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Original Paper

Free Access

Repeated Intrauterine Exposures to Inflammatory Stimuli Attenuated Transforming Growth Factor-β Signaling in the Ovine Fetal Lung

Collins J.J.P.a · Kallapur S.G.b, c · Knox C.L.d · Kemp M.W.c · Kuypers E.a · Zimmermann L.J.I.a · Newnham J.P.c · Jobe A.H.b, c · Kramer B.W.a

Author affiliations

aDepartment of Pediatrics, School of Oncology and Developmental Biology, School of Mental Health and Neuroscience, Maastricht University Medical Center, Maastricht, The Netherlands; bCincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USA; cSchool of Women's and Infant's Health, The University of Western Australia, Perth, W.A., and dInstitute of Health and Biomedical Innovation, Faculty of Health, Queensland University of Technology, Brisbane, Qld., Australia

Corresponding Author

Boris W. Kramer, MD, PhD

Department of Pediatrics, School of Oncology and Developmental Biology

School of Mental Health and Neuroscience, Maastricht University Medical Center

PB 5800, NL-6202 AZ Maastricht (The Netherlands)

E-Mail b.kramer@mumc.nl

Related Articles for ""

Neonatology 2013;104:49-55

Abstract

Background: Bronchopulmonary dysplasia (BPD) is one of the most common complications after preterm birth and is associated with intrauterine exposure to bacteria. Transforming growth factor-β (TGFβ) is implicated in the development of BPD. Objectives: We hypothesized that different and/or multiple bacterial signals could elicit divergent TGFβ signaling responses in the developing lung. Methods: Time-mated pregnant Merino ewes received an intra-amniotic injection of lipopolysaccharide (LPS) and/or Ureaplasma parvum serovar 3 (UP) at 117 days' and/or 121/122 days' gestational age (GA). Controls received an equivalent injection of saline and or media. Lambs were euthanized at 124 days' GA (term = 150 days' GA). TGFβ1, TGFβ2, TGFβ3, TGFβ receptor (R)1 and TGFβR2 protein levels, Smad2 phosphorylation and elastin deposition were evaluated in lung tissue. Results: Total TGFβ1 and TGFβ2 decreased by 24 and 51% after combined UP+LPS exposure, whereas total TGFβ1 increased by 31% after 7 days' LPS exposure but not after double exposures. Alveolar expression of TGFβR2 decreased 75% after UP, but remained unaltered after double exposures. Decreased focal elastin deposition after single LPS exposure was prevented by double exposures. Conclusions: TGFβ signaling components and elastin responded differently to intrauterine LPS and UP exposure. Multiple bacterial exposures attenuated TGFβ signaling and normalized elastin deposition.

© 2013 S. Karger AG, Basel


Background

Bronchopulmonary dysplasia (BPD), one of the most common adverse outcomes after extremely preterm birth, is characterized by arrested alveolar development resulting in fewer but larger alveoli [1]. The development of BPD is associated with pulmonary inflammation, which may result from antenatal exposure to pathogens associated with chorioamnionitis [2]. Although many different microbes have been identified in amniotic fluid [3], the most common bacteria found in the placenta and membranes of preterm infants are Ureaplasma spp. [4]. Culture-positive placental tissue of 41% of preterm neonates delivered before 27 weeks was however polymicrobial [5]. It is unclear how this exposure to multiple bacteria affects the fetal immune response and which Toll-like receptors (TLR) process their signals. A single inflammatory and immunologic trigger will elicit variable fetal inflammatory responses in several animal models, including fetal baboons, rhesus macaques and sheep [6,7,8,9]. Interestingly, repeated exposure to lipopolysaccharide (LPS) in fetal sheep induced tolerance to a second challenge with LPS in blood and lung monocytes and suppressed TLR2, 4, 5 and 9 signaling [10]. Recently, we reported that the fetal immune response to LPS was only suppressed by a long, but not short, intra-amniotic (IA) exposure to ureaplasmas in fetal sheep [11]. The interactions of the immune system with both ureaplasmas and LPS may be complex, as each is recognized by different TLRs. LPS, a cell wall component of Gram-negative bacteria, activates TLR4 by binding to the CD14 receptor, which in turn triggers myeloid differentiation factor-88 (MyD88)-dependent and -independent pathways [12]. In contrast, Ureaplasma spp. activate TLR1, 2 and 6 with cell membrane-associated lipoproteins, as they lack a cell wall [13].

The links between inflammation and arrested alveolar development are a focus of ongoing experimental and clinical studies. Transforming growth factor-β (TGFβ), an anti-inflammatory cytokine, has an ambiguous role in the pathogenesis of BPD, as it is also a growth factor for lung development and repair [14]. TGFβ is expressed in three functionally distinct isoforms, TGFβ1, TGFβ2 and TGFβ3, and is produced in a latent form which is cleaved to be activated [14]. TGFβ1 and 2 are needed for surfactant production and postnatal respiratory function, whereas TGFβ3-/- mice showed severe alveolar hypoplasia [14]. Inflammation-mediated changes in TGFβ activity may contribute to the arrested alveolar development leading to BPD [2]. Because chorioamnionitis is frequently polymicrobial, we hypothesized that different and/or multiple bacterial signals could elicit divergent TGFβ signaling responses in the developing lung. We used models of chorioamnionitis [6,11,15] in which fetal sheep received short-term IA exposures of LPS or U. parvum serovar 3 (UP), or both. Expression and activation of TGFβ1, 2 and 3 and their main receptors, TGFβ receptors 1 and 2, were measured in fetal lungs. Intracellular activation of the canonical TGFβ signaling pathway was assessed by phosphorylation of mothers against decapentaplegic homolog 2 (Smad2; pSmad2 when phosphorylated), a signal transducer following coupling and activation of TGFβ receptors 1 and 2 [14]. Focal elastin deposition, crucial for secondary septation [16], was quantified to assess alveolar development.

Methods

Animal Model

Studies were approved by the Animal Ethics Committees at The University of Western Australia and at the Cincinnati Children's Hospital Medical Center. The description of the animals has previously been published [6,11,15]. Briefly, ureaplasmas were cultured and prepared for the IA injections as reported [6]. Time-mated Merino ewes with singleton fetuses were randomized to ultrasound-guided IA injection of either (2 × 107 colony-forming units) UP at 117 or 121 days' gestational age (GA) and/or an IA injection of LPS (10 mg Escherichia coli 055:B5; Sigma Chemical, St. Louis, Mo., USA) at 117 and/or 122 days' GA (fig. 1). Controls were injected with either saline or 10B media inoculums [6]. Preterm lambs were delivered and euthanized at 124 days' GA (term = 150 days' GA). Tissue from the right lower lobe of the lung was snap frozen and the right upper lobe was inflation-fixed at 30 cm H2O in 10% buffered formalin for 24 h.

Fig. 1

Study design. d = Day.

http://www.karger.com/WebMaterial/ShowPic/170844

ELISA of TGFβ1, TGFβ2 and TGFβ3

Frozen right lower lobe tissue was homogenized (PRO Quick Connect Generators part No. 02-07095; PRO Scientific Inc., Oxford, Conn., USA) in ice-cold RIPA buffer (Sigma-Aldrich) containing 0.1% protease inhibitors (Sigma-Aldrich) and subsequently centrifuged at 12 rcf for 5 min at 4°C [17]. Free, bound and total TGFβ1, TGFβ2 and TGFβ3 (referred to by R&D Systems as active, latent and total TGFβ) were measured with ELISA kits (human TGFβ1: DY240, human TGFβ2: DY302, human TGFβ3: DY243; R&D Systems, Minneapolis, Minn., USA) according to the manufacturer's instructions [17]. TGFβ1 and TGFβ2 protein concentrations were calculated per kilogram body weight and reported as a mean fold change compared to controls.

Immunohistochemistry

Paraffin-embedded right upper lobe sections (4 µm, transverse) were stained for TGFβ receptor 1 (TGFβR1) (ab31013; Abcam, Cambridge, UK), TGFβ receptor 2 (TGFβR2) (ab28382; Abcam) and pSmad2 (Ser465/467) (#3101; Cell Signaling Technology, Boston, Mass., USA). Sections were deparaffinized and endogenous peroxidase activity was blocked with 0.3% H2O2 in 1× PBS (pH 7.4) (for TGFβR1 and 2) or 3% H2O2 in milli-Q (for pSmad2). Antigen retrieval was performed with heated citrate buffer (10 mM, pH 6.0). Non-specific binding was blocked with 20% normal goat serum (NGS) in PBS (for TGFβR1 and 2) or 5% NGS in 1× Tris-buffered saline (TBS, pH 7.6) with 0.1% Tween (for pSmad2). Sections were incubated at 4°C with the primary antibody (TGFβR1: 1/100, TGFβR2: 1/500, pSmad2: 1/2,000). After incubation with the secondary antibody (swine-anti-rabbit Ig*biotin, E0353; Dako, Glostrup, Denmark), immunostaining was enhanced with Vectastain ABC peroxidase Elite kit (PK-6200; Vector Laboratories, Burlingame, Calif., USA) and visualized with nickel sulfate-diaminobenzidine (NiDAB). The sections were rinsed and incubated with Tris/cobalt. After counterstaining with 0.1% Nuclear Fast Red, sections were washed, dehydrated and coverslipped.

Evaluation was performed by light microscopy (Axioskop 40; Zeiss, Göttingen, Germany) with LeicaQWin Pro v.3.4.0 software (Leica Microsystems, Wetzlar, Germany). For each animal three random locations of the section were photographed at 200× and 400× magnification. Sections were semiquantitatively scored for positive TGFβR1, TGFβR2 and pSmad2 by ranking all sections by ascending staining intensity by a blinded observer. The scores of each experimental group were standardized to the average score of controls.

Elastin Staining

Elastin staining was performed on right upper lobe lung sections as described [6]. Elastin foci were counted using ImageJ software (W.S. Rasband, ImageJ; US National Institutes of Health, Bethesda, Md., USA) [6], corrected for photomicrograph surface area, and expressed as elastin foci/mm2. The values of each experimental group were standardized to the average value of controls. Results for 3- and 7-day Ureaplasma exposure were reported previously [6].

Data Analysis

Results of ELISAs are given as means ± SEM; results of immunohistochemical and histological stainings are given as median with interquartile range. For ELISAs, groups were compared using one-way ANOVA with Dunnett's test for post hoc analysis. Two group comparisons were done by Student's t test. For all immunohistochemical and histological analyses, groups were compared using a Kruskal-Wallis one-way ANOVA with Dunn's test for post hoc analysis. Two group comparisons were done by Mann-Whitney test. Statistical analysis was performed by GraphPad Prism v.5.0. Significance was accepted at p < 0.05.

Results

Modulated Expression of TGFβ Signaling Components after Single IA LPS Injection

After LPS exposure, protein levels of TGFβ2 slightly decreased at 2 days compared to controls, a result not reaching statistical significance (p = 0.0516 for total TGFβ2) (table 1). This was accompanied by a trend towards increased alveolar TGFβR2. The focal expression of elastin on secondary septa also decreased (table 1).

Table 1

Effect of single and repeat LPS exposures on TGFβ pathway components and elastin deposition

http://www.karger.com/WebMaterial/ShowPic/170847

Seven days after LPS exposure there were increases in free and total TGFβ1 and 2 levels, which was only significant for total TGFβ1. In contrast, the alveolar expression of both TGFβ receptors, pSmad2 and elastin foci were not significantly different from controls. No TGFβ3 could be detected by ELISA in protein extracts of the lungs of any lambs (data not shown).

Repeated LPS Exposure Did Not Affect TGFβ Expression and Signaling

Free and total TGFβ1 and free TGFβ2 levels in the lungs of fetal lambs exposed to repeated LPS were not significantly different from those in controls (table 1). Total TGFβ2 levels however were decreased, similar to single 2-day LPS exposure, reaching a p value of 0.0516 (table 1). The intensity of both TGFβ receptors and pSmad2 was not significantly different from controls (table 1). In contrast to single 2-day LPS exposure, elastin foci were not significantly decreased (table 1).

Fetal Colonization with UP Did Not Consistently Affect TGFβ Pathway Members

Three days after IA UP injection, levels of both free and total TGFβ1 and 2 remained unaffected, with no sign of pathway activity as indicated by pSmad2 (table 2). Contrasting with a single LPS injection after a similar exposure time, there was a steep decline of TGFβR2, whereas TGFβR1 immunointensity was unchanged. Focal elastin deposition was not significantly altered.

Table 2

Effect of single UV exposures on TGFβ pathway components and elastin deposition

http://www.karger.com/WebMaterial/ShowPic/170846

After an incubation of 7 days, none of the tested pathway members differed significantly from levels in the lungs of controls.

Simultaneous Exposure to LPS and UP Lowered TGFβ Pathway Components

Levels of free TGFβ1 and TGFβ2 were unchanged compared to controls after sequential exposure to UP and LPS, despite a marked decrease in levels of total TGFβ1 and TGFβ2 (table 3). Downstream of TGFβ, intensity of TGFβR1 and 2 and pSmad2 was not significantly different from controls. Likewise, the density of elastin foci on secondary septa was not significantly changed.

Table 3

Effect of simultaneous exposure to UP and LPS on TGFβ pathway components and elastin deposition

http://www.karger.com/WebMaterial/ShowPic/170845

Discussion

When infants are diagnosed with BPD at 28 days' or 36 weeks' GA [1], their lungs have been exposed to various potentially damaging situations. Epidemiological studies however suggest that infants exposed to intrauterine inflammation are more likely to develop BPD, but do not provide information why their lungs are more susceptible [18]. Increased TGFβ1 levels were identified as a marker for the development of BPD in the bronchoalveolar lavage of preterm babies [19]. Whether intrauterine inflammation caused this increase in TGFβ1 levels associated with BPD remains unclear, as clinical findings on this matter are inconsistent [20,21]. Because a variety of bacteria can induce chorioamnionitis, the nature of the intrauterine inflammation may vary. We therefore injected LPS, ureaplasmas or both to determine their effects on the TGFβ expression profile in the fetal ovine lung.

There were very different outcomes for TGFβ signaling after LPS exposure when compared to ureaplasmas. Ureaplasma exposure, which caused a modest inflammatory response in fetal sheep lungs [6], only caused a marked decrease in TGFβR2 expression. In contrast, total TGFβ1 increased after LPS exposure, a stimulus which induced the immune system [15]. These effects were not apparent in lungs that were exposed to LPS twice. Remarkably, sequential exposures to ureaplasmas and LPS, decreased total TGFβ1 and 2. Elastin foci were only decreased after single LPS exposure, but not after continuous UP or sequential exposures.

The clinical implication of these findings remains to be shown. Clinical findings suggest that in utero exposure to inflammation decreases the risk of chronic lung disease and sepsis [22]. It is unclear by which mechanisms this protection is mediated but the responsiveness of immune cells may play a role. We previously showed that fetal lung exposure to inflammation matured monocytes to alveolar macrophages with adult functional properties [23]. The role and function of this cell population remains to be determined. ‘Mature' alveolar macrophages can provide a better protection against infectious agents, but can also initiate an inflammatory response after mechanical ventilation by activating TGFβ for example [14]. The outcome reported here is highly reminiscent of the immune tolerance seen in fetal lung and blood monocytes after repeated LPS exposure, in which subsequent exposure to different bacterial agents failed to elicit a second inflammatory response [10,24]. It is therefore possible that the decreased or lack of involvement of TGFβ pathway components is a direct result of immune tolerance triggered by the repeated exposures.

TGFβ is implicated in the pathogenesis of BPD, but our data underline the multifactorial character of this process. Intrauterine inflammation by itself may not lead to the high levels of TGFβ as seen in BPD, but it could very well prime the fetal lung for future responses. All clinical data are based on samples obtained from ventilated infants. A frequent second hit like ventilation-induced injury, postnatal sepsis or respiratory infection, could trigger an exaggerated TGFβ response leading to BPD [25]. Antenatally, the duration of bacterial exposure might also influence pulmonary TGFβ induction. Lungs of preterm lambs exposed to ureaplasmas for 70 days, with or without additional acute LPS exposure, contained over tenfold higher total TGFβ1 levels [11]. This suggests that long-term colonization with Ureaplasma spp. of the IA pulmonary environment could well cause the elevated TGFβ levels at birth in children that later develop BPD [19]. Whether other Gram-negative or -positive bacteria associated with chorioamnionitis would elicit a similar increase in TGFβ expression remains to be elucidated.

Although our study underlines that multiple microbial exposures may have an attenuating effect on TGFβ signaling, it is subject to several limitations. Firstly, our study only looked at the effect of antenatal inflammation on TGFβ signaling in fetal lung tissue. We could not replicate the dramatic postnatal increase in TGFβ found in preterm infants developing BPD. We would therefore like to stress that the results presented here cannot be readily translated into the clinical reality. Further mechanical and clinical studies must be done to validate the significance of our findings, in which special attention should be given to the role of TGFβ2 and TGFβR2. Secondly, some of our results currently only show trends, and are not statistically significant. The authors feel that these results are nonetheless biologically relevant, as they are probably a result of the small group sizes that are inherent for this large animal model.

In conclusion, this study shows that TGFβ signaling components responded differently to intrauterine LPS and Ureaplasma exposure, but were decreased after exposure to both LPS and ureaplasmas. Contrary to observations after single exposures, focal elastin deposition was unchanged after exposure to two inflammatory mediators. This outcome may be the result of fetal immune tolerance after multiple bacterial exposures.

Acknowledgments

The authors thank Samantha Dando, Carryn McLean, Andrea Lee, Richard Dalton, Eva Schwaiger, Jennifer Henderson, Shaofu Li, Masatoshi Saito, Nico Kloosterboer, Leon Janssen and Sanne Lievense for their excellent technical support in the generation of this data. In addition, we would like to thank Jasper V. Been for his statistical advice.

This study was supported by NIH R-01 HL97064 (to A.H.J. and S.G.K.) and HD-57869 (to S.G.K.) from the National Institute of Health (NIH), USA, the National Health and Medical Research Council of Australia, the Women and Infants' Research Foundation, W.A., Australia, Veni BWK 016.096.141 from the Dutch Scientific Research Organization and the Research School for Oncology and Developmental Biology (GROW), Maastricht University.

Disclosure Statement

The authors have no conflicts of interest to disclose.


References

  1. Jobe AH, Bancalari E: Bronchopulmonary dysplasia. Am J Respir Crit Care Med 2001;163:1723-1729.
  2. Speer CP: Inflammation and bronchopulmonary dysplasia. Semin Neonatol 2003;8:29-38.
  3. DiGiulio DB, Romero R, Kusanovic JP, Gomez R, Kim CJ, Seok KS, Gotsch F, Mazaki-Tovi S, Vaisbuch E, Sanders K, Bik EM, Chaiworapongsa T, Oyarzun E, Relman DA: Prevalence and diversity of microbes in the amniotic fluid, the fetal inflammatory response, and pregnancy outcome in women with preterm pre-labor rupture of membranes. Am J Reprod Immunol 2010;64:38-57.
  4. Yoon BH, Romero R, Park JS, Chang JW, Kim YA, Kim JC, Kim KS: Microbial invasion of the amniotic cavity with Ureaplasma urealyticum is associated with a robust host response in fetal, amniotic, and maternal compartments. Am J Obstet Gynecol 1998;179:1254-1260.
  5. Onderdonk AB, Delaney ML, DuBois AM, Allred EN, Leviton A: Detection of bacteria in placental tissues obtained from extremely low gestational age neonates. Am J Obstet Gynecol 2008;198:110.e1-e7.
  6. Collins JJ, Kallapur SG, Knox CL, Nitsos I, Polglase GR, Pillow JJ, Kuypers E, Newnham JP, Jobe AH, Kramer BW: Inflammation in fetal sheep from intra-amniotic injection of Ureaplasma parvum. Am J Physiol Lung Cell Mol Physiol 2010;299:L852-L860.
  7. Novy MJ, Duffy L, Axthelm MK, Sadowsky DW, Witkin SS, Gravett MG, Cassell GH, Waites KB: Ureaplasma parvum or Mycoplasma hominis as sole pathogens cause chorioamnionitis, preterm delivery, and fetal pneumonia in rhesus macaques. Reprod Sci 2009;16:56-70.
  8. Viscardi RM, Atamas SP, Luzina IG, Hasday JD, He JR, Sime PJ, Coalson JJ, Yoder BA: Antenatal Ureaplasma urealyticum respiratory tract infection stimulates proinflammatory, profibrotic responses in the preterm baboon lung. Pediatr Res 2006;60:141-146.
  9. Kramer BW, Moss TJ, Willet KE, Newnham JP, Sly PD, Kallapur SG, Ikegami M, Jobe AH: Dose and time response after intra-amniotic endotoxin in preterm lambs. Am J Respir Crit Care Med 2001;164:982-988.
  10. Kramer BW, Kallapur SG, Moss TJ, Nitsos I, Newnham JP, Jobe AH: Intra-amniotic LPS modulation of TLR signaling in lung and blood monocytes of fetal sheep. Innate Immun 2009;15:101-107.
  11. Kallapur SG, Kramer BW, Knox CL, Berry CA, Collins JJ, Kemp MW, Nitsos I, Polglase GR, Robinson J, Hillman NH, Newnham JP, Chougnet C, Jobe AH: Chronic fetal exposure to Ureaplasma parvum suppresses innate immune responses in sheep. J Immunol 2011;187:2688-2695.
  12. Elgert KD: Immunology: Understanding the Immune System, ed 2. Hoboken/NJ, Wiley-Blackwell, 2009.
  13. Shimizu T, Kida Y, Kuwano K: Ureaplasma parvum lipoproteins, including MB antigen, activate NF-κB through TLR1, TLR2 and TLR6. Microbiology 2008;154:1318-1325.
  14. Bartram U, Speer CP: The role of transforming growth factor-β in lung development and disease. Chest 2004;125:754-765.
  15. Kallapur SG, Jobe AH, Ball MK, Nitsos I, Moss TJ, Hillman NH, Newnham JP, Kramer BW: Pulmonary and systemic endotoxin tolerance in preterm fetal sheep exposed to chorioamnionitis. J Immunol 2007;179:8491-8499.
    External Resources
  16. Burri PH: Structural aspects of postnatal lung development - alveolar formation and growth. Biol Neonate 2006;89:313-322.
  17. Lee AJ, Lambermont VA, Pillow JJ, Polglase GR, Nitsos I, Newnham JP, Beilharz MW, Kallapur SG, Jobe AH, Kramer BW: Fetal responses to lipopolysaccharide-induced chorioamnionitis alter immune and airway responses in 7-week-old sheep. Am J Obstet Gynecol 2011;204:364 e317-e324.
  18. Hartling L, Liang Y, Lacaze-Masmonteil T: Chorioamnionitis as a risk factor for bronchopulmonary dysplasia: A systematic review and meta-analysis. Arch Dis Child Fetal Neonatal Ed 2012;97:F8-F17.
  19. Masterson JC, Molloy EL, Gilbert JL, McCormack N, Adams A, O'Dea S: Bone morphogenetic protein signalling in airway epithelial cells during regeneration. Cell Signal 2011;23:398-406.
  20. Been JV, Debeer A, van Iwaarden JF, Kloosterboer N, Passos VL, Naulaers G, Zimmermann LJ: Early alterations of growth factor patterns in bronchoalveolar lavage fluid from preterm infants developing bronchopulmonary dysplasia. Pediatr Res 2010;67:83-89.
  21. Ichiba H, Saito M, Yamano T: Amniotic fluid transforming growth factor-β1 and the risk for the development of neonatal bronchopulmonary dysplasia. Neonatology 2009;96:156-161.
  22. Lahra MM, Beeby PJ, Jeffery HE: Intrauterine inflammation, neonatal sepsis, and chronic lung disease: a 13-year hospital cohort study. Pediatrics 2009;123:1314-1319.
  23. Kramer BW, Joshi SN, Moss TJ, Newnham JP, Sindelar R, Jobe AH, Kallapur SG: Endotoxin-induced maturation of monocytes in preterm fetal sheep lung. Am J Physiol Lung Cell Mol Physiol 2007;293:L345-L353.
  24. Azizia M, Lloyd J, Allen M, Klein N, Peebles D: Immune status in very preterm neonates. Pediatrics 2012;129:e967-e974.
  25. Van Marter LJ, Dammann O, Allred EN, Leviton A, Pagano M, Moore M, Martin C: Chorioamnionitis, mechanical ventilation, and postnatal sepsis as modulators of chronic lung disease in preterm infants. J Pediatr 2002;140:171-176.

Author Contacts

Boris W. Kramer, MD, PhD

Department of Pediatrics, School of Oncology and Developmental Biology

School of Mental Health and Neuroscience, Maastricht University Medical Center

PB 5800, NL-6202 AZ Maastricht (The Netherlands)

E-Mail b.kramer@mumc.nl


Article / Publication Details

First-Page Preview
Abstract of Original Paper

Received: October 23, 2012
Accepted: March 01, 2013
Published online: May 24, 2013
Issue release date: July 2013

Number of Print Pages: 7
Number of Figures: 1
Number of Tables: 3

ISSN: 1661-7800 (Print)
eISSN: 1661-7819 (Online)

For additional information: http://www.karger.com/NEO


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References

  1. Jobe AH, Bancalari E: Bronchopulmonary dysplasia. Am J Respir Crit Care Med 2001;163:1723-1729.
  2. Speer CP: Inflammation and bronchopulmonary dysplasia. Semin Neonatol 2003;8:29-38.
  3. DiGiulio DB, Romero R, Kusanovic JP, Gomez R, Kim CJ, Seok KS, Gotsch F, Mazaki-Tovi S, Vaisbuch E, Sanders K, Bik EM, Chaiworapongsa T, Oyarzun E, Relman DA: Prevalence and diversity of microbes in the amniotic fluid, the fetal inflammatory response, and pregnancy outcome in women with preterm pre-labor rupture of membranes. Am J Reprod Immunol 2010;64:38-57.
  4. Yoon BH, Romero R, Park JS, Chang JW, Kim YA, Kim JC, Kim KS: Microbial invasion of the amniotic cavity with Ureaplasma urealyticum is associated with a robust host response in fetal, amniotic, and maternal compartments. Am J Obstet Gynecol 1998;179:1254-1260.
  5. Onderdonk AB, Delaney ML, DuBois AM, Allred EN, Leviton A: Detection of bacteria in placental tissues obtained from extremely low gestational age neonates. Am J Obstet Gynecol 2008;198:110.e1-e7.
  6. Collins JJ, Kallapur SG, Knox CL, Nitsos I, Polglase GR, Pillow JJ, Kuypers E, Newnham JP, Jobe AH, Kramer BW: Inflammation in fetal sheep from intra-amniotic injection of Ureaplasma parvum. Am J Physiol Lung Cell Mol Physiol 2010;299:L852-L860.
  7. Novy MJ, Duffy L, Axthelm MK, Sadowsky DW, Witkin SS, Gravett MG, Cassell GH, Waites KB: Ureaplasma parvum or Mycoplasma hominis as sole pathogens cause chorioamnionitis, preterm delivery, and fetal pneumonia in rhesus macaques. Reprod Sci 2009;16:56-70.
  8. Viscardi RM, Atamas SP, Luzina IG, Hasday JD, He JR, Sime PJ, Coalson JJ, Yoder BA: Antenatal Ureaplasma urealyticum respiratory tract infection stimulates proinflammatory, profibrotic responses in the preterm baboon lung. Pediatr Res 2006;60:141-146.
  9. Kramer BW, Moss TJ, Willet KE, Newnham JP, Sly PD, Kallapur SG, Ikegami M, Jobe AH: Dose and time response after intra-amniotic endotoxin in preterm lambs. Am J Respir Crit Care Med 2001;164:982-988.
  10. Kramer BW, Kallapur SG, Moss TJ, Nitsos I, Newnham JP, Jobe AH: Intra-amniotic LPS modulation of TLR signaling in lung and blood monocytes of fetal sheep. Innate Immun 2009;15:101-107.
  11. Kallapur SG, Kramer BW, Knox CL, Berry CA, Collins JJ, Kemp MW, Nitsos I, Polglase GR, Robinson J, Hillman NH, Newnham JP, Chougnet C, Jobe AH: Chronic fetal exposure to Ureaplasma parvum suppresses innate immune responses in sheep. J Immunol 2011;187:2688-2695.
  12. Elgert KD: Immunology: Understanding the Immune System, ed 2. Hoboken/NJ, Wiley-Blackwell, 2009.
  13. Shimizu T, Kida Y, Kuwano K: Ureaplasma parvum lipoproteins, including MB antigen, activate NF-κB through TLR1, TLR2 and TLR6. Microbiology 2008;154:1318-1325.
  14. Bartram U, Speer CP: The role of transforming growth factor-β in lung development and disease. Chest 2004;125:754-765.
  15. Kallapur SG, Jobe AH, Ball MK, Nitsos I, Moss TJ, Hillman NH, Newnham JP, Kramer BW: Pulmonary and systemic endotoxin tolerance in preterm fetal sheep exposed to chorioamnionitis. J Immunol 2007;179:8491-8499.
    External Resources
  16. Burri PH: Structural aspects of postnatal lung development - alveolar formation and growth. Biol Neonate 2006;89:313-322.
  17. Lee AJ, Lambermont VA, Pillow JJ, Polglase GR, Nitsos I, Newnham JP, Beilharz MW, Kallapur SG, Jobe AH, Kramer BW: Fetal responses to lipopolysaccharide-induced chorioamnionitis alter immune and airway responses in 7-week-old sheep. Am J Obstet Gynecol 2011;204:364 e317-e324.
  18. Hartling L, Liang Y, Lacaze-Masmonteil T: Chorioamnionitis as a risk factor for bronchopulmonary dysplasia: A systematic review and meta-analysis. Arch Dis Child Fetal Neonatal Ed 2012;97:F8-F17.
  19. Masterson JC, Molloy EL, Gilbert JL, McCormack N, Adams A, O'Dea S: Bone morphogenetic protein signalling in airway epithelial cells during regeneration. Cell Signal 2011;23:398-406.
  20. Been JV, Debeer A, van Iwaarden JF, Kloosterboer N, Passos VL, Naulaers G, Zimmermann LJ: Early alterations of growth factor patterns in bronchoalveolar lavage fluid from preterm infants developing bronchopulmonary dysplasia. Pediatr Res 2010;67:83-89.
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