TNF induces the expression of the sialyltransferase ST3Gal IV in human bronchial mucosa via MSK1/2 protein kinases and increases FliD/sialyl-Lewis(x)-mediated adhesion of Pseudomonas aeruginosa.

We have shown previously that the pro-inflammatory cytokine TNF (tumour necrosis factor) could drive sLe(x) (sialyl-Lewis(x)) biosynthesis through the up-regulation of the BX transcript isoform of the ST3GAL4 (ST3 ß-galactoside α-2,3-sialyltransferase 4) sialyltransferase gene in lung epithelial cells and human bronchial mucosa. In the present study, we show that the TNF-induced up-regulation of the ST3GAL4 BX transcript is mediated by MSK1/2 (mitogen- and stress-activated kinase 1/2) through the ERK (extracellular-signal-regulated kinase) and p38 MAPK (mitogen-activated protein kinase) pathways, and increases sLe(x) expression on high-molecular-mass glycoproteins in inflamed airway epithelium. We also show that the TNF-induced sLe(x) expression increases the adhesion of the Pseudomonas aeruginosa PAO1 and PAK strains to lung epithelial cells in a FliD-dependent manner. These results suggest that ERK and p38 MAPK, and the downstream kinase MSK1/2, should be considered as potential targets to hamper inflammation, bronchial mucin glycosylation changes and P. aeruginosa binding in the lung of patients suffering from lung diseases such as chronic bronchitis or cystic fibrosis.

Xenobiotic metabolism and disposition in human lung cell models: comparison with in vivo expression profiles.

Numerous lung cell lines are currently used as in vitro models for pharmacological and toxicological studies. However, no exhaustive report about the metabolic capacities of these models in comparison with those of lung tissues is available. In the present study, we used a high-throughput quantitative real-time reverse transcription-polymerase chain reaction strategy to characterize the expression profiles of 380 genes encoding proteins involved in the metabolism and disposition of xenobiotics in 10 commonly used lung cell lines (A549, H292, H358, H460, H727, Calu-1, 16HBE, 1 HAEO, BEAS-2B, and L-132) and four primary cultures of human bronchial epithelial cells. Expression results were then compared with those previously obtained in human nontumoral and tumoral lung tissues. Our results revealed disparities in gene expression between lung cell lines or when comparing lung cell lines with primary cells or lung tissues. Primary cell cultures displayed the highest similarities with bronchial mucosa in terms of transcript profiling and therefore seem to be the most relevant in vitro model for investigating the metabolism and bioactivation of toxicants and drugs in bronchial epithelium. H292 and BEAS-2B cell lines, which exhibited the highest homology in gene expression pattern with primary cells and the lowest number of dysregulated genes compared with nontumoral lung tissues, could be used as surrogates for toxicological and pharmacological studies. Overall, our study should provide references for researchers to choose the most appropriate in vitro model for analyzing the cellular effects of drugs or airborne toxicants on the airway.

Reporting of patient safety incidents in minimally invasive thoracic surgery: a national registered thoracic surgeons experience for improvement of patient safety.

OBJECTIVES: The reporting of patient safety incidents (PSIs) occurring in minimally invasive thoracic surgery (MITS) is crucial. However, previous reports focused mainly on catastrophic events whereas minor events are often underreported. METHODS: All voluntary reports of MITS-related PSIs were retrospectively extracted from the French REX database for 'in-depth analysis'. From 2008 to 2019, we retrospectively analysed and graded events according to the WHO classification of PSIs: near miss events, no harm incidents and harmful incidents. Causes and corrective measures were analysed according to the human-technology-organization triad. RESULTS: Of the 5145 cardiothoracic surgery PSIs declared, 407 were related to MITS. Among them, MITS was performed for primary lung cancer in 317 (78%) and consisted in a lobectomy in 249 (61%) patients. PSIs were: near miss events in 42 (10%) patients, no harm incidents in 81 (20%) patients and harmful incidents in 284 (70%) patients (mild: n = 163, 40%; moderate: n = 78, 19%; severe: n = 36, 9%; and deaths: n = 7, 2%). Human factors represented the most important cause of PSIs with 267/407 (65.6%) cases, including mainly vascular injuries (n = 90; 22%) and non-vascular injuries (n = 43; 11%). Pulmonary arteries were the most affected site with 57/91 cases (62%). In all, there were 7 deaths (2%), 53 patients required second surgery (13%) and 30 required additional lung resection (7%). CONCLUSIONS: The majority of reported MITS -related PSIs were non-catastrophic. Human factors were the main cause of PSIs. Systematic reporting and analysis of these PSIs will allow surgeon and his team to avoid a large proportion of them.

Assessment of non-small cell lung cancer perfusion: pathologic-CT correlation in 15 patients.

PURPOSE: To assess tumor perfusion with multi-detector row computed tomography (CT) in patients with non-small cell lung carcinoma and to correlate CT findings with pathologic results. MATERIALS AND METHODS: This study was approved by the local Ethics Committee, and all patients provided written informed consent, which included information on the radiation exposure at the CT examinations. Fifteen consecutive patients (mean age, 60.5 years ± 7.7 [standard deviation]), including 14 men (mean age, 59.9 years ± 7.5) and one woman (age, 70 years) with histologically proved non-small cell lung carcinoma were prospectively enrolled. Overall, pathologic-CT correlations were examined in 31 focal tumoral zones. Comparative analysis was performed by using the χ(2) or the Fisher exact test for categoric data. For numeric data, group comparisons were performed by using the Mann-Whitney test. RESULTS: Whole-tumor coverage (mean height, 4.3 cm ± 2.1) was possible in all patients with generation of colored parametric maps of volume transfer constant (K(trans)) and blood volume (BV) by using Patlak analysis. Of the 12 areas that showed high BV, 10 (83%) had a high K(trans); in all 12 cases, the vascular score was high, confirming the presence of numerous tumoral vessels. Nineteen areas showed low BV; when observed concurrently with a high K(trans) (seven of 19), the mean vessel number per area was significantly higher than that seen in areas with low BV and low K(trans) (12 of 19) (P = .038), suggestive of tumoral vessels associated with high interstitial pressure. CONCLUSION: Whole-tumor perfusion analysis is technically feasible with 64-detector row CT, with two patterns suggestive of high tumoral vascularity. SUPPLEMENTAL MATERIAL: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.10100181/-/DC1.

The mechanisms of pain-induced pulmonary vasoconstriction: an experimental study in fetal lambs.

BACKGROUND: Nociceptive stimulation induces pulmonary vasoconstriction in fetuses and newborns. The mechanism of this response is not fully understood. As the systemic hemodynamic response to pain is mainly mediated by sympathetic stimulation, we hypothesized that pain-induced pulmonary vasoconstriction results from the activation of catecholaminergic receptors. To test this hypothesis, we studied the pulmonary vascular response to nociceptive stimuli in fetal lambs before and after alpha-adrenoceptor blockade. METHODS: Surgery was performed in fetal lambs. Catheters were placed into the ascending aorta, superior vena cava, and main pulmonary artery. An ultrasonic flow transducer was placed around the left pulmonary artery, and subcutaneous catheters were placed in the limb. The hemodynamic responses to (1) subcutaneous injection of formalin (which is used as nociceptive stimulus in experimental studies), (2) prazosin (specific alpha(1)-adrenoceptor antagonist), and (3) formalin during prazosin infusion were evaluated. Plasma cortisol and catecholamine concentrations were measured. RESULTS: Pulmonary vascular resistance (PVR) increased by 50% (P < 0.01) after the formalin test. PVR did not change after the formalin test during prazosin infusion or during prazosin infusion alone. Catecholamine and cortisol levels did not change during any of the protocols. DISCUSSION: Our results indicate that the fetal pulmonary vasoconstrictive response to pain involves alpha(1)-adrenoceptors activation. As plasma catecholamine concentrations did not change after the formalin test, we speculate that the pulmonary vascular response to nociceptive stimuli could be triggered by a local release of catecholamine induced by sympathetic stimulation.

Tracheal replacement by allogenic aorta in the pig.

BACKGROUND: To assess whether fresh aortic allografts (AAs) can be used for tracheal replacement. METHODS: Twenty-one male minipigs underwent tracheal replacement using AAs harvested from female pigs. The length of replaced segments exceeded 50% of the trachea. A stent was implanted into the lumen of the AA to prevent collapse. The animals were killed at 3-month intervals, and AAs were assessed for ingrowth of respiratory epithelium and cartilage formation and tested for type II collagen formation and the presence of the SRY gene. RESULTS: A high stent migration rate was observed. Only 10 pigs and 4 pigs made it to follow-up periods exceeding 3 months and 9 months, respectively. Neither rejection nor ischemia were observed. At 3 months, a metaplastic epithelium lined the graft. At 10 months, a posterior membrane could be seen with immature cartilage and disorganized elastic fibers. SRY gene assay showed that the cells engrafted in the AAs, particularly at the level of the newly formed cartilage, were of male origin and thus originated from the recipient. CONCLUSION: This study confirms that a fresh AA, replacing more than half of the trachea of the pig, transforms into a conduit containing the major tracheal components. These components are relatively immature and do not as of yet replicate the form and function of the native trachea. Questions remain concerning the exact mechanisms of this process. Further research on the role of tracheal replacement is recommended.

Influence of sympathetic tone on heart rate during vagal stimulation and nitroprusside induced hypotension in ovine fetus.

OBJECTIVE: To characterize effects of sympathetic tone on fetal heart rate (FHR) reflex responses and FHR variability in late gestation. DESIGN/METHODS: Changes in FHR and autonomic tones were studied (i) after electrical vagal stimulation and (ii) during nitroprusside-induced hypotension, in seven late gestation ovine fetus in control condition (ctrl), after dobutamine (beta1-activation) and atenolol (beta1-blockade). Results are expressed as mean +/- SEM. RESULTS: (i) Minimal FHR after vagal stimulation was not influenced by atenolol or dobutamine but dobutamine accelerated FHR normalization. (ii) During nitroprusside induced hypotension atenolol inhibited the initial increases in FHR and FHR variability (measured by SD and LFnu) but not the bradycardia occurring below a mean arterial pressure of 38 +/- 2 mmHg. Dobutamine did not abolish the depressor reflex. During hypotension the positive chronotropic effect of sympathetic tone increased from 15 +/- 2 to 42 +/- 7 bpm then decreased at a rate of -7.6 +/- 1.5 bpm mmHg(-1), vagal negative chronotropic influence steadily increased at a rate of 1.9 +/- 0.4 bpm mmHg(-1). Changes in FHR variability were not correlated with vagal or sympathetic chronotropic effects. CONCLUSIONS: beta1-stimulation does not affect sinus-node response to vagal stimulation but improves the speed of FHR normalization. FHR response to hypotension depends on an initial increase in both sympathetic and parasympathetic chronotropic effects that is associated with a sympathetic dependent increase in FHR variability and is followed by a withdrawal of sympathetic tone.

Outcome at 2 years of infants with congenital diaphragmatic hernia: a population-based study.

BACKGROUND: Management of neonates with congenital diaphragmatic hernia (CDH) has undergone many changes associated with increased survival of high-risk CDH. However, little is known about the long-term outcome of CDH infants. METHODS: Follow-up was performed in 85 newborn infants with CDH admitted in our neonatal intensive care unit between January 1991 and December 1998. Early (< 2 months) and late mortality (> or = 2 months), and respiratory, nutritional, musculoskeletal, and neurosensory outcome at 2 years were recorded. RESULTS: Surgical repair was performed in 59 infants (69%) at a median postnatal age of 124 (range, 38 to 246) hours. Extracorporeal membrane oxygenation was used in 26 (30%) newborn infants. Survival at 2 years was 51 of 85 (60%) (early death, 28/85 [33%]; late death, 6/85 [7%]). Late deaths occurred because of persistent pulmonary hypertension or iatrogenic complications. Twelve of 51 (24%) newborn infants were oxygen dependant at the postnatal age of 28 days, and 1 of 51 (1.9%) was still oxygen dependant at 2 years. Growth failure was noted in 9 of 51 (18%), mainly related to severe gastroesophageal reflux and oral aversion. Scoliosis was diagnosed in 2 infants. Neurologic examination at 2 years was normal in 45 of 51 (88%). Cerebral palsy and developmental delay were observed in 2 and 4 infants, respectively. Four infants (8%) experienced associated problems. Respiratory, nutritional, and musculoskeletal morbidity was higher in infants treated by extracorporeal membrane oxygenation (p < 0.05). CONCLUSIONS: CDH infants are at risk for adverse nutritional and respiratory outcome. Despite severe respiratory failure at birth, prolonged oxygen therapy above 2 years of age is uncommon. Conversely, failure to thrive related at least in part to gastroesophageal reflux and oral dysfunction remains the major problem at 2 years of age. However, both nutritional and respiratory problems tend to improve with age.

Acquired pulmonary vein stenosis as a cause of life-threatening pulmonary hypertension.

We report the case of an infant born prematurely at 27 weeks gestational age with life-threatening pulmonary hypertension crisis as a result of left upper pulmonary vein stenosis. Surgical treatment consisted of a lobectomy, which is a safe and effective procedure. Evidence strongly suggests that the venous stenosis may have resulted from hypertonic drugs infused through an umbilical catheter facing the upper left venous-atrial junction.

TNF regulates sialyl-Lewisx and 6-sulfo-sialyl-Lewisx expression in human lung through up-regulation of ST3GAL4 transcript isoform BX.

Bronchial mucins from severely infected patients suffering from lung diseases such as chronic bronchitis or cystic fibrosis exhibit increased amounts of sialyl-Lewis(x) (NeuAcα2-3Galß1-4[Fucα1-3]GlcNAc-R, sLe(x)) glycan structures. In cystic fibrosis, sLe(x) and its sulfated form 6-sulfo-sialyl-Lewis(x) (NeuAcα2-3Galß1-4[Fucα1-3](HO(3)S-6)GlcNAc-R, 6-sulfo-sLe(x)) serve as receptors for Pseudomonas aeruginosa and are involved in the chronicity of airway infection. However, little is known about the molecular mechanisms regulating the changes in glycosylation and sulfation of mucins in airways. Herein, we show that the pro-inflammatory cytokine TNF increases the expression of α2,3-sialyltransferase gene ST3GAL4, both in human bronchial mucosa and in A549 lung carcinoma cells. The role of sialyltransferase ST3Gal IV in sLe(x) biosynthesis was confirmed by siRNA silencing of ST3GAL4 gene. BX is the major transcript isoform expressed in healthy bronchial mucosa and in A549 cells, and is up-regulated by TNF in both models. Bioinformatics analysis and luciferase assays have confirmed that the 2 kb genomic sequence surrounding BX exon contains a promoter region regulated by TNF-related transcription factors. These results support further work aiming at the development of anti-inflammatory strategy to reduce chronic airway infection in diseases such as cystic fibrosis.

Xenobiotic metabolism and disposition in human lung: transcript profiling in non-tumoral and tumoral tissues.

The lung is directly exposed to a wide variety of inhaled toxicants and carcinogens. In order to improve our knowledge of the cellular processing of these compounds in the respiratory tract, we investigated the mRNA expression level of 380 genes encoding xenobiotic-metabolizing enzymes (XME), transporters, nuclear receptors and transcription factors, in pulmonary parenchyma (PP), bronchial mucosa (BM) and tumoral lung tissues from 12 patients with non-small cell lung cancer (NSCLC). Using a high throughput quantitative real-time RT-PCR method, we found that ADH1B, CYP4B1, CES1 and GSTP1 are the major XME genes expressed both in BM and PP. Our results also documented the predominant role played by the xenosensor AhR in human lung. The gene expression profiles were different for BM and PP, with a tendency toward increased mRNA levels of phase I and phase II XME genes in BM, suggesting major differences in the initial stages of xenobiotic metabolism. Some of the significantly overexpressed genes in BM (i.e. CYP2F1, CYP2A13, CYP2W1, NQO1…) encode proteins involved in the bioactivation of procarcinogens, pointing out distinct susceptibility to xenobiotics and their toxic effects between these two tissue types. Additionally, interindividual differences in transcript levels observed for some genes may be of genetic origin and may contribute to the variability in response to environmental exposure and, consequently, in the risk of developing lung diseases. A global decrease in gene expression was observed in tumoral specimens. Some of the proteins are involved in the metabolism or transport of anti-cancer drugs and their influence in the response of tumors to chemotherapy should be considered. In conclusion, the present study provides an overview of the cellular response to toxicants and drugs in healthy and cancerous human lung tissues, and thus improves our understanding of the mechanisms of chemical carcinogenesis as well as cellular resistance to chemotherapy.

Tracheal replacement with cryopreserved allogenic aorta.

BACKGROUND: Radical resection of primary tracheal tumors may be challenging when more than one-half of the tracheal length is concerned. The present study evaluated the use of cryopreserved aortic allografts (CAAs) to replace long tracheal segments. METHODS: Sixteen adult minipigs underwent tracheal replacement with a CAA. A silicone stent was used to splint the CAA for the first 12 months. Animals were followed-up using bronchoscopic evaluation and killed at predetermined times, for a period up to 18 months long. RESULTS: Intense inflammation and progressive disappearance of typical histologic structures of the aorta were seen within the first 3 months. All animals studied for more than 3 months showed progressive transformation of the graft into a chimerical conduit sharing aortic and tracheal histologic patterns (eg, islands of disorganized elastic fibers/mature respiratory ciliated epithelium, respiratory glands, islets of cartilage). Stent removal was attempted after 12 months in 10 animals, and critical tracheal stenosis was found in six animals and moderate asymptomatic stenosis in four. Clinical course in these latter animals was uneventful until they were killed at 15 to 18 months. In situ hybridization showed that collagen2a1 mRNA was expressed in the cartilage islets at 1 year. Polymerase chain reaction analysis of the SRY gene demonstrated that the newly formed cartilage cells derived from the host. CONCLUSIONS: CAA may be considered as a valuable tracheal substitute for patients with extensive tracheal tumors. Prolonged stenting will be probably mandatory for the clinical application of the procedure in humans.

Profiling gene expression of whole cytochrome P450 superfamily in human bronchial and peripheral lung tissues: Differential expression in non-small cell lung cancers.

Susceptibility to lung diseases, such as lung cancer and chronic obstructive pulmonary disease, is largely influenced by the metabolic capacity of lung tissues. This capacity is partly determined by the expression profile of the cytochromes P450 (CYPs), a superfamily of enzymes that have relevant catalytic properties toward exogenous and endogenous compounds. Using quantitative real-time RT-PCR, we conducted a comprehensive analysis of the expression profile of the 57 human CYP genes in non-tumoral (bronchial mucosa and pulmonary parenchyma) and tumoral lung tissues of 18 patients with non-small cell lung cancer. This study highlights (i) inter-individual variations in lung expression for some CYPs, (ii) different CYP expression patterns between bronchial mucosa and pulmonary parenchyma, that indicate distinctive susceptibility of these tissues toward the deleterious effects of inhaled chemical toxicants and carcinogens, (iii) high intertumoral variability, that could have major implications on lung tumor response to anti-cancer drugs.

Consequences of delayed surgical closure of patent ductus arteriosus in very premature infants.

BACKGROUND: Surgical closure of ductus arteriosus is commonly indicated in premature newborns. The aim of this study was to assess short-term and mid-term effects of delayed surgical closure of the ductus arteriosus on respiratory and digestive outcome in extremely preterm infants. METHODS: We retrospectively studied 58 infants less than 28 weeks gestational age who underwent surgical closure of ductus arteriosus between January 1997 and December 2002. Nine infants with intrauterine growth restriction and major congenital malformation were excluded from the study. Criteria for surgical closure of ductus arteriosus were: (1) medical treatment failure (ie, indomethacin or ibuprofen) and (2) hemodynamically patent ductus arteriosus: systemic arterial pressure less than gestational age in mm Hg, heart failure, left atrial-aortic root ratio greater than 1.6, mean velocity in the left pulmonary artery greater than 0.6 m/s, and ductus arteriosus diameter greater than 3 mm. Infants were divided into two groups: (1) the early group who had surgery before 21 days of life (n = 31), and (2) the late group who had surgery after 21 days of life (n = 27). Preoperative and postoperative criteria were compared between the two groups (ie, gestational age, birth weight, hemodynamic, ventilatory, and echographic [left atrial-aortic root ratio, mean velocity in the left pulmonary artery] parameters). RESULTS: Preoperative gestational age and birth weight did not differ between the two groups. In the early group, gestational age was 26 weeks (range, 23 to 28 weeks and birth weight was 800 g (range, 630 to 1,240 g). In the late group, gestational age was 26 weeks (range, 24 to 28 weeks) and birth weight was 840 g (530 to 1,130 g). Hemodynamic, ventilatory, and echographic parameters were similar in both groups. Rate of bronchopulmonary dysplasia was similar in both groups. However, at 24 hours post surgery, median FiO2 was higher in the late group (28% [range, 21% to 65%]) than in early group (21% [range, 21% to 60%]) (p < 0.05). Furthermore, full oral feeding was acquired later in the late group (57 days of life [range, 30 to 136 days]) than in the early group (37 days of life [range, 27 to 84 days]) (p < 0.01), and body weight at 36 weeks of post-conceptional age was higher in the early group at 1,800 g (range, 1,250 to 2,750 g) than in the late group at 1,607 g (1,274 to 2,200 g) (p < 0.05). CONCLUSIONS: Our findings show that early surgical closure of the ductus arteriosus (< 3 weeks of life) is associated with shortened delay for full oral feeding and improved body growth when compared with late surgical closure (> 3 weeks of life).

Effects of phosphodiesterase 5 inhibitor on pulmonary vascular reactivity in the fetal lamb.

BACKGROUND: Nitric oxide released by pulmonary vascular endothelium is a potent vasodilator related to increased cyclic guanosine monophosphate (cGMP) content. Hydrolysis of cGMP is achieved predominately by cGMP-specific phosphodiesterases. Sildenafil is a selective phosphodiesterase-5 (PDE5) inhibitor. The purpose of the study is to assess the effects of sildenafil on pulmonary vascular circulation during the perinatal period. METHODS: Thirty-two pregnant ewes were operated on at the end of gestation, and fetal lambs were prepared with catheters placed into the aorta, vena cava, pulmonary artery, and left atrium. An ultrasonic flow transducer and an inflatable vascular occluder were placed respectively around the left pulmonary artery and the ductus arteriosus. Fetal lambs were randomly divided into two groups: (1) sildenafil group, infused continuously with sildenafil for 24 hours at a rate of 1 mg/h; or (2) control group, infused with saline for 24 hours. After 24 hours of infusion, we compared basal pulmonary vascular resistance and the pulmonary vascular responses to increase in fetal PaO2 and to acute ductus arteriosus compression causing "shear stress." RESULTS: Sildenafil infusion did not change mean aortic and pulmonary artery pressures, increased mean left pulmonary blood flow by 160%, and decreased pulmonary vascular resistance by 60% (p < 0.05). However, both mean flow (Q) and pulmonary vascular resistance returned to baseline values after 2 hours of sildenafil infusion. Despite similar baseline values, pulmonary vascular resistance during maternal O2 inhalation was lower in the sildenafil group than in the control group (0.21 +/- 0.03 versus 0.33 +/- 0.03 mm Hg.mL(-1).min(-1), respectively; p < 0.01). Furthermore, drop in pulmonary vascular resistance during acute ductus arteriosus compression was greater in the sildenafil group (from 0.56 +/- 0.06 to 0.26 +/- 0.04 mm Hg.mL(-1).min(-1)) than in the control group (from 0.55 +/- 0.05 to 0.39 +/- 0.03 mm Hg.mL(-1).min(-1); p < 0.01). CONCLUSIONS: Although sildenafil induces a transient pulmonary vasodilation, it mediates a sustained change in vascular reactivity, especially to birth-related stimuli in the ovine fetal lung. These data suggest that PDE5 is involved in the regulation of pulmonary vascular reactivity during the perinatal period and may potentiate birth-related pulmonary vasodilator stimuli.

Preoperative ECMO in transposition of the great arteries with persistent pulmonary hypertension.

Persistent fetal circulation in transposition of the great arteries results in severe persistent pulmonary hypertension, which increases the risk of early mortality. We report the case of a newborn with transposition of the great arteries and intact ventricular septum associated with pulmonary hypertension. After the failure of immediate balloon atrial septostomy and supportive therapy including inhaled nitric oxide, preoperative extracorporeal membrane oxygenation reversed pulmonary hypertension and ventricular insufficiency and preceded a safe, delayed, cardiac surgical procedure. Unlike the authors of the other few case reports on this subject, we recommend a preoperative stabilization period after discontinuation of extracorporeal membrane oxygenation to avoid left ventricular "deconditioning" and postoperative deterioration related to recurrent persistent pulmonary hypertension.

Development of a new model to investigate the fetal nociceptive pathways.

OBJECTIVE: The aim of the study was to develop an experimental model to investigate the fetal nociceptive pathways and fetal analgesia. METHODS: We tested the electromyographic (EMG) response from the biceps femoris to electrical stimulation of the sural nerve in chronically-prepared fetal lambs with and without sufentanil. RESULTS: An EMG response could be recorded 140 ms after the electrical stimulation above a threshold of current's intensity. The response presents the characteristics of a nociceptive flexion reflex. The reflex magnitude increased with the stimulus intensity. Sufentanil decreased the response. Bradycardia was noted 10 s after the stimulation and was not observed after sufentanilinfusion. Catecholamine concentrations were not altered by the stimulation. CONCLUSION: Our study shows that a nociceptive flexion reflex can be recorded in the ovine fetus. We suggest that this reflex can be used as a new tool to study the ontogenesis of the nociceptive pathways and the effects of analgesic drugs during fetal life.

Higher risk of persistent pulmonary hypertension of the newborn after cesarean.

Authors suggest that high incidence of persistence pulmonary hypertension among neonates delivered by elective cesarean is related to lower levels of circulating norepinephrine in neonates after cesarean section than after vaginal delivery.

Role of the alpha2-adrenoceptors on the pulmonary circulation in the ovine fetus.

Recent in vitro studies reported that nitric oxide release and pulmonary vasorelaxation can be mediated by endothelial alpha2-adrenoceptor activation. As norepinephrine (alpha1-,alpha2-, and beta1-adrenoceptor agonist) was found to induce pulmonary vasodilation in the ovine fetus, we hypothesized that alpha2-adrenoceptors may modulate basal pulmonary vascular tone and mediate the vascular effect of norepinephrine during fetal life. To determine the role of alpha2-adrenoceptors and the mechanisms of norepinephrine-mediated vasodilation in the fetal pulmonary circulation, we tested, in chronically prepared late-gestation fetal lambs, the hemodynamic response to 1). yohimbine (alpha2 antagonist); 2). UK 14304 (alpha2 agonist) with and without l-nitro-arginine (nitric oxide synthase inhibitor); and 3). norepinephrine infusion with and without yohimbine. We found that yohimbine increased mean pulmonary artery pressure by 15% (p < 0.05), decreased pulmonary flow by 22% (p < 0.01), and increased pulmonary vascular resistance by 51% (p < 0.01). UK 14304 increased pulmonary flow by 145% (p < 0.01) and decreased pulmonary vascular resistance by 58% (p < 0.01). l-Nitro-arginine abolished the UK 14304-mediated pulmonary vasodilation. Norepinephrine (0.5 microg x kg(-1)x min(-1) increased both pulmonary flow by 61% (p < 0.01) and pulmonary arterial pressure by 13% (p < 0.01) and decreased pulmonary vascular resistance by 33% (p < 0.01). Yohimbine abolished the norepinephrine-induced pulmonary vasodilation. This study suggests that 1). a basal alpha2-adrenoceptor activation-induced pulmonary vasodilation exists during fetal life; 2). the pulmonary vascular effects of alpha2-adrenoceptor activation are related at least in part to nitric oxide production; and 3). the norepinephrine-mediated pulmonary vasodilation involves alpha2-adrenoceptor activation. As a surge of norepinephrine exists at birth, we speculate that norepinephrine and endothelial alpha2-adrenoceptor activation may play a significant role in pulmonary vasodilation at birth.