Pulmonary Fibrosis Research Articles

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

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

Exploring the Impact of Molecular Hydrogen Therapy on Oxidative Stress in Bleomycin-Induced Idiopathic Pulmonary Fibrosis: A Research Protocol

Introduction: Idiopathic Pulmonary Fibrosis (IPF) is an intensifying respiratory disorder triggered by bleomycin in cancer patients, characterized by its lack of a definitive remedy. Bleomycin induces mitochondrial leakage and elevates Reactive Oxygen Species (ROS) in the pulmonary cavity, causing a reduction in glutathione (GSH), a vital lung antioxidant. This reduction in GSH levels, coupled with ROS's inactivation of the tumor suppressor gene p53, increases the chance of developing fibrosis. Although no antioxidant treatments that currently target these effects, Molecular Hydrogen Therapy (MHT) has proven effective in mitigating ROS in diseases like Chronic Obstructive Pulmonary Disease (COPD). This study aims to explore the impact of bleomycin-induced IPF on ROS and p53, investigating MHT as a potential treatment to alleviate oxidative stress in fibrosis. Methods: The experimental design includes four groups of mice, two receiving bleomycin injections and two receiving a control buffer solution. Within each subgroup, one group will undergo MHT, while the other will receive sterile air. Bronchoalveolar lavage will be used to measure GSH levels before and after MHT, and RNA sequencing will monitor p53 activity in all treatment and control groups. Results: Anticipated outcomes include elevated GSH levels in the MHT-treated bleomycin group, indicating an antioxidative effect. Consequently, improved p53 activity is expected compared to controls. Discussion: Anticipated results, based on existing literature, suggest that MHT enhances antioxidant defenses and modulates p53 activity, thereby reducing oxidative damage and fibrotic remodeling. These findings highlight the potential of MHT as a therapeutic intervention for IPF, with broader implications for managing other oxidative stress-mediated lung diseases. However, further research, including preclinical studies and clinical trials, is needed to validate these anticipated findings and ensure the long-term safety and efficacy of MHT in clinical practice. Conclusion: The study aims to replicate findings in human populations and proposes a paradigm shift in treating such diseases by addressing the root cause, ROS.

The Thyroid Hormone Analog GC-1 Mitigates Acute Lung Injury by Inhibiting M1 Macrophage Polarization.

Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a life-threatening condition with a high mortality rate of ≈40%. Thyroid hormones (THs) play crucial roles in maintaining homeostasis of the cellular microenvironment under stress. The previous studies confirmed that the clinical-stage TH analog GC-1 significantly alleviates pulmonary fibrosis by improving the function of mitochondria in epithelial cells. However, the effects of GC-1 on macrophages in lung injury and the related mechanisms remain unclear. This study evaluated the therapeutic effects of GC-1 in two murine models of lipopolysaccharide (LPS)- or hydrochloric acid (HCl)-induced ALI. Additionally, mouse alveolar macrophages (AMs) and human THP-1-derived macrophages are utilized to investigate the impact of GC-1 on macrophage polarization. GC-1 effectively reduces the inflammatory response and lung injury in ALI mice, as evidenced by neutrophil infiltration, cytokine levels, alveolar fluid clearance, and pulmonary pathology. Notably, GC-1 selectively inhibits M1 macrophage polarization, which may be achieved by impeding NF-κB signaling activation through the DNMT3b-PPARγ-NF-κB pathway in a TH receptor β1 (TRβ1)-dependent manner, consequently suppressing the polarization of macrophages toward the M1 phenotype and overproduction of inflammatory cytokines. Overall, these findings highlight the immunomodulatory property of GC-1 as an anti-inflammatory strategy for ALI/ARDS and inflammation-related diseases.

TRβ activation confers AT2-to-AT1 cell differentiation and anti-fibrosis during lung repair via KLF2 and CEBPA

Aberrant repair underlies the pathogenesis of pulmonary fibrosis while effective strategies to convert fibrosis to normal regeneration are scarce. Here, we found that thyroid hormone is decreased in multiple models of lung injury but is essential for lung regeneration. Moreover, thyroid hormone receptor α (TRα) promotes cell proliferation, while TRβ fuels cell maturation in lung regeneration. Using a specific TRβ agonist, sobetirome, we demonstrate that the anti-fibrotic effects of thyroid hormone mainly rely on TRβ in mice. Cellularly, TRβ activation enhances alveolar type-2 (AT2) cell differentiation into AT1 cell and constrains AT2 cell hyperplasia. Molecularly, TRβ activation directly regulates the expression of KLF2 and CEBPA, both of which further synergistically drive the differentiation program of AT1 cells and benefit regeneration and anti-fibrosis. Our findings elucidate the modulation function of the TRβ-KLF2/CEBPA axis on AT2 cell fate and provide a potential treatment strategy to facilitate lung regeneration and anti-fibrosis.

Protective effect and mechanism of rapamycin on pulmonary fibrosis induced by Chlormethine in mice

To evaluate the therapeutic effect and mechanism of rapamycin (RAPA) on pulmonary fibrosis induced by chlormethine in C57BL/6N mice. Based on body weight, the 18-20 g C57BL/6N mice were randomly divided into five groups: control group, chlormethine group, chlormethine+dexamethasone (1 mg/kg) group, chlormethine+RAPA (1 mg/kg) group and chlormethine+RAPA (2 mg/kg) group, with ten mice in each group. Mice were put to death on the 21st day after the first administration of chlormethine. HE staining and Masson staining were used to observe the pathological changes and degree of fibrosis in the lung tissue of mice, and RT-PCR was used to detect collagen Ⅰ, E-cadherin, vimentin, and α-SMA mRNA expression. After 21 days of administration of chlormethine to mice, significant pulmonary fibrosis characteristics were observed in the lung tissue of the mice. Compared with the chlormethine group, the weight of mice in the chlormethine+dexamethasone (1 mg/kg) group, chlormethine+RAPA (1 mg/kg) group and chlormethine+RAPA (2 mg/kg) group, significantly increased (P<0.05). Compared with the chlormethine group, the expression of pulmonary fibrosis-related indicators (collagen Ⅰ, E-cadherin, vimentin, and α-SMA) significantly improved (P<0.05) in the chlormethine+dexamethasone (1 mg/kg) group, chlormethine+RAPA (1 mg/kg) group and chlormethine+RAPA (2 mg/kg) group. Compared with the chlormethine group, the pathological changes and collagen deposition in the lung tissue of mice in the chlormethine+dexamethasone (1 mg/kg) group, chlormethine+RAPA (1 mg/kg) group and chlormethine+RAPA (2 mg/kg) group, were significantly improved. Transcriptome analysis of the lung tissue of mice revealed that RAPA treatment of chlormethine-induced pulmonary fibrosis might be related to NF-kappa B signaling pathway. Compared with the chlormethine group, the mRNA expression of p65 in the lung tissue of mice in the chlormethine+dexamethasone (1 mg/kg) group, chlormethine+RAPA (1 mg/kg) group and chlormethine+RAPA (2 mg/kg) group, significantly decreased (P<0.01). RAPA has a protective effect on pulmonary fibrosis induced by chlormethine in mice. Its efficacy is comparable to that of dexamethasone, which is currently being used in clinical practice. It is a new alternative therapy, and its mechanism may be related to inhibiting the activation of the NF-kappa B signaling pathway.

Pulmonary rehabilitation in patients with fibrotic interstitial lung disease

Cough, progressive exertional dyspnea, and exercise limitation are the main presenting symptoms in fibrotic interstitial lung disease (F-ILD). F-ILD is usually progressive, leading to heavy disease and socioeconomic burden. In addition to the drug therapy, pulmonary rehabilitation is an important part of comprehensive treatment in F-ILD patients. In recent years, the application of pulmonary rehabilitation in F-ILD patients has attracted the attention of clinicians and society. Meanwhile, pulmonary rehabilitation has widely applicated in F-ILD patients as it is beneficial to improve their symptoms, functional exercise and quality of life. This article provides a comprehensive review of pulmonary rehabilitation in F-ILD and proposes the principles and strategies, to prevent the progression or acute exacerbation of F-ILD and improve its application in F-ILD patients.

Early pirfenidone treatment enhances lung function in idiopathic pulmonary fibrosis patients.

This editorial comments on the study by Lei et al investigating the efficacy of early treatment with pirfenidone on the lung function of patients with idiopathic pulmonary fibrosis (IPF) published. This study evaluates the efficacy of early treatment with pirfenidone on lung function in patients with IPF. The early and advanced stages of IPF are defined, highlighting the drug's benefits. While prior research indicates pirfenidone's effectiveness in advanced IPF, this study focuses on its advantages in early stages. The study emphasizes the importance of computed tomography imaging alongside biochemical data and lung function tests for a comprehensive analysis of symptom relief. Results show that early intervention with pirfenidone significantly reduces disease progression and preserves lung function, underscoring its potential as a critical treatment strategy in early IPF.

Luteolin-Loaded Hyaluronidase Nanoparticles with Deep Tissue Penetration Capability for Idiopathic Pulmonary Fibrosis Treatment.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease characterized by sustained fibrotic lesions. Orally administered drugs usually fail to efficiently penetrate the interstitial tissue and reach the lesions, resulting in low treatment efficiency. Luteolin (Lut)is a natural flavonoid, active metabolites of which possess antioxidant, anti-inflammatory, anti-fibrotic, and anti-apoptotic properties. In this study, a nano-formulation is developed by loading Lut into hyaluronidase nanoparticles (Lut@HAase). These Lut@HAase nanoparticles (NPs) exhibit small size and good stability, suitable for noninvasive inhalation and accumulation in the lungs, and hyaluronidase at the site of lesions can degrade hyaluronic acid in the interstitial tissue, enabling efficient penetration of Lut. Lut's therapeutic effect, when administered via NPs, is studied both in vitro (using MRC5 cells) and in vivo (using IPF mice models), and its anti-fibrotic properties are found to inhibit inflammation and eliminate reactive oxygen species. Conclusively, this study demonstrates that Lut@HAase can improve lung function and enhance survival rates while reducing lung damage with few abnormalities during IPF treatment.

Hyperpolarized 129Xe MRI and spectroscopy of gas exchange abnormalities in chronic hypersensitivity pneumonitis

PurposeTo evaluate 3D gas-exchange functional imaging characteristics using 129Xe MRI in a group of study participants with chronic hypersensitivity pneumonitis (CHP) as compared with healthy control participants. MethodsIn this prospective study, 11 participants with clinical and CT findings of CHP (4M 7F, mean age 67 ± 6.1 years) as well as 41 healthy subjects (25M 16F, mean age 44 ± 18 years) were enrolled between 2017 and 2022 and underwent 129Xe MRI. Three-dimensional images of ventilation, interstitial membrane uptake, and RBC transfer were rendered into quantitative 3D maps relative to a healthy reference cohort. In addition, 129Xe spectroscopy was used to assess the RBC:membrane ratio (RBC:M), the oxygen-dependent RBC chemical shift, and cardiogenically-driven RBC oscillation amplitude. Differences between the CHP participants and healthy subjects were assessed using the two-sample t-test or Wilcoxon rank-sum test as appropriate. ResultsCHP participants demonstrated significant differences in 6 parameters (p < 0.001) including regions of reduced ventilation, increased membrane uptake, and reduced RBC transfer as compared to healthy subjects. Gas exchange abnormalities measured on spectroscopy included a reduced RBC:M, reduced RBC chemical shift, and increased RBC oscillation amplitude. ConclusionIn participants with CHP, 129Xe MRI demonstrated gas exchange abnormalities common to other fibrotic lung diseases including increased membrane uptake, deficits in RBC transfer, and reduced RBC:M. However, CHP participants also exhibited prominent ventilation abnormalities, which may be reflective of the airway-centric nature of the disease. Further, the high variability observed in the membrane uptake could suggest varying degrees of disease progression or activity.

Physical activity and idiopathic pulmonary fibrosis: A prospective cohort study in UK Biobank and Mendelian randomization analyses

IntroductionThe impact of physical activity on the incidence of idiopathic pulmonary fibrosis (IPF) remains less well studied. This study aimed to investigate the relationship between moderate-to-vigorous physical activity (MVPA) and the risk of developing IPF. MethodsWe analyzed data from a prospective cohort study within the UK Biobank involving 502,476 participants. Participants were categorized as meeting or not meeting the 2017 UK Physical Activity Guidelines (150 min of moderate activity or 75 min of vigorous activity per week). The cumulative incidence and hazard ratios (HRs) for IPF were analyzed using the Kaplan–Meier method, log-rank test, and Cox regression. Two-sample Mendelian randomization (MR) analyses were performed to identify potential causal links between physical activity and IPF risk. ResultsOver a median of 12.2 y follow-up, we identified 1,639 incident IPF cases and 395,172 controls. Individuals who met the physical activity guidelines had a significantly lower risk of IPF than those who did not meet the guidelines (adjusted HR = 0.843, 95 % confidence interval [CI] = 0.765–0.930).The cumulative incidence of IPF was lower in the meeting guideline group than in the nonmeeting guideline group (Log-rank P = 0.0019). Two-sample MR analysis revealed that a 1-standard deviation increase in moderate-to-vigorous physical activity was linked to a reduced IPF risk (odds ratio [OR] = 0.17, 95 % CIs = 0.04 to 0.81, P = 0.026). Moreover, an increase in the number of days per week of moderate physical activity was genetically correlated with decreased IPF risk (OR = 0.32, 95 % CIs = 0.15–0.70, P = 0.003). ConclusionHigher levels of moderate-to-vigorous physical activity are causally associated with a significant reduction in the risk of developing IPF.

SPP1 induces idiopathic pulmonary fibrosis and NSCLC progression via the PI3K/Akt/mTOR pathway

BackgroundThe prevalence of non-small cell lung cancer (NSCLC) is notably elevated in individuals diagnosed with idiopathic pulmonary fibrosis (IPF). Secreted phosphoprotein 1 (SPP1), known for its involvement in diverse physiological processes, including oncogenesis and organ fibrosis, has an ambiguous role at the intersection of IPF and NSCLC. Our study sought to elucidate the function of SPP1 within the pathogenesis of IPF and its subsequent impact on NSCLC progression.MethodsFour GEO datasets was analyzed for common differential genes and TCGA database was used to analyze the prognosis. The immune infiltration was analyzed by TIMER database. SPP1 expression was examined in human lung tissues, the IPF fibroblasts and the BLM-induced mouse lung fibrosis model. Combined with SPP1 gene gain- and loss-of-function, qRT-PCR, Western blot, EdU and CCK-8 experiments were performed to evaluate the effects and mechanisms of SPP1 in IPF progression. Effect of SPP1 on NSCLC was detected by co-cultured IPF fibroblasts and NSCLC cells.ResultsThrough bioinformatics analysis, we observed a significant overexpression of SPP1 in both IPF and NSCLC patient datasets, correlating with enhanced immune infiltration of cancer-associated fibroblasts in NSCLC. Elevated levels of SPP1 were detected in lung tissue samples from IPF patients and bleomycin-induced mouse models, with partial colocalization observed with α-smooth muscle actin. Knockdown of SPP1 inhibits TGF-β1-induced differentiation of fibroblasts to myofibroblasts and the proliferation of IPF fibroblasts. Conversely, SPP1 overexpression promoted IPF fibroblast proliferation via PI3K/Akt/mTOR pathway. Furthermore, IPF fibroblasts promoted NSCLC cell proliferation and activated the PI3K/Akt/mTOR pathway; these effects were attenuated by SPP1 knockdown in IPF fibroblasts.ConclusionsOur findings suggest that SPP1 functions as a molecule promoting both fibrosis and tumorigenesis, positioning it as a prospective therapeutic target for managing the co-occurrence of IPF and NSCLC.

Quantitative CT-analysis of over aerated lung tissue and correlation with fibrosis extent in patients with idiopathic pulmonary fibrosis

IntroductionThe usual interstitial pneumonia (UIP) pattern, hallmark of idiopathic pulmonary fibrosis (IPF), may induce harmful local overdistension during mechanical ventilation given the juxtaposition of different tissue elasticities. Mechanotransduction, linking mechanical stress and strain to molecular pro-fibrotic pathways, likely contributes to fibrosis progression. Understanding the mechanical forces and aeration patterns in the lungs of IPF patients is crucial for unraveling potential mechanisms of disease progression. Quantitative lung computed tomography (CT) can accurately assess the air content of lung regions, thus informing on zonal distension. This study aims to investigate radiological evidence of lung over aeration in spontaneously breathing UIP patients compared to healthy controls during maximal inspiration.MethodsPatients with IPF diagnosis referred to the Center for Rare Lung Diseases of the University Hospital of Modena (Italy) in the period 2020–2023 who underwent High Resolution Computed Tomography (HRCT) scans at residual volume (RV) and total lung capacity (TLC) using standardized protocols were retrospectively considered eligible. Patients with no signs of lung disease at HRCT performed with the same image acquisition protocol nor at pulmonary function test (PFTs) served as controls. Lung segmentation and quantitative analysis were performed using 3D Slicer software. Lung volumes were measured, and specific density thresholds defined over aerated and fibrotic regions. Comparison between over aerated lung at RV and TLC in the two groups and according to lung lobes was sought. Further, the correlation between aerated lung and the extent of fibrosis was assessed and compared at RV and TLC.ResultsIPF patients (N = 20) exhibited higher over aerated lung proportions than controls (N = 15) both at RV and TLC (4.5% vs. 0.7%, p < 0.0001 and 13.8% vs. 7%, p < 0.0001 respectively). Over aeration increased significantly from RV to TLC in both groups, with no intergroup difference (p = 0.67). Sensitivity analysis revealed significant variations in over aerated lung areas among lobes when passing from RV to TLC with no difference within lobes (p = 0.28). Correlation between over aeration and fibrosis extent was moderate at RV (r = 0.62, p < 0.0001) and weak at TLC (r = 0.27, p = 0.01), being the two significantly different at interpolation analysis (p < 0.0001).ConclusionsThis study provides the first evidence of radiological signs of lung over aeration in patients with UIP-pattern patients when passing from RV to TLC. These findings offer new insights into the complex interplay between mechanical forces, lung structure, and fibrosis and warrant larger and longitudinal investigations.

Targeted apoptosis of senescent cells by valproic acid alleviates therapy-induced cellular senescence and lung aging

BackgroundAccumulation of senescent cells in tissues and their downstream effect programs have emerged as key drivers of aging and age-associated pathologies. Recent progresses in senotherapeutics indicated that either selectively killing senescent cells with senolytics or suppressing the senescence-associated secretory phenotype (SASP) secretion using senomorphics contributes to extending of the healthy lifespan and alleviating numerous age-related disorders in mice. PurposeHowever, the potential side-effects and long-term cytotoxicity of the above novel compounds have not yet been determined. Therefore, it seems to be more efficient to explore new senotherapeutical functions from approved drugs. MethodsThe effects of valproic acid (VPA), a derivative of valine, in cellular senescence were evaluated by senescence-associated β galactosidase (SA-β-Gal) staining, flow cytometry and western blot (WB). The cell viability was tested using CCK-8 kits. Cell apoptosis was detected by Annexin V-EGFP/PI apoptosis detection kit. Cell autophagy was checked using GFP-RFP-LC3 ratiometric plasmid. The roles of VPA in lung aging were investigated by in vivo experiments using H&E and Masson staining, WB, as well as electronic microscope strategies. ResultsHere we identified VPA was able to induce an over-accumulation of reactive oxygen species (ROS) (>1.5 times increasing) and apoptosis (>2 times increasing) of senescent cells. Mechanistically, VPA activated the phospholipid modifying enzyme membrane-bound O-acyltransferase domain-containing protein 1 (MBOAT1), which was repressed during senescence, then promoted mitochondrial autophagy and apoptosis. In addition, VPA was also found to alleviate therapy induced abnormal mitochondria and lung aging phenotype (>1.5 times decreasing of lung fibrosis markers and >2.5 times increasing of naïve/memory CD4+ or CD8+ T cells) in vivo. ConclusionTaken together, our study demonstrated that VPA was able to selectively kill senescent cells both in vitro and in vivo, and thus shedding light on new functions and novel potential application of VPA in anti-aging and anti-age-associated diseases.

Role of Transforming Growth Factor-β in Pathogenesis of Pulmonary Fibrosis in COVID-19, Post-COVID Syndrome, Oncological and Chronic Inflammatory Lung Diseases

INTRODUCTION: Persistent post-COVID syndrome is the persistent physical, medical and cognitive sequelae of coronavirus disease 2019 (COVID-19), including persistent immunosuppression, pulmonary, cardiac and vascular fibrosis which lead to increased mortality and impair the quality of life of patients. АIM: To analyze the completed foreign and domestic studies on the pathophysiology of transforming growth factor-β (TGF-β) in conditions of COVID-19, post-COVID syndrome, oncological and chronic inflammatory lung diseases. Mast cells are among the main producers of inflammatory cytokines in COVID-19, their stimulation leads to the release of many proinflammatory cytokines, such as interleukin 1β, tumor necrosis factor α, interleukin 6, and also TGF-β. The basis of the pathogenesis of post-COVID syndrome is the overexpression of TGF-β leading to a prolonged state of immunosuppression and fibrosis. TGF-β acts as a tumor suppressor inhibiting proliferation and inducing apoptosis in the early stages of oncogenesis; plays an important role in most cellular biological processes leading to remodeling of the airway structures; is involved in epithelial changes, in subepithelial fibrosis, remodeling of smooth muscle of airways and in microvascular changes; induces resistance to glucocorticosteroids; stimulates the production of blood coagulation factor XII, thereby leading to development of potentially fatal complications, such as pulmonary embolism and ischemic stroke. CONCLUSION: In this literature review, a structured analysis of a multicomponent role of TGF-β in the pathogenesis of post-COVID syndrome, pulmonary fibrosis in COVID-19, tumors of respiratory system, chronic obstructive pulmonary disease, bronchial asthma, is given. A possible use of TGF-β as a biomarker of severe and moderate degree of COVID-19 is substantiated.

Pulmonary fibrosis followed by severe pneumonia in patients with COVID-19 infection requiring mechanical ventilation: a prospective multicentre study

BackgroundsThe management of lung complications, especially fibrosis, after COVID-19 pneumonia, is an important issue in the COVID-19 post-pandemic era. We aimed to investigate risk factors for pulmonary fibrosis development in...

Influence of echo time on pulmonary ventilation and perfusion derived by phase-resolved functional lung (PREFUL) MRI using multi-echo ultrashort echo time acquisition.

Non-contrast enhanced 1H magnetic resonance imaging (MRI) is promising for ventilation/perfusion (V/Q) assessment of the lung but the influence of the echo time (TE) on V/Q parameters is lacking. Therefore, the purpose of this study was to investigate the influence of different TEs on pulmonary V/Q parameters derived by phase-resolved functional lung (PREFUL) MRI using a multi-echo ultrashort TE (UTE) acquisition. A 2D multi-echo UTE sequence with radial center out readout and tiny golden angle increment was developed. Forty-eight participants were enrolled in this study: 25 healthy subjects, six patients with asthma, and 17 patients with pulmonary fibrosis. Participants underwent two acquisitions of 2D multi-echo UTE MRI with three TEs per acquisition (TE1-6: 0.07, 0.82, 1.72, 2.47, 3.37, and 4.12 ms). Regional ventilation (RVent), flow-volume loop cross-correlation metric (FVL-CM), and normalized perfusion-weighted signal (QN) maps were calculated. V/Q defect percentages (VDP/QDP) were determined. To assess repeatability, the measurement was repeated in healthy subjects. Median and interquartile range of RVent, FVL-CM, QN, VDP, and QDP were calculated. To assess significant differences between parameters obtained at different TEs, Friedman's test and Dunnett's test were performed. Pearson correlation coefficients between RVent derived at TE1 and the difference in RVent between TE2,3 and TE1 were calculated. For repeatability assessment, coefficient of variation (CoV) and intraclass correlation coefficient (ICC) were determined. Significant differences were found comparing V/Q parameters obtained at TE3-6 compared to TE1. CoV increased with TE. For ICC, values between 0.35 (QDP at TE1) and 0.83 (VDPRVent at TE2) were obtained for T1,2. Statistically significant differences for ventilation and perfusion parameters derived by PREFUL were found for TE3-6 compared to TE1. All V/Q parameters were well repeatable for TE1-2. With increasing TE and respiratory volume, RVent shows a T2*-dependency leading to biased ventilation assessment compared to TE1.

Profibrotic monocyte-derived alveolar macrophages are expanded in patients with persistent respiratory symptoms and radiographic abnormalities after COVID-19

Monocyte-derived alveolar macrophages drive lung injury and fibrosis in murine models and are associated with pulmonary fibrosis in humans. Monocyte-derived alveolar macrophages have been suggested to develop a phenotype that promotes lung repair as injury resolves. We compared single-cell and cytokine profiling of the alveolar space in a cohort of 35 patients with post-acute sequelae of COVID-19 who had persistent respiratory symptoms and abnormalities on a computed tomography scan of the chest that subsequently improved or progressed. The abundance of monocyte-derived alveolar macrophages, their gene expression programs, and the level of the monocyte chemokine CCL2 in bronchoalveolar lavage fluid positively associated with the severity of radiographic fibrosis. Monocyte-derived alveolar macrophages from patients with resolving or progressive fibrosis expressed the same set of profibrotic genes. Our findings argue against a distinct reparative phenotype in monocyte-derived alveolar macrophages, highlighting their utility as a biomarker of failed lung repair and a potential target for therapy.

Monocyte-derived macrophages are too much of a good thing in lung fibrosis.

Monocyte-derived macrophages are too much of a good thing in lung fibrosis.

The Evaluation of the Genetic Polymorphisms of TERT (rs2736100) and MUC5B (rs35705950) in Idiopathic Pulmonary Fibrotic patients

Background: Polymorphisms of the TERT and MUC5B genes have been consistently associated with idiopathic pulmonary fibrosis (IPF) in recent genome-wide genetic studies. In Iraq, we did not find research on the role of these polymorphisms in respiratory disorders, so we conducted this study to evaluate the genetic polymorphisms of TERT (rs2736100) and MUC5B (rs35705950) in IPF patients in Iraq. Method: The current study was a case-control study that included 70 patients who were diagnosed with IPF, in addition to, 70 healthy control groups who had no history or clinical evidence of IPF or asthma. blood samples from participants were obtained for DNA extraction, and T-ARMS-PCR was used to determine genetic polymorphisms of TERT (rs2736100) and MUC5B (rs35705950). Result: Current study showed that the mutant/minor homogenous genotype AA and allele A of TERT (rs2736100) appeared at a higher rate in patients (47% and 87% respectively) compared to control (38.5% and 53% respectively), as this indicator appeared as an effective factor (EF = 0.139 and 0.242 respectively), while the wild/major homogenous genotype CC and allele C were appeared in control at a rate of 38.5% and 50% respectively and in patients at rate 23% and 50% respectively. The results of MUC5B (rs35705950) G/T polymorphism showed that the mutant/minor TT genotype and T allele were associated with the occurrence of the disease (EF = 0.177 and 0.192 respectively) while the wild /major GG genotype and G allele appeared as a protective factor (PF= 0.243 and 0.375 respectively) for the control group. Moreover, most of the smoking patients were carriers of the mutant homogenous genotypes of TERT (rs2736100) and MUC5B (rs35705950). Conclusion: TERT (rs2736100) and MUC5B (rs35705950) polymorphisms are significantly associated with IPF, especially among smokers patients.

Family history of pulmonary fibrosis impacts prognosis in patients with sarcoidosis

Family history of pulmonary fibrosis impacts prognosis in patients with sarcoidosis