Acute lung injury syndromes remain common causes of morbidity and mortality in adults and children. Cellular and physiologic mechanisms maintaining pulmonary homeostasis during lung injury remain poorly understood. In the present study, the Stat-3 gene was selectively deleted in respiratory epithelial cells by conditional expression of Cre-recombinase under control of the surfactant protein C gene promoter. Cell-selective deletion of Stat-3 in respiratory epithelial cells did not alter prenatal lung morphogenesis or postnatal lung function. However, exposure of adult Stat-3-deleted mice to 95% oxygen caused a more rapidly progressive lung injury associated with alveolar capillary leak and acute respiratory distress. Epithelial cell injury and inflammatory responses were increased in the Stat-3-deleted mice. Surfactant proteins and lipids were decreased or absent in alveolar lavage material. Intratracheal treatment with exogenous surfactant protein B improved survival and lung histology in Stat-3-deleted mice during hyperoxia. Expression of Stat-3 in respiratory epithelial cells is not required for lung formation, but plays a critical role in maintenance of surfactant homeostasis and lung function during oxygen injury. 29Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) remain a common cause of morbidity and mortality in both infants and adults following infection, trauma, inhalation of toxicants, and drowning. The recent severe acute respiratory syndrome (SARS) outbreak emphasizes the severity of pulmonary outcomes associated with ALI (7). ARDS is associated with surfactant deficiency and dysfunction (8, 9), including abnormalities in surfactant lipids and proteins. Of the surfactant proteins, SP-B is required for maintenance of lung function in both newborn and postnatal periods (10, 11) and for adaptation to lung injury following infection or oxygen exposure. To assess the role of STAT-3 in lung function, we used a conditional system to express Cre-recombinase to selectively delete the Stat-3 gene in bronchiolar and alveolar epithelial cells of the mouse lung. MethodsGene construction and PCR. We generated SP-C-rtTA tg/-transgenic mice and (tetO) 7 CMV-Cre tg/tg or (tetO) 7 CMVCre tg/-mice as described previously (12, 13 -C-rtTA, (tetO) 7 CMV-Cre and Stat-3 flx genes using the primers 5′-GAC ACA TAT AAG ACC CTG GCTA-3′ and 5′-AAA ATC TTG CCA GCT TTC CC-3′ for SP-C-rtTA; 5′-TGC CAC CAA GTG ACA GCA ATG-3′ and 5′-AGA GAC GGA AAT CCA TCG CTCG-3′ for (tetO) 7 CMV-Cre; and 5′-CCT GAA GAC CAA GTT CAT CTG TGT GAC-3′ and 5′-CAC ACA AGC CAT CAA ACT CTG GTC TCC-3′ for Stat-3 flx . Triple transgenic (Stat-3 ∆/∆ ) and nondeleted littermate (Stat-3 flx/flx ) control mice were used for the experiments.Animal use and doxycycline administration. Transgenic Stat-3 ∆/∆ and control mice were kept in a pathogen-free vivarium according to institutional guidelines until oxygen exposure. Doxycycline was administered to the dams in the food at a concentration of 625 mg/kg (Harlan Teklad, Madison, Wisconsin, U...

Although fibroblast growth factor (FGF) signaling is required for the formation of the lung in the embryonic period, it is unclear whether FGF receptor activity influences lung morphogenesis later in development. We generated transgenic mice expressing a soluble FGF receptor (FGFR-HFc) under conditional control of the lung-specific surfactant protein C promoter (SP-CrtTA), to inhibit FGF activity at various times in late gestation and postnatally. Although expression of FGFR-HFc early in development caused severe fetal lung hypoplasia, activation of the transgene in the postnatal period did not alter alveolarization, lung size, or histology. In contrast, expression of the transgene at post-conception day E14.5 decreased lung tubule formation before birth and caused severe emphysema at maturity. FGFR-HFc caused mild focal emphysema when expressed from E16.5 but did not alter alveolarization when expressed after birth. Although FGF signaling was required for branching morphogenesis early in lung development, postnatal alveolarization was not influenced by FGFR-HFc.The lung buds evaginate from the foregut endoderm and undergo stereotypic branching to form conducting and peripheral airspaces critical for gas exchange after birth. In humans and mice, the alveoli are formed primarily in the postnatal period, during which the numbers of alveoli increase and the alveolar capillary gas exchange area expands. Lung morphogenesis is dependent upon autocrine-paracrine signaling between the splanchnic mesenchyme and the endodermally derived lung buds that form the developing respiratory epithelium. A number of growth factors and transcription factors, including fibroblast growth factors (FGFs), 1 plays important roles during lung morphogenesis, regulating cell migration, proliferation, and differentiation (Refs.

This study focuses on the early cerebral base of speech perception by examining functional lateralization in neonates for processing segmental and suprasegmental features of speech. For this purpose, auditory evoked responses of full-term neonates to phonemic and prosodic contrasts were measured in their temporal area and part of the frontal and parietal areas using near-infrared spectroscopy (NIRS). Stimuli used here were phonemic contrast /itta/ and /itte/ and prosodic contrast of declarative and interrogative forms /itta/ and /itta?/. The results showed clear hemodynamic responses to both phonemic and prosodic changes in the temporal areas and part of the parietal and frontal regions. In particular, significantly higher hemoglobin (Hb) changes were observed for the prosodic change in the right temporal area than for that in the left one, whereas Hb responses to the vowel change were similarly elicited in bilateral temporal areas. However, Hb responses to the vowel contrast were asymmetrical in the parietal area (around supra marginal gyrus), with stronger activation in the left. These results suggest a specialized function of the right hemisphere in prosody processing, which is already present in neonates. The parietal activities during phonemic processing were discussed in relation to verbal-auditory short-term memory. On the basis of this study and previous studies on older infants, the developmental process of functional lateralization from birth to 2 years of age for vowel and prosody was summarized.

BackgroundAssessment of the seriousness, expectedness and causality are necessary for any adverse event (AE) in a clinical trial. In addition, assessing AE severity helps determine the importance of the AE in the clinical setting. Standardisation of AE severity criteria could make safety information more reliable and comparable across trials. Although standardised AE severity scales have been developed in other research fields, they are not suitable for use in neonates. The development of an AE severity scale to facilitate the conduct and interpretation of neonatal clinical trials is therefore urgently needed.MethodsA stepwise consensus process was undertaken within the International Neonatal Consortium (INC) with input from all relevant stakeholders. The consensus process included several rounds of surveys (based on a Delphi approach), face-to-face meetings and a pilot validation.ResultsNeonatal AE severity was classified by five grades (mild, moderate, severe, life threatening or death). AE severity in neonates was defined by the effect of the AE on age appropriate behaviour, basal physiological functions and care changes in response to the AE. Pilot validation of the generic criteria revealed κ=0.23 and guided further refinement. This generic scale was applied to 35 typical and common neonatal AEs resulting in the INC neonatal AE severity scale (NAESS) V.1.0, which is now publicly available.DiscussionThe INC NAESS is an ongoing effort that will be continuously updated. Future perspectives include further validation and the development of a training module for users.

Paracrine signaling mediated by FGF-10 and the FGF-R2IIIb receptor is required for formation of the lung. To determine the temporal requirements for FGF signaling during pulmonary morphogenesis, Sprouty-4 (Spry-4), an intracellular FGF receptor antagonist, was expressed in epithelial cells of the fetal lung under control of a doxycycline-inducible system. Severe defects in lobulation and severe lung hypoplasia were observed when Spry-4 was expressed throughout fetal lung development (E6.5-E18.5) or from E6.5 until E13.5. Effects of Spry-4 on branching were substantially reversed by removal of doxycycline from the dam at E12.5, but not at E13.5. In contrast, when initiated late in development (E12.5 to birth), Spry-4 caused less severe pulmonary hypoplasia. Expression of Spry-4 from E16.5 to E18.5 reduced lung growth and resulted in perinatal death due to respiratory failure. Expression of Spry-4 during the saccular and alveolar stages, from E18.5 to postnatal day 21, caused mild emphysema. These findings demonstrate that the embryonic-pseudoglandular stage is a critical time period during which Spry-sensitive pathways are required for branching morphogenesis, lobulation, and formation of the peripheral lung parenchyma.