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The microRNA miR-1 is an important regulator of muscle phenotype including cardiac muscle. Down-regulation of miR-1 has been shown to occur in left ventricular hypertrophy but its contribution to right ventricular hypertrophy in pulmonary arterial hypertension are not known. Previous studies have suggested that miR-1 may suppress transforming growth factor-beta (TGF-β) signalling, an important pro-hypertrophic pathway but only indirect mechanisms of regulation have been identified. We identified the TGF-β type 1 receptor (TGF-βR1) as a putative miR-1 target. We therefore hypothesized that miR-1 and TGF-βR1 expression would be inversely correlated in hypertrophying right ventricle of rats with pulmonary arterial hypertension and that miR-1 would inhibit TGF-β signalling by targeting TGF-βR1 expression. Quantification of miR-1 and TGF-βR1 in rats treated with monocrotaline to induce pulmonary arterial hypertension showed appropriate changes in miR-1 and TGF-βR1 expression in the hypertrophying right ventricle. A miR-1-mimic reduced enhanced green fluorescent protein expression from a reporter vector containing the TGF-βR1 3'- untranslated region and knocked down endogenous TGF-βR1. Lastly, miR-1 reduced TGF-β activation of a (mothers against decapentaplegic homolog) SMAD2/3-dependent reporter. Taken together, these data suggest that miR-1 targets TGF-βR1 and reduces TGF-β signalling, so a reduction in miR-1 expression may increase TGF-β signalling and contribute to cardiac hypertrophy.

Pulmonary arterial hypertension (PAH) is characterised by remodelling of the pulmonary vasculature leading to right ventricular hypertrophy. Here, we show that miR‐322‐5p (the rodent orthologue of miR‐424‐5p) expression is decreased in the right ventricle of monocrotaline‐treated rats, a model of PAH, whereas a putative target insulin‐like growth factor 1 (IGF‐1) is increased. IGF‐1 mRNA was enriched 16‐fold in RNA immunoprecipitated with Ago2, indicating binding to miR‐322‐5p. In cell transfection experiments, miR‐322‐5p suppressed the activity of a luciferase reporter containing a section of the IGF‐1 3′ untranslated region (UTR) as well as IGF‐1 mRNA and protein levels. Taken together, these data suggest that miR‐322 targets IGF‐1, a process downregulated in PAH‐related RV hypertrophy. miRNA regulate various cell processes, which often go awry in disease. Here, we look at miR‐322‐5p, a miRNA downregulated in the hypertrophying right ventricle of rats with drug‐induced pulmonary arterial hypertension (PAH). Concomitantly, IGF‐1 is upregulated in these enlarged right ventricles. We confirmed that miR‐322‐5p targets IGF‐1, raising the possibility that reduced miR‐322‐5p contributes to the development of hypertrophy in PAH. By Mariana Ruiz [Public domain], via Wikimedia Commons.

The lungs are the primary target of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, with severe hypoxia being the cause of death in the most critical cases. Coronavirus disease 2019 (COVID-19) is extremely heterogeneous in terms of severity, clinical phenotype and, importantly, global distribution. Although the majority of affected patients recover from the acute infection, many continue to suffer from late sequelae affecting various organs, including the lungs. The role of the pulmonary vascular system during the acute and chronic stages of COVID-19 has not been adequately studied. A thorough understanding of the origins and dynamic behaviour of the SARS-CoV-2 virus and the potential causes of heterogeneity in COVID-19 is essential for anticipating and treating the disease, in both the acute and the chronic stages, including the development of chronic pulmonary hypertension. Both COVID-19 and chronic pulmonary hypertension have assumed global dimensions, with potential complex interactions. In this Review, we present an update on the origins and behaviour of the SARS-CoV-2 virus and discuss the potential causes of the heterogeneity of COVID-19. In addition, we summarize the pathobiology of COVID-19, with an emphasis on the role of the pulmonary vasculature, both in the acute stage and in terms of the potential for developing chronic pulmonary hypertension. We hope that the information presented in this Review will help in the development of strategies for the prevention and treatment of the continuing COVID-19 pandemic.In this Review, the authors discuss the potential causes of the heterogeneity of COVID-19 and summarize the pathobiology of the disease, with an emphasis on the role of the pulmonary vasculature in the acute stage and the potential for developing chronic pulmonary hypertension.

The microRNA miR-1 is an important regulator of muscle phenotype including cardiac muscle. Down-regulation of miR-1 has been shown to occur in left ventricular hypertrophy but its contribution to right ventricular hypertrophy in pulmonary arterial hypertension are not known. Previous studies have suggested that miR-1 may suppress transforming growth factor-beta (TGF-[beta]) signalling, an important pro-hypertrophic pathway but only indirect mechanisms of regulation have been identified. We identified the TGF-[beta] type 1 receptor (TGF-[beta]R1) as a putative miR-1 target. We therefore hypothesized that miR-1 and TGF-[beta]R1 expression would be inversely correlated in hypertrophying right ventricle of rats with pulmonary arterial hypertension and that miR-1 would inhibit TGF-[beta] signalling by targeting TGF-[beta]R1 expression. Quantification of miR-1 and TGF-[beta]R1 in rats treated with monocrotaline to induce pulmonary arterial hypertension showed appropriate changes in miR-1 and TGF-[beta]R1 expression in the hypertrophying right ventricle. A miR-1-mimic reduced enhanced green fluorescent protein expression from a reporter vector containing the TGF-[beta]R1 3'- untranslated region and knocked down endogenous TGF-[beta]R1. Lastly, miR-1 reduced TGF-[beta] activation of a (mothers against decapentaplegic homolog) SMAD2/3-dependent reporter. Taken together, these data suggest that miR-1 targets TGF-[beta]R1 and reduces TGF-[beta] signalling, so a reduction in miR-1 expression may increase TGF-[beta] signalling and contribute to cardiac hypertrophy.

In summary, among COVID-19 patients admitted to the ICU, IL-6 normalization had a strong negative association with mortality and outcomes reflecting respiratory and renal organ dysfunction. [...]the associations remained significant after adjusting for baseline APACHE-III score. [...]our study suggests that serial IL-6 measurement in clinical practice can support prognostication and off-label application of treatments. All Patients IL-6 < 7 pg/mL IL-6 ≥ 7 pg/mL p-value N 184 25 159 Age 54.8 ± 15.5 50.9 ± 17.1 55.4 ± 15.2 0.224 Male 123 (66.3%) 13 (52.0%) 110 (69.2%) 0.142 Comorbidities DM 62 (33.7%) 10 (40.0%) 52 (32.7%) 0.624 CAD 21 (11.4%) 3 (12.0%) 18 (11.9%) 1.000 COPD 16 (8.7%) 2 (8.0%) 14 (8.8%) 1.000 CKD 39 (21.2%) 3 (12.0%) 36 (22.6%) 0.3436 Cirrhosis 10 (5.4%) 1 (4.0%) 9 (5.7%) 1.00 CHF 21 (11.4%) 1 (4.0%) 20 (12.6%) 0.317 Obesity 83 (45.1%) 11 (44.0%) 72 (45.2%) 1.000 APACHE-III Scores 81.7 ± 36.0 63.0 ± 28.6 84.6 ± 36.3 0.002 ARDS 89 (48.4%) 7 (28.0%) 82 (51.6%) 0.002 Baseline IL-6 (pg/mL) 417.0 ± 1022.7 96.7 ± 233.8 467.37 ± 1088.3 <0.001 Days Since First Presentation 1.9 (IQR 1.0–8.6) 1.6 (IQR 1.1–9.5) 2.0 (IQR 1.0–8.5) 0.581 Race 0.783 White 113 (61.4%) 14 (56.0%) 99 (62.3%) Asian 20 (10.9%) 3 (12.0%) 17 (10.7%) Black 27 (14.7%) 5 (20.0%) 22 (13.8%) Native American 7 (3.8%) 2 (8.0%) 5 (3.1%) Pacific Islander 4 (2.2%) 0 (0%) 4 (2.5%) Other 2 (1.1%) 0 (0%) 2 (1.3%) Unknown 11 (6.0%) 1 (4.0%) 10 (6.3%) Hispanic 0.395 Yes 61 (33.2%) 11 (44.0%) 50 (31.4%) No 115 (62.5%) 13 (52.0%) 102 (64.2%) Unknown 8 (4.3%) 1 (4.0%) 7 (4.4%) COVID-19 targeted therapy Steroids 127 (69.0%) 19 (76.0%) 108 (67.9%) 0.563 Tocilizumab 5 (2.7%) 0 (0%) 5 (3.1%) 1.000 Remdesivir 72 (39.1%) 10 (40.0%) 62 (40.0%) 1.000 Outcomes In-hospital Mortality 71 (38.5%) 1 (4.0%) 71 (44.7%) <0.001 NIH Ordinal Scale ≥6 at 2 weeks 111 (60.3%) 8 (32.0%) 103 (64.8%) <0.001 Incident AKI 86 (46.7%) 5 (20.0%) 81 (50.9%) 0.004 Time to IL-6 normalization (Days) – 7(IQR 3–7) – Table 1 Baseline characteristics and outcomes in patients who did and did not achieve normal IL-6 levels on follow-up testing.

Alveolar macrophages (AM) play a central role in initiation and resolution of lung inflammation, but the integration of these opposing core functions is poorly understood. AM expression of cholesterol 25-hydroxylase (CH25H), the primary biosynthetic enzyme for 25-hydroxycholesterol (25HC), far exceeds the expression of macrophages in other tissues, but no role for CH25H has been defined in lung biology. As 25HC is an agonist for the antiinflammatory nuclear receptor, liver X receptor (LXR), we speculated that CH25H might regulate inflammatory homeostasis in the lung. Here, we show that, of natural oxysterols or sterols, 25HC is induced in the inflamed lung of mice and humans. Ch25h-/- mice fail to induce 25HC and LXR target genes in the lung after LPS inhalation and exhibit delayed resolution of airway neutrophilia, which can be rescued by systemic treatment with either 25HC or synthetic LXR agonists. LXR-null mice also display delayed resolution, suggesting that native oxysterols promote resolution. During resolution, Ch25h is induced in macrophages upon their encounter with apoptotic cells and is required for LXR-dependent prevention of AM lipid overload, induction of Mertk, efferocytic resolution of airway neutrophilia, and induction of TGF-β. CH25H/25HC/LXR is, thus, an inducible metabolic axis that programs AMs for efferocytic resolution of inflammation.

IntroductionChronic lung disease, that is, bronchopulmonary dysplasia (BPD) is the most common complication in preterm infants and develops as a consequence of the misguided formation of the gas-exchange area undergoing prenatal and postnatal injury. Subsequent vascular disease and its progression into pulmonary arterial hypertension critically determines long-term outcome in the BPD infant but lacks identification of early, disease-defining changes.MethodsWe link impaired bone morphogenetic protein (BMP) signalling to the earliest onset of vascular pathology in the human preterm lung and delineate the specific effects of the most prevalent prenatal and postnatal clinical risk factors for lung injury mimicking clinically relevant conditions in a multilayered animal model using wild-type and transgenic neonatal mice.ResultsWe demonstrate (1) the significant reduction in BMP receptor 2 (BMPR2) expression at the onset of vascular pathology in the lung of preterm infants, later mirrored by reduced plasma BMP protein levels in infants with developing BPD, (2) the rapid impairment (and persistent change) of BMPR2 signalling on postnatal exposure to hyperoxia and mechanical ventilation, aggravated by prenatal cigarette smoke in a preclinical mouse model and (3) a link to defective alveolar septation and matrix remodelling through platelet derived growth factor-receptor alpha deficiency. In a treatment approach, we partially reversed vascular pathology by BMPR2-targeted treatment with FK506 in vitro and in vivo.ConclusionWe identified impaired BMP signalling as a hallmark of early vascular disease in the injured neonatal lung while outlining its promising potential as a future biomarker or therapeutic target in this growing, high-risk patient population.