摘要:

Physiologic delays in production of immune factors occur in mammals includingHomo sapiens. This finding is counter to a basic tenet of biologic evolution, because such delays increase the risk of infections. The disadvantage is, however, offset by defense factors in milk of the species in whom the developmental delay occurs. Reciprocal relationships between the production of immune factors by the lactating mammary gland and the production of those defense agents during early infancy are found in all investigated mammalian species. Thus, the evolution of these processes is closely related. Certain immunologic components of milk are highly conserved, whereas others vary according to the species. The variations most likely evolved by genetic mutations and natural selection. In addition, the immune composition of mammalian milks is associated with developmental delays in the same immunologic agents. Furthermore, most closely related mammals, such as humans and chimpanzees, are most similar in the defense agents in their milks and the corresponding developmental delays in their immune systems. Defense factors in human milk include antimicrobial agents (secretory IgA, lactoferrin, lysozyme, glycoconjugates, oligosaccharides, and digestive products of milk lipids), antiinflammatory factors (antioxidants, epithelial growth factors, cellular protective agents, and enzymes that degrade mediators of inflammation), immunomodulators (nucleotides, cytokines, and antiidiotypic antibodies), and leukocytes (neutrophils, macrophages, and lymphocytes). Because of a lack of geographic/ethnic variation in the immunologic composition of human milk and corresponding immunologic delays in infants, these evolutionary processes seem stable. This is supported by investigations of diverse populations that indicate that this evolutionary outcome is highly beneficial to human infants.Abbreviations: mya,millions of years ago;TNF,tumor necrosis factor

ISSN:0031-3998    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Increased nitric oxide (NO) production plays a critical role in the mammalian pulmonary vascular adaptation to extrauterine life. NO activates soluble guanylate cyclase, increasing intracellular cGMP concentrations, thereby inducing relaxation of vascular smooth muscle. cGMP is inactivated by cyclic nucleotide phosphodiesterases (PDEs). One PDE isozyme, PDE5, specifically hydrolyzes cGMP, is abundant in lung tissues, and modifies the pulmonary vasodilatory response to exogenous NO. To investigate the regulation of PDE5 gene expression during pulmonary development, PDE5 mRNA levels, as well as cGMP-metabolizing PDE enzyme activity, were measured in the lungs of perinatal and adult rats. RNA blot hybridization revealed that PDE5 mRNA was detectable in fetal lung tissue as early as 18.5 d of the 22-d term gestation and reached maximal levels in neonatal lungs. mRNA levels in adult rat lungs were 3-4-fold less than the levels measured in lungs of 1- and 8-d-old rats. Pulmonary cGMP hydrolytic activity in 1-d-old animals was 30-fold greater than the cGMP hydrolytic activity of adult rat lungs. Zaprinast, a specific PDE5 antagonist, inhibited 52 and 56% of cGMP hydrolytic activity in lungs of 1- and 8-d-old rats, respectively, but only 18% of the activity in adult lungs.In situhybridization revealed that PDE5 mRNA transcripts were present in the vascular smooth muscle cells of neonatal and adult lungs. PDE5 mRNA was also detected in the alveolar walls of neonatal rat lungs. These results demonstrate that the gene encoding PDE5 is abundantly expressed in the lungs of perinatal rats, and is available to participate in the mammalian pulmonary vascular transition to extrauterine life. Extravascular PDE5 gene expression in neonatal lungs suggests a potentially important nonvascular role for this enzyme during pulmonary development.Abbreviations: PDE,3′:5′-cyclic nucleotide phosphodiesterase;PDE5,cGMP-binding, cGMP-specific phosphodiesterase;NO,nitric oxide;NOS III,constitutive endothelial nitric oxide synthase;sGC,soluble guanylate cyclase

ISSN:0031-3998    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Deficiency of the lipoprotein complex, surfactant, can lead to respiratory distress syndrome (RDS) in the prematurely born infant. The surfactant proteins (SP) play important roles in the function of surfactant. Previously, we have characterized four allelic variants of the SP-A1 gene (6A, 6A2, 6A3, and 6A4) and five allelic variants of the SP-A2 gene (1A, 1A0, 1A1, 1A2, and 1A3). We hypothesized that specific SP-A alleles/genotypes are associated with increased risk of RDS. Because race, gestational age (GA), and sex are risk factors for RDS, we first studied the distribution and frequencies of SP-A alleles/genotypes while adjusting for these factors as confounders or effect modifiers in control(n= 86 white and 12 black subjects) and RDS (n= 106 white and 37 black subjects) populations with GAs ranging from 24 wk to term. Although the odds ratios of several alleles and genotypes were in the opposite directions for black and white subjects, the homogeneity of odds ratio reached statistical significance only in the case of 6A3/6A3. Although differences were observed in subgroups with different GAs (≤28 and >28 wk) of the RDS white population, definitive conclusions cannot be made regarding the effect of modification by GA. No differences were observed as a function of sex. Second, we compared the frequencies of SP-A genotypes and alleles between control (n= 83) and RDS (n= 82) patients in the >28-wk white population. Differences between the two groups were observed for the 1A0allele and 1A0genotypes. Moreover, a significant synergistic positive association was observed between 1A0allele + SP-B polymorphic variant and RDS. We conclude that1) the genetic analyses of RDS and SP-A locus should be performed separately for black and white populations and2) SP-A alleles/genotypes and SP-B variant may contribute to the etiology of RDS and/or may serve as markers for disease subgroups.Abbreviations: SP,surfactant protein;TM,tubular myelin;RDS,respiratory distress syndrome;GA,gestational age;HOR,homogeneity of odds ratio;TGFA,transforming growth factor α;TDT,transmission/disequilibrium test

ISSN:0031-3998    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

The purpose of this work was to determine whether maternal/fetal vitamin A deficiencyin vivohad an effect on fetal lung surfactant protein expression and its response to antenatal maternal dexamethasone (DEX). Weanling female rats at 21 d (30-35 g) were fed control (C) (4 mg of vitamin A/kg of diet) or a vitamin A-deficient (D) (0.06 of mg vitamin A/kg) diet. These females were mated, and at selected pregnancy dates fetal and maternal tissues were obtained. Control mothers had liver retinyl palmitate (RP) concentrations of 246 ± 32 nmol/g of wet weight; those in the D group had 6.1 ± 2.9 nmol/g of wet weight. Control fetal liver RP was 12-fold higher and control fetal lung RP was 3-fold higher than in the D group (liver: 18.5 ± 0.4 nmol/gversus1.5 ± 0.25 nmol/g; lung: 1.8± 0.98 nmol/gversus0.6 ± 0.2 nmol/g). Neither fetal lung surfactant protein (SP)-C mRNA nor SP-A mRNA was affected by vitamin A deficiency. In a second experiment, pregnant rats from both C and D groups were injected with either DEX (1 mg/kg) or an equal volume of saline on d 15-17, and killed on d 18. DEX increased fetal lung SP-C mRNA 2-fold over the level found in the saline-injected group (saline, 1.0 ± 0.2versusDEX, 2.1 ± 0.2,p< 0.02). This increase in SP-C mRNA also occurred in fetal lungs from the D group (saline, 1.8± 0.4versusDEX 3.7 ± 0.2,p< 0.01). Retinoic acid receptor-β mRNA, which responds to vitamin A levels and DEX in many systems, was lower in fetal lungs of the D group that had been treated with DEX. We conclude that fetal rat lung development, as measured by SP-C mRNA and SP-A mRNA, and the SP-C mRNA response to DEX, was not affected by vitamin A deficiency.Abbreviations: SP,surfactant protein;RA,retinoic acid;RAR,retinoic acid receptor;C,control diet C;D,diet D;RP,retinyl palmitate;DEX,dexamethasone;PC,phosphatidylcholine

ISSN:0031-3998    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Obstruction of the fetal trachea causes liquid to accumulate within the future airways, which is a potent stimulus for lung growth. Our aim was to determine the relationship between the increase in fetal lung growth after tracheal obstruction and the increases in lung liquid volume and tracheal pressure to better understand the mechanisms involved in the growth response. The effects of 4 and 10 d of tracheal obstruction on lung DNA and protein contents and DNA synthesis rates were determined; these data were combined with data collected previously after 2 and 7 d of tracheal obstruction. Fetal lung liquid volumes and secretion rates were measured before (d 0) and on d 1, 2, 4, 7, and 10 after tracheal obstruction; fetal tracheal pressures were monitored throughout this period. Tracheal pressures increased from 2.9± 0.8 mm Hg (control) to 4.3 ± 0.4 mm Hg within 1 d of tracheal obstruction and remained at this elevated level for the duration of the obstruction period. Lung liquid volume increased progressively from 24.7± 1.1 mL/kg on d 0 to 97.3 ± 15.2 mL/kg at d 7 of tracheal obstruction, but had not increased further by d 10. Tracheal obstruction significantly increased lung DNA and protein contents above control values; over the 10-d period the increase in lung DNA content was closely related(r= 0.99) to the increase in lung liquid volume, but not to the increase in tracheal pressure. DNA synthesis rates were increased at 4 d of tracheal obstruction (by 66%) but had returned to control levels by d 10. We conclude that:1) the mechanisms responsible for the acceleration in lung growth induced by tracheal obstruction are most active on d 2, remain active at a reduced level on d 4 and 7, and have returned to control levels by d 10; and2) the increase in lung DNA content during tracheal obstruction (d 2-7) is closely related to the increase in lung liquid volume, but not to the increase in intraluminal pressure. Thus, we suggest that an increase in lung expansion is one of the primary factors responsible for the acceleration in fetal lung growth induced by tracheal obstruction.

ISSN:0031-3998    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Impaired pulmonary mechanics can cause chest wall distortion (CWD) so that work of breathing is dissipated in deforming the rib cage. We hypothesized that respiratory mechanical unloading as a technique of assisted mechanical ventilation would reduce CWD in animals with injured lungs. We studied five piglets and five adult rabbits to test across different ages and chest configurations. As a result of intratracheal meconium instillation, lung compliance decreased from 21 (median; range 17-35) to 9.5 (6.7-14) mL/kPa/kg in rabbits and from 26 (18-31) to 7.9 (4.9-11) in piglets. Airway resistance increased from 5.0 (4.6-6.1) to 6.9 (5.8-7.9) kPa/L/s in rabbits only. Respiratory inductive plethysmography was used to measure the phase shift between the rib cage and abdominal compartment movements and the total compartmental displacement ratio. We aimed at unloading at least three-fourths of lung elastance in all animals and 2.0 kPa/L/s of resistance in rabbits. Elastic unloading decreased the phase shift in all but one animal. It reduced the total compartmental displacement ratio from 1.27 (1.14-3.73) to 1.16(1.02-1.82) in piglets and from 1.77 (1.45-5.24) to 1.37 (1.11-4.78) in rabbits. The inspiratory rib cage expansion increased, whereas abdominal expansion did not. The tidal esophageal pressure deflection decreased. Tidal volume increased, whereas respiratory rate remained unaffected so that the partial pressure of arterial CO2decreased. Resistive unloading as an adjunct to elastic unloading further reduced CWD and induced a more rapid, shallower breathing. We conclude that respiratory unloading as a mechanical support to spontaneous breathing reduces CWD. We speculate that the decrease in CWD increases ventilatory efficiency for a given diaphragmatic effort.Abbreviations: CPAP,continuous positive airway pressure;CWD,chest wall distortion;Pao2,partial pressure of arterial O2;PacoO2,partial pressure of arterial CO2;Paw,airway pressure;Pes,esophageal pressure;RIP,respiratory inductive plethysmography;TCD,total compartmental displacement ratio

ISSN:0031-3998    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

To compare the effects of the sustained exposure to inhaled nitric oxide(NO) on pulmonary gas exchange, cardiovascular function and lung mechanics in newborn lambs with pulmonary hypertension induced by tracheal instillation of meconium. Fifteen newborn lambs (<6 d old) were studied in three groups(n= 5): control, and pulmonary hypertension (5 mL·kg-1of a 20% meconium solution) with or without inhaled NO(20 ppm) exposure. Heart rate, systemic and pulmonary arterial pressures, arterial pH and blood gases, cardiac output, and pulmonary mechanics were measured. The exposure to inhaled NO in lambs with pulmonary hypertension, induced by experimental meconium aspiration, produced a transient response. There were a transient improvement in gas exchange, a decrease in pulmonary arterial pressure and airway resistance, without changes in cardiovascular profile. The transient and incomplete response to inhaled NO in experimental MAS might be related to the fact that hypoxemia is not only due to pulmonary vasoconstriction but also to parenchymal lung disease. We hypothesize that this poor and transient response could probably be avoided if strategies that increase lung recruitment, were applied before inhaled NO exposure.Abbreviations: F102,fraction of inspired O2;MAS,meconium aspiration syndrome;NO,nitric oxide;PAP,pulmonary artery pressure;Paco2,partial pressure of arterial CO2;Pao2,partial pressure of arterial O2;PPH,persistent pulmonary hypertension;PVR,pulmonary vascular resistance;Sao2,arterial O2saturation;SAP,systemic arterial pressure;V/Q,ventilation/perfusion ratio;IPPV,intermittent positive pressure ventilation;CI,cardiac index

ISSN:0031-3998    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

We examined the effect of acute systemic blockade of nitric oxide synthesis on blood pressure and renal function in the monogenetically hypertensive TGR(mRen2)27 rat strain. Untreated conscious transgenic rats had significantly(p< 0.01) higher systolic blood pressures (185 ± 9versus130 ± 5 mm Hg) and urinary albumin excretion (32± 5versus6 ± 2 mg/day) than did control animals without evidence of renal insufficiency. Plasma and urinary nitric oxide metabolite levels did not differ between transgenic and control rats. i.v. administration ofNG-nitro-L-arginine methyl ester (10 mg/kg) to both groups caused similar elevations in systemic blood pressure(transgenic 25 ± 3versuscontrol 24 ± 3 mm Hg).NG-Nitro-L-arginine methyl ester induced reductions in whole kidney (1.4 ± 0.2versus0.7 ± 0.1 mL/min), and single nephron (23 ± 3versus11 ± 2 nL/min) glomerular filtration rates were significantly (p< 0.05) larger in transgenic than in control rats. This greater loss of GFR in transgenic animals was caused by a larger reduction in glomerular ultrafiltration coefficient (1.8 ± 0.2versus1.1 ± 0.1 nL·min-1·mm Hg-1,p< 0.05), a larger increase in afferent arteriole resistance (3.4 ± 0.2versus1.4 ± 0.1 dyne·s·cm-5,p< 0.05), and a subsequently smaller rise in glomerular transcapillary pressure (10 ± 1versus5 ± 1 mm Hg,p< 0.05). These results indicate that the renal microvasculature and glomerular hydraulic conductivity or surface area of transgenic rats are more sensitive to nitric oxide inhibition and are consistent with an important role for nitric oxide in TGR(mRen2)27 kidney function.Abbreviations: TGR,TGR(mRen2)27 rats;NO,nitric oxide;L-NAME,NG-nitro-L-arginine methyl ester;NOX,nitric oxide oxidation products;RAS,renin-angiotensin system;SHR,spontaneously hypertensive rats;PAH,p-aminohippuric acid;SNGFR,single nephron GFR;RBF,renal blood flow;RPF,renal plasma flow;RVR,renal vascular resistance;MAP,mean arterial pressure;SNBF,single nephron blood flow;SNPF,single nephron plasma flow;PGC,glomerular capillary hydraulic pressure;PUF,ultrafiltration pressure;RA,afferent arteriole resistance;RE,efferent artriole resistance

ISSN:0031-3998    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

To evaluate the metabolic effects of long-term treatment with recombinant human (rh) GH in short children with chronic renal failure (CRF), annual oral glucose tolerance tests (oGTT) during rhGH therapy for up to 5 y in 53 prepubertal children with CRF on conservative treatment, dialysis, and after renal transplantation were compared with that of 12 age-matched children treated with rhGH for idiopathic short stature. At the start of rhGH treatment, fasting values of glucose, insulin, glycosylated Hb A(HbA1C), triglycerides, cholesterol, glucose, and insulin responses during oGTT were significantly elevated in all patient groups compared with control subjects (p< 0.001). In the total population, fasting and 2-h postprandial glucose concentrations were inversely correlated with GFR and positively with age and methylprednisolone dosage in transplanted patients. Fasting insulin levels were positively correlated with body mass index and inversely with GFR. RhGH treatment was not associated with a change in fasting or stimulated glucose concentrations in any treatment group throughout the observation period. In contrast, serum insulin levels increased during the first treatment year in all groups, resulting in a more marked elevation of integrated insulin levels in transplant (1402 ± 179 pM) and dialysis (1025 ± 114 pM) patients compared with conservatively treated patients (829 ± 94 pM), and control subjects (719 ± 89 pM) (p< 0.01). Hyperinsulinemia persisted in all treatment groups for up to 5 y of follow-up. In conclusion, age, renal function, and obesity are the major independent predictors of glucose tolerance in children with CRF. Long-term rhGH treatment does not affect glucose tolerance, but aggravates the preexisting hyperinsulinemia in children with end-stage renal disease. In concert with the dyslipidemia of uremia, the rhGH-promoted hyperinsulinemia may contribute to the long-term risk for premature atherosclerosis in patients with childhood onset CRF.Abbreviations: BMI,body mass index;CRF,chronic renal failure;oGTT,oral glucose tolerance test;ΔI30/ΔG30,change in insulin/glucose ratio over the first 30 min of oGTT;SDS,SD score;rhGH,recombinant human GH

ISSN:0031-3998    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

In addition to its content of traditional nutrients, milk is a rich source of hormones and peptides, which survive digestion in the neonatal gastrointestinal tract secondary to lower proteolytic activity and increased protein permeability. Previous studies have shown accelerated erythropoiesis or elevated serum erythropoietin (Epo) levels in neonatal (suckling) animals after maternal phlebotomy or maternal hypoxia exposure. We sought to determine whether significant quantities of Epo are present in human milk and whether Epo remains intact under physiologic digestion conditions. Immunoreactive Epo concentrations were determined in 409 human milk samples obtained from mothers of term and premature infants. Samples collected between birth and postpartum d 134 were divided into 11 postpartum day groups. Mean milk-borne Epo concentrations were within the normal range for plasma Epo concentrations and rose with postpartum day (F10,398= 5.82,p< 0.0001). No differences were observed between milk collected from mothers of prematureversusterm infants. Estimated weekly human milk-borne Epo intakes approximated the lower range of published parenteral therapeutic doses. In simulated digestion at physiologic pH levels of 3.2, 5.8, and 7.4, milk-borne Epo resisted degradation at 1 and 2 h, compared with baseline. Therefore, we conclude that human milk contains considerable amounts of Epo which resist degradation after exposure to gastric juices at physiologic pH levels. These results support continued investigation into the fate and developmental roles of Epo in human milk.Abbreviations: Epo,erythropoietin;rhEpo,recombinant human Epo;TCA,trichloroacetic acid

ISSN:0031-3998    

出版商:OVID    

年代:1998

数据来源: OVID