Pulmonary Fibrosis Research Articles

The impact of pulmonary fibrosis on cardiac function in chronic obstructive pulmonary disease

Abstract Background Emerging evidence indicates the coexistence pulmonary fibrosis and emphysema in patients with Chronic Obstructive Pulmonary Disease (COPD). The effect of pulmonary fibrosis on cardiac structure and function in COPD patients remains unclear. Purpose This study aimed to examine the association between the degree of pulmonary fibrosis identified on Computed Tomographic (CT) imaging and echocardiographic measures of cardiac structure and function in individuals with COPD. Methods The study included 456 individuals with COPD, participating in a large prospective cohort study. Patients with available CT scans and echocardiograms were included. Local histogram-based assessments of lung density were utilized to determine the percentage of fibrosis. Fibrosis was defined based on the CT attenuation within the range of -600 and -250 Hounsfield units. The association between percent fibrosis and measures of cardiac structure and function were investigated by univariable and multivariable linear regression models. Multivariable adjustments included age, sex, body mass index (BMI), and smoking. In addition, restricted cubic splines were generated to visually present the relationship between the percentage of fibrosis and specific echocardiographic parameters. Results The mean age was 71 (± 8 years), 48% were female, and the median BMI was 27 kg/m2 (IQR: 22; 30kg/m2). The mean forced expiratory volume in 1 second as a percentage of the predicted value (FEV1pp) was 47% (±18%). The mean forced vital capacity of predicted value was 71% (± 19%). The median percentage of fibrosis in the cohort was 4.9% (IQR: 3.9; 6.0%). Patients were stratified into tertiles based upon fibrosis percentage. BMI, frequency of diabetes, and FEV1pp were increasingly positively associated with fibrosis. Furthermore, significant trends for echocardiographic measures found that the patients with the most extensive fibrosis were seen to have impaired left ventricular (LV) ejection fraction (LVEF), lower absolute global longitudinal strain (GLS), increased left atrial (LA) volume index (LAVi), and higher LV mass as compared to those with less significant fibrosis. There were no significant differences between tertiles of fibrosis and age or sex. In univariable linear regression, significant inverse associations between the percentage of fibrosis, LVEF, GLS, and tricuspid annular plane systolic excursion (TAPSE) were seen (Table). For LV mass index and LAVi, significant direct associations were found (Table). After adjusting for potential confounding factors, only GLS and LAVi remained associated with pulmonary fibrosis (Figure). Conclusion This study found that GLS and LA volume were significantly associated with the degree of pulmonary fibrosis, even after adjusting for confounding variables. This may suggest that fibrosis is primarily linked with impaired left-sided measures of cardiac structure and function.Linear Regression ModelsCubic Spline Curves

Mechanisms of Bone Morphogenetic Protein 2 in Respiratory Diseases.

Bone morphogenetic protein 2 (BMP2) belongs to the transforming growth factor-β (TGF-β) superfamily and plays an important role in regulating embryonic development, angiogenesis, osteogenic differentiation, tissue homeostasis, and cancer invasion. Increasing studies suggest BMP2 is involved in several respiratory diseases. This study aimed to review the role and mechanisms of BMP2 in respiratory diseases. BMP2 signaling pathway includes the canonical and non-canonical signaling pathway. The canonical signaling pathway is the BMP2-SMAD pathway, and the non-canonical signaling pathway includes mitogen-activated protein kinase (MAPK) pathway and phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathway. The BMP2 is related to pulmonary hypertension (PH), lung cancer, pulmonary fibrosis (PF), asthma, and chronic obstructive pulmonary disease (COPD). BMP2 inhibits the proliferation of pulmonary artery smooth muscle cells (PASMCs), promotes the apoptosis of PASMCs to reduce pulmonary vascular remodeling in PH, which is closely related to the canonical and non-canonical pathway. In addition, BMP2 stimulates the proliferation and migration of cells to promote the occurrence, colonization, and metastasis of lung cancer through the canonical and the non-canonical pathway. Meanwhile, BMP2 exert anti-fibrotic function in PF through canonical signaling pathway. Moreover, BMP2 inhibits airway inflammation to maintain airway homeostasis in asthma. However, the signaling pathways involved in asthma are poorly understood. BMP2 inhibits the expression of ciliary protein and promotes squamous metaplasia of airway epithelial cells to accelerate the development of COPD. In conclusion, BMP2 may be a therapeutic target for several respiratory diseases.

Long-acting CRF2 receptor agonist COR-1389 improves cardiopulmonary function parameters in monocrotaline-induced pulmonary hypertension and right heart failure rat model

Abstract Background Pulmonary hypertension (PH) associated with right heart failure (RHF) poses a significant therapeutic challenge. Short term studies have shown that urocortin-2 (UCN-2) administration, either intravenously or subcutaneously, can ameliorate cardiac and/or pulmonary parameters in human heart failure (HF) and in animal models of PH and RHF. Purpose This study aimed to evaluate the potential benefits of COR-1389, a long-acting CRF2 receptor agonist, on cardiopulmonary function and adverse remodeling in a rat model of monocrotaline (MCT)-induced PH and RHF. Method Monocrotaline (40 mg/kg) was administered subcutaneously in rats on Day-0 to induce PH and RHF, while the control group received vehicle. After 14 days, MCT-injected rats were evenly allocated into two groups based on echocardiography parameters of accelerated time/ejection time ratio and tricuspid annular plane systolic excursion (TAPSE), before receiving either COR-1389 (100 ug/kg) or its vehicle subcutaneously every 4 days for 14 days. On Day-28, echocardiography was repeated in all groups, followed by right heart catheterization to directly measure pulmonary hemodynamics. Heart and lung samples were prepared for histological analysis. Results By Day-28, MCT-treated rats exhibited significantly elevated mean pulmonary arterial pressure (mPAP) and right ventricular (RV) mass (Fulton Index/BW), along with decreased RV function (increased TAPSE) and reduced cardiac output (CO) compared to control rats. These changes were accompanied by severe tissue remodeling, including increased vascular muscularization (alpha-smooth muscle actin content) and pulmonary arterial wall thickening, RV fibrosis, and cardiomyocyte hypertrophy. Following 14 days of curative treatment, MCT+COR-1389 compared to MCT, significantly decreased mPAP and RV mass (Fulton Index/BW), while RV function improved (reduced TAPSE) and CO was increased. Moreover, COR-1389 attenuated adverse pulmonary vascular remodeling (reduced muscularization and arterial wall thickening), RV fibrosis, and cardiomyocyte hypertrophy, consistent with its hemodynamic effects. Conclusions Chronic CRF2 agonism with COR-1389 improved dysregulated cardiac and pulmonary function and structure in the MCT rat model, suggesting its potential for the treatment of PH and RHF.

Safety and Tolerability of Nintedanib in Patients with Fibrosing Interstitial Lung Diseases: Post-marketing Data.

Nintedanib is approved for the treatment of idiopathic pulmonary fibrosis (IPF), other forms of progressive pulmonary fibrosis (PPF), and systemic sclerosis-associated interstitial lung disease (ILD). We present global post-marketing safety data for nintedanib in these fibrosing ILDs. Data on adverse events in patients with fibrosing ILDs who were treated with nintedanib were collected via spontaneous reporting and solicited reporting in various studies (excluding clinical trials).Data were collected from 15 October 2014 (first regulatory approval) to 15 October 2023. Adverse events were coded using the Medical Dictionary for Regulatory Activities. Cumulative exposure to nintedanib was estimated using sales data. Cumulative exposure to nintedanib was 380,557 patient-years. Diarrhoea was reported at a rate of 227.5 per 1000 patient-years. Only 2.6% of diarrhoea events were reported as serious. Of 39,788 (33.6%) diarrhoea events with a known time to onset, almost 60% occurred within the first 3months of treatment. The rate of serious liver enzyme and bilirubin elevations (including drug-induced liver injury) was 4.0 per 1000 patient-years. Bleeding was reported at a rate of 24.2 per 1000 patient-years. Most (81.3%) bleeding events were non-serious. The rates of myocardial infarction, ischaemic stroke, and venous thromboembolism were 3.3, 3.3, and 2.0 per 1000 patient-years, respectively. Gastrointestinal perforation was reported at a rate of 0.9 per 1000 patient-years. Post-marketing safety data on established and potential adverse events associated with nintedanib in patients with fibrosing ILDs, collected over 9years, demonstrated a safety profile that was similar to that established in clinical trials and provided in the product labels. Education of patients about the adverse events that may be associated with nintedanib, and the effective management of adverse events when they occur, is important to minimise the impact of adverse events and help patients remain on treatment.

Predictors of B-line count in hospitalized patients with COVID-19

Abstract Background B-lines on lung ultrasound (LUS) are non-specific signs of increased density within lung tissue, which can be secondary to pulmonary congestion, pneumonia, or fibrosis. LUS is recommended for managing acute heart failure (HF); however, its value in non-HF populations is less clear. Purpose To identify clinical, laboratory, and echocardiographic predictors of B-lines in a population with Coronavirus disease 2019 (COVID-19). Methods In the ECHOVID-19 study, hospitalized non-ICU patients ≥18 years with confirmed laboratory diagnosis of COVID-19 in Eastern Denmark underwent 8-zone LUS and echocardiography. We used trend and regression analyses to identify associations with the number of B-lines and adjusted for potential confounders (age, sex, body mass index, C-reactive protein, and pandemic wave). Results Among 270 (89%) patients with adequate LUS images, the mean age was 69±14 years, 58% were male and 11% had prior HF. Median time from hospital admission to LUS was 4 [2-8] days. In total, 263 (97%) had ≥1 B-line (median B-line number 14 [9-22]) and median left ventricular ejection fraction [LVEF] was 59 [54-63]). In adjusted models, more B-lines were associated with higher levels of C-reactive protein with an incidence rate ratio (IRR) of 16% (95%CI: 8%-24%) per log-unit increase (P<0.001) and higher Early Warning Score (IRR 5% [95%CI: 1%-0%] per point, P=0.02). Higher tricuspid regurgitation gradient was associated with more B-lines: IRR 2% (95%CI: 1%-3%) per mmHg, P<0.001) (Figure 1). Echocardiographic measures of left ventricular (LV) function (including LVEF and global longitudinal strain, left atrial volume, and LV filling pressures (E/e’)) and right ventricular function were not significantly associated with the number of B-lines. B-lines were not associated with N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations, even in patients with established HF. Lastly, B-lines were not associated with 30-day mortality. Conclusions Among hospitalized patients with COVID-19, B-lines on LUS are associated with markers of infectious disease severity and pulmonary hypertension but not with markers of left-sided HF.Figure1.Predictors of B-lines

Transpulmonary proteome gradients identify inflammatory pathways involved in the development of pulmonary vasculopathy in heart failure

Abstract Background Some, but not all, patients with heart failure (HF) develop pulmonary vascular disease (PVD), which contributes to poor prognosis. Mechanisms leading to PVD in HF are poorly understood. Unbiased analysis of transpulmonary gradients may identify not only markers but also mediators of PVD by identifying proteins that may be consumed or elaborated across the lungs. Purpose Examine hemodynamics and transpulmonary proteome gradients in HFrEF and controls. Methods 21 non-HF controls and 160 patients with advanced HFrEF underwent pulmonary artery (PA) catheterization with blood sampling from the PA catheter in the wedged position (02sat > 90%, indicating pulmonary venous blood) and the un-wedged position to obtain transpulmonary proteome gradients. Samples from controls and HF from the highest quartile (Q4, n=40) and lowest quartile (Q1, n=40) of pulmonary vascular resistance (PVR) were analyzed using proteomic PEA assay of 275 proteins (Olink Target 96, panels CVII, CVIII, Inflammation). Pulmonary artery concentrations ("markers") or transpulmonary fold-change gradients (i.e. putative "mediators") of normalized protein expression (NPX) were plotted against significance; Benjamini–Hochberg FDR<0.05 considered as significant. Results Patients displayed typical characteristics of HFrEF (age 56±8y, NYHA 3.0 ±0.6, 87% males, LVEF 24±9.6%), Controls had similar anthropometrics, gender and age. Comparing all HF to Con, 38 markers of HF were identified (NPX fold-change>2), including 33 up (top 5: NTproBNP, BNP, GDF15, FGF23, IL8) and 5 down. HF patients in Q1 had median PVR 1.5 (IQR: 0.3-1.7) WU and those in Q4 had PVR 5.4 (4.3-6.6) WU. Comparison of Q1 and Q4 identified 3 protein markers of high PVR in PA blood from HF: chemokine CCL3, TNFRSF13B and surfactant protein-D (PSP-D). Examination of protein gradients from HF lungs (Figure) showed significant uptake of 14 protein mediators, most of which were associated with inflammatory responses (top 5: OSM, MMP9, CCL19, BNP, TR), and release of 8 mediators (top 4: IL-6, IL33, CCL4, CXCL10). In contrast, protein gradients were negligible in controls. Patients in Q4 PVR group were characterized by the highest pulmonary uptake of OSM (Oncostatin-M), lymphatic chemokine CCL19, BNP, MMP9, and had more significant transpulmonary release of IL6 and IL33. Across all patients, OSM lung uptake was the strongest correlate of transpulmonary pressure gradient (r=-0.3, p<0.001). Conclusions Lungs of patients with HF, and particularly those with high PVR, display abnormal uptake and release of proinflammatory CC and CXC chemokines and cytokines from IL1 and IL6 family, along with increased pulmonary uptake of IL6-type cytokine Oncostatin-M, a known mediator of lung inflammation and fibrosis, that acts via gp130/JAK/STAT, suggesting a novel role in PVD due to HF.Transpulmonary proteome in HF patients

Diagnosis and management of hypersensitivity pneumonitis in adults: A position statement from the Thoracic Society of Australia and New Zealand.

Hypersensitivity pneumonitis (HP) is an immune-mediated interstitial lung disease (ILD) relating to specific occupational, environmental or medication exposures. Disease behaviour is influenced by the nature of exposure and the host response, with varying degrees of lung inflammation and fibrosis seen within individuals. The differentiation of HP from other ILDs is important due to distinct causes, pathophysiology, prognosis and management implications. This Thoracic Society of Australia and New Zealand (TSANZ) position statement aims to provide an up-to-date summary of the evidence for clinicians relating to the diagnosis and management of HP in adults, in the Australian and New Zealand context. This document highlights recent relevant findings and gaps in the literature for which further research is required.

Asymptomatic Pulmonary Fibrosis Associated With Ipsilateral Proximal Interruption of a Pulmonary Artery (PIPA)

Asymptomatic Pulmonary Fibrosis Associated With Ipsilateral Proximal Interruption of a Pulmonary Artery (PIPA)

Impact of Pirfenidone on arrhythmic and clinical outcomes in patients with idiopathic pulmonary fibrosis

Abstract Background Atrial fibrosis is an important substrate in atrial fibrillation (AF), particularly in the setting of structural heart disease. Previous study reported that pirfenidone, an antifibrotic agent, was beneficial at reducing myocardial fibrosis. The objective of the present study is to evaluate the effects of pirfenidone on arrhythmic and clinical outcomes in patients with idiopathic pulmonary fibrosis (IPF). Methods Our database of patients diagnosed with IPF from 2008 to 2023 was used to obtain echocardiography, electrocardiogram (ECG), and 24hr-holter monitoring data. Inclusion criteria were all IPF patients with/without Pirfenidone. And we compared arrhythmic events including atrial fibrillation, atrial premature complex, atrial tachycardia, ventricular arrhythmia and clinical outcomes according to use of Pirfenidone. Results Among 257 patients with IPF (74.0±8.9 years), 106 (42.1%) patients took Pirfenidone. Difference in the baseline characteristics was not observed. During the median 36-month follow-up, a lower incidence of arrhythmic events (P=0.001) and diastolic dysfunction (P=0.025) was observed in the Pirfenidone group. In univariate analysis, hypertension, coronary artery disease, higher body weight, longer PR interval, QRS duration, and less use of Pirfenidone were associated with arrhythmic events. In multivariate analysis, higher body weight and less Pirfenidone use were independent risk factors for arrhythmic events. Conclusions The use of Pirfenidone was associated with less arrhythmic events and lower diastolic dysfunction compared with no use of Pirfenidone in the long-term follow-up. And obesity was associated with higher incidence of arrhythmic events in IPF patients.

Assessment of circulating biomarkers and hemodynamic response during stress to detect early cardiopulmonary complications in systemic sclerosis

Abstract Background Systemic sclerosis (SSc) is characterised by persistent immune-inflammatory system activation and excessive extracellular matrix (ECM) accumulation leading to fibrosis. Exercise Doppler Echocardiography (EDE) is a promising method to detect the early changes of fibrosis-related pulmonary and myocardial complications, like elevated left ventricular filling pressure or stress-induced pulmonary hypertension (PH). Aims The study aims to assess the linkage between the activity of fibrosis markers and abnormal exercise haemodynamics during stress in patients with SSc. Methods A total of 18 patients with SSc were enrolled in the single-centre prospective study (age 54±15,5years, 94,4 % women). SSc patients with resting PH and moderate to severe pulmonary fibrosis were excluded. According to a standardised protocol, all subjects underwent resting and exercise echocardiography on a semi-recumbent cycle ergometer with an incremental (25 watts) workload up to the maximally tolerated workload. Measurements focused on the left ventricular diastolic function (E/e’) and right ventricular haemodynamics (estimated systolic pulmonary pressure: PASP, right ventricular coupling: TAPSE/PASP, pulmonary vascular resistance: PVR). Blood samples were taken immediately before the stress test, and the Matrix Metalloproteinase-9 and 2 (MMP-9, MMP-2) levels were assessed with gelatin zymography method. Results During the EDE, PASP from baseline increased significantly (24,6mmHg±11 vs 38±16mmHg, p <0,0001), also PVR (1,2±0,49 vs 1,5±0,15 Wood unit, p<0,001) RV coupling was decreased significantly (1,2±0,68 vs 0,93±0,5, p<0,001). Left ventricular E/e’ was also increased during the stress (8,2±2 vs 10,5±5,1, p<0,05). Enzymatically active MMP-9 level was significantly correlated with RV coupling at rest and stress (p<0,05, r 0,63 at rest and r 0,52 at stress) and negatively correlated with PASP (p<0,05, r:-0,62 at rest and r -0,5 at stress). MMP-2 level only negatively correlated with resting PASP (p<0,05, r:-0,527). The left ventricular parameters did not show any relationship with MMP levels. Conclusions The level of circulating MMP-9 predicts haemodynamic behaviour during stress in SSc. MMPs could be a promising marker for detecting early changes in the right ventricle-pulmonary circulation unit.

Acute vasoreactivity testing for severe pulmonary hypertension associated with lung disease

Abstract Background Pulmonary hypertension results in clinical deterioration and increases mortality risk in patients with lung disease (LD), including chronic obstructive pulmonary disease, interstitial lung disease and combined pulmonary fibrosis and emphysema. Though acute vasoreactivity testing predicts long term-survival of patients with pulmonary arterial hypertension (PAH), its clinical impact for patients with pulmonary hypertension associated with LD (LD-PH) remains unknown. Purpose The purpose of this study is to clarify the clinical impact of acute vasoreactivity testing using inhaled nitric oxide for severe LD-PH. Methods We retrospectively reviewed 65 consecutive patients with LD-PH between January 2014 and December 2022; 48 patients (73 [68–78] years; males, 81%; median follow-up period 23 [7–35] months) with severe pulmonary hypertension who underwent acute vasoreactivity testing were included. We divided the patients based on a median pulmonary vascular resistance (PVR) response (−15%) in acute vasoreactivity testing into the high-responder (PVR response ≦−15%) and the low-responder (PVR response >−15%) groups. Results Acute vasoreactivity testing significantly decreased mean pulmonary arterial pressure (mPAP) (from 41 [34–48] to 36 [31–40] mmHg, P<0.01) and PVR (from 10.7 [8.3–13.8] to 8.9 [6.6–11.4] Wood units, P<0.01). The high-responder group had better long-term survival than the low-responder group (P = 0.03). Univariate Cox regression analysis showed that the prognostic factors for better survival included younger age, high-responder to acute vasoreactivity testing, and PAH-specific therapy (P <0.01, 0.04, 0.03, respectively). There were correlations between the PVR response at acute vasoreactivity testing and improvement in mPAP (R=0.40, P=0.03) or PVR (R = 0.47, P <0.01) with PAH-specific therapy. Conclusions PVR response at acute vasoreactivity testing was associated with better long-term survival and haemodynamic improvement with PAH-specific therapy. Acute vasoreactivity testing may be useful to predict the responders to PAH-specific therapy and long-term survival in patients with severe LD-PH.

Rheumatoid arthritispresenting by combined pulmonary fibrosis and emphysema with clubbing and pulmonary hypertension: A rare case report.

A 60-year-old male smoker came with dyspnea. A rare condition known as combined pulmonary fibrosis and emphysema (CPFE) was observed on a chest CT scan. Decreased DLCO in combination with normal FVC can help diagnose CPFE. Concomitant connective tissue diseases, including rheumatoid arthritis, should be checked in CPFE patients.

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.