RESUMO
Over the last 20 years, there has been a progressive increase in the incidence of pulmonary embolism (PE) diagnosis in the United States, Europe, and Australia. Increased use of computed tomography pulmonary angiography has likely contributed in part to this rising incidence. However, it is pertinent to note that the burden of comorbidities associated with PE, such as malignancy, obesity, and advanced age, has also increased over the past 20 years. Time-trend analysis in North American, European, and Asian populations suggests that mortality rates associated with PE have been declining. The reported improved survival rates in PE over the past 20 years are likely, at least in part, to be the result of better adherence to guidelines, improved risk stratification, and enhanced treatment. Factors contributing to the development of venous thromboembolism (VTE) include stasis of blood, hypercoagulability, endothelial injury, and inflammation. In 70 to 80% of cases of PE, the thrombi embolizes from the proximal deep veins of the lower extremities and pelvis. Strong risk factors for VTE include lower extremity fractures and surgeries, major trauma, and hospitalization within the previous 3 months for acute myocardial infarction or heart failure with atrial fibrillation. Acute PE causes several pathophysiological responses including hypoxemia and right ventricle (RV) failure. The latter is a result of pulmonary artery occlusion and associated vasoconstriction. Hemodynamic compromise from RV failure is the principal cause of poor outcome in patients with acute PE.
RESUMO
BACKGROUND: Preterm birth preceded by spontaneous preterm labour often occurs in the clinical setting of sterile intra-amniotic inflammation (SIAI), a condition that currently lacks treatment. METHODS: Proteomic and scRNA-seq human data were analysed to evaluate the role of IL-6 and IL-1α in SIAI. A C57BL/6 murine model of SIAI-induced preterm birth was developed by the ultrasound-guided intra-amniotic injection of IL-1α. The blockade of IL-6R by using an aIL-6R was tested as prenatal treatment for preterm birth and adverse neonatal outcomes. QUEST-MRI evaluated brain oxidative stress in utero. Targeted transcriptomic profiling assessed maternal, foetal, and neonatal inflammation. Neonatal biometrics and neurodevelopment were tested. The neonatal gut immune-microbiome was evaluated using metagenomic sequencing and immunophenotyping. FINDINGS: IL-6 plays a critical role in the human intra-amniotic inflammatory response, which is associated with elevated concentrations of the alarmin IL-1α. Intra-amniotic injection of IL-1α resembles SIAI, inducing preterm birth (7% vs. 50%, p = 0.03, Fisher's exact test) and neonatal mortality (18% vs. 56%, p = 0.02, Mann-Whitney U-test). QUEST-MRI revealed no foetal brain oxidative stress upon in utero IL-1α exposure (p > 0.05, mixed linear model). Prenatal treatment with aIL-6R abrogated IL-1α-induced preterm birth (50% vs. 7%, p = 0.03, Fisher's exact test) by dampening inflammatory processes associated with the common pathway of labour. Importantly, aIL-6R reduces neonatal mortality (56% vs. 22%, p = 0.03, Mann-Whitney U-test) by crossing from the mother to the amniotic cavity, dampening foetal organ inflammation and improving growth. Beneficial effects of prenatal IL-6R blockade carried over to neonatal life, improving survival, growth, neurodevelopment, and gut immune homeostasis. INTERPRETATION: IL-6R blockade can serve as a strategy to treat SIAI, preventing preterm birth and adverse neonatal outcomes. FUNDING: NICHD/NIH/DHHS, Contract HHSN275201300006C. WSU Perinatal Initiative in Maternal, Perinatal and Child Health.
