Dataset Information

Inflammatory blockade prevents injury to the developing pulmonary gas exchange surface in preterm primates.

ABSTRACT: Perinatal inflammatory stress is associated with early life morbidity and lifelong consequences for pulmonary health. Chorioamnionitis, an inflammatory condition affecting the placenta and fluid surrounding the developing fetus, affects 25 to 40% of preterm births. Severe chorioamnionitis with preterm birth is associated with significantly increased risk of pulmonary disease and secondary infections in childhood, suggesting that fetal inflammation may markedly alter the development of the lung. Here, we used intra-amniotic lipopolysaccharide (LPS) challenge to induce experimental chorioamnionitis in a prenatal rhesus macaque (Macaca mulatta) model that mirrors structural and temporal aspects of human lung development. Inflammatory injury directly disrupted the developing gas exchange surface of the primate lung, with extensive damage to alveolar structure, particularly the close association and coordinated differentiation of alveolar type 1 pneumocytes and specialized alveolar capillary endothelium. Single-cell RNA sequencing analysis defined a multicellular alveolar signaling niche driving alveologenesis that was extensively disrupted by perinatal inflammation, leading to a loss of gas exchange surface and alveolar simplification, with notable resemblance to chronic lung disease in newborns. Blockade of the inflammatory cytokines interleukin-1β and tumor necrosis factor-α ameliorated LPS-induced inflammatory lung injury by blunting stromal responses to inflammation and modulating innate immune activation in myeloid cells, restoring structural integrity and key signaling networks in the developing alveolus. These data provide new insight into the pathophysiology of developmental lung injury and suggest that modulating inflammation is a promising therapeutic approach to prevent fetal consequences of chorioamnionitis.

SUBMITTER: Toth A

PROVIDER: S-EPMC9082785 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Inflammatory blockade prevents injury to the developing pulmonary gas exchange surface in preterm primates.

Toth Andrea A Steinmeyer Shelby S Kannan Paranthaman P Gray Jerilyn J Jackson Courtney M CM Mukherjee Shibabrata S Demmert Martin M Sheak Joshua R JR Benson Daniel D Kitzmiller Joseph J Wayman Joseph A JA Presicce Pietro P Cates Christopher C Rubin Rhea R Chetal Kashish K Du Yina Y Miao Yifei Y Gu Mingxia M Guo Minzhe M Kalinichenko Vladimir V VV Kallapur Suhas G SG Miraldi Emily R ER Xu Yan Y Swarr Daniel D Lewkowich Ian I Salomonis Nathan N Miller Lisa L Sucre Jennifer S JS Whitsett Jeffrey A JA Chougnet Claire A CA Jobe Alan H AH Deshmukh Hitesh H Zacharias William J WJ

Science translational medicine 20220330 638

Perinatal inflammatory stress is associated with early life morbidity and lifelong consequences for pulmonary health. Chorioamnionitis, an inflammatory condition affecting the placenta and fluid surrounding the developing fetus, affects 25 to 40% of preterm births. Severe chorioamnionitis with preterm birth is associated with significantly increased risk of pulmonary disease and secondary infections in childhood, suggesting that fetal inflammation may markedly alter the development of the lung. ...[more]

PMID: 35353543

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Project description:BackgroundPreterm birth preceded by spontaneous preterm labour often occurs in the clinical setting of sterile intra-amniotic inflammation (SIAI), a condition that currently lacks treatment.MethodsProteomic 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.FindingsIL-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.InterpretationIL-6R blockade can serve as a strategy to treat SIAI, preventing preterm birth and adverse neonatal outcomes.FundingNICHD/NIH/DHHS, Contract HHSN275201300006C. WSU Perinatal Initiative in Maternal, Perinatal and Child Health.

Project description:Key pointsImaging techniques such as contrast echocardiography suggest that anatomical intra-pulmonary arteriovenous anastomoses (IPAVAs) are present at rest and are recruited to a greater extent in conditions such as exercise. IPAVAs have the potential to act as a shunt, although gas exchange methods have not demonstrated significant shunt in the normal lung. To evaluate this discrepancy, we compared anatomical shunt with 25-µm microspheres to contrast echocardiography, and gas exchange shunt measured by the multiple inert gas elimination technique (MIGET). Intra-pulmonary shunt measured by 25-µm microspheres was not significantly different from gas exchange shunt determined by MIGET, suggesting that MIGET does not underestimate the gas exchange consequences of anatomical shunt. A positive agitated saline contrast echocardiography score was associated with anatomical shunt measured by microspheres. Agitated saline contrast echocardiography had high sensitivity but low specificity to detect a ≥1% anatomical shunt, frequently detecting small shunts inconsequential for gas exchange.AbstractThe echocardiographic visualization of transpulmonary agitated saline microbubbles suggests that anatomical intra-pulmonary arteriovenous anastomoses are recruited during exercise, in hypoxia, and when cardiac output is increased pharmacologically. However, the multiple inert gas elimination technique (MIGET) shows insignificant right-to-left gas exchange shunt in normal humans and canines. To evaluate this discrepancy, we measured anatomical shunt with 25-µm microspheres and compared the results to contrast echocardiography and MIGET-determined gas exchange shunt in nine anaesthetized, ventilated canines. Data were acquired under the following conditions: (1) at baseline, (2) 2 µg kg-1 min-1 i.v. dopamine, (3) 10 µg kg-1 min-1 i.v. dobutamine, and (4) following creation of an intra-atrial shunt (in four animals). Right to left anatomical shunt was quantified by the number of 25-µm microspheres recovered in systemic arterial blood. Ventilation-perfusion mismatch and gas exchange shunt were quantified by MIGET and cardiac output by direct Fick. Left ventricular contrast scores were assessed by agitated saline bubble counts, and separately by appearance of 25-µm microspheres. Across all conditions, anatomical shunt measured by 25-µm microspheres was not different from gas exchange shunt measured by MIGET (microspheres: 2.3 ± 7.4%; MIGET: 2.6 ± 6.1%, P = 0.64). Saline contrast bubble score was associated with microsphere shunt (ρ = 0.60, P < 0.001). Agitated saline contrast score had high sensitivity (100%) to detect a ≥1% shunt, but low specificity (22-48%). Gas exchange shunt by MIGET does not underestimate anatomical shunt measured using 25-µm microspheres. Contrast echocardiography is extremely sensitive, but not specific, often detecting small anatomical shunts which are inconsequential for gas exchange.

Project description:BackgroundIn patients with chronic obstructive pulmonary disease (COPD), the clinical use of the minute ventilation-carbon dioxide production ([Formula: see text]E-[Formula: see text]CO2) slope has been reported as a measure of exercise efficiency, but the oxygen uptake efficiency slope (OUES), i.e., the slope of oxygen uptake ([Formula: see text]O2) versus the logarithmically transformed [Formula: see text]E, has rarely been reported.MethodsWe hypothesized that the [Formula: see text]E-[Formula: see text]CO2 slope is more useful than OUES in clinical use for the pathophysiological evaluation of COPD. Then, we investigated the cardiopulmonary exercise testing parameters affecting each of these slopes in 122 patients with all Global Initiative for Chronic Obstructive Lung Disease (GOLD) COPD grades selected from our database.ResultsCompared with the GOLD I-II group (n = 51), peak [Formula: see text]O2 (p < 0.0001), OUES (p = 0.0161), [Formula: see text]E at peak exercise (p < 0.0001), and percutaneous oxygen saturation (SpO2) at peak exercise (p = 0.0004) were significantly lower in the GOLD III-IV group (n = 71). The GOLD III-IV group was divided into two groups by the exertional decrease in SpO2 from rest to peak exercise: 3% or less (the non-desaturation group: n = 23), or greater than 3% (the desaturation group: n = 48). OUES correlated only weakly with peak [Formula: see text]O2, [Formula: see text]E at peak exercise, and the difference between inspired and expired mean O2 concentrations (ΔFO2) at peak exercise, i.e., an indicator of oxygen consumption ability throughout the body, in the GOLD III-IV group with exertional hypoxemia. In contrast, the [Formula: see text]E-[Formula: see text]CO2 slope was significantly correlated with ΔFO2 at peak exercise, regardless of the COPD grade and exertional desaturation. Across all COPD stages, there was no correlation between the [Formula: see text]E-[Formula: see text]CO2 slope and [Formula: see text]E at peak exercise, and stepwise analysis identified peak [Formula: see text]O2 (p = 0.0345) and ΔFO2 (p < 0.0001) as variables with a greater effect on the [Formula: see text]E-[Formula: see text]CO2 slope.ConclusionsThe OUES may be less useful in advanced COPD with exertional hypoxemia. The [Formula: see text]E-[Formula: see text]CO2 slope, which is independent of [Formula: see text]E, focuses on oxygen consumption ability and exercise tolerance in COPD, regardless of the exertional hypoxemia level and COPD grade. Therefore, the [Formula: see text]E-[Formula: see text]CO2 slope might be useful in establishing or evaluating tailor-made therapies for individual patient's pathologies in COPD as an indicator focusing on oxygen consumption ability.

Dataset Information

Inflammatory blockade prevents injury to the developing pulmonary gas exchange surface in preterm primates.

Publications

Inflammatory blockade prevents injury to the developing pulmonary gas exchange surface in preterm primates.

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