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BackgroundPulmonary hypertension (PH) can occur as a complication of schistosomiasis. In humans, schistosomiasis-PH persists despite antihelminthic therapy and parasite eradication. We hypothesized that persistent disease arises as a consequence of exposure repetition.MethodsFollowing intraperitoneal sensitization, mice were experimentally exposed to Schistosoma eggs by intravenous injection, either once or three times repeatedly. The phenotype was characterized by right heart catheterization and tissue analysis.ResultsFollowing intraperitoneal sensitization, a single intravenous Schistosoma egg exposure resulted in a PH phenotype that peaked at 7-14 days, followed by spontaneous resolution. Three sequential exposures resulted in a persistent PH phenotype. Inflammatory cytokines were not significantly different between mice exposed to one or three egg doses, but there was an increase in perivascular fibrosis in those who received three egg doses. Significant perivascular fibrosis was also observed in autopsy specimens from patients who died of this condition.ConclusionsRepeatedly exposing mice to schistosomiasis causes a persistent PH phenotype, accompanied by perivascular fibrosis. Perivascular fibrosis may contribute to the persistent schistosomiasis-PH observed in humans with this disease.

In order to intervene appropriately and develop disease-modifying therapeutics for pulmonary arterial hypertension, it is crucial to understand the mechanisms of disease pathogenesis and progression. We herein discuss four topics of disease mechanisms that are currently highly debated, yet still unsolved, in the field of pulmonary arterial hypertension. Is pulmonary arterial hypertension a cancer-like disease? Does the adventitia play an important role in the initiation of pulmonary vascular remodeling? Is pulmonary arterial hypertension a systemic disease? Does capillary loss drive right ventricular failure? While pulmonary arterial hypertension does not replicate all features of cancer, anti-proliferative cancer therapeutics might still be beneficial in pulmonary arterial hypertension if monitored for safety and tolerability. It was recognized that the adventitia as a cell-rich compartment is important in the disease pathogenesis of pulmonary arterial hypertension and should be a therapeutic target, albeit the data are inconclusive as to whether the adventitia is involved in the initiation of neointima formation. There was agreement that systemic diseases can lead to pulmonary arterial hypertension and that pulmonary arterial hypertension can have systemic effects related to the advanced lung pathology, yet there was less agreement on whether idiopathic pulmonary arterial hypertension is a systemic disease per se. Despite acknowledging the limitations of exactly assessing vascular density in the right ventricle, it was recognized that the failing right ventricle may show inadequate vascular adaptation resulting in inadequate delivery of oxygen and other metabolites. Although the debate was not meant to result in a definite resolution of the specific arguments, it sparked ideas about how we might resolve the discrepancies by improving our disease modeling (rodent models, large-animal studies, studies of human cells, tissues, and organs) as well as standardization of the models. Novel experimental approaches, such as lineage tracing and better three-dimensional imaging of experimental as well as human lung and heart tissues, might unravel how different cells contribute to the disease pathology.

Tricuspid annular plane systolic excursion (TAPSE) is usually measured with M‐mode using sector line, however, this may not align with the anatomical shortening of the right ventricular (RV). In this study, we compared the different methods to measure TAPSE using three different reference lines (sector line, anatomical line, and apico‐annular line). We included 148 patients diagnosed with pulmonary arterial hypertension (PAH) who underwent TTE and right heart catheterization within 2 weeks of each other. TAPSE was measured by M‐mode (sector, anatomical), 2D (sector, anatomical), or as tricuspid apico‐annular displacement (TAAD). Agreement between measures was assessed using coefficient of variation (COV), Spearman's correlation, and Bland–Altman analysis. Receiver–operating characteristics and Kaplan–Meier analysis were used to explore associations with the combined outcome of death or lung transplantation at 5 years. There was a good concordance between anatomical and sector M‐mode with a COV of 15.5 ± 1.6% and a bias of −0.6 ± 3.2 mm. In contrast, anatomical M‐mode TAPSE and TAAD differed significantly with the mean difference of 3.3 ± 3.8 mm (COV 30.5 ± 6.1%; p < 0.0001). Among the different 2D methods, anatomical 2D agreed well with anatomical M‐mode TAPSE (COV of 11.8 ± 2.0%; r = 0.89; p < 0.0001). Among the five methods, TADD had the strongest association with the combined endpoint of death or transplantation at 5 years (C‐statistic 0.64, 95% confidence interval [CI] 0.57–0.71). We concluded that different measures of TAPSE are not interchangeable. [ABSTRACT FROM AUTHOR]

Hedgehog (Hh) pathway inhibitors are clinically effective in treatment of basal cell carcinoma and medulloblastoma, but fail therapeutically or accelerate progression in treatment of endodermally derived colon and pancreatic cancers. In bladder, another organ of endodermal origin, we find that despite its initial presence in the cancer cell of origin Sonic hedgehog (Shh) expression is invariably lost during progression to invasive urothelial carcinoma. Genetic blockade of stromal response to Shh furthermore dramatically accelerates progression and decreases survival time. This cancer-restraining effect of Hh pathway activity is associated with stromal expression of BMP signals, which stimulate urothelial differentiation. Progression is dramatically reduced by pharmacological activation of BMP pathway activity with low-dose FK506, suggesting an approach to management of human bladder cancer.

This study analyzed microarray data of right ventricular (RV) tissue from rats exposed to pulmonary embolism to understand the initial dynamic transcriptional response to mechanical stress and compare it with experimental pulmonary hypertension (PH) models. The dataset included samples harvested from 55 rats at 11 different time points or RV locations. We performed principal component analysis (PCA) to explore clusters based on spatiotemporal gene expression. Relevant pathways were identified from fast gene set enrichment analysis using PCA coefficients. The RV transcriptomic signature was measured over several time points, ranging from hours to weeks after an acute increase in mechanical stress, and was found to be highly dependent on the severity of the initial insult. Pathways enriched in the RV outflow tracts of rats at 6 weeks after severe PE share many commonalities with experimental PH models, but the transcriptomic signature at the RV apex resembles control tissue. The severity of the initial pressure overload determines the trajectory of the transcriptomic response independent of the final afterload, but this depends on the location where the tissue is biopsied. Chronic RV pressure overload due to PH appears to progress toward similar transcriptomic endpoints. [ABSTRACT FROM AUTHOR]

Microorganisms colonize the human body. The lungs and respiratory tract, previously believed to be sterile, harbor diverse microbial communities and the genomes of bacteria (bacteriome), viruses (virome), and fungi (mycobiome). Recent advances in amplicon and shotgun metagenomic sequencing technologies and data-analyzing methods have greatly aided the identification and characterization of microbial populations from airways. The respiratory microbiome has been shown to play roles in human health and disease and is an area of rapidly emerging interest in pulmonary medicine. In this review, we provide updated information in the field by focusing on four lung conditions, including asthma, chronic obstructive pulmonary disease, cystic fibrosis, and idiopathic pulmonary fibrosis. We evaluate gut, oral, and upper airway microbiomes and how they contribute to lower airway flora. The discussion is followed by a systematic review of the lower airway microbiome in health and disease. We conclude with promising research avenues and implications for evolving therapeutics. [ABSTRACT FROM AUTHOR]

Dysfunctional bone morphogenetic protein receptor-2 (BMPR2) signaling is implicated in the pathogenesis of pulmonary arterial hypertension (PAH). We used a transcriptional high-throughput luciferase reporter assay to screen 3,756 FDA-approved drugs [...]

S100A4/Mts-overexpressing mice have thick elastic laminae and mild pulmonary arterial hypertension (PAH), and the occasional older mouse develops occlusive neointimal lesions and perivascular inflammation. We hypothesized that a vasculotropic virus could induce neointimal lesions in the SI00A4/Mts1 mouse by facilitating breakdown of elastin and migration and proliferation of smooth muscle cells. To test this hypothesis, we infected SI00A4/Mtsl mice with gammaherpesvirus 68 ([gamma]HV68). We observed, 6 mo after [gamma]HV68 [4 x [l0.sup.3] plaque-forming units (PFU)], perivascular inflammation in 10/15 S 100A4/Mts I mice and occlusive neointimal formation in 3/10 mice, accompanied by striking degradation of elastin. We then compared the early response after high-dose [gamma]HV68 (4 x [10.sup.6] PFU) in C57B1/6 and SI00A4/Mtsl mice. In S100A4/Mtsl mice only, significant PAH, muscularization of distal vessels, and elastase activity were observed 6 wk after [gamma]HV68. These features resolved by 3 mo without neointimal formation. We therefore infected mice with the M1-[gamma]/HV68 strain that reactivates from latency with higher efficiency and observed neointimal lesions at 3 mo in 2/5 C57B1/6 (5-9% of vessels) and in 5/5 S100A4/Mtsl mice (13-40% of vessels) accompanied by mild PAH, heightened lung elastase activity, and intravascular viral expression. This suggested that enhanced generation of elastin peptides in S100A4/Mtsl mice may promote increased viral entry in the vessel wall. Using SI00A4/Mtsl PA organ culture, we showed, in response to elastase activity, heightened production of elastin peptides associated with invasion of inflammatory cells and intravascular viral antigen. We therefore propose that early viral access to the vessel wall may be a critical determinant of the extent of vascular pathology following reactivation. pulmonary hypertension; [gamma] herpes virus; pulmonary vascular occlusive disease