Systemic fetal inflammation and reduced concentrations of macrophage migration inhibitory factor in tracheobronchial aspirate fluid of extremely premature infants
Macrophage migration inhibitory factor is a proinflammatory mediator of innate immunity, enhances cell growth, and plays a role in preterm delivery. We speculated that funisitis, reflecting fetal systemic inflammation, would be associated with higher concentrations of macrophage migration inhibitory factor in airways of extremely premature infants.
We measured macrophage migration inhibitory factor by enzyme linked immunosorbent assay in tracheobronchial aspirate fluid of 35 ventilated infants less than 30 weeks' gestational age, throughout the first week of life. Three groups were distinguished histologically: chorioamnionitis, funisitis, and control.
Unexpectedly, funisitis was associated with significantly decreased macrophage migration inhibitory factor in tracheobronchial aspirate fluid on day 1 (P < .01) and levels remained lower than in the chorioamnionitis group thereafter. For the 35 patients in total, macrophage migration inhibitory factor steadily declined.
Decreased macrophage migration inhibitory factor concentrations in airways of extremely premature infants with systemic fetal inflammation early in life might predispose them to pulmonary infection and interfere with maturation of the lung, contributing to adverse pulmonary outcome.
Available from: Mansoor Syed
- "We previously reported that fetal murine lungs deficient in the growth regulatory and inflammatory cytokine, macrophage migration inhibitory factor (MIF), show impaired lung maturation . In addition, human infants who have adverse pulmonary outcome or develop BPD have been reported to have lower tracheal aspirate levels of MIF [2,3] and are more likely to have a low expression MIF allele . The specific role and mechanism of action of MIF in BPD are not known. "
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The role and mechanism of action of MIF in bronchopulmonary dysplasia (BPD) are not known. We hypothesized that increased MIF signaling would ameliorate the pulmonary phenotype of BPD in the mouse lung.
We studied newborn wild type (WT), MIF knockout (MIFKO), and lung MIF transgenic (MIFTG) mice in room air and a BPD model, and examined the effects of administering a small molecule MIF agonist and antagonist. Lung morphometry was performed and mRNA and protein expression of vascular mediators were analyzed.
The pulmonary phenotype of MIFKO and MIFTG mice lungs in room air (RA) and BPD model were comparable to the WT-BPD mice at postnatal (PN) day 14. Vascular endothelial growth factor (VEGF)-A, -R1 and Angiopoietin (Ang)1 mRNA were decreased, and Ang2 increased in the WT-BPD, MIFKO-RA, MIFKO-BPD, MIFTG-RA and MIFTG-BPD mice lungs, compared to appropriate controls. The protein expression of Ang1 in the MIFKO-RA was similar to WT-RA, but decreased in MIFTG-RA, and decreased in all the BPD groups. Ang2 was increased in MIFKO-RA, MIFTG-RA and in all 3 BPD groups. Tie2 was increased in WT-BPD compared to WT-RA, but decreased in MIFKO- and MIFTG- RA and BPD groups. VEGFR1 was uniformly decreased in MIFKO-RA, MIFTG-RA and in all 3 BPD groups. VEGF-A had a similar expression across all RA and BPD groups. There was partial recovery of the pulmonary phenotype in the WT-BPD model treated with the MIF agonist, and in the MIFTG mice treated with the MIF antagonist.
These data point to the careful regulatory balance exerted by MIF in the developing lung and response to hyperoxia and support the potential therapeutic value of small molecule MIF modulation in BPD.
Respiratory research 02/2013; 14(1):27. DOI:10.1186/1465-9921-14-27 · 3.09 Impact Factor
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ABSTRACT: A systemic inflammatory response of the fetus, reflected by histologic funisitis, is a risk factor for bronchopulmonary dysplasia (BPD). Impaired pulmonary angiogenesis accompanied by simplification and rarification of alveoli is a histologic hallmark of BPD. Angiopoietin-1 mediates vascular development, maturation, and stabilization. Endostatin mainly acts as an angiostatic factor. We hypothesized that funisitis was associated with changes of endostatin and angiopoietin-1 concentrations in the airways and that an imbalance between the factors might be associated with BPD or death. We measured concentrations of angiopoietin-1 and endostatin by enzyme-linked immunosorbent assay in tracheobronchial aspirate fluid samples of 42 ventilated preterm infants during postnatal days 1 through 15. The secretory component for IgA served as reference protein. A standardized histologic examination was used to distinguish three groups: chorioamnionitis, funisitis, and controls without inflammation. Concentrations of the mediators steadily decreased. Funisitis was associated with lower concentrations of both proteins, which might impair their physiologic activities in pulmonary angiogenesis. An increase of the ratio angiopoietin-1/endostatin until day 7 of life indicated a shift of the mediators potentially favoring angiogenesis. However, infants, who developed BPD or died, had a decreased ratio on days 1, 3, and 15, suggesting an imbalance toward inhibition of pulmonary angiogenesis.
Pediatric Research 04/2009; 65(4):468-73. DOI:10.1203/PDR.0b013e3181991f35 · 2.31 Impact Factor
Available from: Máximo Vento
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ABSTRACT: An increasing body of evidence has revealed that interventions performed during resuscitation of extremely-low-gestational-age neonates (ELGANs) may have a direct influence on the immediate survival and also on long-term morbidity. It has been proposed that interventions in the delivery room and/or hypothermia could trigger changes constitutive of chronic lung disease. New approaches in the first minutes of life using more gentle parameters of intervention are being studied. Thus, titrating inspiratory fraction of oxygen, the use of non-invasive ventilation to reduce trauma to the lung, the use of polyethylene/polyurethane wrapping to avoid hypothermia and delaying cord clamping altogether constitute promising initiatives. The first minutes of life are a valuable window for intervention. However, whilst these practice changes make sense and there are emerging data to support them, further evidence including long-term follow up is needed to definitively change resuscitation procedures in ELGANs.
Neonatology 06/2009; 95(4):286-98. DOI:10.1159/000178770 · 2.65 Impact Factor
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