Biomedical subjects

Machiko Ikegami

Publications and source records attributed to Machiko Ikegami.

At least 55 records · Page 3Linked to original sources

PubMed2003

Minimal lung and systemic responses to TNF-alpha in preterm sheep.

TNF-alpha has been associated with chorioamnionitis and the subsequent development of bronchopulmonary dysplasia in preterm infants. We asked whether bioactive recombinant ovine TNF-alpha could induce chorioamnionitis, lung inflammation, lung maturation, and systemic effects in fetal sheep. We compared the responses to IL-1alpha, a cytokine known to induce these responses in preterm sheep. Intra-amniotic TNF-alpha caused no chorioamnionitis, no lung maturation, and a very small increase in inflammatory cells in the fetal lung after 5 h, 2 days (d), and 7 d. In contrast, IL-1alpha induced inflammation and lung maturation. TNF-alpha given into the airways at birth increased granulocytes in the bronchoalveolar lavage fluid of ventilated preterm lungs and decreased the mRNA for surfactant protein C but did not adversely effect postnatal lung function. An intravascular injection of IL-1alpha caused a systemic inflammatory response in fetal sheep, whereas there was no fetal response to intravascular TNF-alpha. Fetal and newborn preterm sheep are minimally responsive to TNF-alpha. Therefore, the presence of a mediator such as TNF-alpha in a developing animal does not necessarily mean that it is causing the responses anticipated from previous results in adult animals.

Amniotic Fluid↗

PubMed2003

Pneumonitis and emphysema in sp-C gene targeted mice.

SP-C-deficient (SP-C -/-) mice developed a severe pulmonary disorder associated with emphysema, monocytic infiltrates, epithelial cell dysplasia, and atypical accumulations of intracellular lipids in type II epithelial cells and alveolar macrophages. Whereas alveolar and tissue surfactant phospholipid pools were increased, levels of other surfactant proteins were not altered (SP-B) or were modestly increased (SP-A and SP-D). Analysis of pressure-volume curves and forced oscillatory dynamics demonstrated abnormal respiratory mechanics typical of emphysema. Lung disease was progressive, causing weight loss and cardiomegaly. Extensive alveolar remodeling was accompanied by type II cell hyperplasia, obliteration of pulmonary capillaries, and widespread expression of alpha-smooth muscle actin, indicating myofibroblast transformation in the lung parenchyma. Dysplastic epithelial cells lining conducting airways stained intensely for the mucin, MUC5A/C. Tissue concentrations of proinflammatory cytokines were not substantially altered in the SP-C (-/-) mice. Production of matrix metalloproteinases (MMP-2 and MMP-9) was increased in alveolar macrophages from SP-C (-/-) mice. Absence of SP-C caused a severe progressive pulmonary disorder with histologic features consistent with interstitial pneumonitis.

Animals↗

PubMed2003

Chorioamnionitis induced by subchorionic endotoxin infusion in sheep.

OBJECTIVE: This study was undertaken to determine whether subchorionic endotoxin infusion causes chorioamnionitis and preterm lung maturation, as occurs after intra-amniotic endotoxin. STUDY DESIGN: From day 118 of pregnancy, sheep received infusions of endotoxin (subchorionic 7.5 mg/d, n=11; intra-amniotic 2.5 mg/d, n=9) until delivery of lambs at 120 or 124 days. Other sheep received a single intra-amniotic injection of endotoxin (10 mg, n=7) at 118 days before delivery at 124 days. Controls (n=9) received equivalent saline solution treatments. RESULTS: Chorioamnionitis accompanied all endotoxin treatments. Lung inflammation occurred after intra-amniotic endotoxin infusion or injection but not after subchorionic endotoxin. Umbilical arterial pH was lower and Pco(2) was higher than control after subchorionic endotoxin. Lung compliance and surfactant were increased after intra-amniotic endotoxin infusion or injection but not after subchorionic endotoxin. CONCLUSION: Chorioamnionitis may result from inflammatory stimuli at various intrauterine sites, with different sites causing different fetal effects and not all cases of chorioamnionitis being accompanied by enhanced lung maturation.

Amnion↗

PubMed2003

Single and multiple prenatal glucocorticoid exposures improve preterm newborn lamb cardiovascular and renal function similarly.

OBJECTIVE: Renal and cardiovascular function improves in preterm newborn lambs after a single prenatal betamethasone treatment. We hypothesized that multiple betamethasone exposures would further improve renal and cardiovascular adaptation. STUDY DESIGN: Pregnant ewes were chosen randomly to receive saline solution, one dose of 0.5 mg/kg betamethasone at 104 days of gestation, or three doses of 0.5 mg/kg betamethasone at 104, 111, and 118 days of gestation. Lambs were delivered at 125 days of gestation (preterm) or 145 days of gestation (term). Renal and cardiovascular responses to phenylephrine were evaluated at 2 hours of age. RESULTS: The preterm single and multiple betamethasone-treated lambs comparably increased glomerular filtration rate, urinary flow and osmolar clearance, and sodium excretion in response to phenylephrine. Term responses were similar and not influenced by betamethasone exposure. CONCLUSION: Multiple courses of betamethasone do not further improve renal and cardiovascular responses from a single betamethasone dose. Renal and cardiovascular function at term is not affected by early prenatal betamethasone exposure.

Aldosterone↗

PubMed2003

Differential effects of maternal betamethasone and cortisol on lung maturation and growth in fetal sheep.

OBJECTIVES: We asked whether maternal or fetal cortisol treatments induced fetal lung maturation and growth restriction compared with betamethasone and whether medroxyprogesterone (MPA) influenced lung maturation. STUDY DESIGN: Pregnant sheep were randomized to receive MPA or saline solution at 100 days of gestation. At 117 days of pregnancy, ewes were randomized to receive maternal or fetal treatments with 0.5 mg/kg betamethasone, four injections of hydrocortisone given over 4.5 hours or saline solution. Body weight and lung maturation were evaluated at 125 days. RESULTS: Maternal betamethasone decreased in birth weight by 16% and induced lung maturation. Fetal cortisol or betamethasone induced only lung maturation. Maternal cortisol caused neither growth restriction nor lung maturation. MPA did not alter lung function in control lambs or in betamethasone-treated preterm lambs. CONCLUSIONS: Maternal cortisol treatments had no apparent effects on the fetus, suggesting that growth restriction caused by betamethasone may result from unidentified effects on the maternal-placental unit.

Animals↗

PubMed2003

Intra-amniotic corticosteroids for preterm lung maturation in sheep.

OBJECTIVE: The purpose of this study was to compare efficacy on fetal lung maturation of intra-amniotic betamethasone or budesonide with the efficacy of maternal intramuscular betamethasone. STUDY DESIGN: Pregnant ewes received intra-amniotic betamethasone (0.5 mg/kg or 2 mg/kg fetal weight), intra-amniotic budesonide (0.5 mg/kg or 2 mg/kg), maternal intramuscular betamethasone (0.5 mg/kg maternal weight), intra-amniotic saline solution, or maternal saline solution. Lambs were delivered 2 or 7 days later, at 124 days of gestation for measurement of respiratory system compliance, ventilatory efficiency index, and surfactant levels. RESULTS: Lung function increased 2 days after maternal betamethasone, intra-amniotic betamethasone (2 mg/kg), and intra-amniotic budesonide (2 mg/kg) administration and 7 days after maternal betamethasone or intra-amniotic budesonide (2.0 mg/kg) administration. Lung function was not improved 7 days after intra-amniotic betamethasone (2.0 mg/kg) administration or 2 days after intra-amniotic betamethasone (0.5 mg/kg) or intra-amniotic budesonide (0.5 mg/kg) administration. Intra-amniotic corticosteroid administration increased fetal death and respiratory morbidity. CONCLUSION: Intra-amniotic corticosteroid administration improved preterm lung function, but the associated morbidity and mortality rates suggest that they are not suitable for clinical use.

Amnion↗

PubMed2003

Betamethasone effects on chorioamnionitis induced by intra-amniotic endotoxin in sheep.

OBJECTIVE: Intra-amniotic administration of endotoxin in sheep is a model of subclinical chorioamnionitis. Intrauterine inflammation alters lung development to improve postnatal lung function and may predispose the infant to lung and brain injury. We describe the effects of intra-amniotic endotoxin on cytokines and white cell responses in the membranes and amniotic fluid and investigate the hypothesis that betamethasone treatment suppresses these responses. STUDY DESIGN: Pregnant ewes were allocated at random to receive either intra-amniotic saline solution (control animals), maternal intramuscular betamethasone, intra-amniotic endotoxin by ultrasound guidance (10 mg Escherichia coli 055:B5), or a combination of the betamethasone and endotoxin treatments. Lambs were delivered abdominally at 110 to 125 days of gestation at time points that ranged from 2 hours to 15 days after treatment. RESULTS: When compared with saline solution-injected control animals, the intra-amniotic injection of endotoxin increased white cell counts in amniotic fluid. Levels of interleukin-8, but not interleukin-6, were significantly increased in amniotic fluid from 5 hours to 15 days after intra-amniotic endotoxin injection, and interleukin-8 levels were not decreased by concurrent treatment with betamethasone. After endotoxin treatment, interleukin-1beta and interleukin-8 messenger RNA were expressed in chorion, and interleukin-6 messenger RNA expression was localized to chorionic blood vessel epithelium. The half-life of endotoxin in the amniotic fluid was 1.7 days, and levels remained measurable 15 days after injection. CONCLUSION: These findings confirm that the fetus can survive within amniotic fluid that contains endotoxin, white cells, and cytokines for periods of weeks or more. Betamethasone treatment can suppress the initial inflammation in the amnion-chorion, but interleukin-8 levels and inflammatory cells in amniotic fluid were not suppressed 5 and 15 days after betamethasone treatment, presumably because of the slow clearance of bioactive endotoxin from the amniotic fluid.

Amnion↗

PubMed2003

Surfactant protein B inhibits endotoxin-induced lung inflammation.

Transgenic mice, in which the level of surfactant protein (SP)-B mature peptide varied 5.6-fold between SP-B(+/-) and SP-B-overexpressing lines (SP-B+/+/+), were used to test the hypothesis that SP-B protects against endotoxin-induced lung inflammation. Intratracheal administration of endotoxin resulted in significantly lower concentration of SP-B mature peptide and elevated levels of total protein in bronchoalveolar lavage fluid of SP-B(+/-) mice compared with SP-B-overexpressing mice, indicating that endotoxin treatment leads to impairment of SP-B expression coincident with increased lung injury in SP-B(+/-) mice. Recruitment of inflammatory cells and elaboration of proinflammatory cytokines in bronchoalveolar lavage fluid were reduced in SP-B-overexpressing mice compared with SP-B(+/-) mice, suggesting that SP-B inhibited endotoxin-induced lung inflammation. Lung compliance and tissue damping were significantly decreased in SP-B(+/+) and SP-B(+/-) mice, but were not changed in SP-B(+/+/+) mice, consistent with a protective effect of SP-B. The minimum surface tension of large aggregate surfactant was significantly lower for surfactant isolated from SP-B-overexpressing mice, both in the absence and the presence of added plasma proteins. These data suggest that SP-B protected against endotoxin-induced lung inflammation by enhancing surfactant function, resulting in reduced lung injury, decreased influx of inflammatory cells, and lower cytokine levels; in contrast, levels of SP-B in SP-B(+/-) mice were further decreased by endotoxin treatment, likely exacerbating lung injury in this group.

Animals↗

PubMed2003

Effects of high PCO2 on ventilated preterm lamb lungs.

High PCO(2) levels attenuate reperfusion injury and ventilation-induced injury in isolated and perfused lungs. We asked whether premature lambs could tolerate 6 h of ventilation with a PCO(2) >80 mm Hg and whether the high PCO(2) modulated the ventilator-induced injury. Preterm surfactant-treated lambs were ventilated for 30 min with a high tidal volume (V(T)) to induce lung injury. The lambs then were ventilated for 5.5 h with a V(T) of 6-9 mL/kg to achieve a PCO(2) of 40-50 mm Hg in the control group. CO(2) was added to the ventilator circuit of a high PCO(2) group to maintain an average PCO(2) of 95 +/- 5 mm Hg. The high PCO(2) lambs had heart rates, blood pressures, plasma cortisol values, and oxygenation equivalent to the control lambs. The lungs of the high PCO(2) group had significantly higher gas volumes and had less lung injury by histopathology. Indicators of inflammation (white blood cells, hydrogen peroxide production, and IL-1beta and IL-8 cytokine mRNA expression in cells from the alveolar wash) qualitatively indicated less injury in the high PCO(2) group, although the differences were not significant. Preterm lambs tolerated a very high PCO(2) without physiologic compromise for 6 h. The high PCO(2) may attenuate ventilator-induced lung injury in the preterm.

Animals↗

PubMed2003

In vivo measurements of changes in respiratory mechanics with age in mice deficient in surfactant protein D.

Mice deficient in surfactant protein D [SP-D (-/-)] develop progressive emphysema with age, associated with loss of parenchymal tissue, subpleural fibrosis, and accumulation of abnormal elastin fibers. We measured the changes in lung function, partitioned into components for the airways and lung parenchyma, occurring with age in SP-D (-/-) mice at three ages (n = 8 per group) (5, 8, and 13 wk). Impedance spectra between 0.25 and 19.625 Hz were calculated and a model, consisting of an airway compartment [airway resistance (Raw) and inertance (Iaw)] and a constant-phase tissue compartment [coefficients of tissue damping (G) and elastance (H)], was fitted to the data. Hysteresivity was calculated as G/H. Adult values of Raw, G, and H are reached by 8 wk of age in wild-type controls. Raw and H were lower at all ages in SP-D (-/-) compared with the wild-type controls (p = 0.006 and 0.029, respectively), and a similar trend was seen in G (p = 0.060). The patterns of change in respiratory mechanics were similar in both SP-D (+/+) and (-/-) groups. There were no changes in hysteresivity with age and no differences between wild-type and SP-D (-/-) mice. These data demonstrate that the changes in lung structure in SP-D (-/-) mice are reflected in the mechanical properties of both airway and lung parenchyma measured in vivo.

Age Factors↗

PubMed2002

Alveolar lipoproteinosis in an acid sphingomyelinase-deficient mouse model of Niemann-Pick disease.

Types A and B Niemann-Pick disease (NPD) are lipid storage disorders caused by the deficient activity of acid sphingomyelinase (ASM). In humans, NPD is associated with the dysfunction of numerous organs including the lung. Gene targeting of the ASM gene in transgenic mice produced an animal model with features typical of NPD, including pulmonary inflammation. To assess mechanisms by which ASM perturbed lung function, we studied lung morphology, surfactant content, and metabolism in ASM-deficient mice in vivo. Pulmonary inflammation, with increased cellular infiltrates and the accumulation of alveolar material, was associated with alterations in surfactant content. Saturated phosphatidylcholine (SatPC) content was increased twofold, and sphingomyelin content was increased 5.5-fold in lungs of the ASM knockout (ASMKO) mice. Additional sphingomyelin enhanced the sensitivity of surfactant inhibition by plasma proteins. Clearance of SatPC from the lungs of ASMKO mice was decreased. Catabolism of SatPC by alveolar macrophages from the ASMKO mouse was significantly decreased, likely accounting for decreased pulmonary SatPC in vivo. In summary, ASM is required for normal surfactant catabolism by alveolar macrophages in vivo. Alterations in surfactant composition, including increased sphingomyelin content, contributed to the abnormal surfactant function observed in the ASM-deficient mouse.

Animals↗

PubMed2002

Maternal glucocorticoids increase endotoxin-induced lung inflammation in preterm lambs.

Antenatal betamethasone (Beta) is widely used in women with asymptomatic chorioamnionitis at risk for preterm delivery, but its effects on fetal inflammation are unstudied. Groups of ewes at 109 +/- 1 days of gestation received the following treatments: intra-amniotic (IA) saline (control), 0.5 mg/kg intramuscular Beta, 10 mg IA endotoxin (Endo), and Beta + 2 h later Endo (Beta + Endo). Beta suppressed Endo-induced lung inflammation at 1 day. However, compared with Endo 5 days after treatment, Beta + Endo lambs had increased alveolar neutrophils, proinflammatory cytokine mRNA expression, and serum amyloid A3 (SAA3) mRNA expression. IL-1beta mRNA expression was localized to the inflammatory cells, whereas SAA3 mRNA expression was induced in the bronchial epithelium and the inflammatory cells. Compared with Endo, Beta + Endo lambs had increased lung inflammation but equivalent lung volumes 15 days after treatment. The late increase in inflammation in the Beta + Endo animals suggests that glucocorticoids impair the ability of the preterm lung to downregulate Endo-induced inflammation after fetal clearance of the glucocorticoids. These results have implications for lung inflammation and bronchopulmonary dysplasia in preterm infants exposed to chorioamnionitis and maternal glucocorticoids.

Acute-Phase Reaction↗

PubMed2002

Reversibility of pulmonary abnormalities by conditional replacement of surfactant protein D (SP-D) in vivo.

Surfactant protein D (SP-D) gene-targeted mice develop severe pulmonary disease associated with emphysema, pulmonary lipidosis, and foamy macrophage infiltrations. To determine the potential reversibility of these abnormalities, transgenic mice were developed in which SP-D was conditionally replaced in the respiratory epithelium of SP-D(-/-) mice. SP-D was not detected in the absence of doxycycline. Treatment with doxycycline after birth restored pulmonary SP-D concentrations and corrected pulmonary pathology at adulthood. When SP-D was replaced in adult SP-D(-/-) mice, alveolar SP-D was restored within 3 days, pulmonary lipid abnormalities were corrected, but emphysema persisted. In corrected adult SP-D(-/-) mice, loss of SP-D caused focal emphysema and pulmonary inflammation but did not cause phospholipid abnormalities characteristic of SP-D(-/-) mice. Thus, abnormalities in surfactant phospholipid homeostasis and alveolar macrophage abnormalities were readily corrected by restoration of SP-D. However, once established, emphysema was not reversed by SP-D. SP-D-dependent processes regulating surfactant lipid homeostasis were disassociated from those mediating emphysema.

Animals↗

PubMed2002

The role of pulmonary collectin N-terminal domains in surfactant structure, function, and homeostasis in vivo.

The N-terminal domains of the lung collectins, surfactant proteins A (SP-A) and D (SP-D), are critical for surfactant phospholipid interactions and surfactant homeostasis, respectively. To further assess the importance of lung collectin N-terminal domains in surfactant structure and function, a chimeric SP-D/SP-A (D/A) gene was constructed by substituting nucleotides encoding amino acids Asn(1)-Ala(7) of rat SP-A with the corresponding N-terminal sequences from rat SP-D, Ala(1)-Asn(25). Recombinant D/A migrated as a 35-kDa band on reducing SDS-PAGE and as a ladder of disulfide-linked multimers under nonreducing conditions. The recombinant D/A bound and aggregated phosphatidylcholine containing vesicles as effectively as rat SP-A. Mice in which endogenous pulmonary collectins were replaced with D/A were developed by human SP-C promoter-driven overexpression of the D/A gene in SP-A(-/-) and SP-D(-/-) animals. Analysis of lavage fluid from SP-A(-/-,D/A) mice revealed that glycosylated, oligomeric D/A was secreted into the air spaces at levels that were comparable with the authentic collectins and that the N-terminal interchange converted SP-A from a "bouquet" to a cruciform configuration. Transmission electron microscopy of surfactant from the SP-A(-/-,D/A) mice revealed atypical tubular myelin containing central "target-like" electron density. Surfactant isolated from SP-A(-/-,D/A) mice exhibited elevated surface tension both in the presence and absence of plasma inhibitors, but whole lung compliance of the SP-A(-/-,D/A) animals was not different from the SP-A(-/-) littermates. Lung-specific overexpression of D/A in the SPD(-/-) mouse resulted in hetero-oligomer formation with mouse SP-A and did not correct the air space dilation or phospholipidosis that occurs in the absence of SP-D. These studies indicate that the N terminus of SP-D 1) can functionally replace the N terminus of SP-A for lipid aggregation and tubular myelin formation, but not for surface tension lowering properties of SP-A, and 2) is not sufficient to reverse the structural and metabolic pulmonary defects in the SP-D(-/-) mouse.

Animals↗

PubMed2002

Complementation of pulmonary abnormalities in SP-D(-/-) mice with an SP-D/conglutinin fusion protein.

Surfactant protein D (SP-D) and serum conglutinin are closely related members of the collectin family of host defense lectins. Although normally synthesized at different anatomic sites, both proteins participate in the innate immune response to microbial challenge. To discern the roles of specific domains in the function of SP-D in vivo, a fusion protein (SP-D/Cong(neck+CRD)) consisting of the NH(2)-terminal and collagenous domains of rat SP-D (rSP-D) and the neck and carbohydrate recognition domains (CRDs) of bovine conglutinin (Cong) was expressed in the respiratory epithelium of SP-D gene-targeted (SP-D(-/-)) mice. While SP-D/Cong(neck+CRD) fusion protein did not affect lung morphology and surfactant phospholipid levels in the lungs of wild type mice, the chimeric protein substantially corrected the increased lung phospholipids in SP-D(-/-) mice. The SP-D/Cong(neck+CRD) fusion protein also completely corrected defects in influenza A clearance and inhibited the exaggerated inflammatory response that occurs following viral infection. However, the chimeric protein did not ameliorate the ongoing lung inflammation, enhanced metalloproteinase expression, and alveolar destruction that characterize this model of SP-D deficiency. By contrast, a single arm mutant (RrSP-D(Ser15,20)) partially restored antiviral activity but otherwise failed to rescue the deficient phenotype. Our findings directly implicate the CRDs of both SP-D and conglutinin in host defense in vivo. Our findings also strongly suggest that the molecular mechanisms underlying impaired pulmonary host defense and abnormal lipid metabolism are distinct from those that promote ongoing inflammation and the development of emphysema.

Administration, Inhalation↗

PubMed2002

Early gestational intra-amniotic endotoxin: lung function, surfactant, and morphometry.

We determined the effects in preterm lambs of endotoxin-induced inflammation at early gestational ages on lung function and structure and on the surfactant system. Pregnant ewes were randomized to one of five intra-amniotic endotoxin (Escherichia coli 055:B5) groups: 1 mg injected at 60 days of gestation, 1 mg at 80 days, 1 mg at 100 days, 1 mg at 60 days plus 100 days, or 0.6 mg/ day infused from Day 80 to Day 108. Control lambs received saline treatments. At 125 days, lung function was improved in all endotoxin groups. Marked increases in saturated phosphatidylcholine in lung tissue but not alveolar lavage samples were seen in all endotoxin groups except the 60- plus 100-day group. Surfactant protein mRNA and protein pool sizes were affected differently according to the timing of endotoxin treatment, but a large increase in the amount of mature surfactant protein B in alveolar lavage samples was observed in all endotoxin groups. Lung-to-body weight ratio, alveolar number, total surface area, and alveolar wall thickness were reduced by 80- to 108-day endotoxin. Intra-amniotic inflammatory stimuli in early gestation can alter pulmonary development, with the net effect of improving preterm lung function, despite changes in surfactant and lung growth that are similar to changes in the lungs of ventilated animals developing bronchopulmonary dysplasia.

Analysis of Variance↗

PubMed2002

Intratracheal endotoxin causes systemic inflammation in ventilated preterm lambs.

Intratracheal endotoxin causes acute inflammation in the adult lung, and injurious styles of mechanical ventilation can result in systemic inflammation derived from the lungs. We asked how ventilated premature and near-term lungs responded to intratracheal endotoxin and if systemic inflammation occurred. Lambs delivered at 130 d gestational age (GA) were treated with surfactant or surfactant plus endotoxin (0.1 mg/kg or 10 mg/kg) (Escherichia coli, serotype O55:B5) and were ventilated for 6 h. Both endotoxin doses resulted in impaired gas exchange and systemic inflammation in the preterm lambs. Lambs at 141 d GA (term 146 d) were given either 10 mg/kg intratracheal endotoxin, 10 mg/kg endotoxin plus high tidal volume ventilation for the first 30 min of life, or 5 microg/kg endotoxin given intravenously. Endotoxin alone (10 mg/kg) caused lung inflammation but no systemic effects after 6 h of ventilation. Lambs given 10 mg/kg endotoxin plus high tidal volume ventilation or 5 microg/kg endotoxin intravenously had decreased gas exchange and systemic inflammation. Endotoxin was detected in the plasma of lambs at 130 d GA but not at 141 d GA. Inflammation in the lungs was more severe in preterm animals. Mechanical ventilation of the endotoxin-exposed preterm lung resulted in systemic effects at a low endotoxin dose and without high tidal volume ventilation.

Animals↗

PubMed2002

The fetal maturational and inflammatory responses to different routes of endotoxin infusion in sheep.

OBJECTIVES: In clinical practice, chorioamnionitis has been observed to enhance fetal lung maturation in the short term but may predispose to chronic lung disease thereafter. Using the sheep model, we have previously shown that injection of endotoxin into the amniotic cavity results in inflammatory responses and profoundly enhances newborn lung function after preterm birth. The fetus tolerates intra-amniotic doses of endotoxin considerably greater than those that are lethal if given intramuscularly. This study aimed to explore the mechanisms by which endotoxin matures the lungs by determining whether the route of administration influenced the maturational responses of the fetus. STUDY DESIGN: Date-mated ewes at 118 days of pregnancy were allocated at random to receive endotoxin (Escherichia coli lipopolysaccharide 055;B5) directly into the trachea (n = 7), stomach (n = 6), amniotic cavity (n = 7), or peritoneal cavity (n = 4) of the fetal lamb by surgical implantation of an osmotic pump delivering 1 mg of endotoxin over a 24-hour period. Results were compared with those obtained in saline solution-infused controls (n = 9). The lambs were delivered by cesarean section at 125 days' gestation (term is 150 days). RESULTS: Endotoxin infusion into the trachea, stomach, and amniotic cavity each resulted in inflammatory responses in lung fluid and improved postnatal lung function, and effects were similar for each route of administration. These effects occurred with minimal features of systemic inflammation. Intraperitoneal infusion resulted in severe fetal acidosis or death. CONCLUSION: These findings provide further evidence that the lung-maturing effects of intra-amniotic endotoxin are mediated by local factors in the respiratory system rather than by systemic inflammatory responses. Chorioamnionitis may alter lung function and possibly lead to chronic injury without clinical features of systemic inflammation or compromise.

Acidosis↗