Antenatal infection/inflammation and postnatal lung maturation and injury

Chorioamnionitis is frequently associated with preterm deliveries before 30 weeks gestation. Chorioamnionitis correlates both with an increased risk of bronchopulmonary dysplasia and with a decreased risk of respiratory distress syndrome. Both interleukin-1α and endotoxin can induce inflammation in the fetal lungs and lung maturation after preterm birth when given by intra-amniotic injection. Inflammation can also result in an arrest of alveolarization, and this lung developmental abnormality is prominent in the lungs of preterm infants that die of bronchopulmonary dysplasia. The mechanisms by which infection/inflammation can have both beneficial and injurious effects on the preterm lung remain to be characterized

Gene expression and biological processes influenced by deletion of Stat3 in pulmonary type II epithelial cells

<p>Abstract</p> <p>Background</p> <p>The signal transducer and activator of transcription 3 (STAT3) mediates gene expression in response to numerous growth factors and cytokines, playing an important role in many cellular processes. To better understand the molecular mechanisms by which <it>Stat3 </it>influences gene expression in the lung, the effect of pulmonary epithelial cell specific deletion of <it>Stat3 </it>on genome wide mRNA expression profiling was assessed. Differentially expressed genes were identified from Affymetrix Murine GeneChips analysis and subjected to gene ontology classification, promoter analysis, pathway mapping and literature mining.</p> <p>Results</p> <p>Total of 791 mRNAs were significantly increased and 314 mRNAs were decreased in response to the deletion of <it>Stat3</it>^Δ/Δin the lung. STAT is the most enriched cis-elements in the promoter regions of those differentially expressed genes. Deletion of <it>Stat3 </it>induced genes influencing protein metabolism, transport, chemotaxis and apoptosis and decreased the expression of genes mediating lipid synthesis and metabolism. Expression of <it>Srebf1 </it>and <it>2</it>, genes encoding key regulators of fatty acid and steroid biosynthesis, was decreased in type II cells from the <it>Stat3</it>^Δ/Δmice, consistent with the observation that lung surfactant phospholipids content was decreased. <it>Stat3 </it>influenced both pro- and anti-apoptotic pathways that determine cell death or survival. <it>Akt</it>, a potential transcriptional target of <it>Stat3</it>, was identified as an important participant in <it>Stat3 </it>mediated pathways including Jak-Stat signaling, apoptosis, Mapk signaling, cholesterol and fatty acid biosynthesis.</p> <p>Conclusion</p> <p>Deletion of <it>Stat3 </it>from type II epithelial cells altered the expression of genes regulating diverse cellular processes, including cell growth, apoptosis and lipid metabolism. Pathway analysis indicates that STAT3 regulates cellular homeostasis through a complex regulatory network that likely enhances alveolar epithelial cell survival and surfactant/lipid synthesis, necessary for the protection of the lung during injury.</p

Rapamycin Regulates Bleomycin-Induced Lung Damage in SP-C-Deficient Mice

Injury to the distal respiratory epithelium has been implicated as an underlying cause of idiopathic lung diseases. Mutations that result in SP-C deficiencies are linked to a small subset of spontaneous and familial cases of interstitial lung disease (ILD) and interstitial pulmonary fibrosis (IPF). Gene-targeted mice that lack SP-C (Sftpc−/−) develop an irregular ILD-like disease with age and are a model of the human SP-C related disease. In the current study, we investigated whether rapamycin could ameliorate bleomycin-induced fibrosis in the lungs of Sftpc−/− mice. Sftpc+/+ and −/− mice were exposed to bleomycin with either preventative administration of rapamycin or therapeutic administration beginning eight days after the bleomycin injury. Rapamycin-treatment increased weight loss and decreased survival of bleomycin-treated Sftpc+/+ and Sftpc−/− mice. Rapamycin did not reduce the fibrotic disease in the prophylactic or rescue experiments of either genotype of mice. Further, rapamycin treatment augmented airway resistance and reduced lung compliance of bleomycin-treated Sftpc−/− mice. Rapamycin treatment was associated with an increased expression of profibrotic Th2 cytokines and reduced expression of INF-γ. These findings indicate that novel therapeutics will be required to treat individuals with SP-C deficient ILD/IPF

Hypertensive patients' perceptions of their physicians' knowledge about them: a cross-sectional study in Japan

<p>Abstract</p> <p>Background</p> <p>In order to evaluate the difference in quality of primary care provided by physicians between the types of medical institutions in Japan, we examined whether the physicians' comprehensive knowledge of their patients is perceived differently by the patients seen at clinics and hospitals.</p> <p>Methods</p> <p>Patients with prescriptions for hypertensive drugs were approached sequentially at 13 pharmacies, and were administered a questionnaire on their perception of their physician's knowledge about them. Data were obtained for 687 patients (362 from clinics and 325 from hospitals). A physician's knowledge of his or her patients was assessed according to six aspects: their medical history, their current medications, history of allergy, what worries patients most about their health, patients' values and beliefs on their health, and patients' roles and responsibilities at work, home, or school. Responses were scored from 1 through 6 (1: knows very well; 6: doesn't know at all).</p> <p>Results</p> <p>Patients treated in clinics were seen more frequently, for a longer period, and had fewer complications than the patients who were treated in hospitals. Among the six aspects of physicians' knowledge assessed, 79.3% of the patients reported that their physicians knew their complete list of medications "very well or well," while 28.3% reported the same about their roles and responsibilities at work, home, or school. Physicians in clinics were considered to know their patients' worries about their health (p = 0.004) and the roles and responsibilities of the patients at work, home, or school (p = 0.028) well. Multiple regression analysis showed that the type of medical institutions remained as a significant variable only for the aspect of patients' worries about their health. The factor that consistently affected the patients' perception of physicians' knowledge about them was the patients' age.</p> <p>Conclusions</p> <p>Hypertensive patients' perceptions of their physicians' knowledge about them did not differ significantly between clinics and hospitals in Japan for most of the aspects. In order to differentiate the roles of physicians in hospitals and clinics better and ensure the quality of primary care, the establishment of a standardized educational system to train primary care physicians better is recommended.</p

SP-B and SP-C containing new synthetic surfactant for treatment of extremely immature lamb lung.

Although superiority of synthetic surfactant over animal-driven surfactant has been known, there is no synthetic surfactant commercially available at present. Many trials have been made to develop synthetic surfactant comparable in function to animal-driven surfactant. The efficacy of treatment with a new synthetic surfactant (CHF5633) containing dipalmitoylphosphatidylcholine, phosphatidylglycerol, SP-B analog, and SP-C analog was evaluated using immature newborn lamb model and compared with animal lung tissue-based surfactant Survanta. Lambs were treated with a clinical dose of 200 mg/kg CHF5633, 100 mg/kg Survanta, or air after 15 min initial ventilation. All the lambs treated with air died of respiratory distress within 90 min of age. During a 5 h study period, Pco(2) was maintained at 55 mmHg with 24 cmH(2)O peak inspiratory pressure for both groups. The preterm newborn lamb lung functions were dramatically improved by CHF5633 treatment. Slight, but significant superiority of CHF5633 over Survanta was demonstrated in tidal volume at 20 min and dynamic lung compliance at 20 and 300 min. The ultrastructure of CHF5633 was large with uniquely aggregated lipid particles. Increased uptake of CHF5633 by alveolar monocytes for catabolism was demonstrated by microphotograph, which might be associated with the higher treatment dose of CHF5633. The higher catabolism of CHF5633 was also suggested by the similar amount of surfactant lipid in bronchoalveolar lavage fluid (BALF) between CHF5633 and Survanta groups, despite the 2-fold higher treatment dose of CHF5633. Under the present ventilation protocol, lung inflammation was minimal for both groups, evaluated by inflammatory cell numbers in BALF and expression of IL-1β, IL-6, IL-8, and TNFα mRNA in the lung tissue. In conclusion, the new synthetic surfactant CHF5633 was effective in treating extremely immature newborn lambs with surfactant deficiency during the 5 h study period

Increased Uptake of CHF5633 by Alveolar Monocyte.

<p>(A) Cell pellet from BALF isolated by 10 min centrifugation at 284× g. The microphotographs were without fixation or staining. Extremely large and soft aggregate of CHF5633 was recovered in the pellet together with cells. Detected Survanta in the cell pellet was minimum after short and low-speed centrifugation and only the cells were detected. Scale bar: 50 µm. (B) Sat PC in pellet and supernatant of input surfactants and BALFs were analyzed. Over 40% of CHF5633 were large and heavy aggregates and were recovered in the pellet. *p<0.001 vs. Survanta. The percent Sat PC in the pellet from the CHF5633 group BALF was higher than that of Input CHF5633. tp<0.05 vs. input CHF5633 pellet. Some of the standard error bars are within the mean value bars. (C) SP-C in pellet and supernatant samples of BALF from CHF5633 group, containing 6.5nmol Sat PC were analyzed by Western blot. SP-C in CHF5633 input sample was given a value of 1. SP-C relative to Sat PC was decreased in supernatant or smaller form surfactant to half of that in input sample and BALF pellet samples. *p<0.05 vs. others. (D) In the surfactant pellet of BALF from the CHF5633 group, a large number of immunogold-labeled SP-C particles (arrow) were associated with surfactant lipid vesicles. Image is representative of findings in n = 3 lambs. Scale bar: 0.1 µm.</p

Surfactant lipid component and its uptake by alveolar monocytes.

<p>(A) Saturated phosphatidylcholine (Sat PC µmol/kg) in CHF5633 (Input), Survanta (Input), lamb lung, and BALF were analyzed. Two fold higher Sat PC was instilled to CHF5633 group than Survanta group and Sat PC in the lung was higher for CHF5633 group than Survanta group. *p<0.001 vs. Survanta In contrast, Sat PC in BALF was similar between the 2 groups, suggesting increased CHF5633 catabolism compared with Survanta. (B) Microphotograph of alveolar cells. Phagocytosis of surfactant by monocytes was higher for the CHF5633 group and monocytes contained lipid droplets. Scale bar: 10 µm. (C) Phosphatidylcholine (PC) and phosphatidylglycerol (PG) were analyzed by thin layer chromatography. There were similar amounts of PC and PG in CHF5633 and the major component of Survanta was PC. The ratio of PC to PG did not change in the ventilated preterm lamb lung and was similar to Input samples.</p