Biomedical subjects

K E Willet

Publications and source records attributed to K E Willet.

13 recordsLinked to original sources

PubMed2000

Effects of antenatal endotoxin and glucocorticoids on the lungs of preterm lambs.

OBJECTIVE: We hypothesized that the proinflammatory response to intra-amniotic endotoxin would induce lung maturation in preterm lambs. STUDY DESIGN: Ewes were randomly assigned to receive 20 mg Escherichia coli endotoxin by intra-amniotic injection, maternal betamethasone (0.5 mg/kg), or sodium chloride solution. Preterm lambs were delivered at 125 days' gestation and underwent ventilation to assess lung function. Lung gas volume, surfactant concentrations, and inflammation were subsequently evaluated, with data analyzed by analysis of variance. RESULTS: Fetal endotoxin exposure 6 days before delivery increased compliance by 59%, increased lung gas volume 2.3-fold, increased concentrations of surfactant lipids, increased surfactant A and B protein levels, and increased messenger ribonucleic acid expressions for surfactant proteins (all P <.01, vs control group). Betamethasone exposure resulted in less consistent effects. White blood cell counts were increased in fetal membranes and lungs after endotoxin exposure, but there was no severe inflammation. CONCLUSION: A single fetal exposure to endotoxin resulted in large improvements in postnatal lung function and increases in surfactant concentrations after preterm delivery. These effects were qualitatively larger than those achieved with betamethasone.

Animals↗

PubMed1999

Lung morphometry and collagen and elastin content: changes during normal development and after prenatal hormone exposure in sheep.

This study examined whether the improvement in lung function after prenatal hormone exposure coincided with changes in lung morphometry or in collagen and elastin content. Fetal lambs received a single intramuscular injection of betamethasone (0.5 mg/kg) plus L-thyroxine (T4) (15 micrograms/kg) or vehicle control 48 h before delivery at 121, 128, or 135 d gestational age (d 121, d 128, d 135, term = 150 d). T4 was administered in conjunction with betamethasone in an attempt to enhance the maturational response. The right-upper lobes were instillation fixed at 30 cm H2O by Karnovsky's fixative after a 40-min period of mechanical ventilation. A number of significant changes occurred between d 121 and d 135 in control animals: alveolar airspace volume increased by 270%; despite a 40% reduction in alveolar septal thickness, alveolar septal volume did not change appreciably, suggesting a "redistribution" of septal tissue into the formation of secondary alveolar septa, which doubled in number; and both parenchymal collagen and elastin volume increased significantly, whereas pleural collagen and elastin volume did not change. In contrast to the changes seen in control animals, exposure to betamethasone plus T4 led to alveolar septal thinning at each gestational age without an associated increase in secondary septal number, a 40% decrease in alveolar septal volume, and a proportionate reduction in parenchymal elastin at d 121. Although attenuation of alveolar septa coincides with redistribution of septal tissue into the formation of secondary septa during normal maturation, exposure to betamethasone plus T4 promotes thinning of alveolar septa in the absence of secondary septal formation, which results in a loss of alveolar septal tissue.

Aging↗

PubMed1998

Environmental effects on pulmonary mechanics and the response to inhaled methacholine.

To investigate the role of environmental exposure from birth on airway and lung parenchymal responsiveness to inhaled methacholine (Mch), three litters of puppies (n = 14) were studied when 8-10 weeks of age. Two litters, one mongrel (n = 7) and one foxhound-beagle cross (n = 3), were born and raised in a clean animal house environment (clean mongrels and clean cross, respectively). Another litter of mongrels was born (n = 4) and raised in an external environment (external mongrels), exposed to normal rural environmental contaminants. Animals were studied open-chested with alveolar capsules used to partition mechanics into airway and parenchymal components. Lung mechanics were measured after abrupt flow interruptions. The animals born and raised in the external environment were significantly more responsive to inhaled Mch than those born and raised in the clean environment. This finding was true for both airway and parenchymal responsiveness. The group mean effective dose of Mch that produced a doubling of airway resistance (ED200Raw) for the external mongrel group was 4.40 mg/ml compared with 19.44 mg/ml for the clean mongrel group and 16.34 mg/ml for the clean cross group (P < 0.02). The group mean effective dose of Mch that produced a doubling of pressure difference in airways after the initial rapid rise in airway pressure (ED200Pdif) for the external mongrel group was 0.79 mg/ml compared with 3.90 mg/ml for the clean mongrel group and 10.78 mg/ml for the clean cross group (P < 0.01). Generalized linear modeling analysis showed that both "environment" and "breed" were significant factors in determining ED200Pdif, but only "environment" significantly influenced ED200Raw. In summary, the present study has demonstrated that the environment in which an animal is born and raised can influence lung mechanics and responsiveness to methacholine. This finding is particularly true for the lung parenchyma.

Animals↗

PubMed1997

Repetitive prenatal glucocorticoids improve lung function and decrease growth in preterm lambs.

We evaluated the effects of multiple fetal exposures to glucocorticoids on postnatal lung function and growth. Ewes were randomized to receive 1 to 4 doses of 0.5 mg/kg betamethasone or saline placebo at 7 d intervals from 104 d to 118 d and at 124 d gestation. All lambs were delivered preterm at 125 d gestation, and postnatal lung function was evaluated. There were sequential improvements in compliance, ventilation efficiency, and lung volumes for two, three, and four doses of betamethasone. The maximal effect was a 150% increase in compliance and a 4-fold increase in lung volume after fetal exposure to four doses of betamethasone. However, birth weights decreased (15% after one dose, 19% after two doses, and 27% after three and four doses). There were no changes in lung to body weight ratios, lung dry to wet weight ratios, lung protein to body weight ratios, or lung hyaluronan content. Prenatal glucocorticoid exposure also altered postnatal cortisol, thyroid, and catecholamine plasma levels. Repetitive 7-d interval exposures of fetal lambs to glucocorticoids progressively enhanced postnatal lung function and resulted in growth and endocrine abnormalities.

Animals↗

PubMed1997

Prenatal glucocorticoid and T4 effects on lung morphology in preterm lambs.

Prenatal glucocorticoid plus T4 treatment of fetal sheep results in improvements in oxygenation, gas exchange, lung mechanics, and lung volumes after preterm delivery. We have evaluated the morphometric changes in the lungs of lambs exposed to betamethasone and T4 48 h before preterm delivery at 121 and 135 d gestation and related those changes to the physiologic improvements in lung function. The lungs used for the morphometric studies were from lambs with postnatal physiologic responses similar to those of the entire group of lambs reported previously (16). At both 121 and 135 d gestation, lung gas volumes and fixed tissue volumes increased, the percent of collapsed (nonaerated) parenchyma decreased, and the percent of perilobular connective tissue decreased with both gestational age and prenatal hormone exposure. Alveolar size, as estimated by mean linear intercept length, did not change with gestation or hormone exposure, but there was a decrease in alveolar wall thickness with advancing gestation and at each gestation with hormone exposure. The major anatomic effect of prenatal hormone exposure was a decrease in alveolar wall thickness and an increase in aerated parenchyma, effects that were consistent with the physiologic improvements in postnatal lung function.

Animals↗

PubMed1997

Postnatal lung function after prenatal steroid treatment in sheep: effect of gender.

The effect of fetal gender on postnatal lung function and response to prenatal steroid exposure were examined retrospectively in a group of 115 preterm lambs. Fetuses received a single intramuscular injection of 0.5 mg/kg betamethasone alone or in conjunction with L-thyroxine 48 h before delivery at 128-d gestational age. Control animals received an equivalent volume of saline. After delivery, respiratory mechanics and blood gas parameters were recorded for 40 min. Deflation pressure volume curves were constructed in excised lungs. Right upper lobes from a randomly selected subgroup of control animals were examined morphometrically. Control (saline-treated) females were able to be ventilated at lower ventilatory pressures with equivalent tidal volumes and more efficient gas exchange. There were no gender differences in compliance, conductance, or excised lung volumes for saline-treated animals. More efficient gas exchange in females could not be explained by thinner alveolar septa or greater alveolar surface area. After hormone treatment, both males and females exhibited significant improvements in respiratory mechanics, gas exchange, and an increase in alveolar surfactant concentration. However, female exhibited a significantly greater improvement than males for compliance, conductance, excised lung volume, and arterial oxygen partial pressure. These data provide a comprehensive description of gender differences in postnatal lung function and response to steroid treatment in preterm animals, and support clinical findings of sexual dimorphism.

Animals↗

PubMed1996

Differing patterns of mechanical response to direct fetal hormone treatment.

A single combined intramuscular dose of betamethasone and l-thyroxine (T4) or placebo was injected into the shoulder of fetal lambs 48 hours prior to delivery at days 121 (n = 14), 128 (n = 25) or 135 (n = 20) of gestation. Respiratory mechanics were calculated using multiple linear regression analysis. Both respiratory system resistance (RRS) and elastance (ERS) decreased approximately 4 fold between gestational days 121 (D121) and 135 (D135). Both variables were also reduced by hormone treatment. Reduction in ERS was due to a reduction in both lung (EL) and chest wall (EW) components. In absolute terms EW decreased with gestational age; however, EW as a proportion of total elastance (% EW) increased. Inclusion of a volume-dependent elastance term in the multiple linear regression model enabled us to separate total elastance into volume-independent (E1) and volume-dependent (E2V) components. E1 decreased almost 8-fold compared with only a 2.5-fold fall in E2V between D121 and D135. %E2, the proportion of ERS which is volume-dependent and which provides an index of overventilation, doubled over this time period. Hormone treatment affected E1 and E2V components equally hence %E2 was not altered. Both excised lung volume and end expiratory alveolar volume increased with gestational age and with treatment. The response to treatment was qualitatively similar at each of the gestational ages examined, however, for all mechanics variables, except resistance and E1, the magnitude of response to treatment was significantly smaller in D135 animals compared with other age groups.

Airway Resistance↗

PubMed1994

Time course of changes in lung mechanics following fetal steroid treatment.

We studied the effect of a single-dose, corticosteroid treatment on preterm lambs (gestational age: 128 d). A low, medium, or high betamethasone dose (0.1, 0.5, and 2.0 mg/kg) or saline control was administered directly to the fetus by ultrasound-guided intramuscular injection 48 h before delivery. A second group received either the high dose of betamethasome or saline 24 h before delivery. The lambs were delivered at 128 d gestation, anesthetized with ketamine, and ventilated for 50 min. Respiratory system elastance and resistance were measured at 10-min intervals using multiple linear regression analysis of pressure, flow, and volume. Similarly, estimates of lung mechanics were calculated from transpulmonary pressure. The viscoelastic time constant (tau) was calculated by fitting an exponential to the pressure changes occurring after occluding the airway during expiration. Excised lung volume at 40 cm H2O and lung weight were used to calculate specific elastance and resistance correcting for lung size using volume or weight, respectively. Of the 13 lambs in the 48-h high-dose betamethasone group, five developed pulmonary interstitial emphysema (PIE) as did 3 of 11 animals in the high-dose group treated 24 h before delivery. These animals were analyzed separately. The lambs receiving medium- or high-dose (24 and 48 h predelivery) betamethasone had significantly lower elastance and a trend toward lower resistance when compared with the control groups. Ten minutes after delivery, the animals that developed PIE all had elastance values comparable to that of the control animals despite corticosteroid treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗

PubMed1990

The role of epithelium in the responsiveness of the bronchi to stimuli.

Airway narrowing in response to different modes of stimuli was measured using a perfused bronchial segment. Acetylcholine, carbachol, histamine, high [K+] and vanadate perfused through the lumen gave small responses as shown by the reduction in flow, but fully constricted the airway when applied to the outside. ACh was 29 times more sensitive on the outside. When the epithelium was removed airway narrowing by these stimuli was increased to equal that on the outside. It was concluded that the role of the epithelia as a barrier is all important. Evidence for an EpDIF released by the epithelium could not be obtained.

Acetylcholine↗

PubMed1990

Airway diameter determines flow-resistance and sensitivity to contractile mediators in perfused bronchial segments.

To study airway reactivity, flow-resistance to carbachol and histamine was measured in perfused bronchial segments. Small-bore airways were more sensitive, flow was reduced to zero and resistance rose very steeply due to mucosal folding while in large-bore airways maximum flow reduction was 50% and resistance increased sigmoidly. Thus the internal diameter of an airway is a crucial determinant of narrowing.

Airway Resistance↗

PubMed1989

Perfused bronchial segment and bronchial strip: narrowing vs. isometric force by mediators.

When bronchial segments were perfused with Krebs solution at a constant pressure (5-6 cmH2O), the resistance rose exponentially with increasing concentrations of either carbachol or histamine in the lumen. The pressure-flow relationship was linear. Histamine and carbachol caused 43 and 47% muscle shortening, respectively, and produced the same maximum effect (Emax) because they both stopped perfusion. In bronchial strips the maximum isometric force or isotonic shortening to carbachol was more than twice that of histamine and the responses showed a plateau. There were no significant differences in sensitivities [negative log of the concentration producing half-maximal response (EC50)] to either carbachol or histamine in the strips (isotonic and isometric) and the segments perfused at constant pressure. When airway segments were perfused at a constant flow, however, responses plateaued and the sensitivities to carbachol and histamine were reduced more than tenfold compared with the strips [4.71 +/- 0.20 and 6.22 +/- 0.08 (SE) for carbachol in segments and isometric strips, respectively, and 3.92 +/- 0.13 and 4.94 +/- 0.11 (SE) for histamine]. We conclude that when segments are perfused at a constant pressure, airway closure occurs before maximal pharmacological activation, as seen in airway strips.

Airway Resistance↗

PubMed1988

Effect of elastase instilled into the trachea on airways mechanics in guinea pigs.

Instilled elastase caused an inflammatory response in the lungs of guinea pigs which was observed at 6 h, 24 h, and 48 h post-treatment. The inflammation was most marked at 24 h and was characterised by a loss of epithelial cilia and detachment of epithelial cells from the basement membrane, a marked increase in polymorphonuclear leukocytes (PMNs) in blood vessels of the tracheal submucosa and an infiltration of macrophages into the parenchyma. Compared with controls, isolated tracheal preparations from 24 h and 48 h elastase pretreated animals were hyperreactive (Emax) to histamine and carbachol. This hyperreactivity persisted in tracheas from 48 h elastase pretreated animals after removal of the epithelial layer. Parenchymal strips were hyperreactive to histamine only. Tissue sensitivity (EC50) was little affected by elastase. Tracheal preparations incubated in 0.01% elastase for 3 h responded normally. In vivo responses of Raw and Cdyn to histamine were unaffected by elastase at 24 h and 48 h. However, the slope of the dose-response curve to acetylcholine was steepened 24 h after elastase instillation, but not at 48 h. In contrast to other models of inflammation elastase evokes in vitro but not in vivo hyperresponsiveness.

Animals↗

PubMedDate not supplied

Pirenzepine blunts the pulmonary parenchymal response to inhaled methacholine.

To determine the role of M1 muscarinic receptors in the response of the pulmonary parenchyma to inhaled methacholine (MCh), 20 mongrel, out-bred puppies, 8-10 weeks of age were challenged following pretreatment with either saline (control), UH-AH37 (a combined M1 & M3 receptor blocker), or pirenzepine (a relatively selective M1 receptor blocker). In addition, eight fox hound-beagle puppies, born and raised in a clean animal house, were studied. Relatively selective doses of pirenzepine produced a dose-dependent shift to the right of the parenchymal dose-response curves (P = 0.031), with no effect on the airway dose-response curve (P = 0.102). The fox hound-beagle puppies showed less parenchymal response (P <0.0005), but equivalent airway response (P = 0.468), to MCh compared with the mongrel puppies. High doses of pirenzepine (10 000 mu g/kg) and UH-AH37 (3 mg/kg) markedly inhibited both the parenchymal and airway responses to MCh. Data from the present study demonstrate that: (1) while both the airway and pulmonary parenchyma respond to inhaled MCh, the mechanisms by which they respond differ; (2) stimulation of M1 subtype muscarinic receptors are responsible, at least partly, for the parenchymal response; and (3) experimental conditions, such as the breed and housing conditions of animals, may have major influences on the parenchymal response to inhalational challenge tests.

Animals↗