摘要:

Exposure of neonatal rats to ≥95% O2for 2 wk, a widely used model of oxidant/antioxidant interactions in neonatal lung injury, results in arrested lung growth without the dysplastic lesions observed in chronic human neonatal lung injury. To determine whether dysplastic lung cell growth would be seen at lesser O2concentrations, we exposed newborn rats to either 95% O2for 1 wk followed by 60% O2for 1 wk, or to 60% O2for 2 wk. Exposure to 95% O2for 1 wk profoundly inhibited lung DNA synthesis. Recovery of synthesis did not occur during the 2nd wk in 60% O2, nor were areas of dysplastic growth evident in lung tissue. In contrast, a continuous 2-wk exposure to 60% O2resulted in a slight increase in lung weight with a significant reduction in lung volume over a range of inflation pressures. Also seen was an overall, but inhomogeneous, reduction in lung cell DNA synthesis. A preliminary analysis of affected cell types suggested that inhibition of DNA synthesis affected endothelial cells more than interstitial cells, whereas DNA synthesis increased in type II pneumocytes. Areas of reduced DNA synthesis were interspersed with patchy areas of parenchymal thickening and active DNA synthesis. These areas of parenchymal thickening, but not other areas, had increased immunoreactive IGF-I and the type I IGF receptor. These data are consistent with a direct effect of O2on growth factor and growth factor receptor expression in causing dysplastic lung cell growth in chronic neonatal lung injury.Abbreviations: BPD,bronchopulmonary dysplasia;IGF-IR,type I IGF receptor;SP-A,surfactant apoprotein A

ISSN:0031-3998    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Surfactant protein D (SP-D) is synthesized and secreted by pulmonary epithelial cells. Like surfactant protein A (SP-A), SP-D is a collagen-like glycoprotein belonging to the “collectin” class of C-type lectins that may play an important role in pulmonary host defense. To begin studies on SP-D gene regulation and function using the mouse as an animal model, we identified the cellular sites of SP-D gene expression in adult mouse lung and trachea and characterized the developmental expression of SP-D mRNA in murine fetal and newborn lungs. We compared these findings with similar studies for murine SP-A, which has an established role in surfactant function and metabolism and a probable role in pulmonary host defense. SP-D mRNA and protein were readily detected byin situhybridization and immunocytochemistry in alveolar type II and nonciliated bronchiolar epithelial cells of the lung, as well as in cells of the tracheal epithelium and tracheal submucosal glands of the adult mouse. Although SP-A mRNA and protein were also localized to alveolar and nonciliated bronchiolar epithelial cells of the murine lung, there was no detectable labeling for either SP-A mRNA or protein in the murine trachea. Expression of murine SP-D mRNA was first detected by Northern blot analysis on d 16 of gestation in timed-pregnant mice, with an average gestational period of 17 d, and this increased dramatically before birth and during the immediate postnatal period. The developmental expression of murine SP-A mRNA paralleled that of SP-D except that there was a small decrease in mRNA content on postnatal d 5. These studies provide the first description of the cellular distribution and developmental expression of SP-D in mouse lung, which will be important for interpreting future studies of SP-D gene expression in transgenic animal models. In addition, these studies provide the first documentation that, unlike SP-A, SP-D is synthesized not only in the lung but also in submucosal glands of the trachea.Abbreviations: CRD,carbohydrate recognition domain;PCR,polymerase chain reaction;SP,surfactant protein;SSC,saline sodium citrate

ISSN:0031-3998    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Surfactant protein A (SP-A) is a 248-residue, water-soluble, lipid-associating protein found in lung surfactant. Analysis of the amino acid sequence using the Eisenberg hydrophobic moment algorithm predicts that the SP-A segment spanning residues 114-144 has high hydrophobic moments, typical of lipid-associating amphipathic domains. The secondary structure,in vitrosurface activity andin vivolung activity of this SP-A sequence were studied with a 31-residue synthetic peptide analog(A114-144). Analysis of the secondary structure using circular dichroism and Fourier transform infrared spectroscopy indicated association with lipid dispersions and a dominant helical content. Surface activity measurements of A114-144with surfactant lipid dispersions and the hydrophobic surfactant proteins B and C (SP-B/C) showed that A114-144enhances surface activity under conditions of dynamic compression and respreading on a Langmuir/Wilhelmy surface balance. Synthetic surfactant dispersions containing A114-144improved lung compliance in spontaneously breathing, 28-d premature rabbits to a greater degree than surfactant dispersions with synthetic SP-B/C and synthetic surfactant lipids alone. These observations indicate that inclusion of A114-144may improve synthetic preparations currently used for surfactant replacement therapy.Abbreviations: SP-A, -B, -C, -D,surfactant proteins A, B, C, D;A114-144,SP-A residues 114-144;B/C,synthetic SP-B and SP-C;CD,circular dichroism;DPPC,dipalmitoylphosphatidylcholine;FTIR,Fourier transform infrared spectroscopy;PL,phospholipid;TFE,trifluoroethanol

ISSN:0031-3998    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

The serum components of C-reactive protein, lysophosphatidylcholine, fibrinogen, and fibrinogen proteolytic products have been shown to reduce surface tension-lowering abilities of lung surfactant. The inhibitory effects of these serum components were compared among four different surfactants: natural lung surfactant, a phospholipid mixture that had no surfactant proteins, KL4surfactant which has a synthetic surfactant protein B(SP-B)-like peptide, and beractant (BER) which has both SP-B and SP-C. The pulsating bubble surfactometer was used to measure the surface tension of these surfactants after the addition of inhibitors. Inhibition of BER and KL4surfactant was observed with some serum components within 1 min of pulsation, but was reversed after 3 min of pulsation for KL4surfactant and to a lesser extent with BER. The surface tension of phospholipid mixture alone was significantly increased and did not improve with further pulsations. Natural lung surfactant was least inhibited and was affected only at very high fibrinogen concentrations (5 mg/mL). At identical concentrations of these inhibitors, KL4surfactant was inhibited less compared with BER. We conclude that the response of a lung surfactant to inhibitory agents may depend on the presence or absence of surfactant-related protein(s) in the surfactant and the concentration of exogenous surfactant used. KL4surfactant, which has a synthetic peptide in lieu of SP-B, resists inhibition to these serum components more than BER at similar phospholipid concentrations.Abbreviations: BER,beractant;PL,phospholipid;NLS,natural lung surfactant;MST,minimum surface tension;FIB,fibrinogen;RDS,respiratory distress syndrome;SP-A,-B, and -C, surfactant proteins A, B, and C;DPPC,diphosphatidylcholine;POPG,palmitoyl-oleoyl phosphatidylglycerol

ISSN:0031-3998    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Surfactant deficiency in premature neonates is a major factor in the development of respiratory distress syndrome (RDS), which is still a significant cause of mortality and morbidity. The aim of this study was to test a noninvasive method of administering surfactant as treatment for RDS. The animal model used was the premature neonatal rabbit of 27-d gestation(full-term being 31 d) primed with an initial oropharyngeal dose of surfactant. The animals were divided into three groups that received either no supplemental surfactant (n= 20), undried nebulized surfactant(n= 21), or dried nebulized surfactant (n= 24). Drying of the surfactant solution was undertaken to create a hygroscopic aerosol that would facilitate surfactant deposition in the lower respiratory tract. The group treated with dried surfactant aerosol showed superior survival (66.7%) and less evidence of RDS. The control and undried aerosol groups each had similar low survival rates (23.8 and 45.0%, respectively). The results indicate that a dried, hygroscopic aerosol is an effective means of administration of surfactant to spontaneously breathing premature rabbit neonates.Abbreviation: RDS,respiratory distress syndrome

ISSN:0031-3998    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

We investigated whether leakage of protein in lungs of preterm ventilated rabbits of 28- and 29-d gestational age is correlated with activation of clotting, complement, and polymorphonuclear leukocytes (PMN) in plasma. We found signs of systemic activation of clotting, complement, and PMN in ventilated 28-d gestational age rabbits, as indicated, respectively, by increased median plasma fibrin monomer concentrations (83versus40% of normal adult rabbit plasma in nonventilated 28-d gestational age rabbits,p< 0.01), decreased median plasma CH50 activity (112versus122 U/L in nonventilated 28-d gestational age rabbits,p< 0.05), and increased median plasma β-glucuronidase concentrations (159versus97% of maximal activated adult rabbit plasma in nonventilated 28-d gestational age rabbits,p< 0.05). We did not find signs of systemic activation in the ventilated 29-d gestational age group. Higher median total protein concentrations in alveolar wash of the ventilated 28-d gestational age rabbits (2.7versus1.3 mg/mL in the nonventilated rabbits,p< 0.01) indicated protein leakage into the lungs, and this protein leakage was more pronounced in the lungs of ventilated 28-d gestational age rabbits than in those of ventilated 29-d gestational age rabbits (2.1 mg/mL,p< 0.01). The total protein concentration in the alveolar wash of all 28-d gestational age rabbits was correlated with the concentration of fibrin monomers (ρ = 0.51,p= 0.035) and β-glucuronidase (ρ = 0.61,p= 0.011), and the CH50 activity (ρ = -0.73,p= 0.002) in plasma. We conclude that leakage of protein in lungs of preterm ventilated rabbits of 28-d gestational age is correlated with activation of clotting, complement, and PMN in plasma. This activation process may contribute to lung injury by intravascular and intraalveolar deposition of fibrin and formation of proteinaceous edema.Abbreviations: RDS,respiratory distress syndrome;PMN,polymorphonuclear leukocytes;CH50,complement hemolytic activity of plasma;VEI,ventilator efficiency index;PIP,peak inspiratory pressure

ISSN:0031-3998    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

We are interested in determining whether premature birth alters expression of counterregulatory cytokines which modulate lung inflammation. Production of proinflammatory cytokines tumor necrosis factor α, IL-1β, and IL-8 is regulated in part by the antiinflammatory cytokine IL-10. For preterm newborns with hyaline membrane disease, deficiencies in the ability of lung macrophages to express antiinflammatory cytokines may predispose to chronic lung inflammation. We compared the expression of pro- and antiinflammatory cytokines at the mRNA and protein level in the lungs of preterm and term newborns with acute respiratory failure from hyaline membrane disease or meconium aspiration syndrome. Four sequential bronchoalveolar lavage (BAL) samples were obtained during the first 96 h of life from all patients. All patients rapidly developed an influx of neutrophils and macrophages. Over time, cell populations in both groups became relatively enriched with macrophages. The expression of proinflammatory cytokine mRNA and/or protein was present in all samples from both patient groups. In contrast, IL-10 mRNA was undetectable in most of the cell samples from preterm infants and present in the majority of cell samples from term infants. IL-10 concentrations were undetectable in lavage fluid from preterm infants with higher levels in a few of the BAL samples from term infants. These studies demonstrate that1) IL-10 mRNA and protein expression by lung inflammatory cells is related to gestational age and2) during the first 96 h of life neutrophil cell counts and IL-8 expression decrease in BAL from term infants, but remain unchanged in BAL samples from preterm infants.Abbreviations: HMD,hyaline membrane disease;MAS,meconium aspiration syndrome;ARF,acute respiratory failure;ARDS,adult respiratory distress syndrome;CLD,chronic lung disease;BAL,bronchoalveolar lavage;TNF,tumor necrosis factor;RT,reverse transcriptase;PCR,polymerase chain reaction;IFN,interferon

ISSN:0031-3998    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

The objective of this study was to define whether IL-6 is an early marker of infection in the newborn. To correlate the occurrence of clinical chorioamnionitis with the levels of IL-6 expression in neonates, IL-6 was measured in cord plasma by ELISA and in mononuclear cells by reverse transcriptase-PCR before and after mitogenic stimulation. Eight neonates were included in each of the following four groups: elective cesarean section, uncomplicated normal spontaneous vaginal delivery, delivery after prolonged rupture of amniotic membranes with no evidence of chorioamnionitis, and delivery with evidence of chorioamnionitis. All 32 neonates were clinically well after delivery, and all 16 babies with prolonged rupture of membranes or clinical chorioamnionitis had negative blood cultures. Elevated IL-6 levels were found only in neonates born to mothers with chorioamnionitis (119.7± 33.5 pg/mLversus2.71 ± 0.59 pg/mL,p< 0.005). Mononuclear cells from five of these neonates expressed no IL-6 mRNAin vivodespite elevated levels of IL-6 in their cord plasma. Cord blood mononuclear cells from healthy term babies were capable of synthesizing IL-6in vitroin response to stimulation with bacterial lipopolysaccharide. These results suggest that IL-6 levels in cord plasma increased with clinical chorioamnionitis, despite the lack of evidence of infection in the neonates. Therefore, we conclude that, although a high level of IL-6 may be a good marker of chorioamnionitis, it may not be a specific marker of infection in the newborn.Abbreviations: RT,reverse transcriptase;PROM,prolonged rupture of membranes;PBMC,peripheral blood mononuclear cells;PHA,phytohemagglutinin

ISSN:0031-3998    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Little is known about the distribution of precore hepatitis B virus mutants and their influence on the outcome of interferon therapy in children with chronic hepatitis B. In this study, serum samples were analyzed from 60 children with chronic hepatitis B e antigen+(HBeAg+) hepatitis. Fifty-two of these children underwent different interferon trials, and a second serum sample was taken from 25 of them at the end of therapy. Fifty-six of the original 60 children were simultaneously infected by wild-type and precore mutant hepatitis B virus variants. The remaining four children were infected by the wild type alone. In 50/56 of children with a mixed viral population, the wild-type variant comprised more than 50% of the total viremia. With respect to the influence of precore variants on the outcome of interferon treatment, the prevalence of mixed viral population was similar in responders and nonresponders (96versus88%, respectively). However, precore mutant variants were prevalent (>50% of the viral population) in 21% of the nonresponders, but in none of the responder children (p< 0.05). Viremia levels were significantly higher in nonresponder than in responder children (p< 0.05). No substantial changes in the prevalence of mutants were observed throughout the interferon therapy. In conclusion, mixed viral infection is found in a high percentage of children with chronic B HBeAg+hepatitis. Response to interferon therapy does not seem to be related to the presence of hepatitis B virus precore mutants, but rather to the levels of viremia.Abbreviations: HBV,hepatitis B virus;anti-HBe,antibody to hepatitis B e antigen;HBeAg,hepatitis B virus e antigen;ALT,alanine aminotransferase;IFN,interferon;rIFN,recombinant IFN;PCR,polymerase chain reaction;b.s.,body surface

ISSN:0031-3998    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Disturbances of the intestinal integrity, reflected by an increased intestinal permeability, are reported in cystic fibrosis (CF). Controversy exists whether the increased intestinal permeability is due to CF itself or a consequence of the concomitant exocrine pancreatic insufficiency (PI). We measured intestinal permeability by the sugar absorption test in 32 PI patients: 20 CF-PI, 12 nonCF-PI with chronic pancreatitis, and 50 controls. In the sugar absorption test, the lactulose/mannitol ratio is measured in 5-h urine samples after oral ingestion of a solution of lactulose and mannitol, hypersmolar by the addition of sucrose. The lactulose/mannitol ratio was increased in both CF-PI and nonCF-PIversuscontrols (p< 0.0001). In CF, the L/M ratio and permeability for lactulose and mannitol did not change by increasing pancreatic enzyme supplementation by 30-50% for 2 wk (p= 0.74,p= 0.97,p= 0.74, respectively) nor by decreasing the osmolarity of the test solution by 75% (p= 0.24,p= 0.10,p= 0.39, respectively). We conclude that an increased intestinal permeability in CF is probably a consequence of PI and is not related to the dose of pancreatic enzyme supplementation nor the osmolarity of the test solution. The increase is due to an increased permeability for lactulose which might point toward a defect in the tight junctions of the villi and/or crypts. The cause of the increased intestinal permeability in the presence of PI is still unclear. An increased intestinal permeability points toward an impaired functional integrity of the small bowel, which may contribute to gastrointestinal dysfunction in CF.Abbreviations: CF,cystic fibrosis;PI,pancreatic insufficiency;L/M ratio,lactulose/mannitol ratio;SAT,sugar absorption test

ISSN:0031-3998    

出版商:OVID    

年代:1996

数据来源: OVID