Search Results (2,222)

Background/Objectives: Post-COVID-19 pulmonary fibrosis (PCPF) and idiopathic pulmonary fibrosis (IPF) exhibit significant clinical and pathophysiological overlap, suggesting convergent molecular pathways driving fibrosis. This prospective longitudinal study investigates the sustained dysregulation of matrix metalloproteinases (MMP)-2 and MMP-9 and its relationship with evolving systemic inflammation and endothelial dysfunction in convalescent COVID-19 patients, with comparative analysis to IPF. Methods: We conducted a prospective observational study of 86 patients at 6 and 12 months post-SARS-CoV-2 infection, stratified by high-resolution CT evidence of PCPF (FB+ group, n = 32) or absence of fibrosis (FB− group, n = 54). Gene expression of MMP-2 and MMP-9 in peripheral blood leukocytes and circulating levels of MMP-2, MMP-9, pro-inflammatory cytokines (TNF-α, IL-6), and endothelial dysfunction markers (Endothelin-1 [ET-1], adhesion molecules) were quantified via qRT-PCR and ELISA. A pre-pandemic healthy control group (HD, n = 20) and an IPF patient group (n = 10) served as comparators. Results: A significant, sustained elevation of MMP-2 and MMP-9 was observed in all post-COVID-19 patients versus HDs, most pronounced in the FB+ group and qualitatively similar to IPF. A critical divergence emerged: FB− patients showed resolution of systemic inflammation (reduced TNF-α, IL-6), whereas FB+ patients exhibited persistent cytokine elevation. Critically, a delayed, severe endothelial dysfunction, characterized by a profound surge in ET-1 and elevated adhesion molecules, manifested exclusively in the FB+ cohort at 12 months. Positive correlations linked plasma MMP-2/9 levels with ET-1 (r_s = 0.65, p = 0.004; r_s = 0.49, p = 0.009) and ET-1 with sICAM-1 (r_s = 0.68, p = 0.01). Conclusions: The development of PCPF is associated with a distinct pathogenic triad: sustained MMP dysregulation, failure to resolve inflammation, and severe late-phase endothelial dysfunction. The correlative links between these components suggest a self-reinforcing loop. This systemic signature mirrors patterns in IPF, underscoring shared final pathways in fibrotic lung disease and identifying the MMP–inflammation–endothelial axis as a promising target for biomarker development and therapeutic intervention. Full article

Objective: To assess whether chronic rhinosinusitis (CRS) severity is associated with obstructive sleep apnea (OSA) in adult people with cystic fibrosis (pwCF). Methods: We conducted a retrospective single-center study of 44 adults with CF who underwent overnight polysomnography (PSG), Epworth Sleepiness Scale (ESS) assessment, and sinus computed tomography (CT). CRS severity was quantified using the Lund–Mackay score (LMS) and the main nasal cavity score (MNCS). OSA was defined by Apnea–Hypopnea Index (AHI) thresholds per American Academy of Sleep Medicine criteria. Results: Participants had a mean age of 31.1 ± 8.4 years and a mean percent predicted FEV1 of 51.8 ± 15.7. Sinus CT showed radiological evidence of CRS in all participants. Mean AHI was 5.3 ± 4.4/h; 48% had AHI ≥ 5/h. There were no significant differences between pwCF with and without OSA in age, sex, BMI, lung function, total sleep time, sleep efficiency, or ESS score (all p > 0.05). Mean LMS and MNCS did not differ between OSA and non-OSA groups (both p > 0.05), and neither score correlated with PSG parameters or ESS (all p > 0.05). Receiver operating characteristic (ROC) analysis demonstrated low discriminative ability of LMS and MNCS for predicting OSA (AUCs < 0.70, p < 0.05). Conclusions: In this cohort of adults with CF, CT-based CRS severity was not associated with OSA. Given the substantial prevalence of OSA observed, PSG screening should be considered irrespective of CRS severity. Full article

Chronic obstructive pulmonary disease (COPD) and tuberculosis (TB) increasingly co-occur in low- and middle-income countries and aging populations. Prior pulmonary TB is a robust, smoking-independent determinant of COPD and is linked to persistent systemic inflammation, endothelial dysfunction, dyslipidemia, and hypercoagulability axes that also amplify cardiovascular disease (CVD) risk. We conducted a targeted narrative non-systematic review (2005–2025) of PubMed/MEDLINE, Embase, Scopus, and Web of Science, selecting studies for clinical relevance across epidemiology, clinical phenotypes, pathobiology, biomarkers, risk scores, sleep-disordered breathing, and management. No quantitative synthesis or formal risk-of-bias assessment was performed. Accordingly, findings should be interpreted as a qualitative synthesis rather than pooled estimates. Prior TB is associated with a distinctive COPD phenotype characterized by mixed obstructive–restrictive defects, reduced diffusing capacity (DLCO), radiographic sequelae, and higher exacerbation/hospitalization burden. Mechanistic insights: Convergent mechanisms chronic immune activation, endothelial injury, prothrombotic remodeling, molecular mimicry, and epigenetic reprogramming provide biologic plausibility for excess CVD, venous thromboembolism, and pulmonary hypertension. Multimarker panels spanning inflammation, endothelial injury, myocardial strain/fibrosis, and coagulation offer incremental prognostic value beyond clinical variables. While QRISK4 now includes COPD, it does not explicitly model prior TB or COPD-TB outcomes, but data specific to post-TB cohorts remain limited. Clinical implications: In resource-constrained settings, pragmatic screening, prioritized PAP access, guideline-concordant pharmacotherapy, and task-shifting are feasible adaptations. A history of TB is a clinically meaningful modifier of cardiopulmonary risk in COPD. An integrated, multimodal assessment history, targeted biomarkers, spirometry/lung volumes, DLCO, 6 min walk test, and focused imaging should guide individualized care while TB-aware prediction models and implementation studies are developed and validated in high-burden settings. Full article

The mammalian lung operates under a biological paradox, requiring architectural fragility for gas exchange while maintaining robust regenerative plasticity to withstand injury. The Hippo signaling pathway has emerged as a central “rheostat” in orchestrating these opposing needs, yet the distinct roles of its downstream effectors remain underappreciated. This review synthesizes recent genetic and mechanobiological advances to propose a “Tale of Two Effectors” model, arguing for the functional non-redundancy of YAP and TAZ. We posit that YAP functions to drive airway progenitor expansion, mechanical force generation, and maladaptive remodeling. Conversely, TAZ—regulated uniquely via transcriptional mechanisms and mechanotransduction—acts as an obligate driver of alveolar differentiation and adaptive repair through an NKX2-1 feed-forward loop. Furthermore, we introduce the “See-Saw” model of tissue fitness, where mesenchymal niche collapse releases the mechanical brake on the epithelium, triggering the bronchiolization characteristic of pulmonary fibrosis. Finally, we extend this framework to malignancy, illustrating how Small Cell Lung Cancer (SCLC) subtypes mirror these developmental and regenerative states. This integrated framework offers new therapeutic distinct targets for modulating tissue fitness and resolving fibrosis. Full article

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with uncertain etiology. Chronic viral infection, including Epstein–Barr virus (EBV), has been implicated as a potential driver of repetitive epithelial injury and dysregulated repair. We sought to evaluate and define the breadth versus specificity of EBV-directed humoral immunity in IPF. We performed proteome-scale serological profiling using an EBV protein microarray (202 proteins) representing all proteins expressed by the EBV proteome (type I and II) on plasma samples from 32 patients with confirmed IPF (87.5% male; mean age 60.9 years) and 15 healthy disease-free controls (40% male; mean age 57.9 years). Per-sample global EBV IgG means were higher in IPF than controls (Welch p = 0.005), and the difference persisted after sex adjustment (p = 0.012). Although no single antigen met a stringent FDR significance threshold, 10 EBV antigen-specific antibody responses showed nominal elevation in IPF, with 2 remaining nominally significant after sex adjustment and 5 additional antibody responses reaching significance only in linear regression models. Overall, these results support the concept that IPF is associated with a diffuse elevation of EBV-directed humoral responses rather than antigen-specific dominance, consistent with ongoing, low-level viral reactivation. The presence of an EBV-negative subgroup within the IPF cohort underscores etiological heterogeneity within IPF. Full article

Interstitial lung diseases (ILDs) encompass a heterogeneous group of disorders characterized by varying degrees of inflammation and fibrosis. Despite advances in understanding the pathogenesis, therapeutic options remain limited, particularly for patients with progressive phenotypes. Current international guidelines for idiopathic pulmonary fibrosis (IPF) and progressive pulmonary fibrosis (PPF) emphasize the need for antifibrotic strategies and call for novel pharmacological interventions targeting key molecular pathways involved in fibrogenesis. This review provides a comprehensive overview of the most promising emerging pharmacological agents for ILDs, with particular attention to their mechanisms of action, efficacy, and safety profiles as reported in recent preclinical and clinical studies. The recent approval of Nerandomilast and the ongoing phase III trials of other agents mark a pivotal transition toward a new generation of antifibrotic therapies, aiming to achieve more effective disease control and improved patient outcomes. In view of an enlargement of active drugs aiming at controlling the disease with different mechanisms, the Authors underline the need for a “precision medicine” model to be applied to each ILD phenotyped patient, mirroring what already happens for other respiratory diseases. Full article

Acute Respiratory Distress Syndrome (ARDS) is a severe complication of acute lung injury (ALI) characterized by acute hypoxemic respiratory failure and diffuse alveolar damage, with a high mortality rate and a current lack of treatments beyond supportive care. Its complex pathophysiology involves immune cell activation, pro-inflammatory cytokine release, and disruption of the alveolar–capillary barrier, leading to pulmonary edema and fibrosis. This review explores the potential of small interfering RNA (siRNA) therapy as a novel pathogenetic treatment for ARDS. The mechanism of RNA interference is described, highlighting its high specificity for silencing target genes. The paper then evaluates various animal models used in ARDS preclinical research, noting the advantages of large animals (pigs) for their physiological similarity to humans and the suitability of rodents for studying long-term fibrotic stages. Finally, the review summarizes promising in vivo studies where siRNA-mediated knockdown of several genes (e.g., TIMP1, BTK, LCN2, HDAC7, CCL2, NOX4, TNFα and TLR4) significantly reduced inflammation, improved lung histology, and increased survival. The collective evidence underscores siRNA’s considerable potential for developing targeted therapies against ARDS, moving beyond symptomatic care to address the root molecular mechanisms of the disease. Full article

Background: idiopathic pulmonary fibrosis (IPF) causes progressive and irreversible changes in the lung parenchyma, leading to respiratory failure. Its pathogenesis involves several damage/repair mechanisms leading to fibrosis, whilst alterations of genes implicated in these processes contribute to the development of the disease. At present, next-generation sequencing (NGS) analyses investigate single-nucleotide or small indel variants, and no evaluation of genomic rearrangements has been so far reported. Methods: In order to identify predisposing variants, we analyzed—both by NGS and by comparative genomic hybridization/single-nucleotide polymorphism (CGH-SNP array) array—37 patients with a diagnosis of familial pulmonary fibrosis. Results: a total of 17 patients (46%) harbored copy number variations (CNVs), 10 (27%) did not harbor any CNVs, 5 (13.5%) showed a mosaic deletion of the Y chromosome, and 5 (13.5%) showed a run of homozygosity (ROH). NGS identified causative variants (including a novel one) in five patients (5/37, 13.5%) and confirmed the high prevalence of MUC5B promoter polymorphism rs35705950, including the detection of a previously unreported form in IPF SNP (indicated as “novel” in the main text), rs141420125 (23/37; 62%). Conclusions: CGH-SNP array identified CNVs containing genes involved in mechanisms (i.e., oxidative stress, mitophagy, NF-Kb pathway) that have been shown to play a role in the pathogenesis of IPF. Therefore, the application of CGH-SNP array or other quantitative tests should be considered in the diagnostic setup of these patients Full article

Background: Nintedanib and pirfenidone are two anti-fibrotic agents for diseases within the interstitial lung diseases (ILDs) spectrum. Here, we provide a comprehensive analysis regarding treatment persistence and adherence rates for the Greek territory. Methods: This was a retrospective cohort study of patients initiating anti-fibrotic treatment during the period 2019–2023, utilizing data extracted from the National Electronic Prescription Database. Treatment persistence was defined as the duration from the date of the first prescription to the end of follow-up, death, or switching to another agent. Adherence was estimated based on the Medication Possession Ratio (MPR) metric. Results: Overall, 2112 patients were analyzed. The majority were naive, male patients with a diagnosis of idiopathic pulmonary fibrosis (IPF). The overall median treatment persistence was 40.2 months (95% CI: 35.5–44.6). Women and treatment-naive patients demonstrated longer median treatment persistence compared to their counterparts, while older patients demonstrated the lowest median persistence rates. Adherence levels remained high across the follow-up period (90%). Diagnosis of IPF and gastrointestinal comorbidities were associated with a higher risk of discontinuation. Conclusions: We have generated novel data concerning the factors that affect patients’ outcomes under anti-fibrotic therapy. These findings may provide helpful insights for the therapeutic management of ILDs. Full article

Background/Objective: Pulmonary involvement in systemic sclerosis (SSc) is typically assessed using pulmonary function tests (PFTs), high-resolution CT (HRCT), and composite indices. Patient-reported outcomes (PRO), including ScleroID, provide insight into quality of life, but their relationship with clinical measures and role in overall disease assessment remain unclear. To assess the correlation between ScleroID scores and both lung involvement and disease activity/damage in a cohort of SSc-ILD patients from a large tertiary care center. Methods: Disease activity [European Scleroderma Study Group Activity Index (EScSG-AI), Scleroderma Clinical Trials Consortium Activity Index (SCTC-AI)], disease severity [Medsger severity scale (MSS)], and PRO measure ScleroID were assessed for associations with the extent and severity of SSc-ILD. Results: In 82 patients with SSc-ILD (mean age 56.0 ± 10.8 years; median disease duration 4.2 ± 4.7 years), higher fibrosis extent (>20%) was associated with worse lung function, greater exercise limitation, and higher ScleroID scores, particularly in fatigue, social life, and body mobility domains (all p ≤ 0.03). Patients with >20% fibrosis also had worse NYHA class and Borg scores during 6-MWD (p < 0.001). Cross-sectional correlations showed that ScleroID total and individual domains were negatively associated with FVC% and 6-MWD, and positively with ILD extent on HRCT. Fatigue, social impact, and mobility domains correlated most strongly with disease activity and severity scores, especially in patients with > 20% fibrosis (r = 0.384–0.635, all p ≤ 0.016), whereas breathlessness showed minimal associations (r < 0.2). Conclusions: In SSc-ILD, greater lung fibrosis and functional impairment are associated with worse patient-reported quality of life, particularly in fatigue, mobility, and social domains. ScleroID scores reflect both physiological severity and disease burden highlighting its value as a multidimensional outcome measure in patients with more advanced disease. Full article

Pulmonary involvement in cystic fibrosis (CF) is characterised by respiratory infections caused by bacteria, viruses, and fungi, as well as by dysregulated inflammatory and immune responses. Although essential for the host’s initial defence against these microorganisms, the innate immune response is altered in its main cellular (airway epithelial cells (AECs), monocytes, macrophages, and neutrophils) and molecular (cytokines, chemokines, signal transduction pathways, and transcription factors) components. MicroRNAs (miRNAs) form a regulatory network at the level of inflammatory and immune responses, and their dysregulation has been observed in immortalised and primary CF AECs as well as in monocytes, macrophages, and neutrophils from CF patients. Although the study of individual miRNAs is helping to dissect the specific altered events in CF lung disease (CFLD), large-scale genomic and transcriptomic studies are more likely to capture its full complexity. The studies we identified suggest that miRNAs are involved in various processes related to CFLD, including impaired pathogen response, compensation for hyperinflammation, altered antigen presentation, and wound healing in AECs and macrophages. However, clinical studies involving large cohorts of patients are needed to obtain meaningful results and identify new therapeutic targets. Equally important will be the study of the miRNome as circulating biomarkers for the purposes of diagnostic and prognostic precision medicine. Full article

Idiopathic Pulmonary Fibrosis (IPF) is a severe, chronic, progressive lung disease classified within interstitial lung disorders. It predominantly affects individuals aged 50 to 70 years, with a prognosis of 3–5 years post-diagnosis. The pathophysiology of IPF is complex, involving an interplay of genetic predisposition, environmental exposures, and age-related factors. A significant genetic component is evident, with key contributions from rare variants in telomere maintenance genes (e.g., TERT and TERC) and surfactant protein genes (e.g., SFTPA and SFTPC), as well as a strong association with a common promoter variant in the MUC5B gene. The diagnosis is established through high-resolution computed tomography (HRCT) and, when necessary, histopathological analysis. The search for reliable biomarkers is a key area of research, with molecules such as KL-6, SP-A, SP-D, and MMP-7 showing potential for aiding in diagnosis, prognosis, and monitoring disease activity. While antifibrotic therapies (Pirfenidone and Nintedanib) have revolutionized management by slowing the decline in lung function, the therapeutic landscape continues to evolve. Ongoing research efforts are focused on integrating clinical, radiological, genetic, and biomarker data to facilitate early diagnosis and develop personalized treatment strategies to improve patient outcomes. Full article

Idiopathic pulmonary fibrosis is a chronic, progressive, interstitial lung disease for which specific and effective drug therapies are still lacking. Lathyrol is a diterpene compound with broad pharmacological activities that can be extracted from the traditional Chinese medicine Leptochloa chinensis (L.) Nees. To investigate the anti-pulmonary fibrosis effect of lathyrol and its underlying mechanism. In vivo, a mouse model of pulmonary fibrosis was induced by bleomycin, treated with intraperitoneal injections of lathyrol. In vitro, myofibroblast conversion was induced in three fibroblast cell lines by stimulating them with TGF-β1, followed by treatment with lathyrol. Transcriptomic analysis was performed to assess the regulation of signaling pathways and gene expression patterns modulated by lathyrol. The effects of lathyrol on PPARγ activation, as well as on the nuclear translocation and ubiquitination of phosphorylated Smad3, were examined. The interaction among Nedd4, PPARγ, and phosphorylated Smad3 was detected. In vivo, lathyrol ameliorated pathological fibrosis in the lungs of mice with pulmonary fibrosis and this effect was blocked by a PPARγ inhibitor. In vitro, lathyrol inhibited the transdifferentiation of fibroblasts into myofibroblasts, and these effects were suppressed by either inhibiting PPARγ activation or specifically silencing the PPARγ gene. Lathyrol inhibited the nuclear translocation of phosphorylated Smad3 and promoted its ubiquitination, while also enhancing the interaction among Nedd4, PPARγ, and phosphorylated Smad3. These effects were abolished following the specific silencing of either PPARγ or Nedd4. In conclusion, Lathyrol inhibits myofibroblast transformation by suppressing TGF-β/Smad pathway activation through PPARγ activation, thereby exerting its anti-pulmonary fibrosis effects. Full article

Background/Objectives: Systemic sclerosis (SSc) is a rare and severe autoimmune disease with limited treatment options. Autologous hematopoietic stem cell transplantation (HSCT) and mesenchymal stem cell transplantation (MSCT) have emerged as promising therapeutic strategies, especially for patients with refractory or rapidly progressive forms of the disease. However, no comparative synthesis has yet evaluated the clinical outcomes, safety, and applicability of these two distinct stem-cell-based interventions. This systematic review aimed to perform a comparative qualitative synthesis of clinical outcomes, safety profiles, and evidence quality for HSCT and MSCT in patients with systemic sclerosis, focusing on survival, skin fibrosis, pulmonary function, and adverse events. Methods: A comprehensive search was conducted in PubMed, ScienceDirect, Cochrane Library, and Google Scholar for the period between 2015 and May 2025. Studies were included if they reported on adult patients with a confirmed diagnosis of SSc treated with either autologous HSCT or MSCT and provided clinical outcome data. Risk of bias was assessed using the Newcastle-Ottawa Scale. Due to heterogeneity across studies, results were synthesized qualitatively. Results: Eleven studies met the inclusion criteria, comprising 504 patients (316 HSCT, 188 MSCT). HSCT showed consistent improvement in survival (1-, 5-, and 10-year), reduction in modified Rodnan skin scores (mRSS), and s ilization or improvement in pulmonary function (DLCO, FVC), albeit with a higher incidence of serious adverse events, including transplant-related mortality (up to 10%) and infectious complications. MSCT demonstrated favorable effects on skin fibrosis and lung involvement with a significantly lower toxicity profile. However, long-term survival data and methodological robustness were limited were more limited. HSCT was supported by multiple randomized controlled trials and international guidelines, while MSCT remains under clinical investigation with promising but still preliminary evidence. Conclusions: Both HSCT and MSCT demonstrate potential clinical benefits in systemic sclerosis, but they differ substantially in evidence strength and risk profiles. HSCT provides the most robust evidence for long-term disease modification in carefully selected patients, whereas MSCT represents a promising and safer investigational option, particularly for patients ineligible for intensive therapy. Further well-designed comparative studies are required to define their optimal clinical roles. Full article

The reactivation of Wnt signaling pathways plays an important role in driving myofibroblast differentiation in fibrotic diseases; however, the mechanism is not clearly understood. In this study, we investigate the role of non-canonical Wnt11 signaling in human lung fibroblasts and its contributions to myofibroblast differentiation. Our results show that components of the non-canonical Wnt pathway are upregulated in bleomycin-induced pulmonary fibrosis and that in vivo depletion of Wnt11 in mouse lung fibroblasts significantly reduces lung fibrosis. Furthermore, co-culture studies using fibroblasts and alveolar type II epithelial cells (AECII) revealed a Wnt11-mediated mechanism that promotes myofibroblast differentiation. Finally, we demonstrate that in human lung fibroblasts, TGFβ can increases Wnt11 transcription by regulating Smad3 binding to the Wnt11 promoter and by modulating Wnt11 promoter activity. Together, these findings identify non-canonical Wnt11 as a regulator of myofibroblast differentiation and lung fibrosis. Full article