmonary fibrosis (IPF) and connective tissue disease associated interstitial lung disease (CTD-ILD). Currently, only disease modifying treatment options are available for IPF and progressive fibrotic CTD-ILD, leading to reduction or stabilization in the rate of lung function decline at best. Management of these patients would greatly advance if we identify new strategies to improve (1) early detection of ILD, (2) predicting ILD progression, (3) predicting response to therapy and (4) understanding pathophysiology. Over the last years, positron emission tomography (PET) and single photon emission computed tomography (SPECT) have emerged as promising molecular imaging techniques to improve ILD management. Both are non-invasive diagnostic tools to assess molecular characteristics of an individual patient with the potential to apply personalized treatment. In this review, we encompass the currently available pre-clinical and clinical studies on molecular imaging with PET and SPECT in IPF and CTD-ILD. We provide recommendations for potential future clinical applications of these tracers and directions for future research.

Interstitial lung diseases (ILD) are relatively rare and sometimes become life threatening. In particular, rapidly progressive ILD, which frequently presents as acute lung injury (ALI) on lung histopathology, shows poor prognosis if proper and immediate treatments are not initiated. These devastating conditions include acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF), clinically amyopathic dermatomyositis (CADM), epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI)-induced lung injury, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection named coronavirus disease 2019 (COVID-19). In this review, clinical information, physical findings, laboratory examinations, and findings on lung high-resolution computed tomography and lung histopathology are presented, focusing on majorly damaged cells in each disease. Furthermore, treatments that should be immediately initiated in clinical practice for each disease are illustrated to save patients with these diseases.

The study aims to identify potential diagnostic markers of idiopathic pulmonary fibrosis (IPF) and analyze the significance of immune cell infiltration in this pathology.

Download two publicly available gene expression profiles (GSE10667 and GSE24206 datasets) from the GEO database including 48 Idiopathic pulmonary fibrosis (IPF) samples and 21 human control samples and select for distinctly expressed genes (DEG) from them. Lasso regression model and support vector machine recursive feature elimination S,V,R,F analysis were used to check candidate biomarkers. The area under the subject's work characteristic curve (AUC) value is used to evaluate its recognition ability. The GSE53845 dataset (40 IPF patients and 8 controls) continue to validate the expression level and diagnostic value of biomarkers in IPF. Comprehensive analysis of immune infiltrated cells of IPF was performed using R software and immune cell infiltration estimation analysis tool- deconvolution algorithm (CIBERSORT).

43 DEGs were identified in total. The identified DEGs mostly involve pneumonia, lung disease, collagen disease, obstructive pulmonary disease and other diseases. The activation of IL-17 signaling pathways, amoebic disease, interaction of viral proteins with cytokines and cytokine receptors, protein digestion and absorption, and flaccid hormone signaling pathways in IPF were different from the control group. The expression degree of CRTAC1, COL10A1, COMP, RPS4Y1, IGFL2, NECAB1, SCG5, SLC6A4, and SPP1 in IPF tissue were prominently higher than the normal group. Immune cell infiltration analysis showed that CRTAC1, COL10A1, COMP, IGFL2, NECAB1, SCG5, SLC6A4, and SPP1 were associated with monocytes, plasma cells, neutrophils, and regulatory (treg) T cells.

CRTAC1, COL10A1, COMP, IGFL2, NECAB1, SCG5, SLC6A4, and SPP1 can be used as diagnostic markers for IPF, providing new ideas for the future study of IPF occurrence and molecular mechanisms.

Acute exacerbation-idiopathic pulmonary fibrosis (AE-IPF) is a life-threatening condition. In the treatment of AE-IPF, corticosteroid medication is commonly utilized. However, there is insufficient evidence to justify its usage. Pirfenidone (PFD) has recently been discovered to be effective in the treatment of AE-IPF patients. However, regenerative therapy, such as stem cell therapy or tissue engineering, is necessary due to ineffective and limited therapies. Combining MSC transplantation with pharmacological therapy may also give additional benefits; nevertheless, its use must be proven experimentally. As a result, the goal of this study was to assess the therapeutic effects of adipose-derived mesenchymal stem cells (AD-MSCs) on corticosteroid resistance in an animal model of AE-IPF caused by bleomycin compared to PFD.

Seventy C57BL/6J male mice were randomly divided into seven groups, control, BLM, methylprednisolone (MP), PFD, AD-MSCs, PFD +MP, and AD-MSCs +MP.

In terms of survival, collagen deposition, the acute lung injury score (ALI), and the Ashcroft score, AD-MSCs exceeded PFD. AD-MSCs + MP provided protection and preserved the lung's architecture in BLM-induced AE. In addition, AD-MSCs successfully decreased chemokine (CC motif) ligand-2 (CCL2) positive cells and lower pro-fibrotic and pro-inflammatory cytokines.

AD-MSCs enhanced histological structure, Ashcroft and ALI scores, lung collagen deposition, survival, and cytokines in an animal model of AE-IPF. As a result, we believe that AD-MSCs may be more therapeutically helpful for AE-IPF than presently available therapies, either alone or in conjunction with MP.

Idiopathic pulmonary fibrosis, a condition with likely genetic and environmental etiology, is relatively more prevalent with poor prognosis in human males. However, the underlying mechanisms for these gender-associated differences in the severity of fibrosis remain unknown. Here, we tested the hypothesis that the transcriptomic repertoire of myeloid cells determines the higher susceptibility of male mice to bleomycin (BLM)-induced lung fibrosis. Adult mice were oropharyngeally challenged with saline or BLM. Lung injury, inflammation, and fibrosis outcomes were assessed, and airspace myeloid-cells were subjected to RNA-sequencing. As compared with the female mice, the male mice manifested significantly increased lung injury, inflammation, proinflammatory cytokines (IL-6, IL-1β, IL-7, and IP-10), and fibrosis in response to BLM challenge. Interestingly, several pro-inflammatory and extracellular matrix-associated genes were significantly up-regulated in male myeloid-cells compared to female myeloid-cells in the saline-control group. Similarly, BLM challenge resulted in greater pro-inflammatory and pro-fibrotic transcriptomic changes in male compared to female myeloid cells. On the other hand, anti-inflammatory and regulatory cytokine, Il10 and Ifng respectively, were uniquely upregulated in BLM-challenged female but not in male myeloid cells when compared to their respective saline-control groups. Further, cross-sex bone marrow transplantation experiments revealed that male hematopoietic progenitor cells (HPCs) increased the granulocytic infiltration in female mice while female HPCs decreased the granulocytic infiltration in male mice post-BLM challenge. These findings suggest that there are inherent transcriptomic differences between the male and female lung myeloid cells and that the pro-inflammatory nature of male myeloid cells is sufficient to increase the susceptibility of female mice to BLM-induced inflammation.

Acute exacerbation of idiopathic interstitial pneumonias (AE-IIPs) has a high mortality. However, there is no established treatment for AE-IIPs. Therefore, we aimed to compare the efficacy of high- and low-dose corticosteroid therapies in AE-IIPs patients.

Data were retrospectively collected from the Japanese Diagnosis Procedure Combination database from July 2010 to March 2018. Adult patients with AE-IIPs who received high-dose (methylprednisolone at a dose of 500-1000 mg/day for 3 days starting within 4 days after admission) or low-dose (methylprednisolone at a dose of 100-200 mg/day for at least 5 days starting within 4 days after admission) corticosteroid therapy were identified. Eligible patients (n = 17,317) were divided into the high-dose (n = 16,998) and low-dose (n = 319) groups. A stabilized inverse probability of treatment weighting using propensity scores was performed to compare outcomes between the groups.

The primary outcome was in-hospital mortality, and the secondary outcomes were 28-day mortality, infections during hospitalization, length of hospitalization, duration of steroid use, and discharge to home. The in-hospital mortality rates of the high- and low-dose corticosteroid groups were 50.6% and 47.0%, respectively. In-hospital mortality did not significantly differ between the two groups after stabilized inverse probability of treatment weighting, and the odds ratio in the low-dose corticosteroid group was 0.86 (95% confidence interval: 0.64-1.16; p = 0.33). The secondary outcomes also did not significantly differ between the groups.

There was no significant difference in outcomes between patients with AE-IIPs who received high- and low-dose corticosteroid therapies.