Search Results (164)

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

This study aimed to investigate the tyrosine kinase inhibitor Nintedanib and its potential role in reversing epithelial–mesenchymal transition (EMT) induced by transforming growth factor beta 2 (TGF-β2) in retinal pigment epithelial (RPE) cells, along with its therapeutic potential using a mouse model of subretinal fibrosis. We hypothesized that the blockade of angiogenesis promoting and fibrosis inducing signaling using the receptor tyrosine kinase inhibitor Nintedanib (OfevTM) can prevent or reverse EMT both in vitro and in our in vivo model of subretinal fibrosis. Primary human retinal pigment epithelial cells (phRPE) and adult retinal pigment epithelial cell line (ARPE-19) cells were treated with TGF-β210 ng/mL for two days followed by four days of Nintedanib (1 µM) incubation. Epithelial and mesenchymal phenotypes were assessed by morphological examination, quantitative real-time polymerase chain reaction(qPCR) (ZO-1, Acta2, FN, and Vim), and immunocytochemistry (ZO-1, vimentin, fibronectin, and αSMA). Metabolites were measured using luciferase-based assays. Extracellular acidification and oxygen consumption rates were measured using the Seahorse XF system. Metabolic-related genes (GLUT1, HK2, PFKFB3, CS, LDHA, LDHB) were evaluated by qPCR. A model of subretinal fibrosis using the two-stage laser-induced method in C57BL/6J mice assessed Nintedanib’s therapeutic potential. Fibro-vascular lesions were examined 10 days later via fluorescence angiography and immunohistochemistry. Both primary and ARPE-19 RPE stimulated with TGF-β2 upregulated expression of fibronectin, αSMA, and vimentin, and downregulation of ZO-1, consistent with morphological changes (i.e., elongation). Glucose consumption, lactate production, and glycolytic reserve were significantly increased in TGF-β2-treated cells, with upregulation of glycolysis-related genes (GLUT1, HK2, PFKFB3, CS). Nintedanib treatment reversed TGF-β2-induced EMT signatures, down-regulated glycolytic-related genes, and normalized glycolysis. Nintedanib intravitreal injection significantly reduced collagen-1+ fibrotic lesion size and Isolectin B4+ neovascularization and reduced vascular leakage in the two-stage laser-induced model of subretinal fibrosis. Nintedanib can induce Mesenchymal-to-Epithelial Transition (MET) in RPE cells and reduce subretinal fibrosis through metabolic reprogramming. Nintedanib can therefore potentially be repurposed to treat retinal fibrosis. Full article

Mycobacterium tuberculosis—an acid-fast staining bacterium—is a serious global health challenge that can have both short-term and long-term complications. Although the immune response helps trap the infection, it can also cause necrosis and calcification, leading to lung tissue damage. Calcification is a known outcome of chronic granuloma evolution in TB. Multiple pathways contribute to fibrosis and calcification; some examples are IL-1β, TGF-β, and TNF-α. Current antifibrotic drugs, such as nintedanib and pirfenidone, are effective but may increase the risk of latent tuberculosis reactivation in certain patients. Experimental therapies such as artemisinin derivatives have shown promise in preclinical TB fibrosis models, while cell-based therapies like bone marrow-derived mononuclear cells are also under early investigation for dual antifibrotic and immunomodulatory effects. This literature review will explore recent studies on the pathogenesis of M. tuberculosis, the mechanisms underlying calcification in granuloma formation, and subsequent complications of the disease process. 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

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: Interstitial lung disease (ILD) is a prominent complication in the course of rheumatoid arthritis (RA), with a prevalence ranging from 5% to 60% and several phenotypes. The existing knowledge on the impact of different pharmacological interventions in individuals with rheumatoid arthritis-related interstitial lung disease (RA-ILD) is inconclusive, and this variable response to treatment highlights the need for a personalized approach to the management of RA-associated ILD. Therefore, we aimed to evaluate the therapeutic effect and safety of different pharmacological agents, including conventional synthetic DMARDs (Cs DMARDs), biologic DMARDs (bDMARDs), targeted synthetic DMARDs (Ts DMARDs), and antifibrotic agents, in patients with RA-ILD. Method: This systematic review and meta-analysis searched for available randomized controlled trials (RCTs) and prospective cohort studies. A search was performed in the PubMed, Google Scholar, and Cochrane Central Register of Controlled Trials (CENTRAL) databases. Eligible studies comprised those involving hospitalized patients diagnosed with RA-ILD, regardless of concomitant medications, who were of adult age (≥18 years); the studies measured the effect of pharmacological interventions, including methotrexate, leflunomide, tumor necrosis factor inhibitors (anti-TNF), abatacept, rituximab, JAK inhibitors, and antifibrotic agents, compared to placebo or other therapies for RA. Results: Out of 446 studies from 2002 to 2024, only 16 were included in this systematic review, including 14 prospective cohort studies and 2 placebo-controlled studies. Unfortunately, no RCTs were found that address our research question. The most relevant studies (n = 4) were performed in different countries (mainly Spain and the UK), with sample sizes varying from 23 to 381 patients (total: 2199 patients). The current study reveals that non-anti-TNF biologics were associated with a decreased risk of radiologic progression, while advanced therapies improved disease-related outcomes in patients requiring oxygen therapy. Methotrexate and other DMARDs were found to have inconsistent effects on ILD progression and mortality. Conclusions: Our review supports the integration of personalized medicine into the management of RA-ILD. By considering patient-specific factors and therapeutic responses, clinicians can better tailor interventions. We confirmed the high methodological quality of the trials, yielding solid evidence for the clinical management of RA-ILD. This review adds to the existing literature by identifying nintedanib as a potential disease-modifying therapy with the potential to slow the progression of lung disease. Full article

Background: Idiopathic pulmonary fibrosis (IPF) and progressive pulmonary fibrosis (PPF) are chronic conditions often accompanied by a prothrombotic state. Antifibrotic therapies, including nintedanib and pirfenidone, have demonstrated efficacy in slowing disease progression. Despite the known interactions between coagulation pathways and fibrotic processes, there is a lack of data in the literature on the safety of the concomitant use of anticoagulants and antifibrotics. Objectives: This study aimed to evaluate the safety and clinical impact of combining antifibrotics and anticoagulants in patients with IPF or PPF. A single-center, retrospective study was conducted on 137 patients diagnosed with IPF or PPF, 25 of whom were on concurrent anticoagulant therapy (AC+). Baseline demographics, pulmonary function tests (PFTs), bleeding risk scores (HAS-BLED, RIETE), and clinical outcomes were analyzed over a 12-month follow-up period. Methods: Statistical analyses included t-tests, χ² tests, Kaplan–Meier survival analysis, and multivariate logistic regression. Results: Two clinically relevant bleeding events were observed, with one in the AC+ group. No major bleeding episodes occurred in either group. Baseline forced vital capacity (FVC) was lower in the AC+ group (73.4 ± 16.9% vs. 83.0 ± 21.9%; p = 0.04), but no significant differences were observed in FVC, forced expiratory volume (FEV1), or diffusing capacity for carbon monoxide (DLCO) at 6 and 12 months. Survival rates and radiological progression were comparable between groups. Multivariate analysis revealed that DLCO was an independent predictor of mortality (HR 0.84; p = 0.005), while anticoagulant use was not. Conclusions: The concomitant use of antifibrotics and anticoagulants appears safe, with no significant increase in bleeding risk or adverse effects on disease progression. Future prospective studies are required to confirm these findings and explore the long-term impact of this therapeutic combination. Full article

Pulmonary fibrosis (PF) is a progressive and fatal interstitial lung disease characterized by chronic epithelial injury and excessive deposition of extracellular matrix (ECM) driven by dysregulated repair. Increasing evidence has shown that epithelial cell dysfunction plays a key role in PF, involving epithelial–mesenchymal transition (EMT), chronic oxidative stress, disruption of epithelial–immune interactions, and promoting pathological remodeling. Single-cell analyses have identified functionally distinct subpopulations of type 2 alveolar (AT2) cells with pro-fibrotic potential. Epithelial cells exhibit metabolic and epigenetic alterations during PF, which provide new approaches for therapeutic targets. This review summarizes the molecular mechanisms driving epithelial dysfunction in fibrosis progression, with a focus on key regulatory pathways, including transforming growth factor-beta (TGF-β), Wnt, and Notch signaling pathways, as well as miRNA-mediated networks. We also explored emerging epithelial-targeted therapies, ranging from FDA-approved agents (pirfenidone, nintedanib) to experimental inhibitors targeting Galectin-3 and Wnt/β-catenin, providing insights into precision anti-fibrosis strategies for clinical translation. Full article

Alveolar macrophages (AM) must perform three seemingly opposing roles including homeostasis, driving inflammation, and facilitating tissue repair. Whilst there is now consensus (supported by a large body of human single cell RNA sequencing (scRNA-seq) data) that the cell subsets that perform these tasks can readily be found based on their transcriptome, their ontogeny has remained unclear. Moreover, there is agreement that in all types of pulmonary fibrosis (PF) there is an expanded population of profibrotic AM that may aberrantly drive PF. From a therapeutic viewpoint, there is great appeal in the notion that the transcriptional program in different AM subsets is not fixed but remains plastic and amenable to pharmacological reprogramming. Accordingly, this study addresses this question by performing scRNA-seq on human AM following treatment with drugs or perturbagens including pioglitazone, trametinib, nintedanib, lipopolysaccharide and the natural compound endiandrin A. Each treatment induced a unique global transcriptional change, driving the cells towards distinct subsets, further supported by trajectory analysis, confirming a high level of plasticity. Confirmatory experiments using qPCR demonstrated that single exposure to a compound induced a relatively stable transcriptome, whereas serial exposure to a different compound allowed the cells to be reprogrammed yet again to a different phenotype. These findings add new insight into the biology of AM and support the development of novel therapies to treat PF. Full article

Background: Juvenile scleroderma (JS) comprises a group of rare chronic autoimmune and fibrosing disorders in children, primarily presenting as juvenile localized scleroderma (jLS) or juvenile systemic sclerosis (jSS). While jLS predominantly affects the skin and subcutaneous tissues, jSS may involve multiple internal organs and is associated with increased morbidity and mortality. Due to the scarcity of pediatric-specific clinical trials, the current treatment strategies are largely empirical and often adapted from adult protocols. Objective: This narrative review aims to provide a comprehensive update on emerging systemic therapies for juvenile scleroderma, focusing on biologics, small molecule inhibitors, and advanced cellular interventions, to support the development of more personalized and effective pediatric treatment approaches. Methods: A literature search was conducted through PubMed and a manual bibliographic review, covering publications from 2001 to 2024. Only English-language studies involving pediatric populations were included, comprising randomized controlled trials, reviews, and case reports. Additional searches were performed for drugs that are specifically used in juvenile scleroderma. Results: Biologic agents such as tocilizumab, rituximab, and abatacept, along with small molecules including Janus kinase (JAK) inhibitors and imatinib, have demonstrated potential in managing refractory cases by reducing skin fibrosis and pulmonary involvement. Novel approaches—such as pamrevlumab, nintedanib, and chimeric antigen receptor (CAR-T) cell therapy—target fibrotic and autoimmune pathways but remain investigational in children. Autologous stem cell transplantation (ASCT) has also been explored in severe, treatment-resistant cases, although data are extremely limited. The overall evidence base is constrained by small sample sizes, a lack of controlled pediatric trials, and reliance on adult extrapolation. Conclusions: While innovative systemic therapies show promise for juvenile scleroderma, their widespread clinical application remains limited by insufficient pediatric-specific evidence. Large, multicenter, long-term trials are urgently needed to establish safety, efficacy, and optimal treatment algorithms that are tailored to the pediatric population. Full article

Great progress has been made in the treatment of pulmonary arterial hypertension (WHO group 1 PAH) over the past two decades, which has significantly improved the morbidity and mortality in this patient population. Likewise, the more recent availability of antifibrotic medications for interstitial lung disease (ILD) have also been effective in slowing down the progression of disease. There is no known cure for either of these disease states. When this combination coexists, treatment can be challenging. Interstitial lung disease is a heterogenous group of chronic inflammatory and/or fibrotic parenchymal lung disorders. A subset of patients with ILD, not related to connective tissue disease, can initially present with inflammatory-predominant disease which progresses to irreversible fibrosis. This population of patients is also at risk for developing pulmonary hypertension (PH) or World Health Organization (WHO) group 3 PH. This coexistence of ILD and PH is associated with early morbidity and mortality. The early identification, diagnosis, and treatment of this combination of ILD and PH is vital. Medications available for both ILD and PH require an individualized approach with the intention of slowing down disease progression. Referral to expert centers for clinical trials and transplant evaluation is recommended. The combination of PH-ILD can be challenging to diagnose and treat effectively. Patients require a thorough clinical evaluation to enable the most accurate diagnosis. A vital part of that evaluation is the early recognition of PH. Medications can help improve disease progression along with clinical trials that will further improve our gaps in knowledge. Full article

This paper investigates the ability of our selective small molecule TG2 inhibitor 1-155 in reducing fibrosis in a bleomycin-induced pulmonary fibrosis mouse model. Formulated as a fine stable suspension, 1-155 was delivered intranasally (IN) at 3 mg/kg via IN delivery once daily. It significantly inhibited collagen deposition in the lungs in the bleomycin-challenged mice. Compared to its vehicle control treatment, a significant reduction in a key myofibroblast marker α smooth muscle actin and TG2 was also detected in the 1-155-treated animals. Most importantly, 1-155 treatment significantly improved several key lung function parameters, such as cord compliance, vital capacity, and dynamic compliance, which are comparable to that found for the positive control nintedanib at a much higher dosage of 60 mg/kg twice daily via oral delivery. The 1-155-treated mice showed a trend in improvement of average body weight. For the first time, our study demonstrates the effectiveness of a selective small molecule TG2 inhibitor in reducing pulmonary fibrosis in a pre-clinical model. Importantly, we were able to correlate this effect of 1-155 with the improvement of animal lung function showing the potential of the use of TG2 inhibitors as a therapeutic treatment for fibrotic lung conditions like IPF. Full article

Idiopathic pulmonary fibrosis (IPF) is a progressive and incurable chronic interstitial lung disease characterized by excessive fibrosis and impaired lung function. Current treatments, such as pirfenidone and nintedanib, slow disease progression but fail to halt or reverse fibrosis, highlighting the need for novel approaches. Activin A, which belongs to the TGF-β superfamily, is implicated in various fibrosis-related mechanisms, including epithelial–mesenchymal transition (EMT), a process where epithelial cells acquire mesenchymal characteristics, and fibroblast–myofibroblast transformation (FMT), in which fibroblasts differentiate into contractile myofibroblasts. It also promotes inflammatory cytokine release and extracellular matrix buildup. This study aimed to inhibit Activin A activity using synthetic peptides identified through phage display screening. Of the ten peptides isolated, A7, B9, and E10 demonstrated high binding affinity and inhibitory activity. Computational modeling confirmed that these peptides target the receptor-binding domain of Activin A, with peptide E10 exhibiting superior efficacy. Functional assays showed that E10 reduced cell migration, inhibited EMT in A549 cells, and suppressed FMT in fibroblast cultures, even under pro-fibrotic stimulation with TGF-β. These findings underscore the therapeutic potential of targeting Activin A with synthetic peptides, offering a promising avenue for IPF treatment and expanding the arsenal of anti-fibrotic strategies. Full article

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease of unknown aetiology. Evidence on the progression of idiopathic pulmonary fibrosis (IPF) following the introduction of antifibrotic therapies still indicates a generally poor prognosis. IPF is associated with both respiratory and non-respiratory comorbidities, which can worsen symptoms and impact overall survival. Background/Objectives: The study aimed to investigate the effect of these comorbidities on the early and permanent discontinuation of pirfenidone or nintedanib in IPF patients. Methods: In this single-centre retrospective study, 101 patients diagnosed with IPF according to ATS/ERS/JRS/ALAT guidelines were treated with AFT. Clinical data were collected at 12 months prior to and up to 24 months following treatment initiation, including age, gender, smoking history, and the presence of respiratory and non-respiratory comorbidities. Results: The data showed that 21 patients (20.8%) discontinued treatment within the first 12 months. Additionally, pre-treatment comorbidities were not statistically correlated with the suspension of antifibrotic treatment. Among the overall cohort, 77 patients (76.2%) had at least one comorbidity and 27 (26.7%) had three or more comorbidities. Notably, 24 (23.8%) had respiratory comorbidities, while 75 (74.3%) had non-respiratory comorbidities. Conclusions: This real-life study emphasises the complexities involved in managing IPF, particularly regarding adherence to treatment when significant comorbidities are present. The evidence suggests that in patients with IPF, pre-treatment respiratory or non-respiratory conditions do not affect AFT discontinuation. Full article

Filtration bleb (FB) fibrosis represents the primary risk factor for glaucoma filtration surgery (GFS) failure. We reviewed the most recent literature on post-GFS fibrosis in humans, focusing on novel molecular pathways and antifibrotic treatments. Three main literature searches were conducted. First, we performed a narrative review of two models of extra-ocular fibrosis, idiopathic pulmonary fibrosis and skin fibrosis, to improve the comprehension of ocular fibrosis. Second, we conducted a systematic review of failed FB features in the PubMed, Embase, and Cochrane Library databases. Selected studies were screened based on the functional state and morphological features of FB. Third, we carried out a narrative review of novel potential antifibrotic molecules. In the systematic review, 11 studies met the criteria for analysis. Immunohistochemistry and genomics deemed SPARC and transglutaminases to be important for tissue remodeling and attributed pivotal roles to TGFβ and M2c macrophages in promoting FB fibrosis. Four major mechanisms were identified in the FB failure process: inflammation, fibroblast proliferation and myofibroblast conversion, vascularization, and tissue remodeling. On this basis, an updated model of FB fibrosis was described. Among the pharmacological options, particular attention was given to nintedanib, pirfenidone, and rapamycin, which are used in skin and pulmonary fibrosis, since their promising effects are demonstrated in experimental models of FB fibrosis. Based on the most recent literature, modern patho-physiological models of FB fibrosis should consider TGFβ and M2c macrophages as pivotal players and favorite targets for therapy, while research on antifibrotic strategies should clinically investigate medications utilized in the management of extra-ocular fibrosis. Full article