Bronchopulmonary dysplasia is a common pulmonary complication of extreme prematurity. Arrested lung development leads to bronchopulmonary dysplasia, but the molecular pathways that cause this arrest are unclear. Lung injury and inflammation increase disease risk, but the cellular site of the inflammatory response and the potential role of localized inflammatory signaling in inhibiting lung morphogenesis are not known. Here we show that tissue macrophages present in the fetal mouse lung mediate the inflammatory response to lipopolysaccharide and that macrophage activation inhibits airway morphogenesis. Macrophage depletion or targeted inactivation of the NF-κB signaling pathway protected airway branching in cultured lung explants from the effects of lipopolysaccharide. Macrophages also appear to be the primary cellular site of IL-1β production following lipopolysaccharide exposure. Conversely, targeted NF-κB activation in transgenic macrophages was sufficient to inhibit airway morphogenesis. Macrophage activation in vivo inhibited expression of multiple genes critical for normal lung development, leading to thickened lung interstitium, reduced airway branching, and perinatal death. We propose that fetal lung macrophage activation contributes to bronchopulmonary dysplasia by generating a localized inflammatory response that disrupts developmental signals critical for lung formation.

Bronchopulmonary dysplasia (BPD) is a frequent complication of preterm birth. This chronic lung disease results from arrested saccular airway development and is most common in infants exposed to inflammatory stimuli. In experimental models, inflammation inhibits expression of fibroblast growth factor-10 (FGF-10) and impairs epithelial–mesenchymal interactions during lung development; however, the mechanisms connecting inflammatory signaling with reduced growth factor expression are not yet understood. In this study we found that soluble inflammatory mediators present in tracheal fluid from preterm infants can prevent saccular airway branching. In addition, LPS treatment led to local production of mediators that inhibited airway branching and FGF-10 expression in LPS-resistant C.C3-Tlr4Lpsd/J fetal mouse lung explants. Both direct NF-κB activation and inflammatory cytokines (IL-1β and TNF-α) that activate NF-κB reduced FGF-10 expression, whereas chemokines that signal via other inflammatory pathways had no effect. Mutational analysis of the FGF-10 promoter failed to identify genetic elements required for direct NF-κB–mediated FGF-10 inhibition. Instead, NF-κB activation appeared to interfere with the normal stimulation of FGF-10 expression by Sp1. Chromatin immunoprecipitation and nuclear coimmunoprecipitation studies demonstrated that the RelA subunit of NF-κB and Sp1 physically interact at the FGF-10 promoter. These findings indicate that inflammatory signaling through NF-κB disrupts the normal expression of FGF-10 in fetal lung mesenchyme by interfering with the transcriptional machinery critical for lung morphogenesis.

It is unknown whether or not tight junction formation plays any role in morula to blastocyst transformation that is associated with development of polarized trophoblast cells and fluid accumulation. Tight junctions are a hallmark of polarized epithelial cells and zonula occludens-1 (ZO-1) is a known key regulator of tight junction formation. Here we show that ZO-1 protein is first expressed during compaction of 8-cell embryos. This stage-specific appearance of ZO-1 suggests its participation in morula to blastocyst transition. Consistent with this idea, we demonstrate that ZO-1 siRNA delivery inside the blastomeres of zona-weakened embryos using electroporation not only knocks down ZO-1 gene and protein expressions, but also inhibits morula to blastocyst transformation in a concentration-dependent manner. In addition, ZO-1 inactivation reduced the expression of Cdx2 and Oct-4, but not ZO-2 and F-actin. These results provide the first evidence that ZO-1 is involved in blastocyst formation from the morula by regulating accumulation of fluid and differentiation of nonpolar blastomeres to polar trophoblast cells.

This paper presents the numerical simulations of the reinforced concrete (RC) panels and the RC shear walls under monotonic and cyclic loading in order to validate the ability of the proposed model which is based on the Rigid-Body-Spring Model (RBSM) to predict the crack propagation behaviours. The authors have already developed constitutive models for the three-dimensional RBSM with random geometry in order to quantitatively evaluate the mechanical responses including softening and localization fractures, and have shown that the model can well simulate the cracking and failure behaviours of RC members. In this study, the constitutive models were extended to include cyclic effects and the model was validated through the simulations of the RC panel tests under cyclic loadings, which were reported in the literatures. Furthermore, the simulations of the RC shear wall tests, which were tested in the context of the international benchmark ConCrack (http://www. concrack.org/) were carried out, and the capability of the model to predict the detailed cracking information, such as crack width, spacing and direction of propagation is discussed.

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A sister and brother with Vici syndrome are described. They both had oculocutaneous albinism, agenesis of the corpus callosum, cataracts, and cardiomyopathy. They were born to healthy unrelated parents, and had postnatal growth retardation, profound developmental delay, hypotonia, and cataracts. The sister had recurrent infections, and died of progressive heart failure at age 19 months. The brother is alive at age six months with mild cardiomyopathy, and had a single episode of acute bronchitis at age three months. Review of the clinical manifestations of the sibs we described and six children reported in the literature indicates that Vici syndrome is a distinct clinical entity. Its main clinical manifestations include growth retardation, profound developmental delay, hypotonia, albinism, agenesis of the corpus callosum, cataracts, cardiomyopathy, and recurrent infections. The occurrence of the syndrome in three pairs of sibs of both sexes born to unaffected parents supports autosomal recessive inheritance.

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Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disease with a high prevalence in females of childbearing age. Thus, reproduction in SLE patients is a major concern for clinicians. In the past, SLE patients were advised to defer pregnancy because of poor pregnancy outcomes and fear of SLE flares during pregnancy. Investigations to date show that maternal and fetal risks are higher in females with SLE than in the general population. However, with appropriate management of the disease, sufferers may have a relatively uncomplicated pregnancy course. Factors such as appropriate preconception counseling and medication adjustment, strict disease control prior to pregnancy, intensive surveillance during and after pregnancy by both the obstetrician and rheumatologist, and appropriate interventions when necessary play a key role. This review describes the strategies to improve pregnancy outcomes in SLE patients at different time points in the reproduction cycle (preconception, during pregnancy, and postpartum period) and also details the neonatal concerns.