Signs of Reduced Basal Progenitor Levels and Cortical Neurogenesis in Human Fetuses with Open Spina Bifida at 11-15 Weeks of Gestation.

Open spina bifida (OSB) is one of the most prevalent congenital malformations of the CNS that often leads to severe disabilities. Previous studies reported the volume and thickness of the neocortex to be altered in children and adolescents diagnosed with OSB. Until now, the onset and the underlying cause of the atypical neocortex organization in OSB patients remain largely unknown. To examine the effects of OSB on fetal neocortex development, we analyzed human fetuses of both sexes diagnosed with OSB between 11 and 15 weeks of gestation by immunofluorescence for established neuronal and neural progenitor marker proteins and compared the results with healthy controls of the same, or very similar, gestational age. Our data indicate that neocortex development in OSB fetuses is altered as early as 11 weeks of gestation. We observed a marked reduction in the radial thickness of the OSB neocortex, which appears to be attributable to a massive decrease in the number of deep- and upper-layer neurons per field, and found a marked reduction in the number of basal progenitors (BPs) per field in the OSB neocortex, consistent with an impairment of cortical neurogenesis underlying the neuronal decrease in OSB fetuses. Moreover, our data suggest that the decrease in BP number in the OSB neocortex may be associated with BPs spending a lesser proportion of their cell cycle in M-phase. Together, our findings expand our understanding of the pathophysiology of OSB and support the need for an early fetal therapy (i.e., in the first trimester of pregnancy).SIGNIFICANCE STATEMENT Open spina bifida (OSB) is one of the most prevalent congenital malformations of the CNS. This study provides novel data on neocortex development of human OSB fetuses. Our data indicate that neocortex development in OSB fetuses is altered as early as 11 weeks of gestation. We observed a marked reduction in the radial thickness of the OSB neocortex, which appears to be attributable a decrease in the number of deep- and upper-layer neurons per field, and found a marked reduction in the number of basal progenitors per field, indicating that impaired neurogenesis underlies the neuronal decrease in OSB fetuses. Our findings support the need for an early fetal therapy and expand our understanding of the pathophysiology of OSB.

Human cerebral organoids recapitulate gene expression programs of fetal neocortex development.

Cerebral organoids-3D cultures of human cerebral tissue derived from pluripotent stem cells-have emerged as models of human cortical development. However, the extent to which in vitro organoid systems recapitulate neural progenitor cell proliferation and neuronal differentiation programs observed in vivo remains unclear. Here we use single-cell RNA sequencing (scRNA-seq) to dissect and compare cell composition and progenitor-to-neuron lineage relationships in human cerebral organoids and fetal neocortex. Covariation network analysis using the fetal neocortex data reveals known and previously unidentified interactions among genes central to neural progenitor proliferation and neuronal differentiation. In the organoid, we detect diverse progenitors and differentiated cell types of neuronal and mesenchymal lineages and identify cells that derived from regions resembling the fetal neocortex. We find that these organoid cortical cells use gene expression programs remarkably similar to those of the fetal tissue to organize into cerebral cortex-like regions. Our comparison of in vivo and in vitro cortical single-cell transcriptomes illuminates the genetic features underlying human cortical development that can be studied in organoid cultures.

Isolated Cleft Lip and Palate: Maxillary Gap Sign and Palatino-Maxillary Diameter at 11-13 Weeks.

OBJECTIVE: To evaluate the maxillary gap sign and describe markers for the first-trimester diagnosis of isolated cleft lip and palate (CLP) at 11-13 weeks. METHODS: Firstly, this was a prospective assessment of 1,087 fetuses including 5 cases of isolated CLP in 2 centers which were referred for the 11-13 weeks scan. Secondly, intra- and interobserver variability of the maxillary gap sign was evaluated for observers R.L. and A.B. in 2 sessions (affected cases vs. 50 normal fetuses in each session) to reduce the bias of different ultrasound manufacturer visualizations (Philips, GE). Thirdly, the palatino-maxillary diameter (PMD) was examined in stored images, DICOM loops and volumes of the midsagittal and parasagittal view of the fetal head and brain at 11+0-13+6 weeks of gestation from 5 fetuses with isolated CLP and 302 consecutively assessed normal controls. The PMD values in fetuses with isolated CLP and normal controls were compared. RESULTS: Firstly, 5 out of 6 referred pregnancies with isolated CLP were detected prospectively using the midsagittal view for measurement of nuchal translucency due to an abnormal appearance. One out of 6 patients with isolated CLP declined the 11-13 weeks scan. Secondly, intra- and interobserver variability showed no false positive cases; all cases with isolated CLP were identified by both sonographers; however, in 2 cases the maxillary gap sign was doubtful. Therefore, thirdly, we developed the PMD measurement which increased significantly with crown-rump length (CRL) from respective mean values at CRL of 45 mm to 4.66 mm and to 8.95 mm at CRL of 84 mm. In the CLP group, the PMD was below the 5th percentile of the control group in 4 out of 5 (80%) cases. CONCLUSIONS: The midsagittal view for measurement of nuchal translucency shows a high reproducibility regarding abnormal views for maxillary gap sign. In the midsagittal view of the fetal head, face, and brain at 11-13 weeks, the majority of fetuses with isolated CLP have a measurable abnormality in addition, the PMD.

Transcriptomes of germinal zones of human and mouse fetal neocortex suggest a role of extracellular matrix in progenitor self-renewal.

The expansion of the neocortex during mammalian brain evolution results primarily from an increase in neural progenitor cell divisions in its two principal germinal zones during development, the ventricular zone (VZ) and the subventricular zone (SVZ). Using mRNA sequencing, we analyzed the transcriptomes of fetal human and embryonic mouse VZ, SVZ, and cortical plate. In mouse, the transcriptome of the SVZ was more similar to that of the cortical plate than that of the VZ, whereas in human the opposite was the case, with the inner and outer SVZ being highly related to each other despite their cytoarchitectonic differences. We describe sets of genes that are up- or down-regulated in each germinal zone. These data suggest that cell adhesion and cell-extracellular matrix interactions promote the proliferation and self-renewal of neural progenitors in the developing human neocortex. Notably, relevant extracellular matrix-associated genes include distinct sets of collagens, laminins, proteoglycans, and integrins, along with specific sets of growth factors and morphogens. Our data establish a basis for identifying novel cell-type markers and open up avenues to unravel the molecular basis of neocortex expansion during evolution.

Effect of blood on ROM diagnosis accuracy of PAMG-1 and IGFBP-1 detecting rapid tests.

Vaginal bleeding may be present in up to 30% of patients presenting with signs and symptoms of a rupture of the fetal membranes (ROM). The presence of blood may lead to false positive results with biochemical markers. The data presented in this study came from a multi-centric prospective observational clinical study that, for the first time, systematically evaluated the performance of placental alpha microglobulin-1 (PAMG-1) and insulin-like growth factor binding protein-1 (IGFBP-1) detecting tests in 151 women with vaginal bleedings as well as signs and symptoms indicative of ROM. Our data showed better performance for the PAMG-1 compared with the IGFBP-1 detecting tests in all quality parameters evaluated. In detail, sensitivity (SN) was 97.8% (91.0%), specificity (SP) was 91.5% (75.0%), positive predictive value (PPV) was 94.6% (83.5%) and negative predictive value (NPV) was 96.4% (85.7%) for PAMG-1 tests (and IGFBP-1 tests, respectively). A major difference between both tests was related to the number of non-evaluable test results (e.g., hidden bands due to blood smear on the test strips). While 2% of all results were not evaluable for PAMG-1 tests, this artifact appeared in 11% of the results obtained with IGFBP-1 tests. This difference and also those in Specificity and PPV were statistically significant, demonstrating superiority of PAMG-1 over IGFBP-1 detecting tests. In conclusion, the PAMG-1 detecting test was significantly less susceptible to interference by blood than the IGFBP-1 detecting test.

Explorative investigation of vascular endothelial growth factor receptor expression in primary ovarian cancer and its clinical relevance.

OBJECTIVES: The identification of novel molecular biomarkers, predicting outcome of ovarian cancer, is highly desirable. Considering that angiogenesis is a critical factor for ascites development and peritoneal dissemination in ovarian cancer and given that the vascular endothelial growth factor (VEGF) receptor signaling axis is a major driver of angiogenesis, we sought to analyze expression and compartmental distribution of VEGF-receptor family in ovarian cancer and to assess its clinical relevance with regard to established clinicopathological parameters, tumor cell dissemination to the bone marrow (BM) and the patient's survival. METHODS: A total of 73 patients with primary ovarian cancer were enrolled into this study. Primary tumor tissue was analyzed for the expression of VEGF-R1, VEGF-R2 and VEGF-R3 by immunohistochemistry. The presence of disseminated tumor cells (DTC) in the BM was analyzed by immunocytochemistry using the pancytokeratin antibody A45B/B3 and subsequent automatic detection based on staining and cytomorphology. RESULTS: In primary ovarian cancer tissue, VEGF-receptor expression, detected with an overall frequency of 44%, was mostly located in the vascular wall and across the stroma; positivity rates for VEGF-R1, VEGF-R2 and VEGF-R3 were 34%, 18% and 26%, respectively. Total VEGF-receptor expression correlated with residual tumor after primary debulking surgery and the presence of DTC at primary diagnosis (p=0.035, p=0.023, respectively). Interestingly, VEGF-R1 positivity significantly correlated with decreased progression-free survival (p=0.026). CONCLUSIONS: This is the first report, suggesting total VEGF-receptor status as a molecular biomarker for monitoring tumor cell spread to the BM and, particularly, revealing prognostic significance of VEGF-R1.

Midbrain and falx in fetuses with absent corpus callosum at 11-13 weeks.

OBJECTIVE: To describe the first trimester diagnosis of agenesis of the corpus callosum (ACC). METHODS: The midbrain and falx cerebri were examined in stored images of the midsagittal view of the fetal brain at 11(+0)-13(+6) weeks' gestation from 15 fetuses with ACC and 500 normal controls. The midbrain diameter and falx diameter were measured and their ratio was calculated. The values in fetuses with ACC and normal controls were compared. RESULTS: In the control group, the midbrain and falx diameters increased significantly with crown-rump length (CRL) from respective mean values of 5.1 and 6.9 mm at CRL of 45-6.9 mm and 12.1 mm at CRL of 84 mm. In the ACC group the midbrain diameter was above the 95th percentile of the control group in 8 (53.3%) cases, the falx diameter was below the 5th percentile in 6 (40.0%) cases and the midbrain diameter-to-falx diameter ratio was above the 95th percentile in 13 (86.7%) cases. CONCLUSIONS: In the midsagittal view of the fetal brain at 11-13 weeks, the majority of fetuses with ACC have measurable abnormalities in the midbrain and falx area of the brain.

Posterior brain in fetuses with Dandy-Walker malformation with complete agenesis of the cerebellar vermis at 11-13 weeks: a pilot study.

OBJECTIVE: This study aimed to measure the changes in the posterior brain in fetuses with Dandy-Walker malformation (DWM) with complete agenesis of the cerebellar vermis between 11(+0) and 13(+6) weeks of gestation. METHODS: In the midsagittal view, the brain stem (BS) diameter and the brain stem to occipital bone (BSOB) diameter were measured, and the BS/BSOB ratio was calculated in four fetuses with confirmed DWM and 40 normal fetuses. Delta values corrected for CRL were compared between both groups. RESULTS: In contrast to the normal controls, in fetuses with DWM at 11(+0) to 13(+6) weeks of gestation, the border between the fourth ventricle and the cisterna magna was not visible. There were no significant differences in the BS diameter between the two groups (p<0.3). In the DWM group, the mean diameter of the BSOB was found to be significantly higher than in the controls (p=0.0011), and it was above the 95th centile in all four cases. In addition, the BS/BSOB ratio was significantly decreased in fetuses with DWM (p=0.0011). CONCLUSIONS: At 11-13 weeks, fetuses with DWM have measurable abnormalities in the posterior brain. An abnormal appearance of the fourth ventricle-cisterna magna complex was present in all four cases of DWM.

Temporal effect of Afro-Caribbean race on serum pregnancy-associated plasma protein-a at 9-13 weeks' gestation in screening for aneuploidies.

OBJECTIVE: It was the aim of this study to investigate the pregnancy characteristics that influence the measured concentrations of maternal serum-free ß-human chorionic gonadotropin (ß-hCG) and pregnancy-associated plasma protein-A (PAPP-A) at 9(+0)-13(+6) weeks' gestation. METHODS: In singleton pregnancies attending for routine care, serum-free ß-hCG and PAPP-A were measured at 9(+0)-13(+6) weeks' gestation and fetal nuchal translucency was measured at 11(+0)-13(+6) weeks. The population included 27,908 chromosomally normal and 104 trisomy 21 pregnancies. Multiple regression analysis was used to examine the pregnancy characteristics that have a significant effect on the measured concentrations of free ß-hCG and PAPP-A. We also examined the impact of incorporating temporal effects on performance of screening for trisomy 21. RESULTS: Serum-free ß-hCG and PAPP-A concentrations were significantly affected by gestational age, maternal weight, racial origin, parity, preexisting diabetes mellitus type 2, smoking and conception by in vitro fertilization. There was a significant gestational age-dependent effect of Afro-Caribbean race on PAPP-A levels (p = 0.0005), with a weekly increase of 4.9% (95% CI 2.1-7.8). CONCLUSIONS: Serum-free ß-hCG and PAPP-A concentrations at 9(+0)-13(+6) weeks' gestation are affected by several pregnancy characteristics and the effect of Afro-Caribbean race on PAPP-A increases with gestational age.

Congenital idiopathic dilatation of the right atrium: antenatal appearance, postnatal management, long-term follow-up and possible pathomechanism.

INTRODUCTION: Idiopathic dilatation of the right atrium (IDRA) is a rare abnormality usually detected by chance at any time between antenatal and adult life. It is defined as isolated enlargement of the right atrium in the absence of other cardiac lesions causing right atrial dilatation. IDRA can be associated with atrial arrhythmia and systemic embolism. The clinical presentation shows high variability ranging from the lack of any symptoms up to cardiac failure. METHODS/RESULTS: We describe 2 children with antenatally diagnosed IDRA, the intrauterine course in 1 case, the postnatal management and its long-term follow-up. There has been no need for surgical intervention so far because of the lack of arrhythmias and no further progression of right atrial diameters. Thrombus formation in the right atrium, which is a potential risk for pulmonary embolism, led us to initiate anticoagulation in our cases to prevent such complications. Furthermore, we suggest one possible pathomechanism of congenital right atrial dilatation. CONCLUSION: Optimal management of severe IDRA depends on the individual case. Long-term follow-up of these patients is necessary to monitor a possible further progression of right atrial size and occurrence of arrhythmias. As a possible pathomechanism, a functional partial anomalous pulmonary venous insertion may imitate a structural abnormal pulmonary vein connection in some idiopathic cases of congenital right atrial dilatation.

Posterior brain in fetuses with open spina bifida at 11 to 13 weeks.

OBJECTIVE: To measure the changes in the posterior fossa in first-trimester fetuses with open spina bifida (OSB). METHODS: The brain stem diameter and brain stem to occipital bone (BSOB) diameter were measured in stored images of the mid-sagittal view of the fetal face at 11(+0) to 13(+6) weeks from 30 fetuses with OSB and 1000 normal controls. RESULTS: In the control group, the brain stem and BSOB diameter increased significantly with crown-rump length (CRL) and the brain stem to BSOB ratio decreased. In the spina bifida group, the brain stem diameter was above the 95th percentile of the control group in 29 (96.7%) cases, the BSOB diameter was below the 5th percentile in 26 (86.7%) and the brain stem to BSOB ratio was above the 95th percentile in all cases. CONCLUSIONS: At 11 to 13 weeks the majority of fetuses with OSB have measurable abnormalities in the posterior brain.

Sevoflurane ameliorates gas exchange and attenuates lung damage in experimental lipopolysaccharide-induced lung injury.

BACKGROUND: Acute lung injury is a common complication in critically ill patients. Several studies suggest that volatile anesthetics have immunomodulating effects. The aim of the current study was to assess possible postconditioning with sevoflurane in an in vivo model of endotoxin-induced lung injury. METHODS: Rats were anesthetized, tracheotomized, and mechanically ventilated. Lipopolysaccharide (saline as control) was administered intratracheally. Upon injury after 2 h of propofol anesthesia, general anesthesia was continued with either sevoflurane or propofol for 4 h. Arterial blood gases were measured every 2 h. After 6 h of injury, bronchoalveolar lavage was performed and lungs were collected. Total cell count, albumin content, concentrations of the cytokines cytokine-induced neutrophil chemoattractant-1 and monocyte chemoattractant protein-1, and phospholipids were analyzed in bronchoalveolar lavage fluid. Expression of messenger RNA for the two cytokines and for surfactant protein B was determined in lung tissue. Histopathologic examination of the lung was performed. RESULTS: Significant improvement of the ratio of oxygen tension to inspired oxygen fraction was shown with sevoflurane (mean + or - SD: 243 + or - 94 mmHg [32.4 kPa]) compared with propofol (88 + or - 19 mmHg [11.7 kPa]). Total cell count representing effector cell recruitment as well as albumin content as a measure of lung permeability were significantly decreased in the sevoflurane-lipopolysaccharide group compared with the propofol-lipopolysaccharide group in bronchoalveolar lavage fluid. Expression of the cytokines protein in bronchoalveolar lavage fluid as well as messenger RNA in lung tissue was significantly lower in the sevoflurane-lipopolysaccharide group compared with the propofol-lipopolysaccharide group. CONCLUSIONS: Postconditioning with sevoflurane attenuates lung damage and preserves lung function in an in vivo model of acute lung injury.

High positive end-expiratory pressure levels promote bacterial translocation in experimental pneumonia.

OBJECTIVE: A previous study in piglets with experimental pneumonia showed that reducing atelectasis by means of open lung ventilation attenuated bacterial translocation compared to conventional ventilation settings. This study examined the effect of open lung ventilation with higher than necessary positive end-expiratory pressures (PEEP) on bacterial translocation. DESIGN AND SETTING: Prospective animal study in a university-affiliated research laboratory. SUBJECTS: Thirty piglets. INTERVENTIONS: Animals were surfactant-depleted by whole-lung lavage and infected with group B streptococci. Thereafter the animals were ventilated for 5 h according to either a conventional ventilation strategy, open lung strategy, or open lung/high-PEEP strategy. Blood samples for blood gas analysis and blood bacterial counts were taken every hour. After 5 h of ventilation surviving animals were killed, and lung colony forming units and lung mechanics parameters were determined. RESULTS: All animals in both open lung groups survived but only 30% of those in the conventional ventilation group. Open lung ventilation resulted in significantly less bacterial translocation than either conventional or high-PEEP ventilation. Lung function in the conventional ventilated group was significantly less than in the two open lung groups. CONCLUSIONS: The lowest level of bacterial translocation was observed during optimal ventilation (open lung) which was achieved by using individually tailored settings. Deviation to either side can be harmful, as shown by the increased bacterial translocation during conventional and high-PEEP ventilation.

Low-dose inhalation of an endothelin-A receptor antagonist in experimental acute lung injury: ET-1 plasma concentration and pulmonary inflammation.

Inhalation of endothelin (ET)-A receptor antagonists has been shown to improve gas exchange in experimental acute lung injury (ALI) but may induce side effects by increasing circulating ET-1 levels. We investigated whether the inhaled ET(A) receptor antagonist, LU-135252, at low doses, improves gas exchange without affecting ET-1 plasma concentrations and lung injury in an animal model of ALI. Twenty-two piglets were examined in a prospective, randomized, controlled study. In anesthetized animals, ALI was induced by surfactant depletion. Animals received either LU-135252 at a dose of 0.3 mg/kg during 20 mins (LU group; n = 11), or nebulization of saline buffer (control group; n = 11). The Mann-Whitney U test was used to compare groups (P < 0.05). In the LU group, arterial partial pressure of oxygen (PaO2) and mean pulmonary artery pressure (MPAP) improved compared with the control group (PaO2, 319 +/- 44 mm Hg vs. 57 +/- 3 mm Hg; MPAP, 32 +/- 2 mm Hg vs. 41 +/- 2 mm Hg; values at 6 hrs after induction of ALI; P < 0.05). Mean arterial pressure and cardiac output were not different between groups. ET-1 plasma concentrations increased from 0.96 +/- 0.06 fmol/ml after induction of ALI to a maximum of 1.17 +/- 0.09 fmol/ml at 3 hrs after ALI onset in the LU group and did not differ significantly from the control group (1.21 +/- 0.08 fmol/ml, not significant). On histologic examination, we found no differences in total lung injury score between groups. However, the LU group revealed significantly reduced interstitial inflammation and hemorrhage (P < 0.05 vs. control group). In this animal model of ALI, inhalation of LU-135252 at a dose of 0.3 mg/kg induced a significant and sustained improvement in gas exchange, whereas there were no changes in ET-1 plasma concentrations. Furthermore, our data indicate a trend toward decreased pulmonary inflammation in the group receiving the inhaled ET(A) receptor antagonist.

Differences and similarities between human and chimpanzee neural progenitors during cerebral cortex development.

Human neocortex expansion likely contributed to the remarkable cognitive abilities of humans. This expansion is thought to primarily reflect differences in proliferation versus differentiation of neural progenitors during cortical development. Here, we have searched for such differences by analysing cerebral organoids from human and chimpanzees using immunohistofluorescence, live imaging, and single-cell transcriptomics. We find that the cytoarchitecture, cell type composition, and neurogenic gene expression programs of humans and chimpanzees are remarkably similar. Notably, however, live imaging of apical progenitor mitosis uncovered a lengthening of prometaphase-metaphase in humans compared to chimpanzees that is specific to proliferating progenitors and not observed in non-neural cells. Consistent with this, the small set of genes more highly expressed in human apical progenitors points to increased proliferative capacity, and the proportion of neurogenic basal progenitors is lower in humans. These subtle differences in cortical progenitors between humans and chimpanzees may have consequences for human neocortex evolution.

Human-specific gene ARHGAP11B promotes basal progenitor amplification and neocortex expansion.

Evolutionary expansion of the human neocortex reflects increased amplification of basal progenitors in the subventricular zone, producing more neurons during fetal corticogenesis. In this work, we analyze the transcriptomes of distinct progenitor subpopulations isolated by a cell polarity-based approach from developing mouse and human neocortex. We identify 56 genes preferentially expressed in human apical and basal radial glia that lack mouse orthologs. Among these, ARHGAP11B has the highest degree of radial glia-specific expression. ARHGAP11B arose from partial duplication of ARHGAP11A (which encodes a Rho guanosine triphosphatase-activating protein) on the human lineage after separation from the chimpanzee lineage. Expression of ARHGAP11B in embryonic mouse neocortex promotes basal progenitor generation and self-renewal and can increase cortical plate area and induce gyrification. Hence, ARHGAP11B may have contributed to evolutionary expansion of human neocortex.

Alveolar preservation with high inflation pressure and intermediate oxygen concentration reduces ischemia-reperfusion injury of the lung.

BACKGROUND: This study investigated the optimal alveolar oxygen concentration and inflation pressure during ischemia that reduces lung ischemia-reperfusion injury (LIRI). METHODS: Male Sprague-Dawley rats (n = 66) underwent 150 minutes of left lung ischemia by hilar clamping at an airway inflation pressure (P) of 5 or 30 cm H(2)O and an oxygen (O) concentration of 0%, 30%, or 100% (P(5)O(0), P(5)O(30), P(5)O(100), P(30)O(0), P(30)O(30) and P(30)O(100) groups). Lungs preserved with 0% oxygen were inflated with 100% nitrogen. Measurements of arterial blood gas values, pulmonary compliance, histology, flow cytometry of bronchoalveolar lavage fluid were performed on day 2 postoperatively. RESULTS: Inflation with 30 cm H(2)O resulted in increased partial pressure of arterial oxygen (Pao(2)) and lung compliance, decreased diffuse alveolar damage, and less infiltration of CD4(+) and CD8(+) lymphocytes and major histocompatibility complex class II-positive (MHCII(+)) antigen-presenting cells (APCs) in the left lung on day 2 compared with clamping at an airway inflation pressure of 5 cm H(2)O. The 100% oxygen groups demonstrated a lower Pao(2) and a decreased pulmonary compliance than 30% oxygen groups. More CD8(+) lymphocytes and MHCII(+) APCs were found in the P(5)O(100) group than in the P(5)O(0) and P(5)O(30) groups. CONCLUSION: Alveolar inflation with a pressure of 30 cm H(2)O and an oxygen concentration of 30% decreases the severity of LIRI. The protective effect is mainly due to hyperinflation and, to a lesser extent, through oxygen concentration.

Open lung in ARDS.

Every year, millions of patients worldwide receive ventilator support during surgery. Mechanical ventilation has become an important therapy in the treatment of patients with impaired pulmonary function and particularly in patients suffering from adult respiratory distress syndrome (ARDS). ARDS is caused by multiple factors and is characterized by respiratory dysfunction including hypoxemia and decreased lung compliance. It is known that the decrease in lung distensibility is due to a disturbed surfactant system with an elevated surface tension. This increase in surface tension leads to an increase in forces acting at the air-liquid interface, resulting finally in end-expiratory collapse, atelectasis, an increase in right-to-left shunt and a decrease in paO2.