Fibrotic diseases of the skin and lung, such as systemic sclerosis, hypertrophic scars, keloids, and pulmonary fibrosis, share core molecular mechanisms despite their distinct anatomical settings. Central to their pathogenesis are persistent fibroblast activation, immune dysregulation, ECM remodeling, and failure of resolution pathways, all modulated by an ever-changing environment and epigenetic regulation. Increasing evidence reveals that chronic injury from air pollution, ultraviolet radiation, climate stressors, and occupational hazards accelerates fibroinflammatory remodeling across these barrier organs. Moreover, shared signaling networks, including TGF-β, IL-4/IL-13, Wnt/β-catenin, and epigenetic regulators like miR-21 and miR-29, suggest convergent fibrotic programs may be subject to cross-organ therapeutic targeting. This review integrates recent insights into the exposome’s role in driving fibrosis, highlights novel RNA- and epigenetic-based interventions, and evaluates the repurposing of antifibrotic agents approved for pulmonary disease within dermatologic contexts. We emphasize the emerging concept of fibrosis-aware precision medicine and propose a unifying framework to guide integrated therapeutic strategies. In the face of global climate change and rising environmental insults, a cross-organ perspective on fibrosis offers a timely and translationally relevant approach to addressing this growing burden on human health.

Background: We have previously shown that SHP2 downregulation may predispose fibroblasts to differentiate into myofibroblasts and proposed a role for SHP2 downregulation in the pathogenesis of idiopathic pulmonary fibrosis (IPF). Recent data have shown that SHP2 localizes to the mitochondrial intercristae, and its overexpression enhances mitochondrial metabolism leading to oxidative stress and senescence. Objective: To determine the effect of SHP2 on fibrotic responses. Methods and Results: Primary mouse lung fibroblasts derived from mice carrying a conditional knock-in mutation (D61G/+), rendering the SHP2 catalytic domain constitutively active, had reduced proliferation (1.6-fold, p < 0.05), migration (2-fold, p < 0.05), as well as reduced responsiveness of TGFB-1 induced fibroblasts-to-myofibroblasts differentiation, compared to wild-type ones. Electron microscope analysis revealed that SHP2 ^D61G/+ mouse lung fibroblasts were characterized by mitochondrial abnormalities, including swollen mitochondria with disrupted electron-lucent cristae and an increased number of autophagosomes compared to wild-type ones. SHP2 ^D61G/+ MLFs exhibited increased protein levels of autophagy markers, including LC3B-II and p-62, evidence that was confirmed by immunofluorescence analysis. Mitochondrial function analysis revealed that stable (genotype D61G/+) overexpression of SHP2 led to impaired mitochondrial function, as assessed by decreased mitochondrial membrane potential (1.29-fold, p < 0.05), coupling efficiency (1.82 fold, p < 0.05), oxygen consumption rate (1.9-fold, p < 0.05), and increased reactive oxygen species production both at baseline (1.75-fold, p < 0.05) and following H₂O₂ stimulation (1.63-fold, p < 0.05) compared to wild-type ones (SHP2^+/+). SHP2 ^D61G/+ mouse lung fibroblasts showed enhanced AMPK activity, as well as decreased activation of the mTORC1 signaling pathway, potentially leading to ineffective mitochondrial metabolism and increased autophagy. Conclusions: SHP2 attenuates fibrotic responses in fibroblast cell lines through negative regulation of mitochondrial metabolism and induction of autophagy. SHP2 activation may represent a promising therapeutic strategy for patients with fibrotic lung diseases.

Background: Real-world data on currently used biologic agents in patients with severe asthma are lacking. Methods: In this retrospective study, we recorded between 16 May 2020 and 31 December 2024 consecutive patients who presented to our asthma outpatient clinic received a diagnosis of uncontrolled severe asthma and were treated with biologic agents. Outcomes included a comparison of disease phenotypic characteristics, as well as asthma control, lung function, longitudinal use of corticosteroids, and hospitalizations due to exacerbations at baseline and post-biologic treatment at 6-month follow-up. Results: We identified 80 patients with uncontrolled severe asthma treated with biologic agents. The median age (95% CI) at the time of diagnosis was 67.0 (61.0 to 70.0) years. Most patients were female (65.0%, n = 52) and never smokers (51.3%, n = 41). The median value of ACT (95% CI) was 15 (15 to 16) at the time of diagnosis. The mean FEV₁% predicted ±SD at the baseline was 68.9 ± 22.0. The median value of blood eosinophils (95% CI) was 365 (252 to 448) K/μL in the overall population. One-third (36.3%) of patients were hospitalized due to severe asthma exacerbation in the previous year. Longitudinal use of oral corticosteroids was recorded in 11.3% of included patients. Three patients (3.8%) were treated with omalizumab, 23 patients (28.8%) with mepolizumab, 33 patients (41.2%) with benralizumab and 21 patients (26.2%) with tezepelumab. The median value of ACT (95% CI) post-biologic treatment at 6-month follow-up was 20 (20 to 21), p < 0.0001. The mean FEV₁% predicted ±SD at 6-month follow-up was 77.6 ± 25.2, p = 0.12. The median value of blood eosinophils (95% CI) 6 months after initiation of biologic treatment was 100 (40 to 121) K/μL, p < 0.0001. Elimination of hospitalizations due to asthma flares was recorded in 97.5% of patients (p < 0.0001). With regard to the longitudinal use of oral corticosteroids, we noticed that 96.2% of patients achieved discontinuation. No treatment-related adverse events were noticed. Conclusions: The administration of current biologic agents in patients with severe asthma seems to be both effective and safe, sparing the toxicity of oral corticosteroids.

Background and Objectives: Despite the devastating impact of acute exacerbations of fibrotic interstitial lung diseases (AE-fILDs), established treatment strategies are majorly lacking. The therapeutic potential of intravenous immunoglobulin (IVIG) in AE-fILDs was explored considering its anti-inflammatory and immunomodulatory effects, as well as the immunocompromised status of fILD patients and the high frequency of infections that AE-fILDs triggers. Materials and Methods: This was an observational, retrospective study. We investigated the therapeutic potential of IVIG in patients hospitalized for AE-fILDs between May 2021 and November 2024. Results: We included 39 patients diagnosed with AE-fILDs. All patients received IVIG (total dose of 1 g/kg, divided into three daily doses), pulse corticosteroids for three days and broad-spectrum antibiotics. No adverse events were considered to be related to IVIG therapy during the study period. The in-hospital and the 90-day mortality were 10 (26%) and 13 (33%) patients, respectively. Twenty-nine patients (74%) were discharged and 18 of them (62%) were in need of long-term oxygen therapy. The mean PaO₂/FiO₂ ratio (P/F ratio) was 183 mmHg on admission and 294 mmHg on discharge (t-test, p < 0.0001). Conclusions: This study suggests a potential therapeutic signal, indicating that IVIG is a relatively harmless, well-tolerated, and a potentially effective add-on treatment to current therapeutic approaches. Further research is essential to clarify the role of IVIG, determine optimal treatment protocols, and assess its efficacy in different ILD subtypes.

Background: Hypereosinophilic syndrome (HES) is a heterogeneous group of rare disorders defined by the presence of marked eosinophilia resulting in end organ damage. The diagnostic approach is multidisciplinary and treatment goals include reductions in flares and eosinophils with minimal drug-related side effects. Results: Eleven patients (n = 11) with a diagnosis of idiopathic HES were included in the study [M/F: 6/5, median age: 54 (95% CI: 38.2 to 68.5), smokers/never smokers: 5/6]. Asthma was present in the majority of them (n = 8, 72.7%); four patients (n = 4, 36.4%) presented with eosinophilic pleural effusions, two patients (n = 2, 18.2%) with cardiac arrhythmias, and one with bilateral eyelid angioedema. Eight patients (72.7%) were treated with mepolizumab (300 mg/month) and three (27.3%) with benralizumab (30 mg/4 weeks). The median values of eosinophils at baseline and 12 months after initiation of biologic agent were 3000 (95% CI: 2172 to 11,365) K/μL and 50 (95% CI: 3 to 190) K/μL, respectively, p = 0.0002. All patients with concomitant asthma (n = 8) experienced elimination of asthma flares, asthma control (ACQ < 0.75), functional improvement (mean ΔFEV1: 857 ± 594 mL), and an 82% reduction in oral corticosteroids, p = 0.0001. Materials and Methods: Patients with highly characterized idiopathic HES treated with anti-eosinophilic agents between 1 October 2019 and 1 October 2023 were retrospectively included in the study. The aim of this study was to present clinical, laboratory, and functional features and outcomes in patients with thoroughly investigated idiopathic HES treated with biologic agents targeting eosinophils. Conclusions: Biologic agents in patients with idiopathic HES—following thorough diagnostic investigation—are both safe and effective, sparing the toxicity of immunosuppressive agents. Real-life data from larger registries are greatly anticipated.

Introduction: Small airways disease (SAD) is increasingly recognized in patients with interstitial lung diseases (ILDs). Spirometry cannot reliably assess airflow through peripheral airways. Forced oscillation technique (FOT) has been reliably applied in the evaluation of SAD. Aim: To investigate the frequency of SAD in different forms of ILDs using both functional (FOT) and imaging (HRCT) modalities. Methods: Patients with ILD were prospectively enrolled in the study between 1/9/2023 and 1/2/2024. FOT was performed using Resmon Pro Full device. Results: Eighty-seven(n=87) patients were analyzed [females:43, median age (95%CI): 71.0(69 to 75), mean baseline FVC%pred ±SD: 79.3±18.9, connective tissue disease-ILD:21, idiopathic pulmonary fibrosis:20, hypersensitivity pneumonitis:8, non-specific interstitial pneumonia:8]. The frequency of small airways abnormalities based on the difference between resistance at 5 and 20Hz (R5-20) >0,7cmH2O was 30%(n=26). Thirteen patients(50%) were on bronchodilators and twelve(46%) on antifibrotics at the time of FOT. Imaging features indicative of SAD were only detected in ten patients(38%). The difference between expiratory and inspiratory reactance at 5Hz(DX5) was significantly higher and the area under reactance curve (AX) was increased in SAD group compared to patients without SAD [(0.58, 95%CI: -0.01 to 0.99, vs. -0.22, 95%CI: -0.35 to -0.1, p<0.001) and (7.43, 95%CI: 4.97 to 7.29, vs. 7.43, 95%CI: 6.18 to 10.53, p=0.02)]. Conclusion: FOT can play a significant role in the early detection of SAD in ILDs. Larger cohorts are needed to establish cut-offs points, to improve reproducibility and to explore more applications of this clinician’s and patients’ friendly modality.