Search Results (417)

Fibrosis emerges when normally self-limiting tissue repair fails to resolve and overlapping phases of injury, stromal activation, extracellular matrix (ECM) deposition and remodelling become sustained. MicroRNAs (miRNAs) shape this transition by coordinating signalling, cell-state and matrix programmes. Functionally, pro-fibrotic fibro-miRs amplify fibrogenic pathways, whereas anti-fibrotic miRNAs restrain fibroblast activation and ECM production; the miR-29 family is a principal member of the latter group. This review examines miR-29 family organisation, the regulation of miR-29b by transforming growth factor-β (TGF-β)/Smad and additional transcriptional and inflammatory inputs, and the molecular targets through which miR-29b controls collagen synthesis, processing and crosslinking. Direct canonical targets are distinguished from experimentally supported, predicted and indirect pathway components. Evidence is evaluated across fibroblasts and myofibroblasts, epithelial and endothelial cells, and pulmonary, hepatic, renal, cardiac, dermal and ocular fibrosis models. Therapeutic translation is considered in relation to miR-29b mimics and agomirs, local and tissue-targeted delivery, pharmacokinetics, dose control, off-target repression, immune activation and long-term safety. Overall, miR-29b remains a credible network-level anti-fibrotic candidate, but successful translation requires cell- and disease-specific target validation, selective delivery and preservation of physiological wound repair. Full article

In the current paper, pulmonary emphysema is hypothesized to emerge from a nonlinear breakdown of cooperation across two tightly coupled systems: the extracellular matrix (ECM) crosslink network and the cellular populations responsible for its maintenance. To formalize this concept, we construct a game-theoretic model that unifies the mechanical failure, inflammatory changes, and percolation-driven tissue collapse that are recognized features of the disease. At the ECM level, elastin and collagen crosslinks are modeled as players in an iterated Prisoner’s Dilemma, where cooperation corresponds to maintaining structural integrity, and defection corresponds to rupture under mechanical stress. At the cellular level, fibroblasts, macrophages, and neutrophils engage in a parallel strategic game in which repair reflects cooperative activity, and protease- or oxidant-producing phenotypes are indicative of defection. These parallel games are coupled through bidirectional payoff modulation, generating a dynamical system with bistability, tipping points, and runaway positive feedback. As the fraction of intact crosslinks falls below a critical percolation threshold, global network connectivity collapses and lung function drops precipitously. This framework explains the characteristic features of pulmonary emphysema, including spatial heterogeneity, abrupt acceleration, and irreversibility as emergent properties of coupled cooperation–defection dynamics, and identifies new leverage points for stabilizing cooperation and preventing catastrophic network failure in early disease. In support of this hypothesis, we present previously published studies from our laboratory involving measurements of elastin-specific desmosine crosslinks in human postmortem emphysematous lungs showing a marked increase in tissue crosslink density at the early stage of the disease, and accelerating loss of these crosslinks as airspace enlargement progresses, consistent with initial cooperation followed by defection. This conceptual framework is then applied to the poorly understood lung disease, Combined Pulmonary Fibrosis and Emphysema, to provide a potential mechanism for its pathogenesis. Full article

Background and Clinical Significance: Solitary fibrous tumor (SFT), historically termed hemangiopericytoma (HPC), is a rare fibroblastic mesenchymal neoplasm with variable biological behavior. Pulmonary involvement is uncommon and may represent either a primary thoracic tumor or metastatic disease from an extrapulmonary site. Its clinical course ranges from indolent, surgically curable disease to aggressive malignancy with local recurrence and distant dissemination. In this retrospective case, confirmatory STAT6 immunohistochemistry was unavailable; therefore, the tumor is described as a hemangiopericytoma/solitary fibrous tumor spectrum neoplasm. Case Presentation: We report the case of a 33-year-old woman who presented with sudden-onset hemoptysis and was found to have two large, well-defined bilateral pulmonary masses. Initial clinical and radiological evaluation raised suspicion of primary pulmonary tumors or other benign lesions. Because both lesions were considered resectable, staged pulmonary resections were performed. Subsequent reassessment of the patient’s medical history revealed previous surgeries for a poorly documented recurrent thigh tumor, later confirmed to represent the primary malignant hemangiopericytoma/solitary fibrous tumor spectrum neoplasm. Despite staged pulmonary resections, systemic chemotherapy, and further oncologic management, the disease progressed rapidly, with cerebral, bilateral pulmonary, mediastinal, and subcutaneous metastases. The patient died within 18 months of the initial pulmonary diagnosis. Conclusions: This case highlights the diagnostic difficulty of metastatic pulmonary hemangiopericytoma, particularly when the primary soft tissue tumor is inadequately documented. It emphasizes the importance of detailed clinical history, retrieval of previous histopathological reports, and long-term surveillance in patients with soft tissue tumors, even when initially considered benign. Full article

Background: Idiopathic pulmonary fibrosis (IPF) is closely associated with fibroblast proliferation, macrophage polarization, and the accumulation of extracellular matrix (ECM). Targeting CSF-1R can rebalance macrophages, reduce ECM deposition, and block pro-fibrotic signaling. Methods: A Fab fragment targeting CSF-1R was screened via phage display. After sequence optimization, it was constructed into an IgG1 antibody (BC006). In vitro activity, domain binding, and signaling blockade were investigated, and in vitro safety indicators were evaluated. Efficacy was assessed using an induced IPF organoid-on-a-chip and bleomycin-induced mouse model. In vivo safety evaluation was conducted in cynomolgus monkeys. Results: BC006 showed an EC₅₀ value of 226 ± 57 nM and a KD of 30 ± 2 nM. It specifically bound to the Ig4-5 domain of CSF-1R by inhibiting receptor dimerization without blocking ligand binding. It could dose-dependently inhibit the differentiation of monocytes into M2 macrophages and exert anti-IPF effects. In the induced IPF organoid-on-a-chip model, BC006 maintained lung barrier function and decreased α-SMA and Collagen I. It also improved lung function and attenuated the degree of fibrosis in the mouse model. Moreover, BC006 had no ADCC, CDC, cytokine release, or hemagglutination, and demonstrated favorable safety profiles in cynomolgus monkeys. Conclusions: BC006 is a novel anti-fibrosis antibody specifically targeting the CSF-1R Ig4-5 domain and offers a new therapeutic strategy for IPF. Full article

Skeletal muscle dysfunction and exercise intolerance are major extrapulmonary manifestations of chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF), yet their severity is not fully predicted by pulmonary impairment. This narrative review examines extracellular vesicles (EVs) as candidate mediators of lung–muscle communication within a broader network of inflammatory, metabolic, vascular, nutritional, and inactivity-related mechanisms. The evidence is asymmetrical. COPD provides direct human skeletal muscle evidence for quadriceps microRNA dysregulation, impaired protein synthesis and mitochondrial function, oxidative stress, and abnormalities of the regenerative microvascular niche; however, none of these observations demonstrates delivery of pathogenic cargo from the lung by EVs. In IPF, EV-mediated epithelial–mesenchymal signalling, fibroblast activation, and profibrotic remodelling are well supported within the lung, whereas skeletal muscle effects remain indirect. Accordingly, the lung–muscle EV axis should be viewed as a biologically plausible, evidence-weighted hypothesis rather than an established causal pathway. Progress will require experiments that identify the cellular source of EVs, trace their vascular transit and skeletal muscle uptake, and demonstrate functional cargo transfer using EV-depletion, rescue, and integrated muscle readouts. Conventional size and morphology measurements do not reliably distinguish muscle- from lung-derived EVs; source discrimination currently depends more on molecular cargo and cell-associated markers. Hypoxia and transient or sustained oxygen desaturation may modify EV release and cargo through HIF- and redox-sensitive signalling, but disease-specific evidence connecting these changes to lung-to-muscle transfer in COPD or IPF remains limited. Full article

Initially identified as a hormone linking obesity to insulin resistance, resistin is now recognized as a pleiotropic mediator whose cellular sources and biological functions differ substantially between humans and rodents. Beyond its established roles in metabolic dysfunction and inflammation, emerging evidence suggests that resistin may contribute to tissue remodeling and fibrosis in a context-dependent manner. This review critically synthesizes mechanistic, translational, and clinical evidence across the heart, liver, lung, and kidney. Reported interactions with candidate receptors or binding partners, including adenylyl cyclase-associated protein 1 (CAP1) and Toll-like receptor 4 (TLR4), link resistin-associated signaling to inflammatory, oxidative-stress, and profibrotic pathways that can influence fibroblast activation, hepatic stellate cell responses, extracellular matrix production, and structural tissue remodeling. However, the strength and nature of the available evidence differ markedly among organ systems. Direct profibrotic effects are most strongly supported in cardiac experimental models and selected hepatic systems, whereas pulmonary mechanistic evidence is derived largely from studies of other RELM/FIZZ family members, particularly RELMα/FIZZ1 and RELMβ/FIZZ2, rather than human resistin itself, and renal evidence remains predominantly associative. We, therefore, propose a mechanistic paradigm shift that expands, rather than replaces, the established inflammatory role of resistin. Within this framework, the “fibrotic switch” is presented as a unifying hypothesis whereby persistent resistin-associated signaling may couple chronic inflammatory and metabolic stress to progressive fibrogenic remodeling, requiring further organ-, species-, and cell-specific validation. Defining the relevant cellular sources, receptors, and causal pathways will be essential for evaluating resistin as a biomarker and potential therapeutic target in fibrotic disease. Full article

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease with limited treatment options. Depression and anxiety are common comorbidities in patients with IPF, and emerging evidence suggests that neuroactive pathways may also influence fibrotic remodeling. On this basis, we investigated desipramine, a tricyclic antidepressant, as a potential modulator of fibroblast state in lung fibrosis. Desipramine was identified in an FDA-approved compound screen as a pro-lipogenic hit in TGF-β-stimulated fibroblasts and was subsequently evaluated across a stepwise validation pipeline of increasing biological complexity. In WI-38 fibroblasts, desipramine was well tolerated at 10 μM and reduced myofibroblast-associated features while increasing lipid-associated staining. In a fibroblast-supported alveolosphere assay, desipramine altered qualitative organoid clustering and changed the transcript levels of specific mesenchymal markers under profibrotic stimulation, whereas direct treatment of MLE-12 epithelial cells did not elicit a consistent response. While desipramine demonstrated pro-lipogenic and anti-myofibroblastic phenotypic shifts in reductionist 2D cultures, these effects failed to translate robustly into complex 3D human lung tissue slices or in vivo disease models. Ultimately, our findings highlight the critical necessity of utilizing complex translational pipelines to rigorously validate early screening hits before therapeutic efficacy is assumed. Full article

Oxidative stress contributes to heart failure (HF) progression by mechanisms that go beyond hemodynamic overload, including mitochondrial dysfunction, endothelial injury, inflammation, and fibrotic remodeling. This review evaluates the relationship between redox imbalance, Galectin-3 (Gal-3), fibrosis, and imaging findings in HF. Reactive oxygen species (ROS) generated by mitochondria, nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, and xanthine oxidase may disturb calcium handling, impair mitochondrial function, activate fibroblasts, and promote ferroptosis. Biomarkers of oxidative injury and antioxidant reserve, including malondialdehyde (MDA), 8-hydroxy-2′-deoxyguanosine (8-OHdG), and circulating thiols, provide information complementary to natriuretic peptides. Experimental evidence supports a context-dependent role of Gal-3 in fibro-inflammatory remodeling, whereas circulating Gal-3 should be regarded as a complementary biomarker rather than as a direct measure of myocardial fibrosis. Echocardiography assesses functional remodeling through diastolic indices, myocardial deformation, and right ventricular–pulmonary arterial (RV–PA) coupling, while cardiac magnetic resonance characterizes focal scar and diffuse interstitial remodeling using late gadolinium enhancement, native T1 mapping, and extracellular volume fraction. Therapeutic strategies are increasingly shifting from nonspecific antioxidant supplementation toward targeting ROS sources and downstream pathways, with SGLT2 inhibitors emerging as clinically relevant agents with indirect redox-modulating effects. Integrated redox, fibro-inflammatory, hemodynamic, and imaging phenotyping may refine risk stratification, although prospective validation is required before routine implementation. Full article

Background/Objectives: Silicosis is a progressive occupational lung disease characterized by persistent inflammation and irreversible pulmonary fibrosis. Reliable circulating biomarkers for the early detection of fibrotic remodeling and monitoring of disease progression remain limited. Prolidase, a key enzyme involved in collagen turnover and extracellular matrix remodeling, has emerged as a potential biomarker in fibrotic disorders. Therefore, this study aimed to evaluate the potential role of serum prolidase as a biomarker for fibrotic remodeling and treatment monitoring in an experimental rat model of silicosis. Methods: Male Wistar rats were divided into three groups: control, silicosis, and silicosis plus nintedanib. Silicosis was induced by intratracheal crystalline silica instillation. Nintedanib was administered by gastric gavage at 50 mg/kg/day from day 10 to day 30. Lung tissues were evaluated histopathologically using hematoxylin and eosin and Masson’s trichrome staining. Serum prolidase, fibroblast growth factor-2 (FGF-2), platelet-derived growth factor (PDGF), and transforming growth factor-beta (TGF-β) levels were measured by enzyme-linked immunosorbent assay (ELISA). Results: Histopathological injury scores were significantly increased in the silicosis group and were attenuated by nintedanib treatment. Serum prolidase levels were significantly higher in both silica-exposed groups than in controls (p = 0.017), but did not differ significantly between untreated and nintedanib-treated animals. TGF-β, FGF-2, and PDGF levels were also significantly elevated following silica exposure. Serum prolidase showed a strong positive correlation with TGF-β (r = 0.69, p < 0.001). ROC analysis demonstrated good diagnostic performance for prolidase (AUC = 0.877), while the combined Prolidase + TGF-β model further improved discrimination (AUC = 0.969). The internally validated multivariable biomarker panel maintained high diagnostic accuracy after leave-one-out cross-validation (LOOCV) (AUC = 0.892). Conclusions: Serum prolidase may serve as a potential circulating biomarker of silica-associated fibrotic remodeling. Although nintedanib improved histopathological lung injury, persistently elevated prolidase levels suggest ongoing extracellular matrix remodeling rather than short-term treatment response. Further longitudinal experimental and clinical studies are warranted to validate its diagnostic and prognostic utility. Full article

Background/Objectives: Pulmonary fibrosis is a progressive and fatal disease characterized by excessive extracellular matrix deposition and irreversible lung remodeling. Although modified mRNA (modRNA) therapeutics offer a promising strategy for regulating disease-driving pathways, effective pulmonary delivery remains challenging due to the inherent liver tropism of conventional lipid nanoparticles (LNPs). This study aimed to establish an optimized platform for lung-selective modRNA delivery and therapeutic screening for pulmonary fibrosis. Methods: A panel of charge-modified LNP formulations was evaluated in vivo for pulmonary tropism following systemic administration of luciferase (Luc) modRNA. Administration routes, biodistribution in healthy and bleomycin (BLM)-induced fibrotic lungs, and endogenous microRNA (miRNA)-mediated de-targeting strategies were assessed. Candidate antifibrotic modRNAs targeting the transforming growth factor-beta (TGF-β) signaling pathway were subsequently evaluated in normal human lung fibroblasts (NHLFs). Results: Among the formulations tested, 50% DOTAP MC3 LNPs demonstrated the most favorable balance of pulmonary transfection, physicochemical properties, and limited off-target expression. Intravenous (IV) administration achieved robust lung expression with a superior safety profile compared with intratracheal (IT) delivery. Importantly, pulmonary biodistribution was preserved in BLM-induced fibrotic lungs despite extensive tissue remodeling. Incorporation of miR-122 recognition sites further enhanced selectivity, resulting in 94.5% of total transgene expression being localized to the lungs while substantially reducing residual hepatic expression. In vitro screening identified dominant-negative TGF-β receptor II (DNTGFBR2) modRNA as a potent inhibitor of TGF-β-induced fibrotic activation, significantly suppressing α-SMA and CTGF expression. Conclusions: These findings establish a comprehensive platform for pulmonary modRNA therapeutic development by integrating lung-selective LNP engineering, optimal systemic delivery, miRNA-mediated de-targeting, and therapeutic payload screening. This strategy provides a foundation for the development of targeted RNA therapies for pulmonary fibrosis and other organ-specific diseases. Full article

Idiopathic pulmonary fibrosis (IPF) is one of the most severe forms of idiopathic interstitial pneumonia. Increasing evidence indicates that the gradual accumulation of senescent fibroblasts and alveolar epithelial cells contributes significantly to IPF pathogenesis, suggesting senescence as a potentially targetable process. Recurrent injury to the alveolar epithelium promotes senescence in epithelial cells, impairing their regenerative capacity and thereby predisposing the tissue to fibrotic degeneration. Although epithelial senescence is strongly implicated in the initiation and progression of lung fibrosis, the mechanisms through which it drives IPF remain challenging, partially due to the lack of physiologically relevant in vitro models capable of recapitulating lung architecture under both normal and pathological conditions. The objective of the present study was to develop a reproducible alveolosphere model in healthy and senescent conditions as a preliminary approach to investigate epithelial features that may be relevant to aspects of the IPF microenvironment. An alveolosphere system was generated by culturing alveolar epithelial cells with or without basement membrane components in combination with alveolar/epithelial optimized medium. Cultures were maintained for 3, 6, and 8 days, and cell viability together with morphological assessment confirmed the absence of cytotoxicity. The expression of keratin 8/18 and AQP5 was consistent with the maintenance of epithelial and alveolar-associated features. Cellular senescence was induced by exposing alveolospheres to doxorubicin for 24 h. Subsequent analyses of viability, along with the expression of senescent and pro-fibrotic markers, inflammatory mediators, and tissue remodeling factors, such as MMPs, were carried out in senescent 3D structures. The results demonstrated robust cell viability at all time points, supported by morphological observations. Marker expression suggested preservation of key epithelial characteristics, while senescence-inducing conditions were associated with an increase in senescence-associated, pro-fibrotic, inflammatory, and matrix-modulating markers. Collectively, these findings describe the preliminary establishment of a cost-effective and reproducible alveolosphere platform that may represent a useful starting point for studying epithelial senescence and its potential association with pro-fibrotic signaling relevant to aspects of IPF pathogenesis. Furthermore, this model may provide a basis for the preliminary evaluation of senotherapeutic compounds aimed at delaying or preventing the onset of cellular senescence. Full article

Pulmonary fibrosis (PF) is a progressive lung condition characterized by irreversible scarring and high mortality, with limited effective treatments. Mitochondrial dysfunction has emerged as a critical factor in fibroblast activation in PF, although approaches to restore mitochondrial function remain underexplored. The present study investigated whether mitochondrial transfer from alveolar type II epithelial cells (A549) to patient-derived fibroblasts could restore mitochondrial function and bioenergetics. Histological analysis of fibrotic lungs reveals increased collagen deposition and elevated profibrotic markers, accompanied by reduced expression of mitochondrial biogenesis and respiratory proteins compared to non-fibrotic controls, indicating mitochondrial impairment. Freshly isolated donor mitochondria were functionally validated before mitoception using Seahorse analysis and patient-derived fibroblasts were confirmed by qRT-PCR using fibroblast-specific markers. In vitro transfer of mitochondria to diseased patient-derived fibroblasts exhibited a modest, dose and time-dependent increase in mitochondrial membrane potential compared to normal fibroblasts. Gene expression analysis revealed decreased fibrosis-associated markers and increased expression of mitochondrial and antioxidant genes following mitoception. Seahorse analysis after mitoception revealed enhanced ATP-linked respiration and improved selected mitochondrial bioenergetic parameters, whereas maximal respiration and spare respiratory capacity demonstrated variable responses. In contrast, normal fibroblasts displayed minimal changes. Collectively, these findings indicate that mitochondrial transfer modulates fibroblast bioenergetics and profibrotic signaling, supporting its potential as a therapeutic strategy for pulmonary fibrosis. Full article

Neuroendocrine neoplasms (NENs) are a heterogeneous family of tumors that have traditionally been regarded as “immune cold” and largely refractory to PD-1/PD-L1 checkpoint blockade, with notable exceptions such as Merkel cell carcinoma (MCC). The advent of single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics has enabled unprecedented dissection of the NEN tumor microenvironment (TME), but a cross-subtype synthesis is lacking. This review aims to integrate single-cell and spatial transcriptomic findings across major NEN subtypes to reframe NEN immunosuppression and delineate translational implications. To this end, we performed a structured narrative review of PubMed-indexed studies up to 30 April 2026, prioritizing original human scRNA-seq, single-nucleus RNA-seq, spatial transcriptomic, and spatial proteomic studies of NENs, supplemented by mechanistic, clinical, and biomarker-focused reports providing essential context. Across these studies, synthesis spanning pancreatic, pulmonary, gastrointestinal, cutaneous, pituitary, adrenal, and other NEN subtypes highlights conserved features beyond the PD-1/PD-L1 axis, including myeloid-dominated infiltration with alternative checkpoints (VISTA, TIM-3, Galectin-9), cancer-associated fibroblast-mediated immune exclusion, lineage-state-dependent immune visibility, and direct immunomodulation by neuroendocrine secretory products such as calcitonin gene-related peptide. We propose a four-layer framework integrating these mechanisms and linking them to emerging biomarkers and therapies, including DLL3-directed bispecifics, alternative checkpoint inhibitors, stromal-targeting agents, and peptide receptor radionuclide therapy combinations. Together, these findings indicate that single-cell and spatial transcriptomic studies reframe NEN immunosuppression as a multilayered, subtype-dependent process, providing a conceptual scaffold for biomarker-guided, subtype-adapted therapeutic strategies and prospective clinical trial design in neuroendocrine oncology. Full article

This study investigated the mechanism of TGF-β1-induced Nox4 expression in pulmonary fibrosis (PF) and the anti-fibrotic effects of Tanshinone IIA (Tan-IIA). In a bleomycin-induced pulmonary fibrosis mouse model and in TGF-β1-stimulated fibroblasts, Tan-IIA attenuated fibrosis, oxidative stress, and fibroblast activation. Pharmacological inhibition revealed that the JNK/c-Jun and Smad3 pathways cooperatively mediate TGF-β1-induced expression of Nox4 and fibrotic markers (Collagen I/III, α-SMA). Tan-IIA exerted these effects by dually inhibiting the JNK/c-Jun and Smad2/3 pathways, reducing their phosphorylation and nuclear signaling, which consequently suppressed Nox4 transcription and protein expression. The combination of Tan-IIA with JNK or Smad3 inhibitors synergistically enhanced these effects. We identified a tandem c-Jun/Smad binding element in the Nox4 promoter that is critical for TGF-β1 response. Reporter assays and CUT&RUN experiments confirmed that TGF-β1-induced transcriptional activation depends on an intact c-Jun/Smad binding element and recruitment of c-Jun and Smad2/3. Moreover, Tan-IIA inhibited the enrichment of c-Jun and Smad2/3 at the Nox4 promoter. Collectively, our findings demonstrate that a c-Jun/Smad element integrates profibrotic JNK and Smad signaling to drive Nox4 expression. Tan-IIA presents a novel therapeutic strategy for fibrosis by simultaneously targeting these two key pathways, thereby mitigating Nox4-dependent oxidative stress and fibroblast activation. Full article