Modeling blood-brain barrier formation and cerebral cavernous malformations in human PSC-derived organoids.

The human blood-brain barrier (hBBB) is a highly specialized structure that regulates passage across blood and central nervous system (CNS) compartments. Despite its critical physiological role, there are no reliable in vitro models that can mimic hBBB development and function. Here, we constructed hBBB assembloids from brain and blood vessel organoids derived from human pluripotent stem cells. We validated the acquisition of blood-brain barrier (BBB)-specific molecular, cellular, transcriptomic, and functional characteristics and uncovered an extensive neuro-vascular crosstalk with a spatial pattern within hBBB assembloids. When we used patient-derived hBBB assembloids to model cerebral cavernous malformations (CCMs), we found that these assembloids recapitulated the cavernoma anatomy and BBB breakdown observed in patients. Upon comparison of phenotypes and transcriptome between patient-derived hBBB assembloids and primary human cavernoma tissues, we uncovered CCM-related molecular and cellular alterations. Taken together, we report hBBB assembloids that mimic the core properties of the hBBB and identify a potentially underlying cause of CCMs.

Intravenous surfactant protein D inhibits lipopolysaccharide-induced systemic inflammation.

BACKGROUND: Surfactant protein D (SP-D) is an innate host defense protein that clears infectious pathogens from the lung and regulates pulmonary host defense cells. SP-D is also detected in lower concentrations in plasma and many other non-pulmonary tissues. Plasma levels of SP-D increase during infection and other proinflammatory states; however, the source and functions of SP-D in the systemic circulation are largely unknown. We hypothesized that systemic SP-D may clear infectious pathogens and regulate host defense cells in extrapulmonary systems. METHODS: To determine if SP-D inhibited inflammation induced by systemic lipopolysaccharide (LPS), E.coli LPS was administered to mice via tail vein injection with and without SP-D and the inflammatory response was measured. RESULTS: Systemic SP-D has a circulating half-life of 6 h. Systemic IL-6 levels in mice lacking the SP-D gene were similar to wild type mice at baseline but were significantly higher than wild type mice following LPS treatment (38,000 vs 29,900 ng/ml for 20 mg/kg LPS and 100,700 vs 73,700 ng/ml for 40 mg/kg LPS). In addition, treating wild type mice with purified intravenous SP-D inhibited LPS induced secretion of IL-6 and TNFα in a concentration dependent manner. Inhibition of LPS induced inflammation by SP-D correlated with SP-D LPS binding suggesting SP-D mediated inhibition of systemic LPS requires direct SP-D LPS interactions. CONCLUSIONS: Taken together, the above results suggest that circulating SP-D decreases systemic inflammation and raise the possibility that a physiological purpose of increasing systemic SP-D levels during infection is to scavenge systemic infectious pathogens and limit inflammation-induced tissue injury.

Comparison of Airway Pressure Release Ventilation to High-Frequency Oscillatory Ventilation in Neonates with Refractory Respiratory Failure.

Background: Airway pressure release ventilation (APRV) is a relatively new mode of ventilation in neonates. We hypothesize that APRV is an effective rescue mode in infants failing conventional ventilation and it is comparable in survival rates to rescue with high-frequency oscillatory ventilation (HFOV). Methods: This is a 6-year retrospective cohort study of infants that failed synchronized intermittent mandatory ventilation (SIMV) and were rescued with either APRV or HFOV. For comparison, we divided infants into two groups (28-37 and >37 weeks) based on their corrected gestational age (CGA) at failure of SIMV. Results: Ninety infants were included in the study. Infants rescued with APRV (n = 46) had similar survival rates to those rescued with HFOV (n = 44)-28-37 weeks CGA (APRV 78% vs. HFOV 84%, p = 0.68) and >37 weeks CGA (APRV 76% vs. HFOV 72%, p = 0.74). Use of APRV was not associated with an increase in pneumothorax (APRV 0% and HFOV 10%, p = 0.31, in 28-37 weeks CGA, and APRV 0% and HFOV 4%, p = 0.22, in >37 weeks CGA). Conclusion: APRV can be effectively used to rescue infants with refractory respiratory failure on SIMV. When compared to HFOV, rescue with APRV is not associated with an increase in mortality or pneumothorax.