Pulmonary Fibrosis Research Articles

Clinical usefulness of the serum levels of neuroinflammatory and lung fibrosis biomarkers in the assessment of cognitive dysfunction in post-COVID19 patients

A growing body of evidence indicates there is an increasing incidence of cognitive dysfunction in patients after coronavirus disease 2019 (COVID-19) infection. However, still lack diagnostic tools, which allow us to predict prognosis in such cases and improve the stratification of the disease. This study aims to evaluate the usefulness of the biomarkers that could allow to predict the severity and progression of COVID-19 in patients with post-COVID syndrome and cognitive problems. Data regarding clinical history, pre-existing conditions, chest CT scan, and therapy (remdesivir, steroids) were acquired. A total of 44 patients with hospitalized COVID-19, and healthy controls were enrolled in the investigation, and serum blood was obtained. After 6 months of observations, patients with COVID-19 were divided into two groups: first - without post-COVID syndrome and memory complaints, and second - with post-COVID and cognitive problems. Measurements of YKL-40 and MR-pro-ADM were taken in the serum with enzyme immunoassay kits at the time of admission (visit 1) and 6 months after discharge from the hospital (visit 2). Significantly higher concentrations of YKL-40 were found in patients with COVID-19 as compared to healthy individuals (p = 0.016). Moreover, YKL-40 ratio allowed to differentiate patients with and without post-COVID syndrome (median: 0.94 vs. 1.55, p = 0.004). Additionally, COVID-19 patients with dyspnea presented significantly elevated levels of MR-pro-ADM as compared to the group of COVID-19 survivors without dyspnea (p = 0.015). In the group of patients without post-COVID syndrome, the concentrations of YKL-40 and MR-pro-ADM decreased after treatment as compared to levels before therapy (77 vs. 36 ng/ml and 607 vs. 456 pmol/L). However, in patients with post-COVID syndrome and cognitive problems, the levels of both markers did not alter 6 months after hospital discharge in comparison to basal levels. Furthermore, after dexamethasone treatment the YKL-40 concentrations declined significantly (p = 0.003) in patients with COVID-19. This study demonstrated the predictive usefulness of YKL-40 as an indicator of successful treatment in patients with COVID-19 infection allowing risk stratification of hospitalized patients. It seems that indicators of neuroinflammation might have the potential to track development of cognitive complaints, however, it requires further investigations.

Ca2+ Signaling in Cardiovascular Fibroblasts

Fibrogenesis is a physiological process required for wound healing and tissue repair. It is induced by activation of quiescent fibroblasts, which first proliferate and then change their phenotype into migratory, contractile myofibroblasts. Myofibroblasts secrete extracellular matrix proteins, such as collagen, to form a scar. Once the healing process is terminated, most myofibroblasts undergo apoptosis. However, in some tissues, such as the heart, myofibroblasts remain active and sensitive to neurohumoral factors and inflammatory mediators, which lead eventually to excessive organ fibrosis. Many cellular processes involved in fibroblast activation, including cell proliferation, protein secretion and cell contraction, are highly regulated by intracellular Ca2+ signals. This review summarizes current research on Ca2+ signaling pathways underlying fibroblast activation. We present receptor- and ion channel-mediated Ca2+ signaling pathways, discuss how localized Ca2+ signals of the cell nucleus may be involved in fibroblast activation and present Ca2+-sensitive transcription pathways relevant for fibroblast biology. When investigated, we highlight how the function of Ca2+-handling proteins changes during cardiac and pulmonary fibrosis. Many aspects of Ca2+ signaling remain unexplored in different types of cardiovascular fibroblasts in relation to pathologies, and a better understanding of Ca2+ signaling in fibroblasts will help to design targeted therapies against fibrosis.

S-RBD-modified and miR-486-5p-engineered exosomes derived from mesenchymal stem cells suppress ferroptosis and alleviate radiation-induced lung injury and long-term pulmonary fibrosis

BackgroundRadiation-induced lung injury (RILI) is associated with alveolar epithelial cell death and secondary fibrosis in injured lung. Mesenchymal stem cell (MSC)-derived exosomes have regenerative effect against lung injury and the potential to intervene of RILI. However, their intervention efficacy is limited because they lack lung targeting characters and do not carry sufficient specific effectors. SARS-CoV-2 spike glycoprotein (SARS-CoV-2-S-RBD) binds angiotensin-converting enzyme 2 (ACE2) receptor and mediates interaction with host cells. MiR-486-5p is a multifunctional miRNA with angiogenic and antifibrotic potential and acts as an effector in MSC-derived exosomes. Ferroptosis is a form of cell death associated with radiation injury, its roles and mechanisms in RILI remain unclear. In this study, we developed an engineered MSC-derived exosomes with SARS-CoV-2-S-RBD- and miR-486-5p- modification and investigated their intervention effects on RIPF and action mechanisms via suppression of epithelial cell ferroptosis.ResultsAdenovirus-mediated gene modification led to miR-486-5p overexpression in human umbilical cord MSC exosomes (p < 0.05), thereby constructing miR-486-5p engineered MSC exosomes (miR-486-MSC-Exo). MiR-486-MSC-Exo promoted the proliferation and migration of irradiated mouse lung epithelial (MLE-12) cells in vitro and inhibited RILI in vivo (all p < 0.05). MiR-486-MSC-Exo suppressed ferroptosis in MLE-12 cells, and an in vitro assay revealed that the expression of fibrosis-related genes is up-regulated following ferroptosis (both p < 0.05). MiR-486-MSC-Exo reversed the up-regulated expression of fibrosis-related genes induced by TGF-β1 in vitro and improved pathological fibrosis in RIPF mice in vivo (all p < 0.05). SARS-CoV-2-S-RBD-modified and miR-486-5p-engineered MSC exosomes (miR-486-RBD-MSC-Exo) were also constructed, and the distribution of DiR dye-labeled miR-486-RBD-MSC-Exo in hACE2CKI/CKI Sftpc-Cre+ mice demonstrated long-term retention in the lung (p < 0.05). MiR-486-RBD-MSC-Exo significantly improved the survival rate and pathological changes in hACE2CKI/CKI Sftpc-Cre+ RIPF mice (all p < 0.05). Furthermore, miR-486-MSC-Exo exerted anti-fibrotic effects via targeted SMAD2 inhibition and Akt phosphorylation activation (p < 0.05).ConclusionsEngineered MSC exosomes with SARS-CoV-2-S-RBD- and miR-486-5p-modification were developed. MiR-486-RBD-MSC-Exo suppressed ferroptosis and fibrosis of MLE-12 cells in vitro, and alleviated RILI and long-term RIPF in ACE2 humanized mice in vivo. MiR-486-MSC-Exo exerted anti-fibrotic effects via SMAD2 inhibition and Akt activation. This study provides a potential approach for RIPF intervention.Graphical

Protective effects of Silibinin and cinnamic acid against paraquat-induced lung toxicity in rats: impact on oxidative stress, PI3K/AKT pathway, and miR-193a signaling.

Levels of reactive oxygen species (ROS) are the primary determinants of pulmonary fibrosis. It was discovered that antioxidants can ameliorate pulmonary fibrosis caused by prolonged paraquat (PQ) exposure. However, research on the precise mechanisms by which antioxidants influence the signaling pathways implicated in pulmonary fibrosis induced by paraquat is still insufficient. This research utilized a rat model of pulmonary fibrosis induced by PQ to examine the impacts of Silibinin (Sil) and cinnamic acid (CA) on pulmonary fibrosis, with a specific focus on pro-fibrotic signaling pathways and ROS-related autophagy. Lung injury induced by paraquat was demonstrated to be associated with oxidative stress and inflammation of the lungs, downregulated (miR-193a), and upregulated PI3K/AKT/mTOR signaling lung tissues. Expression levels of miR-193a were determined with quantitative real-time PCR, protein level of protein kinase B (Akt), and phosphoinositide 3-Kinase (PI3K) which were determined by western blot analysis. Hydroxyproline levels (HYP) and transforming growth factor-β1 (TGF-β1) were measured by ELISA, malondialdehyde (MDA), total antioxidant capacity (TAC), glutathione peroxidase (GSH), and catalase and were measured in lung tissue homogenates colorimetrically using spectrophotometer. Long-term exposure to paraquat resulted in decreased PI3K/AKT signaling, decreased cell autophagy, increased oxidative stress, and increased pulmonary fibrosis formation. Silibinin and cinnamic acid also decreased oxidative stress by increasing autophagy and miR-193a expression, which in turn decreased pulmonary fibrosis. These effects were associated by low TGF-β1. Silibinin and cinnamic acid inhibited PQ-induced PI3K/AKT by stimulating miR-193-a expression, thus attenuating PQ-induced pulmonary fibrosis.

Monitoring the Cascade of Monocyte-Derived Macrophages to Influenza Virus Infection in Human Alveolus Chips.

Respiratory viruses ravage the world and seriously threaten people's health. Despite intense research efforts, the immune mechanism underlying respiratory virus-induced acute lung injury (ALI) and pulmonary fibrosis (PF) has not been fully elucidated. Here, the cascade of monocyte-derived macrophages to influenza A virus infection is monitored on an optimized human alveolus chip to reveal the role of macrophages in the development of ALI and PF. We find that viral infection causes damage to the alveolar air-liquid barrier and the release of inflammatory cytokines, which induce the M0 macrophages to gather and polarize to the M1 phenotype at the damaged site through recruitment, adhesion, migration, and activation, leading to ALI. Afterward, M1 macrophages polarize into the M2 phenotype, and then transform into myofibroblasts, followed by enhanced secretion of various anti-inflammatory cytokines and profibrotic cytokines, to promote PF. Our study provides an insight into the pathogenesis of virus-induced ALI and PF, which will assist in the development of therapeutic strategies and drugs for treating influenza and other respiratory virus infections.

Polyhexamethylene Guanidine Phosphate Induces Restrictive Ventilation Defect and Alters Lung Resistance and Compliance in Mice

Polyhexamethylene guanidine phosphate (PHMG-p), a major ingredient of humidifier disinfectants, is known to induce inflammation, interstitial pneumonitis, and fibrosis in the lungs. While its histopathologic toxicities have been studied in rodents, research on pulmonary function test (PFT) changes following PHMG-p exposure is limited. This study aimed to investigate the acute and chronic effects, as well as the dose and time response, of PHMG-p on the lungs in mice using PFT and histopathologic examinations. In the single instillation model, mice received PHMG-p and were sacrificed at 2, 4, and 8 weeks. In the five-time instillation model, PHMG-p was administered five times at one-week intervals, and mice were sacrificed 10 weeks after the first instillation. Results showed that PHMG-p exposure reduced lung volume, increased resistance, and decreased compliance, indicating a restrictive ventilation defect. Histopathologic examination showed increases in lung inflammation and fibrosis scores. Changes in several lung volume and compliance parameters, as well as histopathology, were dose-dependent. Lung resistance and compliance parameters had significant correlations with lung inflammation and fibrosis scores. PHMG-p exposure in mice resulted in a restrictive ventilation defect with altered lung resistance and compliance, along with histopathologic lung inflammation and fibrosis.

Phagocytic activity of neutrophil blood granulocytes in children with chronic non-specific lung diseases with post-inflammatory pneumofibrosis

One of the reasons for the development of chronic forms of lung diseases and pneumofibrosis as a pathological outcome of this inflammation may be an insufficient immune response. The key position belongs to neutrophilic granulocytes. Given the importance and renewed interest in neutrophils as tools for regulating immunity, leading to the progression of the fibrous process in children with CKD is an urgent problem. The purpose of the study was to study the phagocytic activity of blood neutrophils as an important component of innate immunity in patients with CNLD. Seventy children with CNLD with focal or segmental post-inflammatory pulmonary fibrosis were examined. Of these, 27 were children with progression of PPF (main group) and 43 children with PPF without progression (comparison group). The controls were the indicators of 23 healthy children, comparable by gender and age. The studies were carried out during clinical remission. The phagocytic activity of neutrophils (PНAN), phagocytic number (PN), spontaneous and stimulated NBT test were determined. The stimulation index of the NBT test (NBTst-NBTsp) was calculated. The mitochondrial membrane potential was determined using a BD FACS Calibur cytometer (USA) (BD Pharmigen, USA). PN in children with chronic heart disease with progressive PF was significantly reduced in comparison with patients in the comparison group and with the control group. The PHAN in children with CKD in both groups was within the standard values, however, it was lower than in the control group. The activity of the spontaneous HBT test in children of the main group was 1.7 times higher than in children in the comparison group and 3 times higher than in children from the control group. However, the stimulation index in the main group was significantly lower than in the control group. An increase in cells with a reduced membrane potential of granulocyte mitochondria was revealed in children of the main group compared with the control group. Children with CKD with the progression of fibrosis processes develop changes in the functional and metabolic activity of peripheral blood neutrophils typical for an inflammatory reaction, characterized by an increase in oxygen-dependent and a decrease in phagocytic cell activity.

Parishin Alleviates Pulmonary Fibrosis by Reducing CD38 Levels in Naturally Aging Mice.

Parishin, a natural compound, has demonstrated significant potential in mitigating age-related phenotypes and improving outcomes in age-associated diseases. Given that aging is a major risk factor for numerous chronic conditions, including pulmonary fibrosis, we investigated parishin's effects on cellular senescence and lung health. In our study, we treated mouse lung epithelial cells with parishin and observed a reduction in cellular senescence markers alongside an upregulation of sirtuin 1 (SIRT1). Building on these in vitro findings, we administered parishin to naturally aged mice. The treatment resulted in decreased pulmonary fibrosis and reduced DNA damage in lung tissue. Notably, we found that parishin treatment led to a reduction in Cluster of differentiation 38 (CD38) levels, concomitant with an increase in SIRT1 expression. These findings indicate that parishin may enhance lung function in aged mice, suggesting its potential as a therapeutic agent for treating age-related pulmonary disorders.

PCLAF-DREAM drives alveolar cell plasticity for lung regeneration

Cell plasticity, changes in cell fate, is crucial for tissue regeneration. In the lung, failure of regeneration leads to diseases, including fibrosis. However, the mechanisms governing alveolar cell plasticity during lung repair remain elusive. We previously showed that PCLAF remodels the DREAM complex, shifting the balance from cell quiescence towards cell proliferation. Here, we find that PCLAF expression is specific to proliferating lung progenitor cells, along with the DREAM target genes transactivated by lung injury. Genetic ablation of Pclaf impairs AT1 cell repopulation from AT2 cells, leading to lung fibrosis. Mechanistically, the PCLAF-DREAM complex transactivates CLIC4, triggering TGF-β signaling activation, which promotes AT1 cell generation from AT2 cells. Furthermore, phenelzine that mimics the PCLAF-DREAM transcriptional signature increases AT2 cell plasticity, preventing lung fibrosis in organoids and mice. Our study reveals the unexpected role of the PCLAF-DREAM axis in promoting alveolar cell plasticity, beyond cell proliferation control, proposing a potential therapeutic avenue for lung fibrosis prevention.

Application of Forced Oscillation Technique in Assessing Pulmonary Fibrosis in Hermansky–Pudlak Syndrome

Application of Forced Oscillation Technique in Assessing Pulmonary Fibrosis in Hermansky–Pudlak Syndrome

The Discovery of MORF-627, a Highly Selective Conformationally-Biased Zwitterionic Integrin αvβ6 Inhibitor for Fibrosis.

Inhibition of integrin αvβ6 is a promising approach to the treatment of fibrotic disease such as idiopathic pulmonary fibrosis. Screening a small library combining head groups that stabilize the bent-closed conformation of integrin αIIbβ3 with αv integrin binding motifs resulted in the identification of hit compounds that bind the bent-closed conformation of αvβ6. Crystal structures of these compounds bound to αvβ6 and related integrins revealed opportunities to increase potency and selectivity, and these efforts were accelerated using accurate free energy perturbation (FEP+) calculations. Optimization of PK parameters including permeability, bioavailability, clearance, and half-life resulted in the discovery of development candidate MORF-627, a highly selective inhibitor of αvβ6 that stabilizes the bent-closed conformation and has good oral PK. Unfortunately, the compound showed toxicity in a 28-day NHP safety study, precluding further development. Nevertheless, MORF-627 is a useful tool compound for studying the biology of integrin αvβ6.

Assessment of pulmonary fibrosis using weighted gene co-expression network analysis

Assessment of pulmonary fibrosis using weighted gene co-expression network analysis

Neutrophils and Lymphocytes: Yin and Yang of Lung Fibrosis and Patient Outcome in Diffuse Interstitial Lung Diseases

Neutrophils and Lymphocytes: Yin and Yang of Lung Fibrosis and Patient Outcome in Diffuse Interstitial Lung Diseases

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

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

Transforming respiratory diseases management: a CMO-based hospital pharmaceutical care model

IntroductionRespiratory diseases encompass a diverse range of conditions that significantly impact global morbidity and mortality. While common diseases like asthma and COPD exhibit moderate symptoms, less prevalent conditions such as pulmonary hypertension and cystic fibrosis profoundly affect quality of life and mortality. The prevalence of these diseases has surged by approximately 40% over the past 3 decades. Despite advancements in pharmacotherapy, challenges in drug administration, adherence, and adverse effects persist. This study aimed to develop and perform an interim validation of a Capacity-Motivation-Opportunity (CMO) model tailored for respiratory outpatients to enhance pharmaceutical care, which is the direct, responsible provision of medication-related care for the purpose of achieving definite outcomes that improve a patient’s quality of life, and overall wellbeing.MethodologyThis cross-sectional, multicenter study was conducted from March 2022 to March 2023. It comprised four phases: 1) forming an expert panel of 15 hospital pharmacists, 2) selecting respiratory pathologies based on prevalence and severity, 3) developing the CMO model’s pillars, and 4) integrating and conducting an interim validation of the model. The Capacity pillar focused on patient stratification and personalized care; the Motivation pillar aligned therapeutic goals through motivational interviewing; and the Opportunity pillar promoted the use of information and communication technologies (ICTs) for telemedicine.ResultsThe model included eight respiratory diseases based on expert assessment. For the Capacity pillar, 22 variables were defined for patient stratification, leading to three priority levels for personalized pharmaceutical care. In a preliminary test involving 201 patients across six hospitals, the stratification tool effectively classified patients according to their needs. The Motivation pillar adapted motivational interviewing techniques to support patient adherence and behavior change. The Opportunity pillar established teleconsultation protocols and ICT tools to enhance patient monitoring and care coordination.ConclusionThe CMO model, tailored for respiratory patients, provides a comprehensive framework for improving pharmaceutical care. By focusing on patient-centered care, aligning therapeutic goals, and leveraging technology, this model addresses the multifaceted needs of individuals with respiratory conditions. Future studies are necessary to validate this model in other healthcare systems and ensure its broad applicability.

Clustering-aided prediction of outcomes in patients with idiopathic pulmonary fibrosis

BackgroundBlood biomarkers predictive of the progression of idiopathic pulmonary fibrosis (IPF) would be of value for research and clinical practice. We used data from the IPF-PRO Registry to investigate whether the addition of “omics” data to risk prediction models based on demographic and clinical characteristics improved prediction of the progression of IPF.MethodsThe IPF-PRO Registry enrolled patients with IPF at 46 sites across the US. Patients were followed prospectively. Median follow-up was 27.2 months. Prediction models for disease progression included omics data (proteins and microRNAs [miRNAs]), demographic factors and clinical factors, all assessed at enrollment. Data on proteins and miRNAs were included in the models either as raw values or based on clusters in various combinations. Least absolute shrinkage and selection operator (Lasso) Cox regression was applied for time-to-event composite outcomes and logistic regression with L1 penalty was applied for binary outcomes assessed at 1 year. Model performance was assessed using Harrell’s C-index (for time-to-event outcomes) or area under the curve (for binary outcomes).ResultsData were analyzed from 231 patients. The models based on demographic and clinical factors, with or without omics data, were the top-performing models for prediction of all the time-to-event outcomes. Relative changes in average C-index after incorporating omics data into models based on demographic and clinical factors ranged from 1.7 to 3.2%. Of the blood biomarkers, surfactant protein-D, serine protease inhibitor A7 and matrix metalloproteinase-9 (MMP-9) were among the top predictors of the outcomes. For the binary outcomes, models based on demographics alone and models based on demographics plus omics data had similar performances. Of the blood biomarkers, CC motif chemokine 11, vascular cell adhesion protein-1, adiponectin, carcinoembryonic antigen and MMP-9 were the most important predictors of the binary outcomes.ConclusionsWe identified circulating protein and miRNA biomarkers associated with the progression of IPF. However, the integration of omics data into prediction models that included demographic and clinical factors did not materially improve the performance of the models.Trial registrationClinicalTrials.gov; No: NCT01915511; registered August 5, 2013; URL: www.clinicaltrials.gov.

Beneficial effect of sequential treatment with high-dose steroids and short-course oral glucocorticoids in patients with severe influenza virus-associated pneumonia

Accumulating evidence supports that glucocorticoid treatment for viral pneumonia (VPA) can shorten the disease course and improve survival. However, currently, the use of glucocorticoids in treating VPA remains controversial. Moreover, a unified standard for the dosage and duration of glucocorticoid therapy has not been presented in published articles. A retrospective analysis was conducted in patients who were hospitalized for severe influenza virus-associated pneumonia, and they received sequential treatment with high-dose glucocorticoids and short-course oral glucocorticoids. Patients were followed up for 3 months. A total of 11 patients were included in the study (average age 56 years). There was no gender difference, but age and underlying diseases could be risk factors for severe influenza virus-associated pneumonia. The types of viruses causing pneumonia included influenza A/B. The main clinical symptoms of patients were fever, cough, sputum production, and dyspnea. Chest computed tomography showed multiple ground-glass shadows in the lobes, and the presence of bacterial and fungal infections was accompanied by consolidation shadows. After glucocorticoid therapy, the symptoms improved. None of the patients underwent tracheal intubation, and all survived. After a 3-month follow-up, lung CT absorption in all patients had reached more than 80%, and lung imaging absorption in 20% patients was complete. No serious complications occurred in any of the patients. Sequential treatment with high-dose steroids and short-course oral glucocorticoids may be helpful for reducing the tracheal intubation rate and mortality rate in patients with severe influenza virus-associated pneumonia. Additionally, short-course oral glucocorticoids may reduce pulmonary fibrosis in patients with severe influenza virus-associated pneumonia without any serious complications.

Impact of GAP score on surgical prognosis of non-small-cell lung cancer with usual interstitial pneumonia.

Post-surgical survival outcomes in patients with non-small-cell lung cancer (NSCLC) and idiopathic pulmonary fibrosis (IPF) are expected to be worse than those in patients with other idiopathic interstitial pneumonias (IIPs). However, these remain unclear regarding patients with NSCLC and IPF histologically diagnosed as usual interstitial pneumonia [IPF(UIP)]. We aimed to assess the surgical and survival outcomes and identify prognostic factors in patients with NSCLC and IPF(UIP). This retrospective cohort study included patients with pathological stage I-III NSCLC and UIP. Prognostic factors and their association with lung cancer deaths (LCDs) and non-LCDs (NLCDs) were investigated. The overall survival of patients with UIP was significantly poorer than that of others with IIPs. The main causes of death were lung cancer (36%) and respiratory disease (44%). Multivariate analyses revealed the pathological stage of NSCLC ≥ II (hazard ratio [HR], 2.196; p = 0.009) and GAP stage ≥ II (HR, 2.821; p = 0.016) to be significant prognostic factors. NLCD incidence was significantly high in patients with GAP stage ≥ II. Recurrence occurred in 26 patients (36.1%); the period from recurrence to death was shorter in patients with IPF(UIP) than in patients without IPF(UIP). Patients with NSCLC and IPF(UIP) had poor prognosis after surgery. However, the prognosis varied greatly depending on the GAP stage. Considering the difficulty in managing post-surgical recurrence and high incidence of LCDs in patients with IPF(UIP), pursuing a radical resection is recommended in patients with GAP stage I. For patients with GAP stage ≥ II, comprehensive management of UIP is also necessary.

Longitudinal Micro-Computed Tomography Detects Onset and Progression of Pulmonary Fibrosis in Conditional Nedd4-2 Deficient Mice.

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease which is usually diagnosed late in advanced stages. Little is known about the subclinical development of IPF. We previously generated a mouse model with conditional Nedd4-2 deficiency (Nedd4-2-/-) that develops IPF-like lung disease. The aim of this study was to characterize the onset and progression of IPF-like lung disease in conditional Nedd4-2-/- mice by longitudinal micro-computed tomography (CT). In vivo micro-CT was performed longitudinally in control and conditional Nedd4-2-/- mice at 1, 2, 3, 4 and 5 months after doxycycline induction. Further, terminal in vivo micro-CT followed by pulmonary function testing and post mortem micro-CT was performed in age-matched mice. Micro-CT images were evaluated for pulmonary fibrosis using an adapted fibrosis scoring system. Histological assessment of lung collagen content was conducted as well. Micro-CT is sensitive to detect onset and progression of pulmonary fibrosis in vivo and to quantify distinct radiological IPF-like features along disease development in conditional Nedd4-2-/- mice. Nonspecific interstitial alterations were detected from 3 months, whereas key features such as honeycombing-like lesions were detected from 4 months onwards. Pulmonary function correlated well with in vivo (r=-0.738) and post mortem (r=-0.633) micro-CT fibrosis scores and collagen content. Longitudinal micro-CT enables in vivo monitoring of onset and progression and detects radiologic key features of IPF-like lung disease in conditional Nedd4-2-/- mice. Our data support micro-CT as sensitive quantitative endpoint for preclinical evaluation of novel antifibrotic strategies.

Quantifying Spatial Distribution of Ventilation Defects in Multiple Pulmonary Diseases With Hyperpolarized 129Xenon MRI.

Hyperpolarized 129Xe MRI assesses lung ventilation, often using the ventilation defect percentage (VDP). Unlike VDP, defect distribution index (DDI) quantifies spatial clustering of defects. To quantify spatial distribution of 129Xe ventilation defects using DDI across pulmonary diseases. Retrospective. Four hundred twenty-one subjects (age = 23.1 ± 17.1, female = 230), comprising healthy controls (N = 60) and subjects with obstructive conditions (asthma [N = 25], bronchiolitis obliterans syndrome [BOS, N = 18], cystic fibrosis [CF, N = 90], lymphangioleiomyomatosis [LAM, N = 50]), restrictive conditions (bleomycin-treated cancer survivors [BLEO, N = 14]; fibrotic lung diseases [FLD, N = 92]), bone marrow transplantation (BMT, N = 53), and bronchopulmonary dysplasia (BPD, N = 19). 3 T, two-dimensional multi-slice gradient echo. Whole-lung mean DDI was extracted from DDI maps; correlated with VDP (percent of pixels <60% of whole-lung mean signal intensity) and pulmonary function tests (PFTs) including FEV1, FVC, and FEV1/FVC. DDI and DDI/VDP, a marker of defect clustering, were compared across diseases. Pearson correlation analysis and Kruskal-Wallis tests. P < 0.0056 for disease groups, P < 0.0125 for categories. DDI was significantly elevated in BMT (8.3 ± 11.5), BOS (30.1 ± 57.5), BPD (16.0 ± 46.8), CF (15.4 ± 27.2), and LAM (12.6 ± 34.2) compared to controls (1.8 ± 3.1). DDI correlated significantly with VDP in all groups (r ≥ 0.56) except BLEO, and with PFTs in CF, FLD, and LAM (r ≥ 0.56). Obstructive groups had significantly higher mean DDI (14.0 ± 32.0) than controls (1.8 ± 3.0) and restrictive groups (4.0 ± 12.0). DDI/VDP was significantly lower in the restrictive group (0.6 ± 0.6) than controls (0.8 ± 0.6) and obstructive group (1.0 ± 1.0). DDI may provide insights into the distribution of ventilation defects across diseases. 3 TECHNICAL EFFICACY: Stage 2.