Fibrosing diseases are causes of morbidity and mortality around the world, and they are characterized by excessive extracellular matrix (ECM) accumulation. The bHLH transcription factor scleraxis (SCX) regulates the synthesis of ECM proteins in heart fibrosis. SCX expression was evaluated in lung fibroblasts and tissue derived from fibrotic disease patients and healthy controls. We also measured SCX in sera from 57 healthy controls, and 56 Idiopathic Pulmonary Fibrosis (IPF), 40 Hypersensitivity Pneumonitis (HP), and 100 Systemic Sclerosis (SSc) patients. We report high SCX expression in fibroblasts and tissue from IPF patients versus controls. High SCX-serum levels were observed in IPF (0.663 ± 0.559 ng/mL, p < 0.01) and SSc (0.611 ± 0.296 ng/mL, p < 0.001), versus controls (0.351 ± 0.207 ng/mL) and HP (0.323 ± 0.323 ng/mL). Serum levels of the SCX heterodimerization partner, TCF3, did not associate with fibrotic illness. IPF patients with severely affected respiratory capacities and late-stage SSc patients presenting anti-topoisomerase I antibodies and interstitial lung disease showed the highest SCX-serum levels. SCX gain-of-function induced the expression of alpha-smooth muscle actin (α-SMA/ACTA2) in fibroblasts when co-overexpressed with TCF3. As late and severe stages of the fibrotic processes correlated with high circulating SCX, we postulate it as a candidate biomarker of fibrosis and a potential therapeutic target.

Pulmonary fibrosis (PF) is characterized by excessive collagen deposition and impaired lung function. Pulmonary surfactant may modulate fibroblast activity and offer therapeutic benefits. We developed a natural porcine pulmonary surfactant (NPPS) enriched with 1,2-dipalmitoyl-rac-glycero-3-phosphatidylethanolamine (PE) and evaluated its biophysical and biological properties. Biophysical analysis showed that PE improved surfactant performance by increasing surface pressure and stability. In vitro, NPPS-PE reduced collagen expression and induced apoptosis in normal human lung fibroblasts; in addition, it decreased proliferation in fibroblasts stimulated with TGF-β. In vivo, NPPS-PE improved gas exchange and significantly reduced collagen deposition in bleomycin-treated mice. These findings suggest that NPPS-PE may be a promising therapeutic strategy for fibrosing lung diseases.

Lung cancer is a prevalent and aggressive neoplasm worldwide, contributing to significant mortality rates. Dehydroepiandrosterone (DHEA) constitutes the bulk of the steroid hormone in human plasma, has a robust antiproliferative effect, and induces cell death in various tumor cells. However, its role in lung cancer cells remains unexplored. This study aimed to investigate the influence of DHEA on the proliferation, viability, autophagy, and migration of several lung cancer cell lines, including A549, HCC827, and NCI-H2347. Cell proliferation was assessed through crystal violet staining; cell number and viability were evaluated using trypan blue staining; viability was confirmed by MTT reduction, a method that is also an indicator of metabolic activity; migration was assessed via a wound healing assay. Autophagy was evaluated using a specific kit, while cell death was determined by annexin-V-FITC/propidium iodide staining and caspase-3/7 activity assay. The results indicate that DHEA significantly reduced proliferation, cell number, metabolic activity, and migration in all examined lung tumor cells. These effects correlate with an increased autophagy induced by DHEA. No signs of apoptosis or necrosis were observed across the range of DHEA concentrations used. Although these findings are preliminary, they suggest that DHEA could hold promise as an alternative treatment option for various subtypes of lung cancer.

Pulmonary surfactant may play a protective role in fibrosing lung diseases by modulating fibroblast activity. In our lab, we found that surfactant enriched with 1,2-dipalmitoyl-rac-glycero-3-phosphatidylethanolamine (PE) induces apoptosis, reduces proliferation, and lowers collagen expression in normal human lung fibroblasts. To explore its therapeutic potential, we developed a natural porcine surfactant enriched with PE (NPPS-PE) obtained by organic synthesis and evaluated its biophysical properties, in vitro antifibrotic effects, and in vivo impact on collagen deposition in a bleomycin-induced fibrosis model. NPPS was extracted via bronchoalveolar lavage and analyzed biophysically. Its efficacy was evaluated in surfactant-deficient animals and in bleomycin-treated mice. In vitro, NPPS-PE effects on fibroblasts were assessed. Histological and biochemical analyses were performed to quantify collagen deposition. PE improved NPPS biophysical properties, increasing stability and surface pressure. In animal models, NPPS-PE enhanced oxygenation and reduced CO₂. In TGF-β-treated fibroblasts, NPPS-PE reduced proliferation and Col1A1 expression, and increased apoptosis. In bleomycin-treated mice, NPPS-PE significantly decreased collagen deposition and fibrosis, as shown by hydroxyproline levels and image analysis, confirming its antifibrotic potential in vivo and in vitro. PE-enriched porcine surfactant reduces fibroblast proliferation, induces apoptosis, and lowers collagen expression, showing therapeutic potential to improve respiratory function and attenuate fibrosis in pulmonary diseases.

Metabolic syndrome (MetS) is associated with ectopic fat deposition, chronic systemic inflammation, oxidative stress, and increased susceptibility to organ dysfunction. While its cardiovascular consequences have been extensively studied, pulmonary al-terations remain less well characterized, particularly with respect to ferropto-sis-regulatory pathways. In this study, we evaluated ectopic fat deposition, TLR4/NF-κB signaling pathway, and ferroptosis-regulatory markers in a MetS rat model and analyzed the therapeutic potential of combined resveratrol plus quercetin (combined R + Q) supplementation. Rats were maintained for five months with 30% sucrose in drinking water to induce MetS and subsequently treated for 4 weeks with the R + Q combination (50 and 0.95 mg/kg/day, respectively). Lung tissue was analyzed by fluorescence microscopy to assess fat deposition, by colorimetric histology to evaluate hemosiderin-containing cells, including the quantification of hemosiderin-laden macrophages (HLMs), and by immunoblotting to determine TLR4, p-p65, and glutathione peroxidase 4 (GPX4), as well as cystine/glutamate antiporter SLC7A11 (xCT) protein expression. Lungs from MetS rats exhibited significantly higher fat deposits, pathological HLMs accumulation, upregulated TLR4/p-p65 signaling, elevated compensatory GPX4 expression, and depressed xCT levels compared with controls. Notably, the combined R + Q treatment markedly attenuated alterations in TLR4/NF-κB signaling and successfully restored xCT expression (p = 0.0116), stabilizing pulmonary redox homeostasis and limiting overall tissue susceptibility to lipotoxic injury.