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Intestinal failure-associated liver disease (IFALD), initially manifesting as cholestasis, is a complication in neonates receiving parenteral nutrition (PN). Soybean oil lipid emulsion (SOLE), though implicated in IFALD, was the only US Food and Drug Administration (FDA)-approved initial intravenous lipid emulsion (ILE) for infants and children in the United States. A mixed-oil lipid emulsion (MOLE) gained popularity in patients at risk for IFALD and was recently FDA approved as an initial ILE in children. Given the presence of soybean oil in MOLE, we hypothesized that MOLE would not be effective at preventing cholestasis in surgical neonates.Neonates with gastrointestinal surgical conditions necessitating PN for ≥14 days and receiving MOLE (SMOFlipid) from July 2016 to July 2019 were analyzed retrospectively. Unpaired and pair-matched historical surgical neonates treated with SOLE (Intralipid) served as controls. The primary outcome measure was development of cholestasis (direct bilirubin ≥2 mg/dl).Overall, 63% (10 of 16) of MOLE patients and 22% (30 of 136) of SOLE patients developed cholestasis after ≥14 days of therapy (P = 0.005). The latency to developing cholestasis was significantly shorter in MOLE patients compared with SOLE patients.In surgical neonates, MOLE may not prevent cholestasis and should not be considered hepatoprotective. Regardless of ILE source, all surgical neonates should be closely monitored for development of IFALD. To date, there is still no ILE able to prevent IFALD.

Morbidity and mortality for neonates with congenital diaphragmatic hernia-associated pulmonary hypoplasia remains high. These patients may be deficient in vascular endothelial growth factor (VEGF). Our lab previously established that exogenous VEGF164 accelerates compensatory lung growth (CLG) after left pneumonectomy in a murine model. We aimed to further investigate VEGF-mediated CLG by examining the role of the heparin-binding domain (HBD). Eight-week-old, male, C57BL/6J mice underwent left pneumonectomy, followed by post-operative and daily intraperitoneal injections of equimolar VEGF164 or VEGF120, which lacks the HBD. Isovolumetric saline was used as a control. VEGF164 significantly increased lung volume, total lung capacity, and alveolarization, while VEGF120 did not. Treadmill exercise tolerance testing (TETT) demonstrated improved functional outcomes post-pneumonectomy with VEGF164 treatment. In lung protein analysis, VEGF treatment modulated downstream angiogenic signaling. Activation of epithelial growth factor receptor and pulmonary cell proliferation was also upregulated. Human microvascular lung endothelial cells (HMVEC-L) treated with VEGF demonstrated decreased potency of VEGFR2 activation with VEGF121 treatment compared to VEGF165 treatment. Taken together, these data indicate that the VEGF HBD contributes to angiogenic and proliferative signaling, is required for accelerated compensatory lung growth, and improves functional outcomes in a murine CLG model.

Obesity is a global epidemic that drives morbidity and mortality through cardiovascular disease, diabetes, and non-alcoholic fatty liver disease (NAFLD). No definitive therapy has been approved to improve glycemic control and treat NAFLD in obese patients. Here, we investigated a semi-synthetic, long chain, structurally-engineered fatty acid-1024 (SEFA-1024), as a treatment for obesity-induced hyperglycemia, insulin-resistance, and fatty liver disease in rodent models. A single dose of SEFA-1024 was administered to evaluate glucose tolerance and active glucagon-like peptide 1 (GLP-1) in lean rats in the presence and absence of a DPP-4 inhibitor. The effects of SEFA-1024 on weight loss and glycemic control were assessed in genetic (ob/ob) and environmental (high-fat diet) murine models of obesity. Liver histology, serum liver enzymes, liver lipidomics, and hepatic gene expression were also assessed in the high-fat diet murine model. SEFA-1024 reversed obesity-associated insulin resistance and improved glycemic control. SEFA-1024 increased active GLP-1. In a long-term model of diet-induced obesity, SEFA-1024 reversed excessive weight gain, hepatic steatosis, elevated liver enzymes, hepatic lipotoxicity, and promoted fatty acid metabolism. SEFA-1024 is an enterohepatic-targeted, eicosapentaenoic acid derivative that reverses obesity-induced dysregulated glucose metabolism and hepatic lipotoxicity in genetic and dietary rodent models of obesity. The mechanism by which SEFA-1024 works may include increasing aGLP-1, promoting fatty acid oxidation, and inhibiting hepatic triglyceride formation. SEFA-1024 may serve as a potential treatment for obesity-related diabetes and NAFLD.

Emphysema is a progressive and fatal lung disease with no cure that is characterized by thinning, enlargement, and destruction of alveoli, leading to impaired gas exchange. Disease progression is due in part to dysregulation of VEGF (vascular endothelial growth factor) signaling in the lungs and increased lung-cell apoptosis. Here we asked whether PR1P (Prominin-1–derived peptide), a novel short peptide we designed that increases VEGF binding to endothelial cells, could be used to improve outcome in in vitro and in vivo models of emphysema. We used computer simulation and in vitro and in vivo studies to show that PR1P upregulated endogenous VEGF receptor-2 signaling by binding VEGF and preventing its proteolytic degradation. In so doing, PR1P mitigated toxin-induced lung-cell apoptosis, including from cigarette-smoke extract in vitro and from LPS in vivo in mice. Remarkably, inhaled PR1P led to significantly increased VEGF concentrations in murine lungs within 30 minutes that remained greater than twofold above that of control animals 24 hours later. Finally, inhaled PR1P reduced acute lung injury in 4- and 21-day elastase-induced murine emphysema models. Taken together, these results highlight the potential of PR1P as a novel therapeutic agent for the treatment of emphysema or other lung diseases characterized by VEGF signaling dysregulation.

Children with hypoplastic lung disease associated with congenital diaphragmatic hernia (CDH) continue to suffer significant morbidity and mortality secondary to progressive pulmonary disease. Recently published work from our lab demonstrated the potential of Roxadustat (FG-4592), a prolyl hydroxylase inhibitor, as a treatment for CDH-associated pulmonary hypoplasia. Treatment with Roxadustat led to significantly accelerated compensatory lung growth (CLG) through downregulation of pigment epithelium-derived factor (PEDF), an anti-angiogenic factor, rather than upregulation of vascular endothelial growth factor (VEGF). PEDF and its role in pulmonary development is a largely unexplored field. In this study, we sought to further evaluate the role of PEDF in accelerating CLG. PEDF-deficient mice demonstrated significantly increased lung volume, total lung capacity, and alveolarization compared to wild type controls following left pneumonectomy without increased VEGF expression. Furthermore, Roxadustat administration in PEDF-deficient mice did not further accelerate CLG. Human microvascular endothelial lung cells (HMVEC-L) and human pulmonary alveolar epithelial cells (HPAEC) similarly demonstrated decreased PEDF expression with Roxadustat administration. Additionally, downregulation of PEDF in Roxadustat-treated HMVEC-L and HPAEC, a previously unreported finding, speaks to the potential translatability of Roxadustat from small animal studies. Taken together, these findings further suggest that PEDF downregulation is the primary mechanism by which Roxadustat accelerates CLG. More importantly, these data highlight the critical role PEDF may have in pulmonary growth and development, a previously unexplored field.

Background: Pulmonary hypoplasia (PH) is a major cause of morbidity and mortality in newborns with congenital diaphragmatic hernia (CDH). PH is characterized by immature pulmonary growth and development. Neonates with severe PH necessitating extracorporeal membrane oxygenation (ECMO) and therapeutic anticoagulation have mortality rates of nearly 50%. Previously, we demonstrated that following pneumonectomy, therapeutic or high-dose heparin administration significantly decreased compensatory lung growth and development. While only a minority of neonates with CDH-associated PH will …

Children with hypoplastic lung disease associated with congenital diaphragmatic hernia (CDH) continue to suffer significant morbidity and mortality secondary to progressive pulmonary disease. Current management of CDH is primarily supportive and mortality rates of the most severely affected children have remained unchanged in the last few decades. Previous work in our lab has demonstrated the importance of vascular endothelial growth factor (VEGF)-mediated angiogenesis in accelerating compensatory lung growth. In this study, we evaluated the potential for Roxadustat (FG-4592), a prolyl hydroxylase inhibitor known to increase endogenous VEGF, in accelerating compensatory lung growth. Treatment with Roxadustat increased lung volume, total lung capacity, alveolarization, and exercise tolerance compared to controls following left pneumonectomy. However, this effect was likely modulated not only by increased VEGF, but rather also by decreased pigment epithelium-derived factor (PEDF), an anti-angiogenic factor. Furthermore, this mechanism of action may be specific to Roxadustat. Vadadustat (AKB-6548), a structurally similar prolyl hydroxylase inhibitor, did not demonstrate accelerated compensatory lung growth or decreased PEDF expression following left pneumonectomy. Given that Roxadustat is already in Phase III clinical studies for the treatment of chronic kidney disease-associated anemia with minimal side effects, its use for the treatment of pulmonary hypoplasia could potentially proceed expeditiously.

Background: Prolapse can occur in up to 20% of newborn end colostomies and may be associated with significant morbidities that require operative intervention. Prolapse repair is traditionally performed through an open parastomal or laparotomy incision. We report on 2 cases that utilized a novel laparoscopic transabdominal colopexy technique, which offered a minimally invasive solution uniquely suited to neonates and infants while obviating the morbidity of open reoperative surgery. Materials and Methods: Retrospective review of 2 patients at a single center undergoing a laparoscopic transabdominal colopexy for end colostomy prolapse. The primary outcome measure was prolapse recurrence. Secondary outcomes included intraoperative or immediate postoperative complications. Results: Both patients who underwent the laparoscopic transabdominal colopexy procedure had prolapsed end colostomies. There were no intraoperative or immediate postoperative complications. Both patients had no additional episodes of recurrence during the follow-up period. One patient has since had their colostomy reversed without complications. Conclusion: We present our initial results in the utilization of a novel technique for repair of a newborn end colostomy prolapse-laparoscopic transabdominal colopexy. Our technique thus far has demonstrated success in preventing recurrent prolapse through a minimally invasive technique with no significant morbidity.