Oral, nasal and pharyngeal exposure to lipopolysaccharide causes a fetal inflammatory response in sheep.

BackgroundA fetal inflammatory response (FIR) in sheep can be induced by intraamniotic or selective exposure of the fetal lung or gut to lipopolysaccharide (LPS). The oral, nasal, and pharyngeal cavities (ONP) contain lymphoid tissue and epithelium that are in contact with the amniotic fluid. The ability of the ONP epithelium and lymphoid tissue to initiate a FIR is unknown.ObjectiveTo determine if FIR occurs after selective ONP exposure to LPS in fetal sheep.MethodsUsing fetal recovery surgery, we isolated ONP from the fetal lung, GI tract, and amniotic fluid by tracheal and esophageal ligation and with an occlusive glove fitted over the snout. LPS (5 mg) or saline was infused with 24 h Alzet pumps secured in the oral cavity (n = 7-8/group). Animals were delivered 1 or 6 days after initiation of the LPS or saline infusions.ResultsThe ONP exposure to LPS had time-dependent systemic inflammatory effects with changes in WBC in cord blood, an increase in posterior mediastinal lymph node weight at 6 days, and pro-inflammatory mRNA responses in the fetal plasma, lung, and liver. Compared to controls, the expression of surfactant protein A mRNA increased 1 and 6 days after ONP exposure to LPS.ConclusionONP exposure to LPS alone can induce a mild FIR with time-dependent inflammatory responses in remote fetal tissues not directly exposed to LPS

Effect of bosentan therapy in persistent pulmonary hypertension of the newborn

Background: Persistent pulmonary hypertension of the newborn (PPHN) contributes to neonatal hypoxemia and is associated with a high mortality. Some PPHN patients are unresponsive to inhaled nitric oxide (iNO). Bosentan, an oral endothelin-1 receptor antagonist, reduces pulmonary vascular resistance and hence may play a role in the treatment of PPHN. Methods: A retrospective medical records review was performed in newborns who received oral bosentan as an adjunctive therapy for treatment of PPHN between January 2013 and February 2016 at the neonatal intensive care unit of Songklanagarind Hospital. The main outcomes were the effect of bosentan on oxygenation and hemodynamic status after commencement of treatment and the safety of bosentan. Results: Forty neonates at a median (IQR) gestation of 38 (36.8–40) weeks and an initial median (IQR) oxygen index (OI) of 29.2 (13.4–40.1) received bosentan therapy. Oral bosentan was commenced at a median (IQR) age of 27 (14.5–40.2) hours and the mean (SD) duration of treatment was 6.2 (3.1) days. The OI, alveolar-arterial oxygen difference (AaDO2) and oxygen saturation (SpO2) improved significantly at 2 h after treatment (p = 0.002, p = 0.01 and p < 0.001, respectively). In 21 (52.5%) neonates who received iNO and bosentan, the median OI (IQR) was 34.2 (29.0–42.6) with a significant decrease of OI at 6 h (p = 0.005) after treatment. In 19 (47.5%) neonates who received bosentan alone, the median OI (IQR) was 13.0 (9.8–30.9) with a significant decrease of OI in 2 h (p = 0.01) after treatment. The blood pressures before and after bosentan treatment were not statistically significantly different. The mortality rate was 12.5% (5/40). Conclusion: Oral bosentan may be a safe and effective treatment to improve oxygenation in neonates with PPHN. Bosentan can be used as an adjuvant therapy with iNO and can be an alternative therapy option in mild-to-moderate PPHN

Oral, nasal and pharyngeal exposure to lipopolysaccharide causes a fetal inflammatory response in sheep.

BackgroundA fetal inflammatory response (FIR) in sheep can be induced by intraamniotic or selective exposure of the fetal lung or gut to lipopolysaccharide (LPS). The oral, nasal, and pharyngeal cavities (ONP) contain lymphoid tissue and epithelium that are in contact with the amniotic fluid. The ability of the ONP epithelium and lymphoid tissue to initiate a FIR is unknown.ObjectiveTo determine if FIR occurs after selective ONP exposure to LPS in fetal sheep.MethodsUsing fetal recovery surgery, we isolated ONP from the fetal lung, GI tract, and amniotic fluid by tracheal and esophageal ligation and with an occlusive glove fitted over the snout. LPS (5 mg) or saline was infused with 24 h Alzet pumps secured in the oral cavity (n = 7-8/group). Animals were delivered 1 or 6 days after initiation of the LPS or saline infusions.ResultsThe ONP exposure to LPS had time-dependent systemic inflammatory effects with changes in WBC in cord blood, an increase in posterior mediastinal lymph node weight at 6 days, and pro-inflammatory mRNA responses in the fetal plasma, lung, and liver. Compared to controls, the expression of surfactant protein A mRNA increased 1 and 6 days after ONP exposure to LPS.ConclusionONP exposure to LPS alone can induce a mild FIR with time-dependent inflammatory responses in remote fetal tissues not directly exposed to LPS

Intra-amniotic Ureaplasma parvum-Induced Maternal and Fetal Inflammation and Immune Responses in Rhesus Macaques

Background. Although Ureaplasma species are the most common organisms associated with prematurity, their effects on the maternal and fetal immune system remain poorly characterized. Methods. Rhesus macaque dams at approximately 80% gestation were injected intra-amniotically with 10(7) colony-forming units of Ureaplasma parvum or saline (control). Fetuses were delivered surgically 3 or 7 days later. We performed comprehensive assessments of inflammation and immune effects in multiple fetal and maternal tissues. Results. Although U. parvum grew well in amniotic fluid, there was minimal chorioamnionitis. U. parvum colonized the fetal lung, but fetal systemic microbial invasion was limited. Fetal lung inflammation was mild, with elevations in CXCL8, tumor necrosis factor (TNF) alpha, and CCL2 levels in alveolar washes at day 7. Inflammation was not detected in the fetal brain. Significantly, U. parvum decreased regulatory T cells (Tregs) and activated interferon gamma production in these Tregs in the fetus. It was detected in uterine tissue by day 7 and induced mild inflammation and increased expression of connexin 43, a gap junction protein involved with labor. Conclusions. U. parvum colonized the amniotic fluid and caused uterine inflammation, but without overt chorioamnionitis. It caused mild fetal lung inflammation but had a more profound effect on the fetal immune system, decreasing Tregs and polarizing them toward a T-helper 1 phenotype

Intra-amniotic Ureaplasma parvum–Induced Maternal and Fetal Inflammation and Immune Responses in Rhesus Macaques

BackgroundAlthough Ureaplasma species are the most common organisms associated with prematurity, their effects on the maternal and fetal immune system remain poorly characterized.MethodsRhesus macaque dams at approximately 80% gestation were injected intra-amniotically with 107 colony-forming units of Ureaplasma parvum or saline (control). Fetuses were delivered surgically 3 or 7 days later. We performed comprehensive assessments of inflammation and immune effects in multiple fetal and maternal tissues.ResultsAlthough U. parvum grew well in amniotic fluid, there was minimal chorioamnionitis. U. parvum colonized the fetal lung, but fetal systemic microbial invasion was limited. Fetal lung inflammation was mild, with elevations in CXCL8, tumor necrosis factor (TNF) α, and CCL2 levels in alveolar washes at day 7. Inflammation was not detected in the fetal brain. Significantly, U. parvum decreased regulatory T cells (Tregs) and activated interferon γ production in these Tregs in the fetus. It was detected in uterine tissue by day 7 and induced mild inflammation and increased expression of connexin 43, a gap junction protein involved with labor.ConclusionsU. parvum colonized the amniotic fluid and caused uterine inflammation, but without overt chorioamnionitis. It caused mild fetal lung inflammation but had a more profound effect on the fetal immune system, decreasing Tregs and polarizing them toward a T-helper 1 phenotype

Physiological variables at delivery and cells in cord blood.

<p>Values are mean ± SD. BW, body weight; WBC, white blood cells; GA, gestational age</p><p>*<i>p</i><0.05 vs. Control Saline</p><p>Physiological variables at delivery and cells in cord blood.</p

Fetal lung histology following LPS exposure.

<p>Representative photograph shows mild interstitial thickening in 1 day and 6 days LPS groups <b>(B, C)</b> compared to the saline control group <b>(A).</b> Scale bar represents 50 μm. Magnification x20</p

Summary of the characteristics of fetal inflammatory response (FIR): Contributions of different fetal organs.

<p>Based on the current study and references [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0119281#pone.0119281.ref010" target="_blank">10</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0119281#pone.0119281.ref020" target="_blank">20</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0119281#pone.0119281.ref022" target="_blank">22</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0119281#pone.0119281.ref027" target="_blank">27</a>].</p><p>Summary of the characteristics of fetal inflammatory response (FIR): Contributions of different fetal organs.</p