Micro-premature infants in New Jersey show improved mortality and morbidity from 2000-2018.

BACKGROUND: Micro-premature newborns, gestational age (GA) ≤ 25 weeks, have high rates of mortality and morbidity. Literature has shown improving outcomes for extremely low gestational age newborns (ELGANs) GA ≤ 29 weeks, but few studies have addressed outcomes of ELGANs ≤ 25 weeks. OBJECTIVE: To evaluate the trends in outcomes for ELGANs born in New Jersey, from 2000 to 2018 and to compare two subgroups: GA 23 to 25 weeks (E1) and GA 26 to 29 weeks (E2). METHODS: Thirteen NICUs in NJ submitted de-identified data. Outcomes for mortality and morbidity were calculated. RESULTS: Data from 12,707 infants represents the majority of ELGANs born in NJ from 2000 to 2018. There were 3,957 in the E1 group and 8,750 in the E2 group. Mortality decreased significantly in both groups; E1, 43.2% to 30.2% and E2, 7.6% to 4.5% over the 19 years. The decline in E1 was significantly greater than in E2. Most morbidities also showed significant improvement over time in both groups. Survival without morbidity increased from 14.5% to 30.7% in E1s and 47.2% to 69.9% in E2s. Similar findings held for 501-750 and 751-1000g birth weight strata. CONCLUSIONS: Significant declines in both mortality and morbidity have occurred in ELGANs over the last two decades. These rates of improvements for the more immature ELGANs of GA 230 to 256 weeks were greater than for the more mature group in several outcomes. While the rates of morbidity and mortality remain high, these results validate current efforts to support the micro-premature newborn.

Phorbol ester down-regulation of lung surfactant protein B gene expression by cytoplasmic trapping of thyroid transcription factor-1 and hepatocyte nuclear factor 3.

The lung-specific surfactant protein B (SP-B) is essential for surfactant function and normal respiration. We investigated the role of thyroid transcription factor-1 (TTF-1) and hepatocyte nuclear factor 3 (HNF3) in the down-regulation of SP-B gene expression by phorbol ester in pulmonary adenocarcinoma H441 cells. Responsiveness to 12-O-tetradecanoylphorbol-13-acetate (TPA) localized to the SP-B proximal promoter (-140/-65 bp) and specifically to binding sites for TTF-1 and HNF3, which act as cell-specific enhancers of SP-B expression. Treatment of cells with TPA (10 nM) caused a time-dependent decrease in both TTF-1 and HNF3 in nuclear extracts and accumulation of both factors in the cytoplasm as assessed by electromobility shift, Western, Southwestern, and immunofluorescence assays. Treatment did not alter the mRNA content or DNA binding activity for either transcription factor. We conclude that down-regulation of SP-B gene expression by phorbol ester involves cytoplasmic trapping and loss of TTF-1 and HNF3 from the nucleus. This mechanism of action is independent of AP-1 and other transcription factors known to be influenced by phorbol ester.

Transcriptional regulation of surfactant proteins SP-A and SP-B by phorbol ester.

Phorbol esters such as 12-O-tetradecanoylphorbol-13-acetate (TPA) activate protein kinase C and have been previously shown to down-regulate surfactant proteins SP-A and SP-B in H441 adenocarcinoma cells. We used H441 cells and human fetal lung to further study the mechanism of TPA action and to examine physiologic relevance. In H441 cells, TPA (10 nM) treatment for 24 h decreased SP-A mRNA content to approximately 5% of control cells, with half-maximal effect at approximately 0.5 nM, and reduced SP-A gene transcription rate to 28% of control after 8 h exposure. In cells cultured in the presence of dexamethasone, which increases the low basal level of SP-B expression, TPA decreased both SP-B mRNA content (approximately 8% of control) and rate of transcription (7% of control). In cultured human fetal lung explants, TPA decreased SP-A and SP-B protein and mRNA in a time- and dose-dependent fashion, with half-maximal effect on mRNAs at approximately 3 nM and approximately 50% inhibition after 24 h of exposure, and similarly reduced SP-A and SP-B gene transcription (approximately 55% of control at 8-24 h). We conclude that TPA acts primarily at the level of gene transcription to down-regulate both SP-A and SP-B in H441 and fetal lung cells, and we speculate that inflammatory and other agents that act through PKC may modulate expression of the surfactant proteins and alter surfactant function in vivo.

Partial deficiency of surfactant protein B in an infant with chronic lung disease.

OBJECTIVE: To evaluate components of pulmonary surfactant and identify mutations in the surfactant protein B gene (SP-B) of a term infant with severe respiratory distress and chronic lung disease. PATIENT AND TESTING: Respiratory distress developed in an infant delivered at term, and he required extracorporeal bypass support for 2 weeks. Until his unexpected death at 9.5 months, he was ventilator and oxygen dependent and required continual dexamethasone therapy. Tracheobronchial lavage samples were analyzed for content of surfactant proteins (SPs), and DNA from blood samples were sequenced and analyzed by polymerase chain reaction restriction analysis for the presence of SP-B gene mutations. Surfactant lipid composition and function, the contents of SPs and their messenger RNAs (mRNAs), and the immunostaining pattern for SPs were determined in postmortem lung tissue. RESULTS: The lavage sample contained SP-A but not SP-B, and DNA restriction analysis indicated that the patient and his mother were heterozygous for the previously described 121ins2 mutation of SP-B. Postmortem lung tissue contained normal levels of SP-A and its mRNA, a low but detectable level of SP-B, and near normal content of SP-B mRNA. SP-C was abundant on staining, and some 6-kd precursor was present in tissue. A surfactant fraction was deficient in phosphatidylglycerol and was not surface active. On DNA sequencing, a point mutation was found in exon 7 of the patient's SP-B gene allele without the 121ins2 mutation, resulting in a cysteine for arginine substitution, and the father was a carrier for the same mutation. CONCLUSIONS: We describe a patient who is a compound heterozygote with a new mutation and only a partial deficiency of SP-B. Some forms of inherited SP-B deficiency may have low expression of immunoreactive and possibly functional SP-B with milder lung disease and longer survival. These infants may benefit from glucocorticoid therapy and may not develop antibodies to SP-B after either lung transplant or gene therapy.

Characterization of the promoter of human pulmonary surfactant protein B gene.

Pulmonary surfactant protein B (SP-B) is required for normal surfactant function and for survival at birth. To further study SP-B gene expression, we sequenced genomic clones and examined promoter activity of SP-B DNA fragments by transient transfection. A plasmid construct containing human SP-B fragment -1039/+431 linked to chloramphenicol acetyltransferase (CAT) reporter gene was readily expressed in H441 cells, which are derived from a human lung adenocarcinoma, but was < 4% as active in Hep G2, HeLa, and Calu 6 cell lines. SP-B promoter activity in H441 cells was orientation dependent and increased by linked Rous sarcoma virus (RSV) enhancer and was stronger than for thymidine kinase (tk) and RSV promoters. Deletional mapping of the 5' flanking region with exonuclease III suggested nonspecific negative (-811/-1039)- and positive (-453/-641)-control regions and a cell-specific enhancer region at -208 to -54. When a fragment from -403 to -35 base pairs (bp) was placed upstream or downstream of tkCAT, in either orientation, expression in H441 cells but not other cell lines was increased 4- to 28-fold relative to tkCAT. Deletional analysis of the 3' terminus indicated a requirement for at least 7 bp 3' of the transcription start site. Promoter activity was strongly inhibited in a dose-dependent fashion by phorbol ester, with responsiveness mapped to bp -208/-54, but was not responsive to glucocorticoid.(ABSTRACT TRUNCATED AT 250 WORDS)