Exploiting sweet relief for preeclampsia by targeting autophagy-lysosomal machinery and proteinopathy.

The etiology of preeclampsia (PE), a severe complication of pregnancy with several clinical manifestations and a high incidence of maternal and fetal morbidity and mortality, remains unclear. This issue is a major hurdle for effective treatment strategies. We recently demonstrated that PE exhibits an Alzheimer-like etiology of impaired autophagy and proteinopathy in the placenta. Targeting of these pathological pathways may be a novel therapeutic strategy for PE. Stimulation of autophagy with the natural disaccharide trehalose and its lacto analog lactotrehalose in hypoxia-exposed primary human trophoblasts restored autophagy, inhibited the accumulation of toxic protein aggregates, and restored the ultrastructural features of autophagosomes and autolysosomes. Importantly, trehalose and lactotrehalose inhibited the onset of PE-like features in a humanized mouse model by normalizing autophagy and inhibiting protein aggregation in the placenta. These disaccharides restored the autophagy-lysosomal biogenesis machinery by increasing nuclear translocation of the master transcriptional regulator TFEB. RNA-seq analysis of the placentas of mice with PE indicated the normalization of the PE-associated transcriptome profile in response to trehalose and lactotrehalose. In summary, our results provide a novel molecular rationale for impaired autophagy and proteinopathy in patients with PE and identify treatment with trehalose and its lacto analog as promising therapeutic options for this severe pregnancy complication.

Evidence for lysosomal biogenesis proteome defect and impaired autophagy in preeclampsia.

The etiology of preeclampsia (PE), a serious pregnancy complication, remains an enigma. We have demonstrated that proteinopathy, a pathologic feature of neurodegenerative diseases, is a key observation in the placenta and serum from PE patients. We hypothesize that the macroautophagy/autophagy machinery that mediates degradation of aggregated proteins and damaged organelles is impaired in PE. Here, we show that TFEB (transcription factor EB), a master transcriptional regulator of lysosomal biogenesis, and its regulated proteins, LAMP1, LAMP2, and CTSD (cathepsin D), were dysregulated in the placenta from early and late onset PE deliveries. Primary human trophoblasts and immortalized extravillous trophoblasts (EVTs) showed reduced TFEB expression and nuclear translocation as well as lysosomal protein content in response to hypoxia. Hypoxia-exposed trophoblasts also showed decreased PPP3/calcineurin phosphatase activity and increased XPO1/CRM1 (exportin 1), events that inhibit TFEB nuclear translocation. These proteins were also dysregulated in the PE placenta. These results are supported by observed lysosomal ultrastructural defects with decreased number of autolysosomes in hypoxia-treated primary human trophoblasts. Autophagy-deficient human EVTs exhibited poor TFEB nuclear translocation, reduced lysosomal protein expression and function, and increased MTORC1 activity. Sera from PE patients induced these features and protein aggregation in EVTs. Importantly, trophoblast-specific conditional atg7 knockout mice exhibited reduced TFEB expression with increased deposition of protein aggregates in the placenta. These results provide compelling evidence for a regulatory link between accumulation of protein aggregates and TFEB-mediated impaired lysosomal biogenesis and autophagy in the placenta of PE patients. Abbreviation:atg7: autophagy related 7; CTSD: cathepsin D; ER: endoplasmic reticulum; EVTs: extravillous trophoblasts; KRT7: keratin 7; LAMP1: lysosomal associated membrane protein 1; LAMP2: lysosomal associated membrane protein 2; mSt: mStrawberry; MTORC1: mechanistic target of rapamycin complex 1; NP: normal pregnancy; NPS: normal pregnancy serum; PE: preeclampsia; PES: preeclampsia serum; p-RPS6KB: phosphorylated ribosomal protein S6 kinase B1; SQSTM1/p62: sequestosome 1; TEM: transmission electron microscopy; TFEB: transcription factor EB; XPO1/CRM1: exportin 1.

Clinical Outcomes of Bronchiolitis After Implementation of a General Ward High Flow Nasal Cannula Guideline.

OBJECTIVE: The goal of this study was to assess the association of the introduction of a ward's high-flow nasal cannula (HFNC) guideline with clinical outcomes of infants with bronchiolitis. METHODS: We conducted a retrospective, pre-post intervention study with an interrupted time series analysis of infants admitted with bronchiolitis between 2010 and 2014 at an urban, tertiary care children's hospital. Patients admitted in the 24 months before and after initiation of a guideline for HFNC use on the general wards were compared. The primary outcome was length of hospital stay. Secondary outcomes were PICU transfer rate and length of stay, intubation rate, and 30-day readmission, adjusted for season. RESULTS: A total of 1937 patients met inclusion criteria; 936 were admitted before and 1001 admitted after the introduction of HFNC use on the general wards. Comparing the 2 groups, the hospital-wide rate of HFNC use in bronchiolitis treatment increased after HFNC became available on the wards (23.9% vs 35.2%; P < .001). The ward's HFNC guideline was not associated with a change in preintervention trajectory of total hospital length of stay (P = .48), PICU length of stay (P = .06), or rate of PICU transfer (P = .97). There was also no difference in intubation rate or 30-day readmission between the 2 groups. CONCLUSIONS: Initiating a guideline for HFNC use on the general pediatric wards was associated with an increase in the use of the intervention with no significant change in total hospital length of stay, PICU length of stay and transfer rate, intubation rate, or 30-day readmission for patients with bronchiolitis.

Effect of a Hospital-wide High-Flow Nasal Cannula Protocol on Clinical Outcomes and Resource Utilization of Bronchiolitis Patients Admitted to the PICU.

OBJECTIVE: To assess the association of the introduction of a high-flow nasal cannula (HFNC) protocol with clinical outcomes and hospital charges of infants with bronchiolitis initially admitted to the PICU. METHODS: We conducted a retrospective, nonrandomized, preintervention-postintervention study of infants with bronchiolitis initially admitted to the PICU for HFNC. We compared patients admitted in the 24 months before and after protocol initiation for HFNC use on the general wards. The primary outcome assessed was length of hospital stay (LOS), and the secondary outcomes included total hospital charges, intubation, and 30-day readmission. We conducted bivariate analysis using χ² test for categorical variables and Student's t test or Wilcoxon rank sum test for continuous variables. RESULTS: Two hundred and ninety patients were admitted to the PICU on HFNC; 120 patients were admitted before and 170 admitted after the introduction of HFNC use on the general wards. Comparing the 2 groups, the median LOS was significantly reduced (4 days vs 3 days; P < .001), as was the median total hospital charges ($12 257 vs $9337; P < .001). After starting HFNC use on the wards, 30% of patients initially admitted to the PICU were ultimately transferred to the wards while still on HFNC. There was no difference in intubation rate or 30-day readmission between the 2 groups. CONCLUSIONS: For bronchiolitis patients initially admitted to the PICU, initiating a guideline for HFNC use on the general pediatric wards is associated with reduced total hospital LOS and total hospital charges, with no difference in intubation rates or 30-day readmission.