Idiopathic pulmonary fibrosis (IPF) and progressive pulmonary fibrosis (PPF) are characterised by an irreversible progression of pulmonary fibrosis and functional lung decline. Current antifibrotic therapies (nintedanib and pirfenidone for IPF and nintedanib for PPF) can reduce disease progression but not halt or reverse it. PPF and IPF share common pathophysiological pathways that need to be further elucidated for the development of novel therapeutic strategies. The educational aim of this review is to explain the pathogenic pathways that have led to the discovery of new therapeutic agents and their favourable implementation in phase 2 and 3 studies. This includes phosphodiesterase 4 inhibitors, αvβ6 and αvβ1 integrin inhibitors, lymphosphatidic acid antagonists, inhaled treprostinil, hedgehog inhibitors, tyrosine kinase inhibitors and angiotensin type 2 receptor agonists. The aim is also to better understand current therapeutic challenges and future perspectives, including cellular therapies, exosomes and their cargoes, as well as the integration of transcriptomics and proteomics, plus gene therapy.

Background: Mediastinal lymph node enlargement is prevalent in patients with idiopathic pulmonary fibrosis (IPF). Studies investigating whether this phenomenon reflects specific immunologic activation are lacking. Methods: Programmed cell death-1 (PD-1)/ programmed cell death ligand-1 (PD-L1) expression in mediastinal lymph nodes and lung tissues was analyzed. PD-1, PD-L1 mRNA expression was measured in tracheobronchial lymph nodes of mice following bleomycin-induced injury on day 14. Finally, the effect of the PD-1 inhibitor, pembrolizumab, in bleomycin-induced pulmonary fibrosis was investigated. Results: We analyzed mediastinal lymph nodes of thirty-three patients (n = 33, IPF: n = 14, lung cancer: n = 10, concomitant IPF and lung cancer: n = 9) and lung tissues of two hundred nineteen patients (n = 219, IPF: 123, controls: 96). PD-1 expression was increased, while PD-L1 expression was decreased, in mediastinal lymph nodes of patients with IPF compared to lung cancer and in IPF lungs compared to control lungs. Tracheobronchial lymph nodes isolated on day 14 from bleomycin-treated mice exhibited increased size and higher PD-1, PD-L1 mRNA levels compared to saline-treated animals. Pembrolizumab blunted bleomycin-induced lung fibrosis, as indicated by reduction in Ashcroft score and improvement in respiratory mechanics. Conclusions: Mediastinal lymph nodes of patients with IPF exhibit differential expression profiles than those of patients with lung cancer indicating distinct immune-mediated pathways regulating fibrogenesis and carcinogenesis. PD-1 expression in mediastinal lymph nodes is in line with lung tissue expression. Lower doses of pembrolizumab might exert antifibrotic effects. Clinical trials aiming to endotype patients based on mediastinal lymph node profiling and accordingly implement targeted therapies such as PD-1 inhibitors are greatly anticipated.

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.

The clinical management of COVID-19 in pregnant women, who are considered a vulnerable population, remains uncertain even as the pandemic subsides. SARS-CoV-2 affects pregnant individuals in multiple ways and has been associated with severe maternal morbidity and mortality, as well as neonatal complications. The unique anatomy and physiology of gestation make managing COVID-19 in this population a complex and challenging task, emphasizing the importance of spreading knowledge and expertise in this area. Therapeutic interventions require distinct clinical consideration, taking into account differences in pharmacokinetics, vertical transmission, drug toxicities, and postnatal care. Currently, there is limited data on antiviral and immunomodulating COVID-19 pharmacotherapy in pregnancy. Some medication has been shown to be safe and well tolerated among pregnant women with COVID-19; however, the lack of randomized clinical trials and studies in this patient population is evident. Available vaccines are considered safe and effective, with no evidence of harm to the fetus, embryo development, or short-term postnatal development. Pregnant women should be counseled about the risks of SARS-CoV-2 infection and informed of available ways to protect themselves and their families. Effective treatments for COVID-19 should not be withheld from pregnant individuals, and more research is needed to ensure the best outcomes.

Background: Diagnostic work-up of pulmonary embolism (PE) remains a challenge. Methods: We retrospectively studied all patients referred for computed tomography pulmonary angiography (CTPA) with suspicion of PE during a 12-month period (2018). The diagnostic accuracy of different D-dimer (Dd) cutoff thresholds for ruling out PE was evaluated. Furthermore, the association of Dd and red cell distribution width (RDW) with embolus location, CTPA findings, and patient outcome was recorded. Results: One thousand seventeen (n = 1017) patients were finally analyzed (mean age: 64.6 years (SD = 11.8), males: 549 (54%)). PE incidence was 18.7%. Central and bilateral embolism was present in 44.7% and 59.5%, respectively. Sensitivity and specificity for conventional and age-adjusted Dd cutoff was 98.2%, 7.9%, and 98.2%, 13.1%, respectively. A cutoff threshold (2.1 mg/L) with the best (64.4%) specificity was identified based on Receiver Operating Characteristics analysis. Moreover, a novel proposed Dd cutoff (0.74 mg/L) emerged with increased specificity (20.5%) and equal sensitivity (97%) compared to 0.5 mg/L, characterized by concurrent reduction (17.2%) in the number of performed CTPAs. Consolidation/atelectasis and unilateral pleural effusion were significantly associated with PE (p < 0.05, respectively). Patients with consolidation/atelectasis or intrapulmonary nodule(s)/mass on CTPA exhibited significantly greater median Dd values compared to patients without the aforementioned findings (2.34, (IQR 1.29–4.22) vs. 1.59, (IQR 0.81–2.96), and 2.39, (IQR 1.45–4.45) vs. 1.66, (IQR 0.84–3.12), p < 0.001, respectively). RDW was significantly greater in patients who died during hospitalization (p = 0.012). Conclusions: Age-adjusted Dd increased diagnostic accuracy of Dd testing without significantly decreasing the need for imaging. The proposed Dd value (0.74 mg/L) showed promise towards reducing considerably the need of CTPA. Multiple radiographic findings have been associated with increased Dd values in our study.

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.