In neonates, hyperoxia or positive pressure ventilation causes continued lung injury characterized by simplified vascularization and alveolarization, which are the hallmarks of bronchopulmonary dysplasia. Although endothelial cells (ECs) have metabolic flexibility to maintain cell function under stress, it is unknown whether hyperoxia causes metabolic dysregulation in ECs, leading to lung injury. We hypothesized that hyperoxia alters EC metabolism, which causes EC dysfunction and lung injury. To test this hypothesis, we exposed lung ECs to hyperoxia (95% O 2 /5% CO 2) followed by air recovery (O 2 /rec). We found that O 2 /rec reduced mitochondrial oxidative phosphorylation without affecting mitochondrial DNA copy number or mitochondrial mass and that it specifically decreased fatty acid oxidation (FAO) in ECs. This was associated with increased ceramide synthesis and apoptosis. Genetic deletion of carnitine palmitoyltransferase 1a (Cpt1a), a rate-limiting enzyme for carnitine shuttle, further augmented O 2 /rec-induced apoptosis. O 2 /rec-induced ceramide synthesis and apoptosis were attenuated when the FAO was enhanced by L-carnitine. Newborn mice were exposed to hyperoxia (.95% O 2) between Postnatal Days 1 and 4 and were administered L-carnitine (150 and 300 mg/kg, i.p.) or etomoxir, a specific Cpt1 inhibitor (30 mg/kg, i.p.), daily between Postnatal Days 10 and 14. Etomoxir aggravated O 2 /rec-induced apoptosis and simplified alveolarization and vascularization in mouse lungs. Similarly, arrested alveolarization and reduced vessel numbers were further augmented in EC-specific Cpt1a-knockout mice compared with wild-type littermates in response to O 2 /rec. Treatment with L-carnitine (300 mg/kg) attenuated O 2 /rec-induced lung injury, including simplified alveolarization and decreased vessel numbers. Altogether, enhancing FAO protects against hyperoxia-induced EC apoptosis and lung injury in neonates.

Endothelial cell (EC) apoptosis contributes to cigarette smoke (CS)-induced pulmonary emphysema. Metabolism of glucose, glutamine, and fatty acid is dysregulated in patients with chronic obstructive pulmonary disease (COPD). Whether CS causes metabolic dysregulation in ECs leading to development of COPD remains elusive. We hypothesized that CS alters metabolism, resulting in apoptosis in lung ECs. To test this hypothesis, we treated primary mouse pulmonary microvascular ECs (PMVECs) with CS extract (CSE) and employed PMVECs from healthy subjects and COPD patients. We found that mitochondrial respiration was reduced in CSE-treated PMVECs and in PMVECs from COPD patients. Specifically, oxidation of fatty acids (FAO) was reduced in these cells, which linked to reduced carnitine palmitoyltransferase 1a (Cpt1a), an essential enzyme for carnitine shuttle. CSE-induced apoptosis was further increased when cells were treated with a specific Cpt1 inhibitor etomoxir or transfected with Cpt1a siRNA. L-Carnitine treatment augmented FAO but attenuated CSE-induced apoptosis by upregulating Cpt1a. CSE treatment increased palmitate-derived ceramide synthesis, which was reduced by L-carnitine. Although CSE treatment increased glycolysis, inhibiting glycolysis with 2-deoxy-d-glucose had no effects on CSE-mediated apoptosis in lung ECs. Conclusively, FAO reduction increases ceramide and apoptosis in lung ECs treated with CSE, which may contribute to the pathogenesis of COPD/emphysema.

Dysmorphic pulmonary vascular growth and abnormal endothelial cell (EC) proliferation are paradoxically observed in premature infants with bronchopulmonary dysplasia (BPD) despite vascular pruning. The pentose phosphate pathway (PPP), a metabolic pathway parallel to glycolysis, generates NADPH as a reducing equivalent and ribose 5-phosphate for nucleotide synthesis. It is unknown whether hyperoxia, a known mediator of BPD in rodent models, alters glycolysis and the PPP in lung ECs. We hypothesized that hyperoxia increases glycolysis and the PPP, resulting in abnormal EC proliferation and dysmorphic angiogenesis in neonatal mice. To test this hypothesis, lung ECs and newborn mice were exposed to hyperoxia and allowed to recover in air. Hyperoxia increased glycolysis and the PPP. Increased PPP, but not glycolysis, caused hyperoxia-induced abnormal EC proliferation. Blocking the PPP reduced hyperoxia-induced glucose-derived deoxynucleotide synthesis in cultured ECs. In neonatal mice, hyperoxia-induced abnormal EC proliferation, dysmorphic angiogenesis, and alveolar simplification were augmented by nanoparticle-mediated endothelial overexpression of phosphogluconate dehydrogenase, the second enzyme in the PPP. These effects were attenuated by inhibitors of the PPP. Altogether, neonatal hyperoxia augments the PPP, causing abnormal lung EC proliferation, dysmorphic vascular development, and alveolar simplification. These novel observations provide mechanisms and potential metabolic targets to prevent BPD-associated vascular dysgenesis.

Although observational studies have reported a positive association between obstructive sleep apnea syndrome (OSAS) and breast cancer (BC) risk, causality remains inconclusive. We aim to explore whether OSAS is associated with etiology of BC by conducting a two-sample Mendelian randomization (MR) study in a Chinese population and Asian population from the Breast Cancer Association Consortium (BCAC). We found a detrimental causal effect of OSAS on BC risk in the primary analysis of our samples (IVW OR, 2.47 for BC risk per log-odds increment in OSAS risk, 95% CI = 1.86-3.27; P = 3.6×10-10). This was very similar to results of the direct observational case-control study between OSAS and BC risk (OR = 2.80; 95% CI = 2.24-3.50; P =1.4×10-19). Replication in the Asian population of the BCAC study also supported our results (IVW OR, 1.33 for BC risk per log-odds increment in OSAS risk, 95% CI = 1.13-1.56; P = 0.0006). Sensitivity analyses confirmed the robustness of our findings. We provide novel evidence that genetically determined higher risk of OSAS has a causal effect on higher risk of BC. Further studies focused on the mechanisms of the relationship between OSAS and breast carcinogenesis are needed.

BackgroundPreterm birth can interrupt lung development in utero and is associated with early life factors, which adversely affects the developing respiratory system. Studies on preterm birth and asthma risk are comparatively sparse and the results are not consistent.MethodsMultivariate analyses were performed on a cross-sectional data from the National Survey of Children’s Health (NSCH) collected in 2011 to 2012. The NSCH was a nationally representative telephone survey sponsored by the Maternal and Child Health Bureau and conducted by the National Center for Health Statistics. A cross-sectional analysis using data from the US on 90,721 children was conducted to examine the relationship between preterm birth and asthma risk.ResultsA total of 90,721 children under 17 years were included and 12% of the children were reported as preterm birth. The prevalence of diagnosed asthma was 15%, with a male to female ratio of 1.26:1. Children who were born preterm were 1.64 times (95% confidence interval: 1.45–1.84) more likely to develop asthma compared with those who were born term after controlling for confounders. Similarly, children who were low birth weight were 1.43 times (95% confidence interval: 1.25–1.63) more likely for asthma, and the odds ratio increased to 1.77 for those both preborn and low birth weight. Child’s gender, race/ethnicity, age, family structure, family income levels, and household smoking were significantly associated with the odds of reported asthma.ConclusionsPreterm birth was associated with increased risk of asthma among US children, supporting the notion that preterm birth may play a critical role in asthma development.Electronic supplementary materialThe online version of this article (10.1186/s13052-018-0583-9) contains supplementary material, which is available to authorized users.