Rhizoma coptidis can inhibit the excessive proliferation, inflammation, and transformation of lung fibroblasts into myofibroblasts.

BACKGROUND: Pulmonary fibrosis (PF) is a chronic, progressive, and irreversible heterogeneous disease of lung interstitial tissue. To combat progression of PF, new drugs are required to be developed. Rhizoma coptidis (COP), one of the main alkaloids of Coptis chinensis, is a traditional herbal medicine used to treat various inflammatory diseases. OBJECTIVE: To investigate the possible effects of Coptisine (Cop) on the growth, inflammation, as well as FMT of TNF-ß1-induced HFL1 cells and uncover the mechanism. MATERIAL AND METHODS: Human fetal lung fibroblast 1 (HFL1) was induced using 6ng/mL TGF-ß1 as a model of pulmonary fibrosis. CCK-8, Brdu, and transwell assays indicated the effects on cell growth as well as motility. qPCR and the corresponding kits indicted the effects on cell inflammation. Immunoblot showed the effects on FMT and further confirmed the mechanism. RESULTS: Coptisine inhibits excessive growth as well as motility of TNF-ß1-induced HFL1 cells. It further inhibits inflammation and ROS levels in TNF-ß1-induced HFL1 cells. Coptisine inhibits the FMT process of TNF-ß1-induced HFL1 cells. Mechanically, coptisine promotes the Nrf2/HO-1 pathway. CONCLUSION: Coptisine can inhibit the excessive growth, inflammation as well as FMT of lung fibroblasts into myofibroblasts. It could serve as a promising drug of PF.

RNA-sequencing reveals differential fibroblast responses to bleomycin and pneumonectomy.

Pulmonary fibrosis is characterized by pathological accumulation of scar tissue in the lung parenchyma. Many of the processes that are implicated in fibrosis, including increased extracellular matrix synthesis, also occur following pneumonectomy (PNX), but PNX instead results in regenerative compensatory growth of the lung. As fibroblasts are the major cell type responsible for extracellular matrix production, we hypothesized that comparing fibroblast responses to PNX and bleomycin (BLM) would unveil key differences in the role they play during regenerative versus fibrotic lung responses. RNA-sequencing was performed on flow-sorted fibroblasts freshly isolated from mouse lungs 14 days after BLM, PNX, or sham controls. RNA-sequencing analysis revealed highly similar biological processes to be involved in fibroblast responses to both BLM and PNX, including TGF-ß1 and TNF-α. Interestingly, we observed smaller changes in gene expression after PNX than BLM at Day 14, suggesting that the fibroblast response to PNX may be muted by expression of transcripts that moderate pro-fibrotic pathways. Itpkc, encoding inositol triphosphate kinase C, was a gene uniquely up-regulated by PNX and not BLM. ITPKC overexpression in lung fibroblasts antagonized the pro-fibrotic effect of TGF-ß1. RNA-sequencing analysis has identified considerable overlap in transcriptional changes between fibroblasts following PNX and those overexpressing ITPKC.

Nintedanib Mitigates Radiation-Induced Pulmonary Fibrosis by Suppressing Epithelial Cell Inflammatory Response and Inhibiting Fibroblast-to-Myofibroblast Transition.

Radiation-induced pulmonary fibrosis (RIPF) represents a serious complication observed in individuals undergoing thoracic radiation therapy. Currently, effective interventions for RIPF are unavailable. Prior research has demonstrated that nintedanib, a Food and Drug Administration (FDA)-approved anti-fibrotic agent for idiopathic pulmonary fibrosis, exerts therapeutic effects on chronic fibrosing interstitial lung disease. This research aimed to investigate the anti-fibrotic influences of nintedanib on RIPF and reveal the fundamental mechanisms. To assess its therapeutic impact, a mouse model of RIPF was established. The process involved nintedanib administration at various time points, both prior to and following thoracic radiation. In the RIPF mouse model, an assessment was conducted on survival rates, body weight, computed tomography features, histological parameters, and changes in gene expression. In vitro experiments were performed to discover the mechanism underlying the therapeutic impact of nintedanib on RIPF. Treatment with nintedanib, administered either two days prior or four weeks after thoracic radiation, significantly alleviated lung pathological changes, suppressed collagen deposition, and improved the overall health status of the mice. Additionally, nintedanib demonstrated significant mitigation of radiation-induced inflammatory responses in epithelial cells by inhibiting the PI3K/AKT and MAPK signaling pathways. Furthermore, nintedanib substantially inhibited fibroblast-to-myofibroblast transition by suppressing the TGF-ß/Smad and PI3K/AKT/mTOR signaling pathways. These findings suggest that nintedanib exerts preventive and therapeutic effects on RIPF by modulating multiple targets instead of a single anti-fibrotic pathway and encourage the further clinical trials to determine the efficacy of nintedanib in patients with RIPF.

Mechanism of action of miR-15a-5p and miR-152-3p in paraquat-induced pulmonary fibrosis through Wnt/ß-catenin signaling mediation.

Background: miRNAs are small, conserved, single-stranded non-coding RNA that are typically transported by exosomes for their functional roles. The therapeutic potential of exosomal miRNAs has been explored in various diseases including breast cancer, pancreatic cancer, cholangiocarcinoma, skin diseases, Alzheimer's disease, stroke, and glioma. Pathophysiological processes such as cellular inflammation, apoptosis, necrosis, immune dysfunction, and oxidative stress are closely associated with miRNAs. Internal and external factors such as tissue ischemia, hypoxia, pathogen infection, and endotoxin exposure can trigger these reactions and are linked to miRNAs. Paraquat-induced fibrosis is a protracted process that may not manifest immediately after injury but develops during bodily recovery, providing insights into potential miRNA intervention treatments. Rationale: These findings could potentially be applied for further pharmaceutical research and clinical therapy of paraquat-induced pulmonary fibrosis, and are likely to be of great interest to clinicians involved in lung fibrosis research. Methodology: Through a literature review, we identified an association between miR-15a-5p and miR-152-3p and their involvement in the Wnt signaling pathway. This allowed us to deduce the molecular mechanisms underlying regulatory interactions involved in paraquat-induced lung fibrosis. Results: miR-15a-5p and miR-152-3p play roles in body repair processes, and pulmonary fibrosis can be considered a form of reparative response by the body. Although the initial purpose of fibrotic repair is to restore normal body function, excessive tissue fibrosis, unlike scar formation following external skin trauma, can significantly and adversely affect the body. Modulating the Wnt/ß-catenin signaling pathway is beneficial in alleviating tissue fibrosis in various diseases. Conclusions: In this study, we delineate the association between miR-15a-5p and miR-152-3p and the Wnt/ß-catenin signaling pathway, presenting a novel concept for addressing paraquat-induced pulmonary fibrosis.

Immune response regulation by transduced mesenchymal stem cells with decorin gene on bleomycin-induced lung injury, fibrosis, and inflammation.

BACKGROUND: Pulmonary fibrosis is a pathological hallmark of lung injury. It is an aggressive disease that replaces normal lung parenchyma by fibrotic tissue. The transforming growth factor-beta-mothers against decapentaplegic homolog 3 (TGF-ß1-Smad3) signaling pathway plays a key role in regulating lung fibrosis. Decorin (DCN), a small leucine-rich proteoglycan, has a modulatory effect on the immune system by reversibly binding with TGF-ß and reducing its bioavailability. Mesenchymal stem cell (MSC) therapy is a new strategy that has an immune-modulatory capacity. OBJECTIVE: The aim of this study was to introduce a new therapeutic approach to harness remodeling in injured lung. MATERIAL AND METHODS: Bone marrow MSCs were isolated and transduced by decorin gene. Lung injury was induced by bleomycin and mice were treated with MSCs, MSCs-decorin, and decorin. Then, oxidative stress biomarkers, remodeling biomarkers, bronchoalveolar lavage cells, and histopathology study were conducted. RESULTS: Reduced catalase and superoxide dismutase increased due to treatments. Elevated malondialdehyde, hydroxyproline, TGF-ß levels, and polymorphonuclear cells count decreased in the treated groups. Additionally, the histopathology of lung tissues showed controlled inflammation and fibrosis. CONCLUSION: Transfected decorin gene to MSCs and used cell therapy could control remodeling and bleomycin-induced lung injury.

Regulation of myofibroblast dedifferentiation in pulmonary fibrosis.

Idiopathic pulmonary fibrosis is a lethal, progressive, and irreversible condition that has become a significant focus of medical research due to its increasing incidence. This rising trend presents substantial challenges for patients, healthcare providers, and researchers. Despite the escalating burden of pulmonary fibrosis, the available therapeutic options remain limited. Currently, the United States Food and Drug Administration has approved two drugs for the treatment of pulmonary fibrosis-nintedanib and pirfenidone. However, their therapeutic effectiveness is limited, and they cannot reverse the fibrosis process. Additionally, these drugs are associated with significant side effects. Myofibroblasts play a central role in the pathophysiology of pulmonary fibrosis, significantly contributing to its progression. Consequently, strategies aimed at inhibiting myofibroblast differentiation or promoting their dedifferentiation hold promise as effective treatments. This review examines the regulation of myofibroblast dedifferentiation, exploring various signaling pathways, regulatory targets, and potential pharmaceutical interventions that could provide new directions for therapeutic development.

Lung quantitative ultrasound to stage and monitor interstitial lung diseases.

Chronic interstitial lung diseases (ILDs) require frequent point-of-care monitoring. X-ray-based methods lack resolution and are ionizing. Chest computerized tomographic (CT) scans are expensive and provide more radiation. Conventional ultrasound can detect severe lung damage via vertical artifacts (B-lines). However, this information is not quantitative, and the appearance of B-lines is operator- and system-dependent. Here we demonstrate novel ultrasound-based biomarkers to assess severity of ILDs. Lung alveoli scatter ultrasound waves, leading to a complex acoustic signature, which is affected by changes in alveolar density due to ILDs. We exploit ultrasound scattering in the lung and combine quantitative ultrasound (QUS) parameters, to develop ultrasound-based biomarkers that significantly correlate (p = 1e-4 for edema and p = 3e-7 for fibrosis) to the severity of pulmonary fibrosis and edema in rodent lungs. These innovative QUS biomarkers will be very significant for monitoring severity of chronic ILDs and response to treatment, especially in this new era of miniaturized and highly portable ultrasound devices.

MMP-3 mediates copper oxide nanoparticle-induced pulmonary inflammation and fibrosis.

BACKGROUND: The increasing production and usage of copper oxide nanoparticles (Nano-CuO) raise human health concerns. Previous studies have demonstrated that exposure to Nano-CuO could induce lung inflammation, injury, and fibrosis. However, the potential underlying mechanisms are still unclear. Here, we proposed that matrix metalloproteinase-3 (MMP-3) might play an important role in Nano-CuO-induced lung inflammation, injury, and fibrosis. RESULTS: Exposure of mice to Nano-CuO caused acute lung inflammation and injury in a dose-dependent manner, which was reflected by increased total cell number, neutrophil count, macrophage count, lactate dehydrogenase (LDH) activity, and CXCL1/KC level in bronchoalveolar lavage fluid (BALF) obtained on day 3 post-exposure. The time-response study showed that Nano-CuO-induced acute lung inflammation and injury appeared as early as day 1 after exposure, peaked on day 3, and ameliorated over time. However, even on day 42 post-exposure, the LDH activity and macrophage count were still higher than those in the control group, suggesting that Nano-CuO caused chronic lung inflammation. The Nano-CuO-induced pulmonary inflammation was further confirmed by H&E staining of lung sections. Trichrome staining showed that Nano-CuO exposure caused pulmonary fibrosis from day 14 to day 42 post-exposure with an increasing tendency over time. Increased hydroxyproline content and expression levels of fibrosis-associated proteins in mouse lungs were also observed. In addition, Nano-CuO exposure induced MMP-3 overexpression and increased MMP-3 secretion in mouse lungs. Knocking down MMP-3 in mouse lungs significantly attenuated Nano-CuO-induced acute and chronic lung inflammation and fibrosis. Moreover, Nano-CuO exposure caused sustained production of cleaved osteopontin (OPN) in mouse lungs, which was also significantly decreased by knocking down MMP-3. CONCLUSIONS: Our results demonstrated that short-term Nano-CuO exposure caused acute lung inflammation and injury, while long-term exposure induced chronic pulmonary inflammation and fibrosis. Knocking down MMP-3 significantly ameliorated Nano-CuO-induced pulmonary inflammation, injury, and fibrosis, and also attenuated Nano-CuO-induced cleaved OPN level. Our study suggests that MMP-3 may play important roles in Nano-CuO-induced pulmonary inflammation and fibrosis via cleavage of OPN and may provide a further understanding of the mechanisms underlying Nano-CuO-induced pulmonary toxicity.

Pulmonary osteoclast-like cells in silica induced pulmonary fibrosis.

The pathophysiology of silicosis is poorly understood, limiting development of therapies for those who have been exposed to the respirable particle. We explored mechanisms of silica-induced pulmonary fibrosis in human lung samples collected from patients with occupational exposure to silica and in a longitudinal mouse model of silicosis using multiple modalities including whole-lung single-cell RNA sequencing and histological, biochemical, and physiologic assessments. In addition to pulmonary inflammation and fibrosis, intratracheal silica challenge induced osteoclast-like differentiation of alveolar macrophages and recruited monocytes, driven by induction of the osteoclastogenic cytokine, receptor activator of nuclear factor κΒ ligand (RANKL) in pulmonary lymphocytes, and alveolar type II cells. Anti-RANKL monoclonal antibody treatment suppressed silica-induced osteoclast-like differentiation in the lung and attenuated pulmonary fibrosis. We conclude that silica induces differentiation of pulmonary osteoclast-like cells leading to progressive lung injury, likely due to sustained elaboration of bone-resorbing proteases and hydrochloric acid. Interrupting osteoclast-like differentiation may therefore constitute a promising avenue for moderating lung damage in silicosis.

Alveolar fibroblast lineage orchestrates lung inflammation and fibrosis.

Fibroblasts are present throughout the body and function to maintain tissue homeostasis. Recent studies have identified diverse fibroblast subsets in healthy and injured tissues1,2, but the origins and functional roles of injury-induced fibroblast lineages remain unclear. Here we show that lung-specialized alveolar fibroblasts take on multiple molecular states with distinct roles in facilitating responses to fibrotic lung injury. We generate a genetic tool that uniquely targets alveolar fibroblasts to demonstrate their role in providing niches for alveolar stem cells in homeostasis and show that loss of this niche leads to exaggerated responses to acute lung injury. Lineage tracing identifies alveolar fibroblasts as the dominant origin for multiple emergent fibroblast subsets sequentially driven by inflammatory and pro-fibrotic signals after injury. We identify similar, but not completely identical, fibroblast lineages in human pulmonary fibrosis. TGFß negatively regulates an inflammatory fibroblast subset that emerges early after injury and stimulates the differentiation into fibrotic fibroblasts to elicit intra-alveolar fibrosis. Blocking the induction of fibrotic fibroblasts in the alveolar fibroblast lineage abrogates fibrosis but exacerbates lung inflammation. These results demonstrate the multifaceted roles of the alveolar fibroblast lineage in maintaining normal alveolar homeostasis and orchestrating sequential responses to lung injury.

Procyanidin C1 inhibits bleomycin-induced pulmonary fibrosis in mice by selective clearance of senescent myofibroblasts.

Pulmonary fibrosis is a formidable challenge in chronic and age-related lung diseases. Myofibroblasts secrete large amounts of extracellular matrix and induce pro-repair responses during normal wound healing. Successful tissue repair results in termination of myofibroblast activity via apoptosis; however, some myofibroblasts exhibit a senescent phenotype and escape apoptosis, causing over-repair that is characterized by pathological fibrotic scarring. Therefore, the removal of senescent myofibroblasts using senolytics is an important method for the treatment of pulmonary fibrosis. Procyanidin C1 (PCC1) has recently been discovered as a senolytic compound with very low toxicity and few side effects. This study aimed to determine whether PCC1 could improve lung fibrosis by promoting apoptosis in senescent myofibroblasts and to investigate the mechanisms involved. The results showed that PCC1 attenuates bleomycin (BLM)-induced pulmonary fibrosis in mice. In addition, we found that PCC1 inhibited extracellular matrix deposition and promoted the apoptosis of senescent myofibroblasts by increasing PUMA expression and activating the BAX signaling pathway. Our findings represent a new method of pulmonary fibrosis management and emphasize the potential of PCC1 as a senotherapeutic agent for the treatment of pulmonary fibrosis, providing hope for patients with pulmonary fibrosis worldwide. Our results advance our understanding of age-related diseases and highlight the importance of addressing cellular senescence in treatment.

Transglutaminase 2 knockout mice are protected from bleomycin-induced lung fibrosis with preserved lung function and reduced metabolic derangements.

Pulmonary fibrosis is an interstitial scarring disease of the lung characterized by poor prognosis and limited treatment options. Tissue transglutaminase 2 (TG2) is believed to promote lung fibrosis by crosslinking extracellular matrix components and activating latent TGFß. This study assessed physiologic pulmonary function and metabolic alterations in the mouse bleomycin model with TG2 genetic deletion. TG2-deficient mice demonstrated attenuated the fibrosis and preservation of lung function, with significant reduction in elastance and increases in compliance and inspiratory capacity compared to control mice treated with bleomycin. Bleomycin induced metabolic changes in the mouse lung that were consistent with increased aerobic glycolysis, including increased expression of lactate dehydrogenase A and increased production of lactate, as well as increased glutamine, glutamate, and aspartate. TG2-deficient mice treated with bleomycin exhibited similar metabolic changes but with reduced magnitude. Our results demonstrate that TG2 is required for a typical fibrosis response to injury. In the absence of TG2, the fibrotic response is biochemically similar to wild-type, but lesions are smaller and lung function is preserved. We also show for the first time that profibrotic pathways of tissue stiffening and metabolic reprogramming are interconnected, and that metabolic disruptions in fibrosis go beyond glycolysis.

Lysophosphatidic acid receptor 1 inhibition: a potential treatment target for pulmonary fibrosis.

Lysophosphatidic acid (LPA)-mediated activation of LPA receptor 1 (LPAR1) contributes to the pathophysiology of fibrotic diseases such as idiopathic pulmonary fibrosis (IPF) and systemic sclerosis (SSc). These diseases are associated with high morbidity and mortality despite current treatment options. The LPA-producing enzyme autotaxin (ATX) and LPAR1 activation contribute to inflammation and mechanisms underlying fibrosis in preclinical fibrotic models. Additionally, elevated levels of LPA have been detected in bronchoalveolar lavage fluid from patients with IPF and in serum from patients with SSc. Thus, ATX and LPAR1 have gained considerable interest as pharmaceutical targets to combat fibrotic disease and inhibitors of these targets have been investigated in clinical trials for IPF and SSc. The goals of this review are to summarise the current literature on ATX and LPAR1 signalling in pulmonary fibrosis and to help differentiate the novel inhibitors in development. The mechanisms of action of ATX and LPAR1 inhibitors are described and preclinical studies and clinical trials of these agents are outlined. Because of their contribution to numerous physiologic events underlying fibrotic disease, ATX and LPAR1 inhibition presents a promising therapeutic strategy for IPF, SSc and other fibrotic diseases that may fulfil unmet needs of the current standard of care.

Biogenesis and Function of circRNAs in Pulmonary Fibrosis.

Pulmonary fibrosis is a class of fibrosing interstitial lung diseases caused by many pathogenic factors inside and outside the lung, with unknown mechanisms and without effective treatment. Therefore, a comprehensive understanding of the molecular mechanism implicated in pulmonary fibrosis pathogenesis is urgently needed to develop new and effective measures. Although circRNAs have been widely acknowledged as new contributors to the occurrence and development of diseases, only a small number of circRNAs have been functionally characterized in pulmonary fibrosis. Here, we systematically review the biogenesis and functions of circRNAs and focus on how circRNAs participate in pulmonary fibrogenesis by influencing various cell fates. Meanwhile, we analyze the current exploration of circRNAs as a diagnostic biomarker, vaccine, and therapeutic target in pulmonary fibrosis and objectively discuss the challenges of circRNA- based therapy for pulmonary fibrosis. We hope that the review of the implication of circRNAs will provide new insights into the development circRNA-based approaches to treat pulmonary fibrosis.

Simultaneous Positron Emission Tomography and Molecular Magnetic Resonance Imaging of Cardiopulmonary Fibrosis in a Mouse Model of Left Ventricular Dysfunction.

BACKGROUND: Aging-associated left ventricular dysfunction promotes cardiopulmonary fibrogenic remodeling, Group 2 pulmonary hypertension (PH), and right ventricular failure. At the time of diagnosis, cardiac function has declined, and cardiopulmonary fibrosis has often developed. Here, we sought to develop a molecular positron emission tomography (PET)-magnetic resonance imaging (MRI) protocol to detect both cardiopulmonary fibrosis and fibrotic disease activity in a left ventricular dysfunction model. METHODS AND RESULTS: Left ventricular dysfunction was induced by transverse aortic constriction (TAC) in 6-month-old senescence-accelerated prone mice, a subset of mice that received sham surgery. Three weeks after surgery, mice underwent simultaneous PET-MRI at 4.7 T. Collagen-targeted PET and fibrogenesis magnetic resonance (MR) probes were intravenously administered. PET signal was computed as myocardium- or lung-to-muscle ratio. Percent signal intensity increase and Δ lung-to-muscle ratio were computed from the pre-/postinjection magnetic resonance images. Elevated allysine in the heart (P=0.02) and lungs (P=0.17) of TAC mice corresponded to an increase in myocardial magnetic resonance imaging percent signal intensity increase (P<0.0001) and Δlung-to-muscle ratio (P<0.0001). Hydroxyproline in the heart (P<0.0001) and lungs (P<0.01) were elevated in TAC mice, which corresponded to an increase in heart (myocardium-to-muscle ratio, P=0.02) and lung (lung-to-muscle ratio, P<0.001) PET measurements. Pressure-volume loop and echocardiography demonstrated adverse left ventricular remodeling, function, and increased right ventricular systolic pressure in TAC mice. CONCLUSIONS: Administration of collagen-targeted PET and allysine-targeted MR probes led to elevated PET-magnetic resonance imaging signals in the myocardium and lungs of TAC mice. The study demonstrates the potential to detect fibrosis and fibrogenesis in cardiopulmonary disease through a dual molecular PET-magnetic resonance imaging protocol.

The role of quercetin in ameliorating bleomycin-induced pulmonary fibrosis: insights into autophagy and the SIRT1/AMPK signaling pathway.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a disease of unknown etiology characterized by a constant incidence rate. Unfortunately, effective pharmacological treatments for this condition are lacking and the identification of novel therapeutic approaches and underlying pathological mechanisms are required. This study investigated the potential of quercetin in alleviating pulmonary fibrosis by promoting autophagy and activation of the SIRT1/AMPK pathway. METHODS: Mouse models of IPF were divided into four treatment groups: control, bleomycin (BLM), quercetin (Q), and quercetin + EX-527 (Q + E) treatment. Pulmonary fibrosis was induced in the mouse models through intratracheal instillation of BLM. Various indexes were identified through histological staining, Western blotting analysis, enzyme-linked immunosorbent assay, immunohistochemistry, and transmission electron microscopy. RESULTS: Quercetin treatment ameliorated the pathology of BLM-induced pulmonary fibrosis of mice by reducing α-smooth muscle actin (α-SMA), collagen I (Col I), and collagen III (Col III) levels, and also improved the level of E-cadherin in lung tissue. Furthermore, Quercetin significantly enhanced LC3II/LC3I levels, decreased P62 expression, and increased the number of autophagosomes in lung tissue. These effects were accompanied by the activation of the SIRT1/AMPK pathway. Treatment with EX-527, an inhibitor for SIRT1, reversed all effects induced by quercetin. CONCLUSION: This study showed that quercetin could alleviate pulmonary fibrosis and improve epithelial-mesenchymal transition by acting on the SIRT1/AMPK signaling pathway, which may be achieved by regulating the level of autophagy.

Effects of a Hydrolyzed Lignin Derivative on Bleomycin-Induced Pulmonary Fibrosis in Mice.

Female C57BL/J mice with pulmonary fibrosis induced by injections of bleomycin (20 mg/kg intraperitoneally, 8 times for 4 weeks) were treated with a lignin derivative-based composition BP-C3 (80 mg/kg, daily intragastric administrations for 4 weeks). Bleomycin treatment increased the severity of pulmonary fibrosis (Ashcroft score increased from 1.43±0.20 to 4.17±0.48) and the percentage of α-SMA+ tissue (from 15.22±1.01 to 33.12±2.30%) and DNA-synthetizing nuclei (from 1.05±0.14 to 3.38±0.375). After treatment with BP-C3, we observed a tendency to a decrease in Ashcroft score (to 3.40±0.51) and a significant decrease in the percentage of α-SMA+ tissue to 24.30±1.70%; the percentage of DNA-synthetizing nuclei decreased to a lesser extent (to 3.03±0.22%). These results suggest that BP-C3 has a moderate antifibrotic activity.

Impaired GPX4 activity elicits ferroptosis in alveolar type II cells promoting PHMG-induced pulmonary fibrosis development.

Inhaling polyhexamethylene guanidine (PHMG) aerosol, a broad-spectrum disinfectant, can lead to severe pulmonary fibrosis. Ferroptosis, a form of programmed cell death triggered by iron-dependent lipid peroxidation, is believed to play a role in the chemical-induced pulmonary injury. This study aimed to investigate the mechanism of ferroptosis in the progression of PHMG-induced pulmonary fibrosis. C57BL/6 J mice and the alveolar type II cell line MLE-12 were used to evaluate the toxicity of PHMG in vivo and in vitro, respectively. The findings indicated that iron deposition was observed in PHMG induced pulmonary fibrosis mouse model and ferroptosis related genes have changed after 8 weeks PHMG exposure. Additionally, there were disturbances in the antioxidant system and mitochondrial damage in MLE-12 cells following a 12-hour treatment with PHMG. Furthermore, the study observed an increase in lipid peroxidation and a decrease in GPX4 activity in MLE-12 cells after exposure to PHMG. Moreover, pretreatment with the ferroptosis inhibitors Ferrostatin-1 (Fer-1) and Liproxstatin-1 (Lip-1) not only restored the antioxidant system and GPX4 activity but also mitigated lipid peroxidation. Current data exhibit the role of ferroptosis pathway in PHMG-induced pulmonary fibrosis and provide a potential target for future treatment.

Pulmonary fibrosis prevalence after adjuvant radiotherapy of Iranian patients with breast cancer: A single-center cross-sectional study.

AIMS: This study aims to investigate the incidence rate of pulmonary fibrosis as a late radiotherapy complication and identify the associated dosimetric and demographic factors using radiological findings between Iranian patients with breast cancer. METHODS AND MATERIAL: Breast cancer patients treated at the education hospital of Shohada-e Tajrish Hospital, Tehran, Iran, from 2017 to 2021 were considered. Patients have included for whom a secondary chest CT scan was available at least six months after radiotherapy. Dose-volume histogram (DVH) parameters of three-dimensional conformal radiotherapy (3D-CRT) treatment plans were exported. Demographic features and data on underlying lung diseases, diabetes, and smoking history were extracted. RESULTS: A total of 250 patients were included in the study with a mean age of 46.1 ± 7.5 yrs and a mean body mass index (BMI) of 24.5 ± 4.2 kg/m2. Pulmonary fibrosis was detected for sixty-two cases. A significant relationship was obtained between the ipsilateral lung DVH parameters of patients with pulmonary fibrosis (P value < 0.05). The V5Gy, V10Gy, V13Gy, V20Gy, V30Gy, MLD, and DMax for individuals with pulmonary fibrosis were significantly higher than those without this injury. CONCLUSIONS: Pulmonary fibrosis was distinguished for 25% of the breast cancer cases at least six months after adjuvant radiotherapy. A significant relationship between the DVH parameters, underlying lung disease, diabetes, radiotherapy fields (i.e., Breast + LN + SC or Breast/Chest-wall only), age, and BMI with the frequency of the ipsilateral pulmonary fibrosis was obtained. V13Gy and V30Gy of the ipsilateral lung may be the most predictor of pulmonary fibrosis incidence.

Immune mechanisms in fibrotic interstitial lung disease.

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