GM-CSF enhances pulmonary host defense and promotes re-establishment of alveolar barrier function. We investigated safety, feasibility and efficacy of nebulized recombinant human (rh)GM-CSF/Molgramostim in pneumonia-related ARDS. In this multicenter/randomized/double-blind/parallel-group/placebo-controlled investigator-initiated phase IIa trial, patients were randomized to receive nebulized low-dose (150mcg) or high-dose (450mcg) rhGM-CSF or placebo for 3d. BAL was performed before first and after dosing. Primary outcome parameter was the composite GI-HOPE score, representing expression changes of CD80/CD86/CD206/HLA-DR on alveolar macrophages after dosing compared to baseline.Secondary outcomes included oxygenation, SOFA scores, and clinical endpoints at d28. 46 participants were randomized, 43 completed treatment (n=15 placebo, n=15 low-dose, n=13 high-dose), and BAL was performed on 38 participants before and after treatment. Although the composite biological GI-HOPE score did not reach significance (p>0.05), high-dose treatment caused upregulation of HLA-DR and CD206 on alveolar macrophages, indicating deposition in the alveolar compartment and beneficial macrophage activation (HLA-DR: p=0.0406 versus low-dose; p=0.1841 versus placebo; CD206: p=0.009 versus low-dose; p=0.0179 versus placebo). High-dose rhGM-CSF treatment revealed a favourable profile of oxygenation at the end of analysis compared to time points before inhalation (p=0.095 and p=0.0175), or compared to low-dose and placebo groups (p=0.0063 and p=0.0198; v13), and was associated with decreased SOFA scores in the high-dose group over time (p=0.0013 and p=0.001 compared to low-dose/placebo). Importantly, inhaled rhGM-CSF did not increase alveolar or systemic inflammation. Inhalation of 450mcg rhGM-CSF was safe,promoted a favourable profile regarding alveolar macrophage activation, oxygenation, and SOFA scores over time, however did not lead to differences in the GI-HOPE score. Funded by DZL and Savara Pharmaceuticals ( NCT02595060 , www.clinicaltrials.gov )

This study highlights the previously unknown association of mosaic loss of the Y chromosome to impaired gas exchange and cardiac dysfunction, implicating mosaicism in immune-mediated, multi-organ decline and revealing a mechanistic basis for sex-biased vulnerability in COPD.

Influenza A virus (IAV)-induced exacerbations are a major contributor to morbidity in chronic obstructive pulmonary disease (COPD), yet the epithelial mechanisms that govern these events remain unknown. We profiled the response to IAV infection of differentiated airway epithelial cells from healthy donors and individuals with COPD at single-cell resolution. The analysis revealed infection-driven shifts across multiple epithelial compartments and distinct alterations in cell-cell communication in COPD, associated with an increased CXCL11 expression. Functional assays demonstrated that CXCL11 augments mucus-associated gene and protein expression, particularly MUC5AC, increases mucus secretion and viscosity and is associated with reduction of virus-related immune pathways. This highlights CXCL11 as a contributor to both mucus hypersecretion and impaired antiviral epithelial responses in COPD exacerbations.

In 567 PH-COPD patients from the PVRI GoDeep Meta-Registry, ACE inhibitor use was associated with improved survival only in severe PH (PVR > 5 WU), supporting prospective trials targeting this high-risk subgroup.

BACKGROUND:Pulmonary vascular diseases are characterized by mean pulmonary artery pressure (mPAP) and pulmonary vascular resistance (PVR), both reflecting the steady-flow component of right ventricular (RV) afterload while neglecting pulsatile elements. Pulmonary artery compliance (PAC) and arterial elastance (Ea) capture complementary aspects of pulmonary vascular load, whereas stroke volume index (SVI) reflects RV functional adaptation. The prognostic significance of these integrated parameters remains incompletely understood, particularly in early-stage disease. RESEARCH QUESTION:Do PAC, Ea, and SVI predict mortality independently of PVR in patients with mild PH and across the full spectrum of pulmonary hypertension (PH)? METHODS:Using the international PVRI GoDeep meta-registry, we first evaluated the prognostic relevance of PAC, Ea, and SVI in patients with mild PH, defined as a mPAP >20 and <25 mmHg. Subsequently, these analyses were extended to the overall PH population across the full spectrum of disease severity. Subgroup analyses were performed according to PH etiology. PAC was calculated as the ratio of SV to pulmonary arterial pulse pressure, and Ea as end-systolic pressure divided by SV. RESULTS:In patients with mild PH (n = 1,097), neither mPAP nor PVR predicted mortality (both p>0.05). In contrast, Ea, PAC, SVI, and heart rate demonstrated independent prognostic value. Expanding the analysis to 16,899 patients across PH groups 1-5, these parameters remained significantly associated with survival, independent of PVR/TPR and after adjustment for multiple potential confounders. Consistent findings were observed across etiological subgroups and IPAH/hPAH. INTERPRETATION:Parameters integrating pulsatile vascular load and interdependent RV function possess predictive power independent of PVR/TPR across the full spectrum of PH. Moreover, they allow meaningful risk stratification in mild PH patients, where conventional parameters lack discriminative prognostic power.

Pulmonary hypertension (PH) is a complex disease characterized by increased pressure in the pulmonary arteries. It encompasses a heterogeneous group of entities that increase right heart afterload and often lead to right heart failure and premature death. Advancing diagnosis, risk stratification, and treatment across the diverse PH spectrum requires large, high-quality, longitudinal datasets that exceed the scope of individual national or regional registries. To address this need, PVRI GoDeep was founded under the umbrella of the Pulmonary Vascular Research Institute (PVRI). This global meta registry harmonizes and integrates anonymized patient-level data from existing PH registries at expert centers worldwide. PVRI GoDeep enables the reuse of locally collected real-world data by mapping heterogeneous datasets to a predefined data dictionary, thorough quality checks, and regular updates. This approach supports phenotyping across all PH groups, enables international comparisons, and allows in-depth analysis of rare subtypes, disease progression, treatment responses, and survival rates. Importantly, GoDeep makes clinically relevant research possible that cannot be conducted at the level of a single center, such as validating risk-stratification tools across PH subgroups, evaluating off-label therapies, and investigating newly recognized entities, such as mild PH. By January 2026, data from more than 45,000 individuals worldwide were integrated into GoDeep, making it one of the largest and most diverse PH registries. Offering a scalable, governed, and disease-independent framework for harmonized real-world evidence generation, PVRI GoDeep is a powerful platform to deepen the understanding of PH and support the development of clinical guidelines for the diagnosis and treatment of PH.

Background: Pulmonary vascular remodeling is a progressive pathological process characterized by functional alterations within pulmonary artery smooth muscle cells (PASMCs) and adventitial fibroblasts (PAAFs). Mechanisms driving the transition to a diseased phenotype remain elusive. Methods: We combined transcriptomic and proteomic profiling with phenotypic characterization of source-matched cells from healthy controls and individuals with idiopathic pulmonary arterial hypertension (IPAH). Bidirectional cellular crosstalk was examined using direct and indirect co-culture models, and phenotypic responses were assessed via transcriptome analysis. Results: PASMC and PAAF undergo distinct phenotypic shifts during pulmonary vascular remodeling, with limited shared features, such as reduced mitochondrial content and hyperpolarization. IPAH-PASMC exhibit increased glycosaminoglycan production and downregulation of contractile machinery, while IPAH-PAAF display a hyperproliferative phenotype. We identified alterations in extracellular matrix components, including laminin and collagen, alongside pentraxin-3 and hepatocyte growth factor, as potential regulators of PASMC phenotypic transitions mediated by PAAF. Conclusions: While PASMCs and PAAFs retain their core cellular identities, they acquire distinct disease-associated states. These findings provide new insights into the dynamic interplay of pulmonary vascular mesenchymal cells in disease pathogenesis. Funding: This work was supported by Cardio-Pulmonary Institute EXC 2026 390649896 (GK) and Austrian Science Fund (FWF) grant I 4651-B (SC).

BACKGROUND: Patients with COPD frequently demonstrate pulmonary hypertension (PH). Severe PH in patients with COPD, identified by pulmonary vascular resistance (PVR) of > 5 Wood units (WU), is closely linked to impaired transplant-free survival. The impact of PH- targeting pharmacotherapy in this context remains unclear. RESEARCH QUESTION: Is PH-targeted therapy associated with improved transplant-free survival in patients with COPD and PH? STUDY DESIGN AND METHODS: This study included Pulmonary Vascular Research Institute GoDeep meta-registry patients with COPD and PH and available right heart catheterization at diagnosis. We investigated PH-targeted therapy prevalence and its association with transplant-free survival using diverse statistical methods, including Cox regression and subgroup analyses based on PH severity, comorbidities, and pulmonary function test results. Immortal time bias was addressed through a landmark approach. RESULTS: As of December 2023, the GoDeep meta-registry included 26,981 patients (28% in PH group 1, 13% in PH group 2, 12% in PH group 3, 10% in PH group 4, 2% in PH group 5, 26% undefined, and 9% control participants). Of these, 836 patients had a diagnosis of COPD with PH and were included in this analysis, with median age of 66 years (interquartile range [IQR], 59-73 years), FEV1 of 51% predicted (IQR, 34%-69% predicted), mPAP of 35 mm Hg (IQR, 28-44 mm Hg), PVR of 5 WU (IQR, 4-8 WU), cardiac index of 2.5 L/min/m(2) (IQR, 2.0-2.9 L/min/m(2)), and mostly World Health Organization functional class III were included. Five-year transplant-free survival was 42%, significantly worse than in group 1 PH. A multivariable Cox proportional hazards model identified PVR, but not FEV1, as a major predictor of outcome. Four hundred eighteen patients (50%) received phosphodiesterase-5 inhibitor (PDE5i) therapy, which was associated with significantly reduced mortality: hazard ratio of 0.65 (IQR, 0.57-0.75) for the entire cohort of patients with COPD and PH and of 0.83 (IQR, 0.74-0.94) when performing landmark analysis. This PDE5i effect was reproduced robustly when performing subgroup analyses for patients with moderate to severe PH, various comorbidities, and supplemental oxygen requirement and when assessing the impact of unobserved confounders. INTERPRETATION: Patients with COPD and PH exhibit poor transplant-free survival, with PVR being a predictor of mortality. In this meta-registry, PDE5i therapy was associated with a significant reduction in mortality across all tested models.

Sarcocystis calchasi is a pathogenic apicomplexan parasite affecting avian species of several orders. To complete its heteroxenous life cycle, S. calchasi infects a wide range of avian intermediate hosts and accipitriform raptors serve as definitive hosts. The mechanism of invasion into host cells is largely understood in other apicomplexan parasites, particularly Toxoplasma gondii, which also belongs to the family of Sarcocystidae. However, Sarcocystis species exhibit several distinguishing features in their life cycles and in their secretory organelles. The composition of secretory pathogenesis determinants, including surface antigens and secretory organelle proteins, has been shown to differ between closely related species, as evidenced by Sarcocystis neurona. In this study, whole-genome sequencing was performed on S. calchasi, and transcriptomes were determined by RNA-seq of S. calchasi sporozoites and bradyzoites derived from intermediate and definitive hosts as well as from merozoites propagated in primary embryonal pigeon liver cells. The S. calchasi genome contains homologs of genes encoding proteins associated with the well-conserved host invasion machinery like AMA1 and rhoptry neck proteins, albeit with a markedly reduced number of genes encoding surface antigens, rhoptry and dense granule proteins in comparison to T. gondii. Our transcriptome analysis revealed different gene expression profiles between S. calchasi sporozoites, merozoites and bradyzoites. Factors associated with host cell attachment (surface antigens and micronemal proteins) were expressed predominantly either in sporozoites and merozoites or in bradyzoites. As sporozoites and merozoites invade various intermediate hosts and cell types whereas bradyzoites enter definitive host intestinal epithelium, their differential expression patterns indicate that S. calchasi utilizes different sets of secretory pathogenesis determinants for host cell attachment and invasion, depending on the type of host and cell.

Chronic thromboembolic pulmonary hypertension (CTEPH) leads to progressive right ventricular (RV) dysfunction. Pulmonary endarterectomy (PEA) is an established treatment for these patients; however, the molecular mechanisms underlying RV remodeling and recovery remain poorly understood. Here we show that RNA sequencing and histological analysis of RV free wall and septal biopsies from patients with CTEPH reveal extracellular matrix enrichment and cytoskeletal remodeling before PEA. These changes were consistent across an exploratory and confirmatory cohort. Post-PEA samples showed reversal of both histological and transcriptional abnormalities. Key signaling molecules-ANKRD1, IL7R and SERPINE1-were implicated in fibrotic and proliferative pathways, as confirmed in human tissues and experimental models. Our findings identify a reversible gene expression and structural remodeling signature in the RV, linking hemodynamic unloading with molecular recovery. These insights suggest potential therapeutic targets to modulate maladaptive RV remodeling in CTEPH and improve outcomes beyond surgical intervention.

RATIONALE: The development of acute respiratory distress syndrome (ARDS) in COVID-19 patients is associated with an excessive systemic inflammatory response, leading to diffuse alveolar damage and endothelial dysfunction. Tumor Necrosis Factor Superfamily Member 10 (TNFSF10) is a proinflammatory immunoregulatory cytokine that directly induces apoptosis in alveolar epithelial cells, resulting in the disruption of the alveolar epithelial barrier's structure and function and the progression of alveolar edema. The role of TNFSF10 in COVID-19-associated lung damage remains undefinedMETHODS: Levels of TNFSF10 were measured in bronchoalveolar lavage fluid (BALF) of patients with COVID-19-ARDS and non-COVID-19 patients. Human precision cut lung slices (hPCLS), human induced pluripotent stem cell (hiPSC)-derived, vascularized lung organoids were infected with SARS-CoV2 (CoV2) and expression of TNFSF10 was analyzed by ELISA and qPCR. C57BL/6 wild-type (wt) mice and Tnfsf10-/- mice were orotracheally infected with mouse-adapted CoV2 and wt mice were treated with TNFSF10-neutralising antibody intraperitoneally. Histopathological changes were analysed by light microscopy of haematoxylin-eosin-stained lung sections on day 7 post-infection. The total protein concentration in BALF was analysed as an indicator of enhanced epithelial-endothelial barrier permeability, LDH activity in BALF was analysed a marker of lung tissue injury. Immune cell populations in BALF of infected mice were assessed by flow cytometry. The relative amount of CoV2 RNA in lungs was measured by qPCR. Whole lung single-cell RNA sequencing (scRNAseq) was performed for wt mice over the course of CoV2 infection. RESULTS: Increased levels of TNFSF10 were observed in BALF of COVID-19-ARDS patients, in supernatant of ex-vivo CoV2-infected hPCLS and in BALF of CoV2-infected wt mice. Tnfsf10-/- mice afterCoV2 infection demonstrated significantly improved survival, reduced barrier dysfunction and less inflammatory pulmonary infiltrates. TNFSF10 significantly induced alveolar epithelial apoptosis in ex vivo and in vivo models. Analysis of scRNAseq data from the lungs of virus-infected wtmice revealed a substantial contribution to TNFSF10 expression from endothelial subsets, including macrovascular (maEC), microvascular (miEC), Car4high, Tmem100high, and lymphatic endothelial cells (EC), along with a notable expansion of defined endothelial cell clusters. Data from CoV2-infected hiPSC-derived vascularized lung organoids confirmed the contribution of the lung endothelium to the inflammatory response. CONCLUSIONS: Obtained results indicate that TNFSF10 considerably contributes to CoV2-induced lung injury. We aim to further identify the molecular mechanisms of TNFSF10-mediated lung damage, and particularly focus on the novel role of the vascular compartment and its contribution to inflammatory lung injury, to ultimately define novel targets for treatment of CoV-induced ARDS.

The protein interactome of p65/RELA, the most active subunit of the transcription factor (TF) NF-κB, has not been previously determined in living cells. Using p65-miniTurbo fusion proteins and biotin tagging, we identify >350 RELA interactors from untreated and IL-1α-stimulated cells, including many TFs (47% of all interactors) and >50 epigenetic regulators belonging to different classes of chromatin remodeling complexes. A comparison with the interactomes of two point mutants of p65 reveals that the interactions primarily require intact dimerization rather than DNA-binding properties. A targeted RNAi screen for 38 interactors and subsequent functional transcriptome and bioinformatics studies identify gene regulatory (sub)networks, each controlled by RELA in combination with one of the TFs ZBTB5, GLIS2, TFE3/TFEB, or S100A8/A9. The large, dynamic and versatile high-resolution interactome of RELA and its gene regulatory logics provides a rich resource and a new framework for explaining how RELA cooperativity determines gene expression patterns.

BACKGROUND:Sex-based differences in morbidity and mortality in pulmonary hypertension (PH) are underexplored, yet understanding these differences is vital for improving clinical management. This study investigates the influence of sex on survival of patients with PH in dependency of various disease conditions. METHODS:The PVRI GoDeep meta-registry integrates data from international PH registries, of which we analysed 21,123 incident hemodynamically fully characterised patients with PH. Survival analyses employed Kaplan-Meier and Cox proportional hazards models, adjusted for confounders and subjected to sensitivity analyses. FINDINGS:Male patients consistently showed significantly higher mortality than females across the overall PH population (hazard ratio 1.36 [1.23, 1.50] after adjustment) and within PAH and non-PAH groups. These sex differences in survival persisted regardless of P(A)H severities, age and obesity, cardiovascular diseases, and PAH-specific therapies. The male survival disadvantage was noted across low-, intermediate-, and high-risk groups of the ESC/ERS 2022, REVEAL lite 2, and COMPERA 4-strata scores, but not the REVEAL 2.0 risk score, which incorporates male sex as non-modifiable factor. Stratification by race revealed that male sex was associated with worse survival in White patients, but not in Black or Asian patients with PH. INTERPRETATION:Male patients with PH exhibit significantly higher mortality risks than females across both PAH and non-PAH PH groups. This disparity persists regardless of PH severity, underlying cause, age, obesity, comorbidities, or treatment status, though race might modify the observed risk difference. These insights provide new avenues for investigating underlying mechanisms and suggest including male sex as an independent factor in clinical risk assessment tools. FUNDING:This work is funded by the Pulmonary Vascular Research Institute (PVRI) and the Cardiovascular Medical Research and Education Fund (CMREF), NIH.

Portopulmonary hypertension (PoPH), a type of pulmonary arterial hypertension (PAH) in patients with liver disease, is associated with high morbidity and mortality. The relationship between cardiopulmonary hemodynamics, PAH therapy, and survival in PoPH remains unclear. We performed a retrospective cohort study of PoPH patients from the international pulmonary hypertension (PH) meta-registry, PVRI GoDeep. PAH was defined by a mean pulmonary arterial pressure > 20 mmHg, pulmonary arterial wedge pressure ≤ 15 mmHg, and a pulmonary vascular resistance (PVR) > 2 Wood Units. PoPH diagnoses were assigned by each center's PH specialist based on international guidelines at the time of enrollment. 246 incident PoPH patients met eligibility criteria and were included in the analysis, equally split between males (51%) and females (49%), with a median age of 54 years. When compared to both patients with IPAH and those with other subtypes of PAH (not classified as PoPH or IPAH), those with PoPH had significantly lower 5-year survival rates (46% vs. 68% vs. 65%, log-rank p < 0.001). Amongst the PoPH patients, however, there was no significant difference in 5-year survival when dichotomized by disease severity, either by a PVR of 5 Wood Units or a CI of 2.5 L/min/m2. Treatment of the PoPH patients with PAH-targeted therapies was associated with significantly higher 5-year survival rates compared to those not receiving such treatments, as shown by Kaplan-Meier analysis. This survival benefit was observed for PDE5i (50% vs. 34%, log-rank p = 0.029), ERA (58% vs. 34%, log-rank p < 0.001), and the combination of PDE5i and/or ERA (51% vs. 22%, log-rank p < 0.001), as well as any PAH-targeting treatment (50% vs. 26%, log-rank p = 0.007). Corresponding survival advantage was noted when including only PoPH patients with MELD Score ≥ 13. PoPH is a disease with significantly worse long-term survival than other PAH subtypes, but targeted PAH therapy is associated with a robust survival benefit. Survival did not differ across high-risk PVR and cardiac index thresholds, suggesting the factors that influence prognosis and survival in PoPH may be unique as compared to other PAH subtypes, and warrant further investigation.

Lung vessel remodeling leads to increased pulmonary vascular resistance, causing pulmonary arterial hypertension (PAH), and consequently right ventricular hypertrophy and failure. In patients suffering from systemic sclerosis (SSc), PAH can occur and is a life-threatening complication. Dysregulation of immune processes plays a crucial role in pulmonary vascular remodeling, as has previously been shown in Fos-related antigen-2 (Fra-2) transgenic (TG) mice, a model of SSc-PAH. Here, we investigate whether vascular remodeling in the Fra-2 TG model is driven by type 2 inflammation and is associated with vascular hyperresponsiveness, an important feature of PAH pathobiology. Basal pulmonary arterial pressure and pulmonary vascular responsiveness to hypoxic ventilation and serotonin were increased in isolated, perfused, and ventilated lungs of Fra-2 TG mice compared with wild-type (WT) littermates. Similarly, contractile responses of isolated intrapulmonary arteries were elevated in Fra-2 TG mice. We also observed increased expression of contractile genes in Fra-2 overexpressing human pulmonary arterial smooth muscle cells (PASMCs) with elevated intracellular calcium levels after interleukin (IL)-13 stimulation. These findings were corroborated by transcriptomic data highlighting dysregulation of vascular smooth muscle cell contraction and type 2 inflammation in Fra-2 TG mice. In vivo, type 2-specific anti-inflammatory treatment with IL-13 neutralizing antibodies improved vascular remodeling in Fra-2 TG mice, similar to corticosteroid treatment with budesonide. Our results underscore the importance of type 2 inflammation and its potential therapeutic value in PAH-associated pulmonary vascular remodeling and hyperresponsiveness in SSc-PAH. NEW & NOTEWORTHY In patients suffering from systemic sclerosis (SSc), pulmonary arterial hypertension (PAH) is a life-threatening complication linked to immune dysregulation. Preclinical analyses in Fos-related antigen-2 (Fra-2) transgenic (TG) mice, a model of SSc-PAH, identify type 2 inflammation as a key driver of vascular remodeling. Anti-inflammatory treatment targeting type 2 inflammation via IL-13 neutralizing antibodies improved pulmonary vascular remodeling. Thus, type 2-specific anti-inflammatory treatment may be a promising therapeutic approach in SSc-PAH.

Introduction Sex-based differences in morbidity and mortality for pulmonary hypertension (PH) are insufficiently addressed in current research. However, recognizing these differences is crucial for optimal clinical management and improving outcomes. This study assesses the effect of sex on survival among PH patients, while accounting for disease severity, comorbidities, treatment, and race. Methods We analyzed data from the PVRI GoDeep meta-registry, including all incident patients with complete hemodynamic profiles. Survival was evaluated using Kaplan-Meier and Cox proportional hazards models, adjusted for various confounders. Analyses included both PAH and non-PAH groups and risk assessment by the ESC/ERS 2022, REVEAL lite 2, and COMPERA 4-strata scores. All analyses were performed using R (The R Foundation). Results A total of 19,663 incident PH patients were included in the analysis, with 5,581 patients (28%) diagnosed with Group 1 PH and a median age of 64 years [IQR: 52-73]. Among these, male patients (8,704, 44%) had a significantly higher mortality risk than female patients across the entire cohort and within all PH subtypes. The adjusted hazard ratio for mortality in male versus female patients was 1.391 [95% CI: 1.260-1.536] in the overall population and 1.404 [95% CI: 1.264-1.561] for those with PAH. This survival difference was consistent across various severity levels, age groups, and in the presence of comorbidities such as obesity and cardiovascular diseases, as well as among those receiving PAH-specific therapies as well as patients who remained without treatment during the observation period. Notably, male disadvantage in survival was observed in low, intermediate, and high-risk categories for ESC/ERS 2022, REVEAL lite 2, and COMPERA scores but not within REVEAL 2.0, which includes male sex as a non-modifiable risk factor. Racial analysis revealed a greater mortality risk for males among White patients, with no significant differences noted in Black or Asian populations. Conclusion Our PVRI GoDeep meta-registry analysis demonstrates that male PH patients face higher mortality risk across both PAH and non-PAH groups, independent of disease etiology, age, severity, comorbidities, and treatment factors, with this risk amplified in White patients. These findings suggest that male sex should be further considered as a risk factor to refine predictive models for survival in PH.