ErbB4 regulates the timely progression of late fetal lung development.

The ErbB4 receptor has an important function in fetal lung maturation. Deletion of ErbB4 leads to alveolar hypoplasia and hyperreactive airways similar to the changes in bronchopulmonary dysplasia (BPD). BPD is a chronic pulmonary disorder affecting premature infants as a consequence of lung immaturity, lung damage, and abnormal repair. We hypothesized that proper ErbB4 function is needed for the timely progression of fetal lung development. An ErbB4 transgenic cardiac rescue mouse model was used to study the effect of ErbB4 deletion on fetal lung structure, surfactant protein (SP) expression, and synthesis, and inflammation. Morphometric analyses revealed a delayed structural development with a significant decrease in saccular size at E18 and more pronounced changes at E17, keeping these lungs in the canalicular stage. SP-B mRNA expression was significantly down regulated at E17 with a subsequent decrease in SP-B protein expression at E18. SP-D protein expression was significantly decreased at E18. Surfactant phospholipid synthesis was significantly decreased on both days, and secretion was down regulated at E18. We conclude that pulmonary ErbB4 deletion results in a structural and functional delay in fetal lung development, indicating a crucial regulatory role of ErbB4 in the timely progression of fetal lung development.

Neuregulin-1, the fetal endothelium, and brain damage in preterm newborns.

OBJECTIVE: To assess the potential role for Neuregulin-1 (NRG1) as a systemic endogenous protector in the setting of perinatal inflammatory brain damage. METHODS: We measured NRG1-protein and mRNA levels in human umbilical venous endothelial cells (HUVECs) of different gestational ages at various durations of exposure to lipopolysaccharide (LPS). In parallel, we genotyped the donor individuals for SNP8NRG221533, a disease-related single nucleotide polymorphism in the 5' region upstream of the NRG1 sequence. Intracellular NRG1 localization was visualized by confocal microscopy. Furthermore we analyzed the relationship between SNP8NRG221533 genotype and neurodevelopmental outcome in children born preterm. RESULTS: We observed a positive dose-response-relationship between NRG1-mRNA and intracellular protein levels with both advancing gestational age and duration of LPS exposure in HUVECs. The presence of allele C at the SNP8NRG221533 locus was associated with an increased cellular production of NRG1 in HUVECs, and with a significantly reduced risk for cerebral palsy and developmental delay in children born preterm. INTERPRETATION: In conclusion, our data indicate that gestational age, duration of LPS exposure, and the SNP8NRG221533 genotype affect NRG1 levels. Our results support the hypothesis that NRG1 may qualify as an endogenous protector during fetal development.

Immaturity, perinatal inflammation, and retinopathy of prematurity: a multi-hit hypothesis.

OBJECTIVE: To explore the relationship among markers of infection/inflammation in their association with retinopathy of prematurity (ROP). METHODS: We studied clinical characteristics and 4 single nucleotide polymorphisms in infection/inflammation-associated genes in a group of 73 children with a gestational age<32 weeks. Forty-four children (60%) had ROP, of whom 13 (30% of those with ROP) progressed to stage 3 ROP. No child had grade 4 or 5 ROP. We employed both descriptive and analytic statistical methods. RESULTS: Clinical variables of infection/inflammation were consistently associated with an increased risk of ROP. Among infants with ROP, they were also associated with progression to ROP grade 3. Genetic markers were not associated with ROP occurrence, but with progression to high grade disease. In tri-variable analyses exploring the effects of gestational age <29 weeks, clinical chorioamnionitis (CAM) and neonatal systemic inflammatory response syndrome (SIRS) on ROP occurrence, low gestational age was the most important antecedent, while additional individual or joint exposure to SIRS and CAM add appreciably to this risk of progression to high grade disease. CONCLUSION: Both antenatal and neonatal exposure to inflammation appear to contribute to the increased ROP risk in preterm infants.

Association of chromosomal locus 8q24 and risk of prostate cancer: a hospital-based study of German patients treated with brachytherapy.

BACKGROUND: Genetic susceptibility contributes to the risk of prostate cancer but the underlying genes are largely unknown. Polymorphic loci on chromosome 8q24 have emerged as possible risk factors for breast and prostate cancer from genome-wide association studies. OBJECTIVE: We aimed to define the risks associated with two single nucleotide polymorphisms, rs1447295 and rs13281615, in a hospital-based series of prostate cancer patients treated with brachytherapy. MATERIAL AND METHODS: We analyzed genomic DNA samples of 488 prostate cancer cases undergoing brachytherapy at Hannover Medical School, and of 462 male controls from the same location. Genotyping was performed using 5'-exonuclease allelic discrimination assays, and results were evaluated with chi(2) tests and logistic regression analyses. RESULTS: We investigated whether rs1447295 and rs13281615 are associated with disease risk in a hospital-based prostate cancer case-control series from Northern Germany. The rare allele of rs1447295 was observed at higher frequency among cases than among hospital-based controls (13.9% vs. 10.2%, P = 0.01), and there was a dose-dependent trend towards a higher prevalence of heterozygous and homozygous carriers among the prostate cancer patients (per allele OR 1.42, 95% CI 1.07; 1.87, P = 0.02). By contrast, the rare allele of rs13281615 did not predispose to prostate cancer (per allele OR 0.84, 95% CI 0.70; 1.00, P = 0.05). The distribution of combined 8q24 genotypes was significantly different between cases and controls (P = 0.01). CONCLUSION: Our results corroborate previous reports of 8q24 as a prostate cancer susceptibility locus and provide evidence for rs1447295 as a potentially important genetic marker. Further studies are required to confirm whether the adjacent breast cancer-associated variant rs13281615 may be inversely associated with prostate cancer risk.

TGFB1 gene polymorphism Leu10Pro (c.29T>C), prostate cancer incidence and quality of life in patients treated with brachytherapy.

OBJECTIVES: Transforming growth factor beta1 gene (TGFB1) variant Leu10Pro (L10P) has previously been implicated in prostate cancer risk and radiation-induced side-effects. We investigated whether prevalence of this polymorphism is increased in prostate cancer patients and whether carriers are at increased risk for treatment-related side effects. METHODS: A series of 445 consecutive patients treated for early-stage prostate cancer receiving definitive I-125 brachytherapy (permanent seed implantation) between 10/2000 and 10/2007 at our institution and a comparison group of 457 healthy male control individuals were screened for TGFB1 L10P (869T>C) polymorphism. Morbidity was assessed prospectively and compared between carriers versus non-carriers using International Prostate Symptom Score (IPSS), disease-specific Quality-of-Life single question added to the IPSS and International Index of Erectile Function with its subgroups. RESULTS: The Leu/Leu genotype was found in 150 patients (34%) versus 180 controls (39%), the Pro/Pro genotype in 75 patients (17%) versus 65 controls (14%) and the Leu/Pro genotype in 220 patients (49%) versus 212 controls (46%) without any statistically significant differences between the two groups. There was a trend towards an increased prevalence of the L10P substitution among patients with a per allele odds ratio of 1.19 (95% CI 0.99-1.44; P = 0.08). After a median follow-up of 18 months (range 1-60 months) there were no statistically significant differences regarding morbidity. CONCLUSIONS: TGFB1 polymorphism L10P is not strongly associated with prostate cancer risk. After 18 months, there was no evidence for increased adverse radiotherapy responses in heterozygote or rare homozygote carriers. Longer follow-up may be necessary to detect a statistically significant difference.

ErbB4 deletion leads to changes in lung function and structure similar to bronchopulmonary dysplasia.

Neuregulin is an important growth factor in fetal surfactant synthesis, and downregulation of its receptor, ErbB4, impairs fetal surfactant synthesis. We hypothesized that pulmonary ErbB4 deletion will affect the developing lung leading to an abnormal postnatal lung function. ErbB4-deleted lungs of 11- to 14-wk-old adult HER4heart mice, rescued from their lethal cardiac defects, were studied for the effect on lung function, alveolarization, and the surfactant system. ErbB4 deletion impairs lung function and structure in HER4heart mice resulting in a hyperreactive airway system and alveolar simplification, as seen in preterm infants with bronchopulmonary dysplasia. It also leads to a downregulation of surfactant protein D expression and an underlying chronic inflammation in these lungs. Our findings suggest that this animal model could be used to further study the pathogenesis of bronchopulmonary dysplasia and might help design protective interventions.

Multiplex measurement of cytokine/receptor gene polymorphisms and interaction between interleukin-10 (-1082) genotype and chorioamnionitis in extreme preterm delivery.

OBJECTIVES: To establish a multiplex amplification refractory mutation system (ARMS) in fluid and dried whole blood, and to perform a pilot study to examine the role for single-nucleotide polymorphisms (SNPs) of inflammation-associated genes (interleukin [IL]-1 and -10, tumor necrosis factor-alpha [TNFA], and toll-like receptor-4 [TLR4]) and their interaction with clinical chorioamnionitis (CAM) in prematurity. METHODS: We established a quadruplex ARMS to detect the four above SNPs. Fifty-four women delivered at gestational age less than 32 weeks and 83 healthy female volunteers were genotyped. We compared (1) mothers of preterm infants with volunteers, and (2) women delivered before 29 weeks' gestation (n = 29) with those delivered at 29 to 31 completed weeks (n = 25). RESULTS: Multiplex ARMS is feasible using both fluid and dried whole blood. We found no overall differences in genotype and allele frequencies between mothers of preterm infants and volunteers. Among women who had a preterm delivery, those with both CAM and IL10(-1082)*G allele, the risk for delivery before 29 weeks was markedly increased (odds ratio [OR] 22, 95% confidence interval [CI] 2.5 - 191). CONCLUSION: The presence of both CAM and IL10(-1082)*G might play a role in extreme preterm delivery less than 29 weeks.