Search Results (627)

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease with limited therapeutic options and increasing global incidence, with a median survival of only 2–5 years. The clinical utility of macrophage polarization to regulate the progression of pulmonary fibrosis remains understudied. This study determined the efficacy of nintedanib and pexidartinib (PLX3397) combination therapy for treating IPF. Combination treatment effectively inhibited the progression of radiation-induced pulmonary fibrosis (RIPF) and prolonged survival in bleomycin-treated mice. Micro-CT analysis revealed a significant tissue repair efficacy. The therapy significantly normalized the abnormal vascular structure observed during RIPF and bleomycin-induced pulmonary fibrosis progression and was accompanied by a decrease in the M2 population. Polarized M1 macrophages enhanced normalized tube formation of irradiated endothelial cells (ECs) in vitro; M2 macrophages increased adhesion in irradiated ECs and abnormal tube formation. Single-cell RNA sequencing data from patients with IPF further supports colony stimulating factor (CSF) 1 upregulation in macrophages and downregulation of capillary EC markers. This study highlights a promising combination strategy to overcome the therapeutic limitations of monotherapy with nintedanib for the treatment of IPF. Full article

Idiopathic pulmonary fibrosis (IPF) is characterized by excessive extracellular matrix (ECM) deposition driven by aberrant fibroblast-to-myofibroblast transition (FMT). However, the upstream regulators and downstream effectors of this process remain incompletely understood. Here, we identify acyl-CoA synthetase long-chain family member 4 (ACSL4), a lipid metabolic enzyme, as a critical mediator linking complement component 5a (C5a)/C5a receptor 1 (C5aR1) signaling to FMT via calcium signaling. In bleomycin (BLM)-induced pulmonary fibrosis of C57BL/6JGpt mice, and in C5a-stimulated primary lung fibroblasts, the expression of ACSL4 was markedly upregulated. Pharmacological inhibition of ACSL4 (PRGL493) or C5aR1 (PMX53) attenuated the deposition of ECM and suppressed the expression of fibrotic markers in vivo and in vitro. Mechanistically, the activation of C5a/C5aR1 signaling increased intracellular calcium levels and promoted the expression of ACSL4, while inhibition of calcium signaling (FK506) reversed the upregulation of ACSL4 and FMT-related changes, including the expression of α-smooth muscle actin (αSMA) and the migration of fibroblasts. Notably, inhibition of ACSL4 did not affect the proliferation of fibroblasts, suggesting its specific role in phenotypic transition. These findings demonstrate that ACSL4 functions downstream of C5a/C5aR1-induced calcium signaling to promote FMT and the progression of pulmonary fibrosis. Targeting ACSL4 may therefore offer a novel therapeutic strategy for IPF. Full article

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrosing lung disease characterized by chronic inflammation, vascular remodeling, and immune dysregulation. COVID-19, caused by SARS-CoV-2, shares several systemic immunohematologic disturbances with IPF, including cytokine storms, endothelial injury, and prothrombotic states. Unlike general comparisons of viral infections and chronic lung disease, this review offers a focused analysis of the shared hematologic and immunologic mechanisms between COVID-19 and IPF. Our aim is to better understand how SARS-CoV-2 infection may worsen disease progression in IPF and identify converging pathophysiological pathways that may inform clinical management. We conducted a narrative synthesis of the peer-reviewed literature from PubMed, Scopus, and Web of Science, focusing on clinical, experimental, and pathological studies addressing immune and coagulation abnormalities in both COVID-19 and IPF. Both diseases exhibit significant overlap in inflammatory and fibrotic signaling, particularly via the TGF-β, IL-6, and TNF-α pathways. COVID-19 amplifies coagulation disturbances and endothelial dysfunction already present in IPF, promoting microvascular thrombosis and acute exacerbations. Myeloid cell overactivation, impaired lymphocyte responses, and fibroblast proliferation are central to this shared pathophysiology. These synergistic mechanisms may accelerate fibrosis and increase mortality risk in IPF patients infected with SARS-CoV-2. This review proposes an integrative framework for understanding the hematologic and immunologic convergence of COVID-19 and IPF. Such insights are essential for refining therapeutic targets, improving prognostic stratification, and guiding early interventions in this high-risk population. Full article

Objectives: COVID-19, caused by the SARS-CoV-2 virus, has infected over 777 million individuals and led to approximately 7 million deaths worldwide. Despite significant efforts to develop effective therapies, treatment remains largely supportive, especially for severe complications like acute respiratory distress syndrome (ARDS). Numerous compounds from diverse pharmacological classes are currently undergoing preclinical and clinical evaluation, targeting both the virus and the host immune response. Methods: Despite the large number of articles published and after a preliminary attempt was published, we discarded the option of a systematic review. Instead, we have done a description of therapies with these results and a tentative mechanism of action. Results: Preliminary studies and early-phase clinical trials have demonstrated the potential of Mesenchymal Stem Cells (MSCs) in mitigating severe lung damage in COVID-19 patients. Previous research has shown MSCs to be effective in treating various pulmonary conditions, including acute lung injury, idiopathic pulmonary fibrosis, ARDS, asthma, chronic obstructive pulmonary disease, and lung cancer. Their ability to reduce inflammation and promote tissue repair supports their potential role in managing COVID-19-related complications. This review demonstrates the utility of MSCs in the acute phase of COVID-19 and postulates the etiopathogenic role of mitochondria in Long-COVID. Even more, their combination with other therapies is also analyzed. Conclusions: While the therapeutic application of MSCs in COVID-19 is still in early stages, emerging evidence suggests promising outcomes. As research advances, MSCs may become an integral part of treatment strategies for severe COVID-19, particularly in addressing immune-related lung injury and promoting recovery. However, a full pathogenic mechanism may explain or unify the complexity of signs and symptoms of Long COVID and Post-Acute Sequelae (PASC). Full article

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive interstitial lung disease associated with high morbidity and mortality. Both pulmonary and extrapulmonary comorbidities significantly influence disease progression and patient outcomes. Despite current therapeutic options, effective treatments remain limited. Quercetin, a naturally occurring flavonoid, has emerged as a promising compound due to its antioxidant, anti-inflammatory, and antifibrotic properties. Preclinical and clinical studies have demonstrated its ability to modulate key molecular pathways involved in IPF, including Nrf2, SIRT1/AMPK, and the regulation of fibrosis-associated microRNAs (miRNAs). Furthermore, quercetin shows therapeutic potential across a range of IPF-related comorbidities, including chronic obstructive pulmonary disease, pulmonary hypertension, lung cancer, cardiovascular disease, diabetes, and psychiatric disorders. Under these conditions, quercetin acts via epigenetic modulation of miRNAs and regulation of oxidative stress and inflammatory signaling pathways. This review highlights the multifunctional role of quercetin in IPF and its comorbidities, emphasizing its gene regulatory mechanisms and potential as an adjunctive or alternative therapeutic strategy. Full article

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disorder characterized by excessive scarring of lung tissue, predominantly affecting middle-aged and elderly populations. Oxidative stress plays a pivotal role in the pathogenesis of pulmonary fibrosis, disrupting redox homeostasis and driving fibrotic progression. Glutathione reductase (GSR), a key antioxidant enzyme, is essential for maintaining cellular glutathione (GSH) levels and mitigating oxidative damage. However, the specific involvement of GSR in IPF remains poorly understood. This study found that GSR levels were downregulated in IPF patients and mice treated with bleomycin (BLM). GSR knockdown enhanced epithelial-to-mesenchymal transition (EMT) in A549 cells and promoted the activation of MRC5 cells. Additionally, GSR depletion promoted cellular migration and senescence in both A549 and MRC5 cells. Mechanistically, silencing GSR in A549 and MRC5 cells led to a marked reduction in intracellular GSH levels, resulting in elevated reactive oxygen species (ROS) accumulation, thereby promoting the activation of the TGF-β/Smad2 signaling pathway. In conclusion, our findings demonstrate that GSR deficiency aggravates pulmonary fibrosis by impairing antioxidant defense mechanisms, promoting EMT, and activating fibroblasts through the TGF-β/Smad2 signaling. These findings suggest that GSR may be essential in reducing the fibrotic progression of IPF. Full article

The neutrophil-to-lymphocyte ratio (NLR) is a simple, inexpensive and easily accessible inflammatory biomarker that reflects the balance between innate and adaptive immunity. In recent years, NLR has emerged as a potential prognostic and disease severity marker for different diseases, including idiopathic pulmonary fibrosis (IPF), a progressive and fatal interstitial lung disease with a highly variable course and poor prognosis. Several studies have highlighted that NLR can be associated with several clinical outcomes such as lung function decline, increased risk of hospitalization, acute exacerbation of IPF, and mortality over time. It might also correlate with overall survival in the course of antifibrotic therapy and validated prognostic score as a gender–age–physiology score. Despite these findings, the clinical use of NLR remains limited due to its non-specific nature, the lack of standardized cut-off values, and high variability related to demographic factors, comorbidities and medications. Hence, NLR may display the underlying immune dysregulation in IPF and could be exploited as a non-invasive tool for risk stratification and disease monitoring. Further studies are needed to confirm and validate its use in IPF and to establish reliable cut-off values in clinical applications. Full article

Interstitial pneumonia is a general term for diseases in which inflammation occurs mainly in the interstitium of the lung. It is also pointed out that interstitial pneumonia reduces alveolar function and makes it difficult to take in oxygen through inspiration, causing symptoms such as dyspnea and coughing, which may eventually lead to respiratory failure. At present, there is no effective treatment, and only conservative treatment exists. This time, we report that the therapeutic effect was confirmed in patients with interstitial pneumonia who took platinum palladium. In this case, improvement tendencies were observed in patients with Idiopathic pulmonary fibrosis (IPF), but improvement tendencies were also observed in many other lung diseases. In order to explore the mechanism, AMPK was measured at the in vitro level, and blood KL-6 and hydrogen peroxide levels in the patient were measured at the in vivo level. AMPK values were significantly elevated by more than 800%, and KL-6 and hydrogen peroxide levels were also significantly decreased by drinking platinum palladium. Platinum palladium exhibits a strong antioxidant effect and is the only substance in the world that can approach all four types of active oxygen. In addition, when it was actually administered to patients, there were cases of dramatic improvement, and it was confirmed that KL-6, a parameter of lung function, decreased in 16 out of 32 patients, and furthermore, oxygen inhalation was completed. Patients were also seen. It was suggested that increasing the number of cases in the future may help improve interstitial pneumonia. Full article

Emerging evidence suggests a significant association between monocytes and the pathophysiology and prognosis of idiopathic pulmonary fibrosis (IPF). This review aims to systematically evaluate current knowledge regarding blood monocyte counts and their relationship with the etiology, progression, and prognosis of IPF. We conducted a systematic search in the PubMed database for articles published through 17 February 2025, using the MeSH terms “lung diseases, interstitial” and “monocytes,” which yielded 314 results. After filtering for full-text articles in English (n = 242), we included only studies focusing on blood monocyte counts with clinical implications in IPF. Articles relating to other cell types or non-IPF lung diseases were excluded. Our systematic search identified 12 relevant articles. Monocytes play an essential role in regulating inflammatory responses and resolution across multiple diseases, with established but incompletely understood contributions to lung fibrosis development in IPF. Correlations have been demonstrated between elevated blood monocyte counts and the following: (1) the presence and progression of interstitial lung abnormalities, (2) the progression from an indeterminate usual interstitial pneumonia (UIP) pattern on CT scans to definitive IPF, and (3) worse lung function parameters, an increased risk of acute exacerbations, and reduced overall survival in IPF patients. Monocytes serve as critical orchestrators throughout IPF’s natural history—from early interstitial changes to disease progression and acute exacerbations. Targeting monocyte recruitment pathways and reprogramming their differentiation represents a promising therapeutic approach, while circulating monocyte counts offer potential as accessible biomarkers for disease progression and treatment response. Future research should characterize stage-specific monocyte phenotypes to enable precision-targeted interventions. Full article

Background and Objectives: Idiopathic pulmonary fibrosis (IPF) is a specific form of chronic, progressive interstitial lung disease with an unknown etiology. It is often accompanied by skeletal muscle mass loss. Chest wall muscles play a crucial role in respiratory movements and form part of the skeletal muscles. The aim of this study is to evaluate the relationship between chest wall muscle thickness and pulmonary function test (PFT) results, as well as other prognostic markers, in patients with IPF. Materials and Methods: A retrospective analysis was conducted on 108 patients diagnosed with IPF and 53 control subjects. Chest wall muscle thickness was measured on thoracic computed tomography (CT) images at specific anatomical levels. PFT parameters, the Gender-Age-Physiology (GAP) index, number of acute exacerbations, and mortality data were evaluated in relation to muscle thickness. Results: IPF patients had significantly reduced thickness in the bilateral external scapular muscles at both the aortic and pulmonary trunk levels compared to controls. Bilateral pectoral muscle thickness at the aortic level was positively correlated with forced vital capacity (FVC) and negatively correlated with the number of exacerbations. Internal scapular muscle thickness at the aortic level showed a significant positive correlation with diffusion capacity of the lung for carbon monoxide (DLCO) and a negative correlation with both GAP scores and exacerbation frequency. External scapular muscle thickness at the pulmonary trunk level was positively associated with PFT parameters and inversely correlated with the GAP index, exacerbations, and mortality. Conclusions: In patients with IPF, the bilateral external scapular muscle thickness at the aortic and pulmonary trunk levels was significantly reduced compared to controls. Significant associations were found between some chest wall muscle thicknesses and the GAP index, pulmonary function, acute exacerbations, and mortality, underscoring the prognostic value of baseline muscle measurements. Measurement of chest wall muscle thickness using routine thoracic CT scans may offer additional prognostic value in IPF. Incorporating this parameter into clinical evaluation may help identify patients who could benefit from supportive interventions, such as nutritional therapy or pulmonary rehabilitation. Full article

The uncontrolled fibrosis of lung tissue can lead to premature death in patients suffering from idiopathic pulmonary fibrosis (IPF), and it complicates the course of chronic obstructive pulmonary disease (COPD) and emphysema. It is also a risk factor for developing lung cancer. Antifibrotic drugs, such as nantedanib and pirfenidone, are able to slow down the progression of pulmonary fibrosis, but more effective treatment is still needed to reverse it. Studies on the pathogenesis of tissue fibrosis have demonstrated that integrins play a crucial role affecting the development of pulmonary fibrosis, for example, by activating transforming growth factor-β (TGF-β). Taking the above into consideration, targeting specific integrins could offer promising opportunities for managing fibroplastic changes in lung tissue. Integrins are a type of transmembrane molecule that mediate interactions between cells and extracellular matrix (ECM) molecules. This review discusses the role of integrins in the pathogeneses of respiratory diseases and carcinogenesis, as well as presents promising approaches to the drug therapy of pulmonary fibrosis of various etiologies based on integrin inhibition. Full article

Background and Objectives: Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease with limited therapeutic options. Current therapies (pirfenidone, nintedanib) exhibit modest efficacy and significant side effects, underscoring the need for novel strategies targeting early pathogenic drivers. Saroglitazar (SGZ), a dual PPARα/γ agonist with anti-inflammatory properties approved for diabetic dyslipidemia, has not been explored for IPF. We aimed to investigate SGZ’s therapeutic potential in pulmonary fibrosis and elucidate its mechanisms of action. Materials and Methods: Using a bleomycin (BLM)-induced murine pulmonary fibrosis model, we administered SGZ therapeutically. A histopathological assessment (H&E, Masson’s trichrome, collagen I immunofluorescence), Western blotting, and qRT-PCR analyzed the fibrosis progression and inflammatory markers. Flow cytometry evaluated the macrophage polarization. In vitro studies used RAW264.7 macrophages stimulated with BLM/LPS and MRC-5 fibroblast co-cultures. The NF-κB/NLRP3 pathway activation was assessed through protein and gene expression. Results: SGZ significantly attenuated BLM-induced histopathological hallmarks, including alveolar wall thickening, collagen deposition, and inflammatory infiltration. Fibrotic markers (OPN, α-SMA) and pro-inflammatory cytokines (IL-1β, TNF-α, IL-6) were downregulated in the SGZ-treated mice. Mechanistically, SGZ suppressed the M1 macrophage polarization (reduced CD86⁺ populations) and inhibited the NF-κB/NLRP3 pathway activation in the alveolar macrophages. In the RAW264.7 cells, SGZ decreased the NLRP3 inflammasome components (ASC, cleaved IL-1β) and cytokine secretion. Co-cultures demonstrated that the SGZ-treated macrophage supernatants suppressed the fibroblast activation (α-SMA, collagen I) in MRC-5 cells. Conclusions: SGZ attenuates pulmonary fibrosis by suppressing macrophage-driven inflammation via NF-κB/NLRP3 inhibition and disrupting the macrophage–fibroblast crosstalk. These findings nominate SGZ as a promising candidate for preclinical optimization and future clinical evaluation in IPF. Full article

Growth Differentiation Factor 15 (GDF15), also known as non-steroidal anti-inflammatory drug-activated gene-1 (NAG-1) or macrophage inhibitory cytokine 1 (MIC-1), is a stress- and inflammation-induced cytokine distantly related to the TGF-β superfamily. Its highly elevated levels showed close association with various pathological conditions, making it an emerging biomarker of disease prognosis. However, most GDF15-mediated effects under normal physiology and various pathological conditions are poorly understood. This is partly because the only known GDF15 receptor is exclusively localized in the brain, and how GDF15 functions peripherally is currently unknown. Mounting recent evidence has shown GDF15’s critical role in fibrosis in multiple organs, such as the liver, lung, and kidney. Evidence further suggests that it can either contribute to fibrosis by promoting inflammation and fibroblast activation or confer protective effects by modulating the immune response and mitigating fibrosis severity. Thus, the exact role of GDF15 in fibrosis can vary depending on the organ involved and the specific disease context. For example, increased GDF15 in idiopathic pulmonary fibrosis (IPF) promotes fibrosis via fibroblast activation and collagen deposition. Conversely, GDF15 might have a protective role in liver fibrosis, with decreased GDF15 levels causing increased fibrosis severity, while GDF15 treatment ameliorates fibrosis. Due to its close association with fibrosis, GDF15 is being investigated as a potential biomarker for disease severity and monitoring treatment response. However, further research unraveling its mechanisms of action is needed to explore the potential of GDF15 as a therapeutic target for treating fibrosis, either by modulating its expression or utilizing its immunomodulatory properties. This review marshals the limited studies addressing the recently appreciated differential role of GDF15 in regulating the fibrotic process in different organs. The review also discusses the aspects of further research needed to highlight GDF 15 as a novel predictor and therapeutic target for fibrosis in different organs. Full article

Progressive fibrosing interstitial lung disease (PF-ILD) is a significant complication of connective tissue diseases (CTDs), particularly in systemic sclerosis (SSc), rheumatoid arthritis (RA), and idiopathic inflammatory myopathies (IIM). Despite clinical similarities with idiopathic pulmonary fibrosis (IPF), CTD-associated ILDs exhibit distinct pathogenetic and immunologic features. Objective: This review aims to summarize key predictive biomarkers and current treatment strategies associated with the progressive fibrosing phenotype in SSc-ILD, RA-ILD, and IIM-ILD. Methods: We conducted a focused literature search of PubMed and Scopus databases covering publications from January 2010 to February 2024. Included studies evaluated serum, cellular, or genetic biomarkers with predictive value for disease progression or treatment response. Only peer-reviewed English-language articles were included. Exclusion criteria encompassed single case reports and editorials. Results: Several biomarkers, including KL-6, SP-D, CXCL4, and anti-MDA5, demonstrate potential in predicting fibrotic progression in CTD-ILDs. However, variability in sensitivity and specificity across CTD subtypes limits broad clinical applicability. Therapeutic agents such as nintedanib and pirfenidone show efficacy in slowing lung function decline. Biologics including rituximab and tocilizumab offer additional options, particularly in immunologically active diseases. Conclusion: Although promising biomarkers and therapies are emerging, no single marker or intervention currently predicts or modifies PF-ILD outcomes across all CTD subsets. Prospective studies and integrative biomarker panels are needed to improve patient stratification and guide therapy. Full article

Background/Objectives: This study aims to distinguish radiological differences between primary idiopathic Usual Interstitial Pneumonia (UIP) and secondary UIP patterns Methods: This retrospective study included patients with HRCT findings consistent with a UIP pattern. Final diagnoses were established via multidisciplinary discussion and classified as primary UIP/IPF or secondary UIP, following the 2022 ATS/ERS/JRS/ALAT guidelines. An expert thoracic radiologist (>10 years of experience), blinded to clinical data, reviewed the earliest available HRCT assessing key imaging features: honeycombing (micro-, macro- or exuberant), fibrosis distribution (symmetry, anterior-upper lobe sign, etc.), ground-glass opacities (GGO), dilatation of esophagus. Additionally, AI software AVIEW Build 1.1.46.28-win Coreline (©Coreline Soft Co., Ltd. All Rights Reserved). performed lung texture analysis, quantifying total lung volume and radiological patterns. Statistical analysis was performed to reveal results. Results: Among 53 cases, 31 were classified as IPF and 22 as secondary UIP cases. The expert radiologist achieved a diagnostic sensitivity of 82.9%, specificity of 889%, with a positive predictive value of 93.5%—in distinguishing between primary and secondary UIP. Primary UIP cases exhibited typical hallmark radiological features, including uniform honeycombing with cranio-caudal distribution (90.3%). Reticulations contributed significantly to the fibrotic texture, maintaining a consistent cranio-caudal gradient and axial symmetry (84.8%). Secondary UIP displayed more significant radiological heterogeneity, including patchy fibrosis with irregular GGO distribution (84.5% versus 53.33%); other findings—such as exuberant honeycombing, four corner sign and wedge-shaped fibrosis—were mainly observed in secondary pattern with respective percentages of 31.8%, 9% and 49%. Conclusions: Experienced thoracic radiologists, leveraging hallmark imaging features, play a critical role in improving diagnostic accuracy between primary and secondary UIP patterns. Full article