Including Idiopathic Pulmonary Fibrosis Research Articles

The role of epithelial-mesenchymal transition in pulmonary fibrosis: lessons from idiopathic pulmonary fibrosis and COVID-19.

Despite the tremendous advancements in the knowledge of the pathophysiology and clinical aspects of SARS-CoV-2 infection, still many issues remain unanswered, especially in the long-term effects. Mounting evidence suggests that pulmonary fibrosis (PF) is one of the most severe complications associated with COVID-19. Therefore, understanding the molecular mechanisms behind its development is helpful to develop successful therapeutic strategies. Epithelial to mesenchymal transition (EMT) and its cell specific variants endothelial to mesenchymal transition (EndMT) and mesothelial to mesenchymal transition (MMT) are physio-pathologic cellular reprogramming processes induced by several infectious, inflammatory and biomechanical stimuli. Cells undergoing EMT acquire invasive, profibrogenic and proinflammatory activities by secreting several extracellular mediators. Their activity has been implicated in the pathogenesis of PF in a variety of lung disorders, including idiopathic pulmonary fibrosis (IPF) and COVID-19. Aim of this article is to provide an updated survey of the cellular and molecular mechanisms, with emphasis on EMT-related processes, implicated in the genesis of PF in IFP and COVID-19.

Exploring the Role of Hemogram-Derived Ratios and Liver Fibrosis Scores in Pulmonary Fibrosis

Background and Objectives: Pulmonary fibrosis, including idiopathic pulmonary fibrosis (IPF) and secondary pulmonary fibrosis (SPF), is a progressive lung disease that significantly impairs respiratory function. Accurate differentiation between IPF and SPF is crucial for effective management. This study explores the association between pulmonary fibrosis and hepatic conditions, evaluating the utility of various hemogram-derived ratios and hepatic fibrosis scores in distinguishing between IPF and SPF. Materials and Methods: We conducted a retrospective study involving patients diagnosed with IPF or SPF at the “Leon Daniello” Clinical Hospital of Pneumology in Cluj-Napoca, Romania. Pulmonary fibrosis was confirmed via imaging techniques, and hepatic steatosis and fibrosis were assessed using non-invasive scores. We analyzed clinical, laboratory, and pulmonary function data, focusing on hemogram-derived ratios and hepatic scores. Statistical analyses, including ROC curves, were used to evaluate the effectiveness of these biomarkers in differentiating IPF from SPF. Results: We included a total of 38 patients with IPF and 28 patients with SPF. Our findings revealed that IPF patients had a significantly higher FIB-4 score compared to SPF patients, suggesting increased hepatic fibrosis risk in IPF, as well as an increased RDW/PLT ratio. Conversely, SPF patients exhibited elevated PLR, PNR, and SII, reflecting a more pronounced inflammatory profile. PLR and PNR demonstrated the highest discriminatory ability between IPF and SPF, while traditional hepatic fibrosis scores showed limited differentiation capabilities. No significant differences in pulmonary function tests were observed across hepatic fibrosis risk categories. Conclusions: The study highlights the value of biomarkers like PLR and PNR in differentiating between IPF and SPF, offering additional diagnostic insights beyond traditional imaging. Integrating hepatic assessments into the management of pulmonary fibrosis could improve diagnostic accuracy and patient care.

CD206+ macrophages are relevant non-invasive imaging biomarkers and therapeutic targets in experimental lung fibrosis

BackgroundInterstitial lung diseases (ILDs) include a large number of diseases associated with progressive pulmonary fibrosis (PPF), including idiopathic pulmonary fibrosis (IPF). Despite the rarity of each of the fibrotic ILDs...

SCARF2 is a target for chronic obstructive pulmonary disease: Evidence from multi-omics research and cohort validation.

Age-related chronic inflammatory lung diseases impose a threat on public health, including idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD). However, their etiology and potential targets have not been clarified. We performed genome-wide meta-analysis for IPF with the largest sample size (2883 cases and 741,929 controls) and leveraged the summary statistics of COPD (17,547 cases and 617,598 controls). Transcriptome-wide and proteome-wide Mendelian randomization (MR) designs, together with genetic colocalization, were implemented to find robust targets. The mediation effect was assessed using leukocyte telomere length (LTL). The single-cell transcriptome analysis was performed to link targets with cell types. Individual-level data from UK Biobank (UKB) were used to validate our findings. Sixteen genetically predicted plasma proteins were causally associated with the risk of IPF and 6 proteins were causally associated with COPD. Therein, genetically-elevated plasma level of SCARF2 protein should reduce the risk of both IPF (odds ratio, OR = 0.9974 [0.9970, 0.9978]) and COPD (OR = 0.7431 [0.6253, 0.8831]) and such effects were not mediated by LTL. Genetic colocalization further corroborated these MR results of SCARF2. The transcriptome-wide MR confirmed that higher expression level of SCARF2 was associated with a reduced risk of both. However, the single-cell RNA analysis indicated that SCARF2 expression level was only relatively lower in epithelial cells of COPD lung tissue compared to normal lung tissue. UKB data implicated an inverse association of serum SCARF2 protein with COPD (hazard ratio, HR = 1.215 [1.106, 1.335]). The SCARF2 gene should be a novel target for COP.

Stimuli-Specific Senescence of Primary Human Lung Fibroblasts Modulates Alveolar Stem Cell Function.

Aging is the main risk factor for chronic lung diseases (CLDs) including idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD). Accordingly, hallmarks of aging like cellular senescence are increased in these patients in different lung cell types including fibroblasts. However, little is known about the different triggers that induce a senescence phenotype in different disease backgrounds and its role in CLD pathogenesis. Therefore, we characterized senescence in primary human lung fibroblasts (phLF) from control, IPF, or COPD patients at baseline and after exposure to disease-relevant insults (H2O2, bleomycin, TGF-β1) and studied their capacity to support progenitor cell potential in a lung organoid model. Bulk-RNA sequencing revealed that phLF from IPF and COPD activate different transcriptional programs but share a similar senescence phenotype at baseline. Moreover, H2O2 and bleomycin but not TGF-β1 induced senescence in phLF from different disease origins. Exposure to different triggers resulted in distinct senescence programs in phLF characterized by different SASP profiles. Finally, co-culture with bleomycin- and H2O2-treated phLF reduced the progenitor cell potential of alveolar epithelial progenitor cells. In conclusion, phLF from COPD and IPF share a conserved senescence response that varies depending on the insult and impairs alveolar epithelial progenitor capacity ex vivo.

Repetitive invasive lung function maneuvers do not accentuate experimental fibrosis in mice

Assessment of lung function is an important clinical tool for the diagnosis and monitoring of chronic lung diseases, including idiopathic pulmonary fibrosis (IPF). In mice, lung function maneuvers use algorithm-based ventilation strategies including forced oscillation technique (FOT), negative pressure-driven forced expiratory (NPFE) and pressure–volume (PV) maneuvers via the FlexiVent system. This lung function test (LFT) is usually performed as end-point measurement only, requiring several mice for each time point to be analyzed. Repetitive lung function maneuvers would allow monitoring of a disease process within the same individual while reducing the numbers of laboratory animals. However, its feasibility in mice and impact on developing lung fibrosis has not been studied so far. Using orotracheal cannulation without surgical exposure of the trachea, we examined the tolerability to repetitive lung function maneuvers (up to four times) in one and the same mouse, both under healthy conditions and in a model of AdTGF-β1 induced lung fibrosis. In essence, we found that repetitive invasive lung function maneuvers were well tolerated and did not accentuate experimental lung fibrosis in mice. This study contributes to the 3R principle aiming to reduce the numbers of experimental animals used in biomedical research.

From pixels to prognosis: unlocking the potential of deep learning in fibrotic lung disease imaging analysis.

The licensing of antifibrotic therapy for fibrotic lung diseases, including idiopathic pulmonary fibrosis (IPF), has created an urgent need for reliable biomarkers to predict disease progression and treatment response. Some patients experience stable disease trajectories, while others deteriorate rapidly, making treatment decisions challenging. High-resolution chest CT has become crucial for diagnosis, but visual assessments by radiologists suffer from low reproducibility and high interobserver variability. To address these issues, computer-based image analysis, called quantitative CT, has emerged. However, many quantitative CT methods rely on human input for training, therefore potentially incorporating human error into computer training. Rapid advances in artificial intelligence, specifically deep learning, aim to overcome this limitation by enabling autonomous quantitative analysis. While promising, deep learning also presents challenges including the need to minimize algorithm biases, ensuring explainability, and addressing accessibility and ethical concerns. This review explores the development and application of deep learning in improving the imaging process for fibrotic lung disease.

A quantitative analysis of progressive fibrosing interstitial lung disease on computed tomography for the assessment of decreased vital capacity.

The results of a quantitative analysis of computed tomography (CT) of interstitial lung disease (ILD) using a computer-aided detection (CAD) technique were correlated with the results of pulmonary function tests. To evaluate the correlation between a quantitative analysis of CT of progressive fibrosing interstitial lung disease (PF-ILD) including idiopathic pulmonary fibrosis (IPF) and non-IPF, which can manifest progressive pulmonary fibrosis and the vital capacity (VC), and to identify indicators for the assessment of a decreased VC. A total of 73 patients (46 patients with IPF and 27 patients with non-IPF) were included in this study. Associations between the quantitative analysis of CT and the %VC using a CAD software program were investigated using Spearman's rank correlation and a logistic regression analysis. The appropriate cutoff vale for predicting a decreased VC was determined (%VC <80) and the area under the curve (AUC) was calculated. A multiple logistic regression analysis showed that the total extent of interstitial pneumonia on CT was a significant indicator of a decreased VC (P = 0.0001; odds ratio [OR]=1.15; 95% confidence interval [CI]=1.06-1.27 in IPF and P = 0.0025; OR=1.16; 95% CI=1.03-1.30 in non-IPF). The cutoff values of the total extent of interstitial pneumonia in IPF and non-IPF for predicting a decreased VC were determined to be 23.3% and 21.5%, and the AUCs were 0.83 and 0.91, respectively. A quantitative analysis of CT of PF-ILD using a CAD software program could be useful for predicting a decreased VC.

Unveiling the Diagnostic Potential: A Comprehensive Review of Bronchoalveolar Lavage in Interstitial Lung Disease.

This comprehensive review examines the diagnostic potential of bronchoalveolar lavage (BAL) in interstitial lung disease (ILD), emphasizing its accuracy and significance in various ILDs, including idiopathic pulmonary fibrosis (IPF), sarcoidosis, hypersensitivity pneumonitis, and connective tissue disease-associated ILD. The analysis underscores the importance of abnormalities in both cellular and non-cellular components of BAL fluid for precise ILD diagnosis. Recommendations advocate for the integration of BAL into clinical guidelines, a multidisciplinary diagnostic approach, and further standardization of procedures. Looking toward the future, ongoing research highlights technological advancements, biomarker discovery, and the integration of artificial intelligence in BAL interpretation. These developments not only promise to enhance ILD diagnosis but also offer prospects for a more personalized approach to patient management based on insightful patient stratification guided by BAL findings. This abstract encapsulates the key findings, recommendations, and future prospects identified in the review, providing a concise overview of the diagnostic potential of BAL in ILD.

Type 1 invariant natural killer T cells in chronic inflammation and tissue fibrosis.

Chronic tissue inflammation often results in fibrosis characterized by the accumulation of extracellular matrix components remodeling normal tissue architecture and function. Recent studies have suggested common immune mechanisms despite the complexity of the interactions between tissue-specific fibroblasts, macrophages, and distinct immune cell populations that mediate fibrosis in various tissues. Natural killer T (NKT) cells recognizing lipid antigens bound to CD1d molecules have been shown to play an important role in chronic inflammation and fibrosis. Here we review recent data in both experimental models and in humans that suggest a key role of type 1 invariant NKT (iNKT) cell activation in the progression of inflammatory cascades leading to recruitment of neutrophils and activation of the inflammasome, macrophages, fibroblasts, and, ultimately, fibrosis. Emerging evidence suggests that iNKT-associated mechanisms contribute to type 1, type 2 and type 3 immune pathways mediating tissue fibrosis, including idiopathic pulmonary fibrosis (IPF). Thus, targeting a pathway upstream of these immune mechanisms, such as the inhibition of iNKT activation, may be important in modulating various fibrotic conditions.

PAI-1 Regulation of p53 Expression and Senescence in Type II Alveolar Epithelial Cells.

Cellular senescence contributes importantly to aging and aging-related diseases, including idiopathic pulmonary fibrosis (IPF). Alveolar epithelial type II (ATII) cells are progenitors of alveolar epithelium, and ATII cell senescence is evident in IPF. Previous studies from this lab have shown that increased expression of plasminogen activator inhibitor 1 (PAI-1), a serine protease inhibitor, promotes ATII cell senescence through inducing p53, a master cell cycle repressor, and activating p53-p21-pRb cell cycle repression pathway. In this study, we further show that PAI-1 binds to proteasome components and inhibits proteasome activity and p53 degradation in human lung epithelial A549 cells and primary mouse ATII cells. This is associated with a senescence phenotype of these cells, manifested as increased p53 and p21 expression, decreased phosphorylated retinoblastoma protein (pRb), and increased senescence-associated beta-galactose (SA-β-gal) activity. Moreover, we find that, although overexpression of wild-type PAI-1 (wtPAI-1) or a secretion-deficient, mature form of PAI-1 (sdPAI-1) alone induces ATII cell senescence (increases SA-β-gal activity), only wtPAI-1 induces p53, suggesting that the premature form of PAI-1 is required for the interaction with the proteasome. In summary, our data indicate that PAI-1 can bind to proteasome components and thus inhibit proteasome activity and p53 degradation in ATII cells. As p53 is a master cell cycle repressor and PAI-1 expression is increased in many senescent cells, the results from this study will have a significant impact not only on ATII cell senescence/lung fibrosis but also on the senescence of other types of cells in different diseases.

A Novel CD206 Targeting Peptide Inhibits Bleomycin-Induced Pulmonary Fibrosis in Mice.

Activated M2-polarized macrophages are drivers of pulmonary fibrosis in several clinical scenarios, including Idiopathic Pulmonary Fibrosis (IPF). In this study, we investigated the effects of targeting the CD206 receptor in M2-like macrophages with a novel synthetic analogue of a naturally occurring Host Defense Peptide (HDP), RP-832c, to decrease profibrotic cytokines. RP-832c selectively binds to CD206 on M2-polarized bone marrow-derived macrophages (BMDM) in vitro, resulting in a time-dependent decrease in CD206 expression and a transient increase in M1-macrophage marker TNF-α. To elucidate the antifibrotic effects of RP-832c, we used a murine model of bleomycin (BLM)-induced early-stage pulmonary fibrosis. RP-832c significantly reduced fibrosis in a dose-dependent manner, and decreased CD206, TGF-β1, and α-SMA expression in mouse lungs. Similarly, in an established model of lung fibrosis, RP-832c significantly decreased lung fibrosis and significantly decreased inflammatory cytokines TNF-α, IL-6, IL-10, IFN-γ, CXCL1/2, and fibrosis markers TGF-β1 and MMP-13. In comparison with the FDA-approved drugs Nintedanib and Pirfenidone, RP-832c exhibited a similar reduction in fibrosis compared to Pirfenidone, and to a greater extent than Nintedanib, with no apparent toxicities observed. In summary, our findings showed that inhibiting the profibrotic alternatively activated M2-like macrophages using a novel peptide, RP-832c, could reduce BLM-induced pulmonary fibrosis in mice, warranting the therapeutic potential of this peptide for patients with pulmonary fibrosis.

New York Heart Association class and pulmonary artery pressure as prognostic factors of interstitial lung disease survival.

The aim of this study was to evaluate New York Heart Association (NYHA) class and systolic pulmonary artery pressure (sPAP) as survival predictors in major interstitial lung diseases (ILD) including idiopathic pulmonary fibrosis (IPF), non-specific interstitial pneumonia (NSIP) and hypersensitivity pneumonitis (HP) and in other ILD like granulomatosis with polyangiitis (GPA). We analyzed survival, NYHA class, sPAP, and Octreoscan uptake index (UI) in 104 ILD patients (59 IPF, 19 NSIP, 10 HP and 16 GPA; median age 60.5 years) all referred to a single centre. Median survival was 68 months, with 1- and 2-year survival of 91% and 78%, respectively. Survival was lower among IPF and NSIP vs. HP and GPA patients (p=0.01). NYHA class 3-4 was more frequent among IPF (76.3%) vs. NSIP patients (31.6%; p<0.001). HP and GPA had NYHA class 1-2. NYHA class was negatively associated with survival (class 1=90.3 months vs. class 3=18.3 months and class 4=5.1 months; p=0.001). sPAP was >55 mmHg in 76.3% of patients with IPF and 35-55 mmHg in 63.2% of patients with NSIP. Patients with HP and GPA had sPAP < 55 mmHg. Among patients with IPF, NYHA and sPAP were negatively associated with survival (p<0.01) both showed a parallel trend. High-resolution computed tomography and survival were worse among IPF and NSIP vs. HP and GPA patients (p<0.001). Octreoscan UI was <10, 10-12, and >12 in IPF, NSIP, HP and GPA, respectively. Octreoscan UI was negatively associated with survival (p=0.002). NYHA class and sPAP are comparable ILD survival predictors. NYHA class is correlated with worse prognosis for IPF and NSIP vs. HP and GPA patients.

Relationship Between Esophageal Disease and Pulmonary Fibrosis

Esophageal disorders are prevalent among patients with chronic lung diseases, including idiopathic pulmonary fibrosis (IPF). Gastroesophageal reflux disease (GERD) has been associated with IPF prevalence, severity, and respiratory decline. The pathophysiologic relationship between GERD and IPF is likely bidirectional, with aspiration of refluxate leading to lung inflammation and fibrosis, while the restrictive pulmonary physiology may contribute to altered transdiaphragmatic pressure gradient and increased reflux. Esophageal symptoms are frequently absent and do not predict esophageal dysfunction or pathologic reflux in patients with IPF, and objective diagnostic tools including upper endoscopy, ambulatory reflux monitoring, and high-resolution manometry are often needed. Impedance-based testing that identifies both weakly/non-acidic and acid reflux may provide important additional diagnostic value beyond pH-based acid testing alone. Novel metrics and maneuvers, including advanced impedance measures on impedance-pH study and provocative testing on HRM, may hold promise to future diagnostic advancements. The main treatment options include medical therapy with acid suppressants and anti-reflux surgery, although their potential benefits in pulmonary outcomes of IPF require further validations. Future directions of research include identifying phenotypes of IPF patients who may benefit from esophageal testing and treatment, determining the optimal testing strategy and protocol, and prospectively assessing the value of different esophageal therapies to improve outcomes while minimizing risks. This review will discuss the pathophysiology, evaluation, and management of esophageal diseases, particularly GERD, in patients with IPF, as informed by the most recent publications in the field, in hopes of identifying targets for future study and research.

Loss of IGFBP2 mediates alveolar type 2 cell senescence and promotes lung fibrosis

Accumulation of senescent cells contributes to age-related diseases including idiopathic pulmonary fibrosis (IPF). Insulin-like growth factor binding proteins (IGFBPs) regulate many biological processes; however, the functional contributions of IGFBP2 in lung fibrosis remain largely unclear. Here, we report that intranasal delivery of recombinant IGFBP2 protects aged mice from weight loss and demonstrated antifibrotic effects after bleomycin lung injury. Notably, aged human-Igfbp2 transgenic mice reveal reduced senescence and senescent-associated secretory phenotype factors in alveolar epithelial type 2 (AEC2) cells and they ameliorated bleomycin-induced lung fibrosis. Finally, we demonstrate that IGFBP2 expression is significantly suppressed in AEC2 cells isolated from fibrotic lung regions of patients with IPF and/or pulmonary hypertension compared with patients with hypersensitivity pneumonitis and/or chronic obstructive pulmonary disease. Altogether, our study provides insights into how IGFBP2 regulates AEC2-cell-specific senescence and that restoring IGFBP2 levels in fibrotic lungs can prove effective for patients with IPF.

ILD-GAP Combined with the Charlson Comorbidity Index Score (ILD-GAPC) as a Prognostic Prediction Model in Patients with Interstitial Lung Disease.

The ILD-GAP scoring system has been widely used to predict the prognosis of patients with interstitial lung disease (ILD). The ability of the ILD-GAP scoring system combined with the Charlson Comorbidity Index score (CCIS) (ILD-GAPC) to predict ILD prognosis was investigated. In ILD patients, including 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), treated between April 2013 and April 2017, the relationships between baseline clinical parameters, including age, sex, CCIS, ILD diagnosis, pulmonary function test results, and disease outcomes, were retrospectively assessed, and the ability to predict prognosis was compared between the ILD-GAP and ILD-GAPC models, respectively. A total of 185 patients (mean age, 71.9 years), all of whom underwent pulmonary function testing, including percentage predicted diffusion capacity for carbon monoxide, were assessed. ILD diagnosis consisted of IPF in 57 cases, iNSIP and CVD-IP in 117 cases, CHP in 6 cases, and UC-ILD in 5 cases. The ILD-GAPC provided a greater area under the receiver operating characteristic curve (0.758) for predicting 3-year ILD-related events than the ILD-GAP (0.721). In addition, log-rank tests showed that the Kaplan-Meier curves differed significantly among low, middle, and high ILD-GAPC scores (P < 0.001), unlike ILD-GAP scores (P = 0.083). The ILD-GAPC model could provide more accurate information for predicting prognosis in patients with ILD than the ILD-GAP model.

Cellular and Molecular Mechanisms in Idiopathic Pulmonary Fibrosis.

The respiratory system is a well-organized multicellular organ, and disruption of cellular homeostasis or abnormal tissue repair caused by genetic deficiency and exposure to risk factors lead to life-threatening pulmonary disease including idiopathic pulmonary fibrosis (IPF). Although there is no clear etiology as the name reflected, its pathological progress is closely related to uncoordinated cellular and molecular signals. Here, we review the advances in our understanding of the role of lung tissue cells in IPF pathology including epithelial cells, mesenchymal stem cells, fibroblasts, immune cells, and endothelial cells. These advances summarize the role of various cell components and signaling pathways in the pathogenesis of idiopathic pulmonary fibrosis, which is helpful to further study the pathological mechanism of the disease, provide new opportunities for disease prevention and treatment, and is expected to improve the survival rate and quality of life of patients.

Potential targeted therapy based on deep insight into the relationship between the pulmonary microbiota and immune regulation in lung fibrosis.

Pulmonary fibrosis is an irreversible disease, and its mechanism is unclear. The lung is a vital organ connecting the respiratory tract and the outside world. The changes in lung microbiota affect the progress of lung fibrosis. The latest research showed that lung microbiota differs in healthy people, including idiopathic pulmonary fibrosis (IPF) and acute exacerbation-idiopathic pulmonary fibrosis (AE-IPF). How to regulate the lung microbiota and whether the potential regulatory mechanism can become a necessary targeted treatment of IPF are unclear. Some studies showed that immune response and lung microbiota balance and maintain lung homeostasis. However, unbalanced lung homeostasis stimulates the immune response. The subsequent biological effects are closely related to lung fibrosis. Core fucosylation (CF), a significant protein functional modification, affects the lung microbiota. CF regulates immune protein modifications by regulating key inflammatory factors and signaling pathways generated after immune response. The treatment of immune regulation, such as antibiotic treatment, vitamin D supplementation, and exosome micro-RNAs, has achieved an initial effect in clearing the inflammatory storm induced by an immune response. Based on the above, the highlight of this review is clarifying the relationship between pulmonary microbiota and immune regulation and identifying the correlation between the two, the impact on pulmonary fibrosis, and potential therapeutic targets.

The matricellular protein CCN3 supports lung endothelial homeostasis and function.

Aberrant vascular remodeling contributes to the progression of many aging-associated diseases, including idiopathic pulmonary fibrosis (IPF), where heterogeneous capillary density, endothelial transcriptional alterations, and increased vascular permeability correlate with poor disease outcomes. Thus, identifying disease-driving mechanisms in the pulmonary vasculature may be a promising strategy to limit IPF progression. Here, we identified Ccn3 as an endothelial-derived factor that is upregulated in resolving but not in persistent lung fibrosis in mice, and whose function is critical for vascular homeostasis and repair. Loss and gain of function experiments were carried out to test the role of CCN3 in lung microvascular endothelial function in vitro through RNAi and the addition of recombinant human CCN3 protein, respectively. Endothelial migration, permeability, proliferation, and in vitro angiogenesis were tested in cultured human lung microvascular endothelial cells (ECs). Loss of CCN3 in lung ECs resulted in transcriptional alterations along with impaired wound-healing responses, in vitro angiogenesis, barrier integrity as well as an increased profibrotic activity through paracrine signals, whereas the addition of recombinant CCN3 augmented endothelial function. Altogether, our results demonstrate that the matricellular protein CCN3 plays an important role in lung endothelial function and could serve as a promising therapeutic target to facilitate vascular repair and promote lung fibrosis resolution.

Diverse Functions of Apolipoprotein A-I in Lung Fibrosis.

Apolipoprotein A-I (apoA-I) mediates reverse cholesterol transport (RCT) out of cells. In addition to its important role in the RTC, apoA-I also possesses anti-inflammatory and anti-oxidative functions including the ability to activate inflammasome and signal via toll-like receptors. Dysfunctional apoA-I or its low abundance may cause accumulation of cholesterol mass in alveolar macrophages leading to the formation of foam cells. Increased numbers of foam cells have been noted in the lungs of mice after experimental exposure to cigarette smoke, silica, or bleomycin and in the lungs of patients suffering from different types of lung fibrosis, including idiopathic pulmonary fibrosis (IPF). This suggests that dysregulation of lipid metabolism may be a common event in the pathogenesis of interstitial lung diseases. Recognition of the emerging role of cholesterol in the regulation of lung inflammation and remodeling provides a challenging concept for understanding lung diseases and offers novel and exciting avenues for therapeutic development. Accordingly, a number of preclinical studies demonstrated decreased expression of inflammatory and profibrotic mediators and preserved lung tissue structure following the administration of the apoA-I or its mimetic peptides. This review highlights the role of apoA-I in lung fibrosis and provides evidence for its potential use in the treatment of this pathological condition.