Background:Fibrotic interstitial lung diseases (ILDs) are characterized by different degrees of inflammation and fibrosis of the lung parenchyma that are associated with progressive loss of breath, high morbidity and mortality. Current therapeutic options are limited, so there remains a significant need for effective and well-tolerated treatments. GTX-11 is an orally available small molecule in development for the treatment of fibrotic diseases. In this study, we aimed to assess the therapeutic potential of GTX-11 in different preclinical models of lung fibrotic disease. Methods:We assessed the activity of GTX-11 and its active metabolite, GTX-11m, in the bleomycin-induced pulmonary fibrosis model and in vitro in primary fibroblast cell cultures, including human normal lung fibroblasts (hNLFs) and ILD patient-derived fibroblasts. Results:In the murine model, GTX-11 treatment improved animal survival and significantly reduced lung fibrosis as measured by Ashcroft score and collagen deposition. GTX-11 also reduced the inflammatory cell count in bronchoalveolar lavage fluid and pro-inflammatory factors in lung tissue. Additionally, GTX-11 significantly improved lung vascular dysfunction and reduced pulmonary vascular remodeling. The preclinical anti-fibrotic effects of GTX-11 were comparable to, or in some cases exceeded, those of currently approved anti-fibrotic drugs used in clinical practice. In vitro, GTX-11m demonstrated anti-fibrotic and anti-inflammatory activity in hNLFs and ILD patient-derived fibroblasts. GTX-11m inhibited TGFβ-induced expression of key fibrotic markers and reduced fibroblast-to-myofibroblast transition and inflammatory cytokine production. The effects were consistent across the different tested ILD cultures and resulted from the prevention of SMAD2 and SMAD3 activation by TGFβ. The GTX-11m anti-fibrotic and anti-inflammatory effects were comparable or better than nintedanib. Conclusion:Altogether, our studies reveal that GTX-11 is an effective antifibrotic both in vivo and in vitro, suggesting that GTX-11 has potential as a therapeutic option for fibrotic ILDs.

Chronic lung diseases are characterized by oxidative stress, inflammation, and fibroproliferation, conditions that impair nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic GMP (cGMP) signaling. Here, we investigated the differential effects of an sGC stimulator (riociguat) and an sGC activator (cinaciguat), alone or combined with the PDE5 inhibitor sildenafil, in primary human pulmonary cells exposed to cigarette smoke extract (CSE). Lung tissue from COPD and asthma patients displayed reduced sGC α1 and β1 expression, and CSE induced concentration-dependent oxidation of the sGC heme group, diminishing responsiveness to NO and to riociguat. Cinaciguat, but not riociguat, maintained cGMP production under oxidizing conditions, while co-treatment with sildenafil further increased cGMP levels for both drugs. In epithelial cells, fibroblasts, neutrophils, and endothelial monolayers, cinaciguat and riociguat attenuated CSE-induced oxidative stress, inflammatory cell adhesion, and profibrotic gene expression, with cinaciguat-particularly in combination with sildenafil-showing more robust effects across endpoints. These findings identify distinct pharmacodynamic profiles for sGC stimulators versus activators under oxidative conditions and support sGC modulation as a potential therapeutic approach in oxidative chronic lung diseases.

BACKGROUND:Chronic obstructive pulmonary disease (COPD) is characterized by sustained oxidative stress, inflammation, and epithelial damage. The transcription factor Nrf2 is a master regulator of antioxidant and cytoprotective defenses, and its dysregulation has been implicated in COPD pathogenesis. METHODS:We first investigated Nrf2 expression and its downstream antioxidant genes in lung tissue and neutrophils from healthy donors and COPD patients, and examined their association with disease severity (GOLD stage). We then compared the efficacy of two mechanistically distinct Nrf2 activators-omaveloxolone (an electrophilic compound) and LAS200813 (a peptide-based Keap1-Nrf2 protein-protein interaction inhibitor)-using bardoxolone methyl as a high-potency reference. Functional analyses were performed in human bronchial epithelial cells (HBECs) and peripheral blood neutrophils from both groups. RESULTS:Nrf2 and target gene expression were significantly reduced in COPD samples and correlated with disease severity, indicating pathway dysfunction. Pharmacological activation promoted Nrf2 nuclear translocation, restored redox balance, increased intracellular glutathione, and reduced ROS levels in epithelial and immune cells. Both activators induced HO-1 and NQO1 expression and attenuated cigarette smoke extract-induced release of IL-8, MMP-9, and IL-6, including in COPD-derived cells. In bronchial epithelial cells, Nrf2 activation was also associated with a reduction in CSE-induced apoptosis. Omaveloxolone showed slightly higher potency, while LAS200813 displayed comparable functional efficacy. CONCLUSION:These results confirm that the Nrf2 pathway is compromised in COPD and support selective Nrf2 activation-particularly via peptide-based approaches-as a promising therapeutic strategy to mitigate oxidative and inflammatory injury in the disease.

Background: Chronic obstructive pulmonary disease (COPD) is characterized by persistent oxidative stress and neutrophilic inflammation, which intensify during acute exacerbations. These processes contribute to epithelial damage, impaired redox balance, and heightened cytokine and protease activity. Pharmacological activation of the transcription factor nuclear factor erythroid 2–related factor 2 (NRF2) represents a promising strategy to counteract these mechanisms. Purpose: This study investigated whether obacunone, a natural limonoid and known activator of NRF2, can attenuate oxidative and inflammatory injury in human airway cells and in a mouse model of COPD‑like exacerbation induced by cigarette smoke and lipopolysaccharide (LPS). Methods: Primary human bronchial epithelial cells (HBECs) from healthy donors and COPD patients, as well as peripheral blood neutrophils, were exposed to cigarette smoke extract with or without obacunone. Redox markers, reactive oxygen species, gene and protein expression of NRF2‑regulated targets, and inflammatory mediators were assessed. In vivo, mice received intratracheal LPS followed by cigarette smoke exposure and daily oral obacunone. Lung injury, bronchoalveolar lavage parameters, cytokines, histology, protease activity, and pulmonary expression of antioxidant and inflammatory genes were evaluated. Results: Obacunone restored glutathione levels, reduced reactive oxygen species, and increased expression of heme oxygenase‑1 and NAD(P)H quinone dehydrogenase 1 in HBECs. In neutrophils, obacunone reduced interleukin‑8 and matrix metalloproteinase‑9 release. In vivo, obacunone mitigated lung edema, inflammatory cell recruitment, tissue injury, cytokine production, and protease activation. These effects aligned with increased pulmonary NRF2 activation and reduced inducible nitric oxide synthase expression. Conclusion: Obacunone exerts dual antioxidant and anti‑inflammatory activity across airway and immune cells and in a COPD‑relevant exacerbation model. These findings support obacunone as a potential therapeutic candidate targeting NRF2‑dependent pathways in acute inflammatory episodes of COPD. define pharmacokinetics-pharmacodynamics and safety, and extend evaluation to chronic models.

BackgroundCigarette smoke exposure is a major risk factor for oral cancer, partly due to its ability to induce early molecular alterations in the oral mucosa. Cellular senescence and the senescence-associated secretory phenotype (SASP) contribute to chronic inflammation and microenvironmental remodeling, favoring carcinogenesis. The PI3K/AKT/mTOR pathway has been implicated in sustaining SASP and senescence, suggesting that its inhibition may represent a promising preventive strategy.MethodsPrimary human oral fibroblasts (hOF) and a 3D oral mucosa model were exposed to cigarette smoke extract (CSE) 2% for 72 h, with or without pre-treatment with the dual pan–class I PI3K/mTOR inhibitor PKI402 (10−7-10−9 M). Senescence markers (p21, p16, lamin B1) were quantified by RT-qPCR; SASP cytokines (IL-6, IL-8) by ELISA; DNA damage by γH2AX immunofluorescence; and senescence-associated β-galactosidase (SA-β-gal) activity by flow cytometry.ResultsCSE exposure induced a senescent phenotype characterized by increased p21 and p16, decreased lamin B1, elevated IL-6 and IL-8 secretion, accumulation of γH2AX foci, and enhanced SA-β-gal activity. PKI402 significantly attenuated these changes in a dose-dependent manner, with the highest concentrations showing statistically significant reductions across all endpoints.ConclusionPharmacological inhibition of PI3K/mTOR mitigates cigarette smoke-induced senescence and SASP in oral fibroblasts, reducing DNA damage and inflammatory signaling. These findings highlight PI3K/mTOR pathway as a potential target for senomorphic interventions aimed at preventing pro-tumorigenic microenvironment remodeling in oral carcinogenesis.

Oral squamous cell carcinoma, a leading global cause of cancer-related morbidity, is strongly associated with tobacco cigarette use. This study investigates the role of cigarette smoke in inducing cellular senescence and inflammation in oral mucosa, which may contribute to the development of oral cancer through mechanisms such as the senescence-associated secretory phenotype (SASP). Biopsies from smokers and non-smokers were analyzed using quantitative polymerase chain reaction to assess the expression of senescence markers p21, p16, and laminB1. Immunohistochemistry was performed to evaluate p21 and p16 expression in the tissues. In vitro experiments were conducted using primary oral keratinocytes (human oral keratinocytes [hOK]) and fibroblasts (human oral fibroblast [hOF]) exposed to increasing concentrations of cigarette smoke extract (CSE) for 72 h. Additionally, a three-dimensional (3D) reconstituted oral mucosa model was exposed to 5% CSE for 72 h, and senescence markers were analyzed by real-time quantitative polymerase chain reaction. Flow cytometry was performed in hOF after 72 h at 2% CSE to assess senescence-associated beta-galactosidase (SA-β-gal) activity. Smokers' biopsies showed a significant increase in p21 and p16 expression and a decrease in laminB1 compared with non-smokers. Immunohistochemistry confirmed increased p21 and p16 in smokers. In vitro, ≥2% CSE induced similar senescence patterns in hOK and hOF, with dose-dependent interleukin (IL)-6 and IL-8 secretion. The 3D oral mucosa model showed comparable changes in all three senescence markers. Exposure to 2% CSE increased SA-β-gal activity in hOF. Taken together, cigarette smoke exposure induces cellular senescence and inflammation in the oral mucosa. The pro-inflammatory response associated with SASP may contribute to the development of a pro-tumoral microenvironment in the oral cavity, promoting early oral carcinogenesis.

Introduction: Cough is a common reflex that serves a protective role, but when persistent, it can severely affect patients’ quality of life. Despite its high prevalence, current treatment options remain limited. Traditional antitussives such as codeine and dextromethorphan present notable side effects, underscoring the need for safer and more effective alternatives. Methods: This study evaluated and compared the antitussive efficacy of classic (codeine, cloperastine, dextromethorphan, levodropropizine) and novel (gefapixant) agents using a citric acid-induced cough model in guinea pigs. Animals were pretreated with the selected compounds, and cough frequency, latency to first cough, and cough intensity were assessed using acoustic recordings and quantitative analysis. Results: Codeine, cloperastine, and gefapixant produced a significant reduction in cough frequency and markedly increased latency to the first cough, with comparable efficacy at the highest doses tested. In contrast, dextromethorphan and levodropropizine did not significantly affect these parameters. Additionally, cloperastine, codeine, and gefapixant reduced cough intensity, while none of the treatments significantly altered cough duration. Conclusions: In this preclinical model, cloperastine and gefapixant demonstrated antitussive effects comparable to codeine but without the known narcotic-associated risks. These findings highlight the potential clinical relevance of both centrally and peripherally acting non-opioid alternatives. Continued investigation of these agents may help address the unmet need for safer and more effective cough treatments.

Mucins are large glycoproteins that form the primary structural component of mucus and can be classified into secreted and transmembrane types. Of the 22 identified mucin genes, 12 encode transmembrane mucins, which play crucial roles in maintaining epithelial barrier integrity, modulating cell signaling, and innate immune responses to pathogens. Transmembrane mucins are expressed in epithelial cells, inflammatory cells, endothelial cells, and fibroblasts, influencing diverse cellular processes. They interact with extracellular ligands and transduce intracellular signals, functioning as membrane receptors with cell type-specific effects, triggering anti-inflammatory, proliferative, fibrotic, or carcinogenic processes. The extracellular domain of mucins can also be shed into the environment, where it exerts biological functions and serves as a biomarker for various chronic diseases. This review presents a comprehensive analysis of the discovery, structure, and molecular composition of different transmembrane mucins, along with their expression patterns and distribution across tissues. It explores their physiological roles and immunomodulatory functions and the diverse cellular processes they regulate. Furthermore, it discusses the contribution of transmembrane mucin gene variants, aberrant expression, and dysregulated activation in chronic diseases such as inflammation, fibrosis, and cancer. Finally, given the role of mucins in the progression of various pathologies, this review describes therapeutic strategies and biomarkers that have been translated into clinical practice with promising results, aiming to provide a comprehensive overview of the current understanding of transmembrane mucins.

There is a pressing medical need for improved treatments in skin fibrosis including keloids and hypertrophic scars (HTS). This study aimed to characterize the role of phosphodiesterase 4 (PDE4), specifically PDE4B in fibrotic skin remodeling in vitro and in vivo.In vitro, effects of PDE4A-D (Roflumilast) or PDE4B (siRNA) inhibition on TGFβ1-induced myofibroblast differentiation and dedifferentiation were studied in normal (NHDF) and keloid (KF) human dermal fibroblasts. In vivo, the role of PDE4 on HOCl-induced skin fibrosis in mice was addressed in preventive and therapeutic protocols.PDE4B (mRNA, protein) was increased in Keloid > HTS compared to healthy skin and in TGFβ-stimulated NHDF and KF. In Keloid > HTS, collagen Iα1, αSMA, TGFβ1 and NOX4 mRNA were all elevated compared to healthy skin confirming skin fibrosis.In vitro, inhibition of PDE4A-D and PDE4B similarly prevented TGFβ1-induced Smad3 and ERK1/2 phosphorylation and myofibroblast differentiation, elevated NOX4 protein and proliferation in NHDF. PDE4A-D inhibition enabled myofibroblast dedifferentiation and curbed TGFβ1-induced reactive oxygen species and fibroblast senescence. In KF PDE4A-D inhibition restrained TGFβ1-induced Smad3 and ERK1/2 phosphorylation, myofibroblast differentiation and senescence. Mechanistically, PDE4A-D inhibition rescued from TGFβ1-induced loss in PPM1A, a Smad3 phosphatase. In vivo, PDE4 inhibition mitigated HOCl-induced skin fibrosis in mice in preventive and therapeutic protocols.The current study provides novel evidence evolving rationale for PDE4 inhibitors in skin fibrosis (including keloids and HTS) and delivered evidence for a functional role of PDE4B in this fibrotic condition.

Idiopathic pulmonary fibrosis (IPF) associated to pulmonary hypertension (PH) portends a poor prognosis, characterized by lung parenchyma fibrosis and pulmonary artery remodeling. Serum and parenchyma levels of Interleukin 11 (IL-11) are elevated in IPF-PH patients and contributes to pulmonary artery remodeling and PH. However, the effect of current approved therapies against IPF in pulmonary artery remodeling induced by IL-11 is unknown. The aim of this study is to analyze the effects of nintedanib and pirfenidone on pulmonary artery endothelial and smooth muscle cell remodeling induced by IL-11 in vitro. Our results show that nintedanib (NTD) and pirfenidone (PFD) ameliorates endothelial to mesenchymal transition (EnMT), pulmonary artery smooth muscle cell to myofibroblast-like transformation and pulmonary remodeling in precision lung cut slices. This study provided also evidence of the inhibitory effect of PFD and NTD on IL-11-induced endothelial and muscle cells proliferation and senescence. The inhibitory effect of these drugs on monocyte arrest and angiogenesis was also studied. Finally, we observed that IL-11 induced canonical signal transducer and activator of transcription 3 (STAT3) and non-canonical mitogen-activated protein kinase 1/2 (ERK1/2) phosphorylation, but, PFD and NTD only inhibited ERK1/2 phosphorylation. Therefore, this study provided evidence of the inhibitory effect of NTD and PFD on markers of pulmonary artery remodeling induced by IL-11.

Abstract Background Epidermal remodeling and hypertrophy are hallmarks of skin fibrotic disorders, and keratinocyte to mesenchymal (EMT)-like transformations drive epidermis alteration in skin fibrosis such as keloids and hypertrophic scars (HTS). While phosphodiesterase 4 (PDE4) inhibitors have shown effectiveness in various fibrotic disorders, their role in skin fibrosis is not fully understood. This study aimed to explore the specific role of PDE4B in epidermal remodeling and hypertrophy seen in skin fibrosis. Methods In vitro experiments examined the effects of inhibiting PDE4A-D (with Roflumilast) or PDE4B (with siRNA) on TGFβ1-induced EMT differentiation and dedifferentiation in human 3D epidermis. In vivo studies investigated the impact of PDE4 inhibition on HOCl-induced skin fibrosis and epidermal hypertrophy in mice, employing both preventive and therapeutic approaches. Results The study found increased levels of PDE4B (mRNA, protein) in keloids > HTS compared to healthy epidermis, as well as in TGFβ-stimulated 3D epidermis. Keloids and HTS epidermis exhibited elevated levels of collagen Iα1, fibronectin, αSMA, N-cadherin, and NOX4 mRNA, along with decreased levels of E-cadherin and ZO-1, confirming an EMT process. Inhibition of both PDE4A-D and PDE4B prevented TGFβ1-induced Smad3 and ERK1/2 phosphorylation and mesenchymal differentiation in vitro. PDE4A-D inhibition also promoted mesenchymal dedifferentiation and reduced TGFβ1-induced ROS and keratinocyte senescence by rescuing PPM1A, a Smad3 phosphatase. In vivo, PDE4 inhibition mitigated HOCl-induced epidermal hypertrophy in mice in both preventive and therapeutic settings. Conclusions Overall, the study supports the potential of PDE4 inhibitors, particularly PDE4B, in treating skin fibrosis, including keloids and HTS, shedding light on their functional role in this condition.

Background and Purpose IL‐11 is a member of the IL‐6 family of cytokine initially considered as haematopoietic and cytoprotective factor. Recent evidence indicates that IL‐11 promotes lung fibrosis and pulmonary hypertension in animal models and is elevated in lung tissue of patients with pulmonary fibrosis and pulmonary hypertension. Fibrocytes are bone marrow‐derived circulating cells that participate in lung fibrosis and pulmonary hypertension, but the role of IL‐11 on fibrocytes is unknown. We investigated the role of IL‐11 system on fibrocyte activation in different in vitro and in vivo models of lung fibrosis associated with pulmonary hypertension. Experimental Approach Human fibrocytes were isolated from peripheral blood of six healthy donors. Recombinant human (rh)‐IL‐11 and soluble rh‐IL‐11 receptor, α subunit (IL‐11Rα) were used to stimulated fibrocytes in vitro to measure:‐ cell migration in a chemotactic migration chamber, fibrocyte to endothelial cell adhesion in a microscope‐flow chamber and fibrocyte to myofibroblast transition. Mouse lung fibrosis and pulmonary hypertension was induced using either IL‐11 (s.c.) or bleomycin (intra‐tracheal), while in the rat monocrotaline (intra‐tracheal) was used. In vivo siRNA‐IL‐11 was administered to suppress IL‐11 in vivo . Key Results RhIL‐11 and soluble rhIL‐11Rα promote fibrocyte migration, endothelial cell adhesion and myofibroblast transition. Subcutaneous (s.c.) IL‐11 infusion elevates blood, bronchoalveolar and lung tissue fibrocytes. SiRNA‐IL‐11 transfection in bleomycin and monocrotaline animal models reduces blood and lung tissue fibrocytes and reduces serum CXCL12 and CXCL12/CXCR4 lung expression. Conclusion and Implications Targeting IL‐11 reduces fibrocyte circulation and lung accumulation in animal models of pulmonary hypertension‐associated lung fibrosis.

N-Acetyl-l-cysteine (NAC) acts as a precursor of the tripeptide glutathione (GSH), one of the principal cell mechanisms for reactive oxygen species (ROS) detoxification. Chronic obstructive pulmonary disease (COPD) is associated with enhanced inflammatory response and oxidative stress and NAC has been used to suppress various pathogenic processes in this disease. Studies show that the effects of NAC are dose-dependent, and it appears that the efficient doses in vitro are usually higher than the achieved in vivo plasma concentrations. However, to date, the inconsistencies between the in vitro NAC antioxidant and anti-inflammatory in vitro effects, by reproducing the in vivo NAC plasma concentrations as well as high NAC concentrations. To do so, A549 were transfected with polyinosinic-polycytidylic acid (Poly (I:C)) and treated with NAC at different treatment periods. Oxidative stress, release of proinflammatory mediators and NFkB activation were analyzed. Results suggest that NAC at low doses in chronic administration has sustained antioxidant and anti-inflammatory effects, while acute treatment with high dose NAC exerts a strong antioxidant and anti-inflammatory response.

Background: Fibrotic interstitial lung diseases are characterized by variable extent of inflammation and fibrosis of lung parenchyma that can affect pulmonary artery remodelling and hypertension, leading to a poor prognosis. GTX-011 is a small molecule in development by GAT Therapeutics for the treatment of fibrotic diseases. It is a TGFβ pathway modulator that has proven to reduce fibrosis progression in different models of advanced hepatic fibrotic disease. Aim: To study the therapeutic potential of GTX-011 in a rat model of pulmonary fibrosis. Methods: A single intratracheal dose of bleomycin (3.75 U/kg) or sham was administered at day 1 of the 28-day procedure (n=12 per group). GTX-011 2mg/kg, 8mg/kg, or nintedanib 50mg/kg were administered orally, once a day, between day 10 and 28. Results: 100% survival was achieved in the GTX-011 treated groups, compared to 67% in the bleomycin control group and 80% in the nintedanib group. GTX-011 significantly reduced total inflammatory cell count in the bronchoalveolar lavage fluid of treated rats at both doses. Lung tissue hydroxyproline deposition induced by bleomycin was effectively suppressed by GTX 8mg/kg. Both GTX-011 doses fully restored to healthy control values the right ventricular systolic pressure and hypertrophy. GTX-011 at 8mg/kg greatly improved the lung vascular disfunction as assessed in the IVIS system. Conclusions: GTX-011 treatment significantly improved the survival, lung and heart vascular function, fibrosis and inflammation of our bleomycin model. GTX-011 effects were comparable or better than nintedanib's. In sum, GTX-011 holds great promise as a therapeutic drug for lung fibrotic diseases.

IntroductionExposure to solar radiation can cause a range of skin damage, including sunburn, erythema, skin carcinogenesis, the release of reactive oxygen species (ROS), inflammation, DNA damage, and photoaging. Other wavelengths beyond UVB, such as UVA, blue light, and infrared radiation, can also contribute to the harmful effects of solar radiation. Reconstructed full-thickness human skin has the potential to serve as effective predictive in vitro tools for evaluating the effects of solar radiation on the skin. The aim of this work was to evaluate the damaging effects of UVA, blue light, and infrared radiation in a full-thickness skin model in terms of viability, inflammation, photoaging, tissue damage, photocarcinogenesis.MethodsFull thickness skin models were purchased from Henkel (Phenion FT; Düsseldorf, Germany), and irradiated with increasing doses of UVA, blue light, or infrared radiation. Different endpoints were analyzed on the tissues: Hematoxylin-eosin staining, inflammation mediators, photoaging-related dermal markers and oxidative stress marker GPX1, evaluated by real-time quantitative PCR, as well as photocarcinogenesis markers by Western Blot.Results and DiscussionThe results showed differential responses in cytokine release for each light source. In terms of photoaging biomarkers, collagen, metalloproteinases 1 and 9, elastin, and decorin were modulated by UVA and blue light exposure, while not all these markers were affected by infrared radiation. Furthermore, exposure to UVA and blue light induced loss of fibroblasts and modulation of the photocarcinogenesis markers p53 and p21. In conclusion, the presented results suggest that the various wavelengths of solar light have distinct and differential damaging effects on the skin. Understanding the differential effects of UVA, blue light, and infrared radiation can serve as a valuable tool to investigate the efficacy of photoprotective agents in full thickness skin models.

IL-11 is linked to fibrotic diseases, but its role in pulmonary hypertension is unclear. We examined IL-11's involvement in idiopathic pulmonary arterial hypertension (iPAH). Using samples from control (n = 20) and iPAH (n = 6) subjects, we assessed IL-11 and IL-11Rα expression and localization through RT-qPCR, ELISA, immunohistochemistry, and immunofluorescence. A monocrotaline-induced PAH model helped evaluate the impact of siRNA-IL-11 on pulmonary artery remodeling and PH. The effects of recombinant human IL-11 and IL-11Rα on human pulmonary artery smooth muscle cell (HPASMC) proliferation, pulmonary artery endothelial cell (HPAEC) mesenchymal transition, monocyte interactions, endothelial tube formation, and precision cut lung slice (PCLS) pulmonary artery remodeling and contraction were evaluated. IL-11 and IL-11Rα were over-expressed in pulmonary arteries (3.2-fold and 75-fold respectively) and serum (1.5-fold and 2-fold respectively) of patients with iPAH. Therapeutic transient transfection with siRNA targeting IL-11 resulted in a significant reduction in pulmonary artery remodeling (by 98%), right heart hypertrophy (by 66%), and pulmonary hypertension (by 58%) in rats exposed to monocrotaline treatment. rhIL-11 and soluble rhIL-11Rα induce HPASMC proliferation and HPAEC to monocyte interactions, mesenchymal transition, and tube formation. Neutralizing monoclonal IL-11 and IL-11Rα antibodies inhibited TGFβ1 and EDN-1 induced HPAEC to mesenchymal transition and HPASMC proliferation. In 3D PCLS, rhIL-11 and soluble rhIL-11Rα do not promote pulmonary artery contraction but sensitize PCLS pulmonary artery contraction induced by EDN-1.In summary, IL-11 and IL-11Rα are more highly expressed in the pulmonary arteries of iPAH patients and contribute to pulmonary artery remodeling and the development of PH.

Solar radiation can cause damage to the skin, leading to various adverse effects such as sunburn, reactive oxygen species production, inflammation, DNA damage, and photoaging. To study the potential of photoprotective agents, full-thickness skin models are increasingly being used as in vitro tools. One promising approach to photoprotection involves targeting the redox-sensitive transcription factor Nrf2, which is responsible for regulating various cellular defense mechanisms, including the antioxidant response, inflammatory signaling, and DNA repair. Obacunone, a natural triterpenoid, has been identified as a potent Nrf2 agonist. The present study aims to evaluate the relevance of full-thickness (FT) skin models in photoprotection studies and to explore the potential photoprotective effects of obacunone on those models and in human keratinocytes. Phenion® full-thickness skin models and keratinocytes were incubated with increasing concentrations of obacunone and irradiated with solar-simulated radiation (SSR). Various photodamage markers were evaluated, including histological integrity, oxidative stress, apoptosis, inflammation, photoaging-related dermal markers, and photocarcinogenesis markers. Increasing doses of SSR were found to modulate various biomarkers related to sun damage in the FT skin models. However, obacunone attenuated cytotoxicity, inflammation, oxidative stress, sunburn reaction, photoaging, and photocarcinogenesis in both keratinocytes and full thickness skin models exposed to SSR. These results suggest that obacunone may have potential as a photoprotective agent for preventing the harmful effects of solar radiation on the skin.

Nowadays, clinical practice encounters the problem of delayed-type hypersensitivity (DTH) induced by several drugs. Antineoplastic treatments are among the drugs which show an elevated proportion of DHT reactions, leading to the worsening of patients' quality of life. The range of symptoms in DHT reactions can vary from mild, such as self-limiting maculopapular eruptions, to severe, such as Stevens-Johnson Syndrome. The development of these reactions supposes a negative impact, not only by limiting patients' quality of life, but also leading to economic loss due to market withdrawal of the affected drugs and high hospitalization costs. However, despite this problem, there are no available standard in vitro or in vivo methods that allow for the evaluation of the sensitizing potential of drugs in the preclinical phase. Therefore, the aim of this review is to summarize the skin reactions caused by the different antineoplastic families, followed by a comprehensive evaluation of the in vitro and in vivo methods used to detect DTHs and that could be suitable to test antineoplastic hypersensitivity reactions.

IntroductionCorticosteroids are the most cost-effective anti-inflammatory drugs available for the treatment of asthma. Despite their effectiveness, several asthmatic patients have corticosteroid resistance or insensitivity and exhibit a poor response. Corticosteroid insensitivity implies a poor prognosis due to challenges in finding alternative therapeutic options for asthma.Areas coveredIn this review, we describe asthma phenotypes and endotypes, as well as their differential responsiveness to corticosteroids. In addition, we describe the mechanism of action of corticosteroids underlying their regulation of the expression of glucocorticoid receptors (GRs) and their anti-inflammatory effects. Furthermore, we summarize the mechanistic evidence underlying corticosteroid-insensitive asthma, which is mainly related to changes in GR gene expression, structure, and post-transcriptional modifications. Finally, various pharmacological strategies designed to reverse corticosteroid insensitivity are discussed.Expert opinionCorticosteroid insensitivity is influenced by the asthma phenotype, endotype, and severity, and serves as an indication for biological therapy. The molecular mechanisms underlying corticosteroid-insensitive asthma have been used to develop targeted therapeutic strategies. However, the lack of clinical trials prevents the clinical application of these treatments.

Delayed-type hypersensitivity (DTH) is caused by a broad number of drugs used in clinic, and antineoplastic drugs show an elevated proportion of DTH, which potentially affects the quality of life of patients. Despite the serious problem and the negative economic impact deriving from market withdrawal of such drugs and high hospitalization costs, nowadays, there are no standard validated methods in vitro or in vivo to evaluate the sensitizing potential of drugs in the preclinical phase. Enhanced predictions in preclinical safety evaluations are really important, and for that reason, the aim of our work is to adapt in vitro DPRA, ARE-Nrf2 luciferase KeratinoSensTM, and hCLAT assays for the study of the sensitizing potential of antineoplastic agents grouped by mechanism of action. Our results reveal that the above tests are in vitro techniques able to predict the sensitizing potential of the tested antineoplastics. Moreover, this is the first time that the inhibition of the VEGFR1 pathway has been identified as a potential trigger of DTH.