Increased expression of heme oxygenase-1 suppresses airway branching morphogenesis in fetal mouse lungs exposed to inflammation.

BACKGROUND: Intrauterine inflammation affects fetal lung development. BTB and CNC homology 1 (Bach1) is a transcriptional repressor of heme oxygenase-1 (HO-1) and interleukin-6 (IL-6) genes. We investigated the role of Bach1 in the development of fetal mouse lungs exposed to lipopolysaccharide (LPS) using a whole fetal lung tissue culture system. METHODS: We isolated and cultured embryonic day 12.5 fetal mouse lungs from pregnant Bach1 knockout (-/-) and wild-type (WT) mice. Airway branching morphogenesis was assessed by microscopically counting peripheral lung buds after incubation with/without LPS. Expression levels of genes related to inflammation and oxidative stress were evaluated using quantitative PCR. Zinc protoporphyrin, HO-1-specific inhibitor, was used. RESULTS: Branching morphogenesis was observed in Bach1-/- and WT fetal mice lungs without LPS exposure; after exposure to LPS, the number of peripheral lung buds was suppressed in Bach1-/- group only. Basal messenger RNA (mRNA) and protein expression of HO-1 was significantly higher in Bach1-/- group than in WT group; IL-6 and monocyte chemoattractant protein-1 mRNA expression was significantly increased after LPS exposure in both groups. Zinc protoporphyrin mitigated the LPS-induced suppression of branching morphogenesis in Bach1-/- mice. CONCLUSION: The ablation of Bach1 suppresses airway branching morphogenesis after LPS exposure by increased basal expression levels of HO-1.

Prostaglandins mediate the fetal pulmonary response to intrauterine inflammation.

Intra-amniotic (IA) lipopolysaccharide (LPS) induces intrauterine and fetal lung inflammation and increases lung surfactant and compliance in preterm sheep; however, the mechanisms are unknown. Prostaglandins (PGs) are inflammatory mediators, and PGE(2) has established roles in fetal lung surfactant production. The aim of our first study was to determine PGE(2) concentrations in response to IA LPS and pulmonary gene expression for PG synthetic [prostaglandin H synthase-2 (PGHS-2) and PGE synthase (PGES)] and PG-metabolizing [prostaglandin dehydrogenase (PGDH)] enzymes and PGE(2) receptors. Our second study aimed to block LPS-induced increases in PGE(2) with a PGHS-2 inhibitor (nimesulide) and determine lung inflammation and surfactant protein mRNA expression. Pregnant ewes received an IA saline or LPS injection at 118 days of gestation. In study 1, fetal plasma and amniotic fluid were sampled before and at 2, 4, 6, 12, and 24 h after injection and then daily, and fetuses were delivered 2 or 7 days later. Amniotic fluid PGE(2) concentrations increased (P < 0.05) 12 h and 3-6 days after LPS. Fetal lung PGHS-2 mRNA and PGES mRNA increased 2 (P = 0.0084) and 7 (P = 0.014) days after LPS, respectively. In study 2, maternal intravenous nimesulide or vehicle infusion began immediately before LPS or saline injection and continued until delivery 2 days later. Nimesulide inhibited LPS-induced increases in PGE(2) and decreased fetal lung IL-1ß and IL-8 mRNA (P ≤ 0.002) without altering lung inflammatory cell infiltration. Nimesulide decreased surfactant protein (SP)-A (P = 0.05), -B (P = 0.05), and -D (P = 0.0015) but increased SP-C mRNA (P = 0.023). Thus PGHS-2 mediates, at least in part, fetal pulmonary responses to inflammation.

Early gestational intrauterine infection induces postnatal lung inflammation and arrests lung development in a rat model.

OBJECTIVE: In order to investigate the early gestational inflammation effect on the prenatal and postnatal lung development, identification of the proinflammatory cytokines (IL-1ß and TNF-α), genes implicated in angiogenesis (Vascular endothelial growth factor [VEGF], fms-like tyrosine kinase-1 [Flt-1], fetal liver kinase-1 [Flk-1]), and surfactant proteins (SPs) were observed. METHODS: Escherichia coli (E. coli) was inoculated into uterine cervix of pregnant rats at embryonic day 15 (E15) during pseudoglandular period of lung development and the control group was inoculated with normal saline. IL-1ß, TNF-α, VEGF, Flt-1, Flk-1, SP-A, and SP-B mRNA in pup's lung at E17, 19, 21 and postnatal day (P) 1, 3, 7, 14 were quantified by real-time RT-PCR. Western blot or immunohistochemistry analysis was also performed for the evaluation of VEGF, Flk-1, Flt-1, and SP-A expression in pup's lung. RESULTS: Compared with the control group, the fetal lung of the E. coli-treated group was more immature, the postnatal lung development was impaired marked by less alveoli, fewer secondary septa, and thicker alveolar wall. The lung weight and lung/body weight ratio were lower in the E. coli-treated group pups. IL-1ß and TNF-α mRNA were increased significantly in E. coli-treated pup's lung after birth, but no significant difference of IL-1ß and TNF-α mRNA levels in fetal lung were found between the two groups. SP-A expression was depressed at E17, E19, and E21 after intrauterine E. coli treated, accompanied with lower SP-B mRNA level at E19 and E21. Furthermore, intrauterine E. coli treated reduced the VEGF mRNA and protein levels in the fetal lung at E17 and E19, while the expression of Flt-1 and Flk-1 were higher at P7, P14 and P1, P7, P14, respectively, compared to the controls. CONCLUSIONS: These results suggested early gestational intrauterine E. coli infection could induce a postnatal pulmonary inflammation and might arrest the alveolarization in developing lung which was involved with the VEGF signaling. However, intrauterine E. coli infection could not induce the increase of proinflammatory cytokines in fetal lung and might fail to accelerate the maturation of fetal lung.

The role of inflammation and infection in the development of chronic lung disease of prematurity.

CLD is a significant cause of infant morbidity and mortality. The lung injury is multifactorial in origin with supplemental oxygen and ventilatory damage being only part of the picture. Antenatal and postnatal infection and inflammation are also important in the development of CLD, although their precise role has still to be fully ascertained. In the future, therapeutic strategies need to be considered to decrease the incidence and severity of CLD. In particular a definitive trial investigating the role of antibiotics against Ureaplasma urealyticum in preventing CLD needs to be performed. Increased use of newer microbiological methods will also improve our understanding of the role of infection in CLD and further guide research and clinical management.

Injury, inflammation, and remodeling in fetal sheep lung after intra-amniotic endotoxin.

Chorioamnionitis is frequent in preterm labor and increases the risk of bronchopulmonary dysplasia. We hypothesized that intra-amniotic endotoxin injures the lung in utero, causing a sequence of inflammation and tissue injury similar to that which occurs in the injured adult lung. Preterm lamb lungs at 125 days gestational age were evaluated for indicators of inflammation, injury, and repair 5 h, 24 h, 72 h, and 7 days after 4 mg of intra-amniotic endotoxin injection. At 5 h, the epithelial cells in large airways expressed heat shock protein 70, and alveolar interleukin-8 was increased. Surfactant protein B (SP-B) decreased in alveolar type II cells at 5 h, and SP-B in lung tissue and alveolar lavage fluid increased by 72 h. By 24 h, neutrophils were recruited into the large airways, and cell death was the highest. Alveolar type II cells decreased by 25% at 24 h, and proliferation was highest at 72 h, consistent with tissue remodeling. Intra-amniotic endotoxin caused surfactant secretion, inflammation, cell death, and remodeling as indications of lung injury. The recovery phase was accompanied by maturational changes in the fetal lung.

[Congenital pneumonia in fetuses and newborns ad inflammatory lesions in the placenta]. / Wrodzone zapalenia pluc plodów i noworodków a zapalenia poplodów.

The authors compared the degree of congenital pneumonia in stillborn and neonates died in first two days of life with inflammation lesions of placenta. The coexistence of those two processes and its significant correlation was found, especially among preterm LBW neonates. This finding supports the hypothesis about infection as a probable cause not only of preterm deliveries but infection of fetuses and neonates as well. Analysis of some cases revealed also that general infection of mother could cause transplacental infection of foetuses.

[Surfactant surface activity and ultrastructural changes in the type-II alveolocytes of fetal and neonatal lungs in experimental inflammation of the maternal lungs]. / Sostoianie poverkhnostnoi aktivnosti surfaktanta i izmeneniia ul'trastruktury al'veolotsitov II tipa legkikh plodov i novorozhdennykh pri vospalenii legkikh materi v éksperimente.

The lungs of 19 guinea pigs, born from 8 females in which acute and chronic pneumonia had been modelled by transtracheal introduction of sterile fishing-line were investigated. It was established, that in guinea pigs, born in females with acute and chronic pneumonia, the functional immaturity of pneumocytes of the 2-nd type took place. The functional immaturity of pneumocytes of the 2-nd type results in suppression of the surface active characteristics of surfactant.

Lung lesions in bovine fetuses aborted by Brucella abortus.

Considering the poor facilities available for microbiological diagnosis in some countries where Brucella abortus is a frequent cause of bovine abortion, a study was conducted to determine if isolation of B. abortus from an aborted bovine fetus could be predicted from a detailed histological study of the formalized lung. Thirty-nine samples of B. abortus positive and 20 negative fetal samples were examined for the presence of 14 different pulmonary lesions. Differences in the frequency of observed lesions between the positive and negative groups, were determined by odds ratios and chi square statistic. The confidence of the prediction was calculated by means of the logistic computer model. The frequency of eight lung lesions was found to be significantly (p less than 0.05) different between the groups; nevertheless, these lesions were not specific enough to be able to incriminate B. abortus as the cause of abortion.

Amniotic fluid infections in an African city.

Amniotic fluid infections were the most common cause of perinatal death in Addis Ababa, Ethiopia (21.8/1,000 live births). Most such infections appear to originate in the fetal membranes near the cervical os. The high rate of spread of these local infections into the amniotic fluid in Addis Ababa appears related to a lack of antimicrobial activity in amniotic fluids. Factors that adversely affected nutrition in the gravid woman, lack of prenatal medical care, and low water usage were associated with the high rate of fatal infections.

PIP: Congenital pneumonia, originating in an amniotic fluid bacterial infection, is a common cause of perinatal death in industrial societies. A study of perinatal mortality was undertaken in Addis Ababa, Ethiopia, in 1974-1975 in the hospitals and clinics affiliated with the Addis Ababa University Faculty of Medicine. 72% of the perinatal deaths had postmortem examinations and the pregnancies associated with the 1019 autopsied infants were compared with 586 systematically selected successful pregnancies drawn from a cross section of the delivery population by using the 1st deliveries after 7:00 a.m. each day. Hospital and clinic records in conjunction with a detained maternal interview and physical examination on the day following delivery provided 124 separate items of information for analysis. Autopsy prosections and gross placental examinations were performed by 1 Ethiopian and 4 US medical students. Amniotic fluid infection syndrome was identified as the prime diagnosis responsible for deaths in 339 cases for a frequency of 21.8/1000 live births. The fatal disorder had a frequency of 0.10%/week at midgestation with little subsequent change until 39 weeks when it markedly increased. 69% of the deaths were stillborn and the rest neonatal. 76% of lung and 66% of placental cultures were positive for 1 or more organisms in the amniotic fluid infection cases. Only 17% of the placentas from control cases had positive cultures. Fatal amniotic fluid infections had a frequency of 1.75% in single born infants and 12.9% in twins. The fatal infections had a frequency of 1.2% when women made clinic visits for prenatal medical care, and 4.2% when they made no such visits. The disorder was 5 times more frequent in the gravid women who had no education than in those who had 12 or more years of education. The influence of mother's education on the frequency of the fatal infections was largely independent on the influence of poverty. There was an excessive frequency of the fatal infections when women reported prior fetal losses. Acute inflammation of the extraplacental fetal membranes was present in 31% of the control cases, acute funisitis in 11%, and acute inflammation of the chorionic plate of the placenta in 13%. Among the perinatal deaths attributed to amniotic fluid infections, all had congenital pneumonia, 86% acute inflammation of the extraplacental fetal membranes, 61% acute funisitis, and 84% acute inflammation of the chorionic plate of the placenta.