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Deleted in Malignant Brain Tumors 1 (DMBT1) is present in hyaline membranes and modulates surface tension of surfactant.

Müller H, End C, Renner M, Helmke BM, Gassler N, Weiss C, Hartl D, Griese M, Hafner M, Poustka A, Mollenhauer J, Poeschl J - Respir. Res. (2007)

Bottom Line: The effect of human recombinant DMBT1 on the function of bovine and porcine surfactant was measured by a capillary surfactometer.In vitro addition of human recombinant DMBT1 to the surfactants increased surface tension in a dose-dependent manner.The DMBT1-mediated effect was reverted by the addition of calcium depending on the surfactant preparation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Neonatology, Department of Pediatrics, University of Heidelberg, Im Neuenheimer Feld 153, 69120 Heidelberg, Germany. Hanna.Mueller@med.uni-heidelberg.de

ABSTRACT

Background: Deleted in Malignant Brain Tumors 1 (DMBT1) is a secreted scavenger receptor cysteine-rich protein that binds various bacteria and is thought to participate in innate pulmonary host defense. We hypothesized that pulmonary DMBT1 could contribute to respiratory distress syndrome in neonates by modulating surfactant function.

Methods: DMBT1 expression was studied by immunohistochemistry and mRNA in situ hybridization in post-mortem lungs of preterm and full-term neonates with pulmonary hyaline membranes. The effect of human recombinant DMBT1 on the function of bovine and porcine surfactant was measured by a capillary surfactometer. DMBT1-levels in tracheal aspirates of ventilated preterm and term infants were determined by ELISA.

Results: Pulmonary DMBT1 was localized in hyaline membranes during respiratory distress syndrome. In vitro addition of human recombinant DMBT1 to the surfactants increased surface tension in a dose-dependent manner. The DMBT1-mediated effect was reverted by the addition of calcium depending on the surfactant preparation.

Conclusion: Our data showed pulmonary DMBT1 expression in hyaline membranes during respiratory distress syndrome and demonstrated that DMBT1 increases lung surface tension in vitro. This raises the possibility that DMBT1 could antagonize surfactant supplementation in respiratory distress syndrome and could represent a candidate target molecule for therapeutic intervention in neonatal lung disease.

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DMBT1 expression in hyaline membranes. Analysis of DMBT1 expression in post-mortem lung sections of preterm infants. Binding of anti-DMBT1p84 displayed as red staining (arrows). (A) Lung section of a preterm infant born at 23 weeks of gestation without infection, who died at the same day because of primary surfactant deficiency and shock after resuscitation, illustrating respiratory DMBT1 expression in hyaline membranes. (B) Lung section of a neonate with primary surfactant deficiency born at 28 weeks and dying on day 2 without infection, which demonstrates DMBT1 expression in hyaline membranes. (C) Higher lung magnification of (B). (D) Lung tissue of a preterm infant with pneumonia born at 27 weeks who died at a gestational age of 28 weeks. (E, F) mRNA in situ hybridization of lung section (D) confirmed the results obtained from immunohistochemical analyses.
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Figure 1: DMBT1 expression in hyaline membranes. Analysis of DMBT1 expression in post-mortem lung sections of preterm infants. Binding of anti-DMBT1p84 displayed as red staining (arrows). (A) Lung section of a preterm infant born at 23 weeks of gestation without infection, who died at the same day because of primary surfactant deficiency and shock after resuscitation, illustrating respiratory DMBT1 expression in hyaline membranes. (B) Lung section of a neonate with primary surfactant deficiency born at 28 weeks and dying on day 2 without infection, which demonstrates DMBT1 expression in hyaline membranes. (C) Higher lung magnification of (B). (D) Lung tissue of a preterm infant with pneumonia born at 27 weeks who died at a gestational age of 28 weeks. (E, F) mRNA in situ hybridization of lung section (D) confirmed the results obtained from immunohistochemical analyses.

Mentions: The expression of DMBT1 was analyzed in postmortem lung sections of preterm and term infants by immunohistochemistry. DMBT1 expression was found in alveolar epithelial and glandular cells as well as in hyaline membranes of preterm infants with respiratory distress syndrome (RDS) and acute shock lung, and in hyaline membranes of term infants with acute shock lungs. Parallel treatments of consecutive lung sections with a DMBT1-specific monoclonal antibody (anti-DMBT1h12) and a DMBT1-specific polyclonal antiserum (anti-DMBT1p84) revealed similar staining patterns of respiratory epithelia cells and glands. The monoclonal antibody anti-DMBT1h12 gave stronger staining signals in epithelial cells, whereas the usage of anti-DMBT1p84 resulted in stronger staining signals of respiratory glands and mucus. In situ hybridizations confirmed the observed expression patterns. DMBT1 mainly localize on the cell surface, i.e. below/above the surfactant layer. Figure 1, panels A, B and C, show lung sections of two preterm infants (no. 1; no. 4 of table 1) who died from severe hyaline membrane disease without infection. DMBT1 expression was found in the hyaline membranes illustrated in the lung section of a preterm infant with primary surfactant deficiency and shock (Fig. 1A) as well as in the lung sections of a preterm infant with RDS caused by primary surfactant deficiency (Fig. 1B, 1C). Figure 1D presents a lung section of a preterm infant born at 27 weeks of gestation (no. 2 of table 1). The infant developed severe bronchopneumonia, surfactant deficiency, and formation of hyaline membranes. The infant received eleven doses of natural bovine surfactant preparation (Alveofact®), but died after 8 days due to bronchopneumonia and pulmonary interstitial emphysema with concomitant respiratory failure. The hyaline membranes stained strongly for DMBT1, which was confirmed by mRNA in situ hybridization revealing corresponding signals in the underlying cells (Fig. 1D – F). In Figure 2 the time course of mechanical ventilation of this preterm infant (no. 2 of table 1) with high DMBT1 levels is presented. High mean airway pressures and different forms of mechanical ventilation (synchronized intermittent mechanical ventilation, high-frequency ventilation) had to be used to reach sufficient oxygenation (Fig. 2). This was accompanied by multiple pneumothoraces and by interstitial emphysema. Multiple applications of surfactant and inhalation of nitric oxide were not able to change this fatal situation. At day 8 the preterm infant died as a consequence of insufficient oxygenation.


Deleted in Malignant Brain Tumors 1 (DMBT1) is present in hyaline membranes and modulates surface tension of surfactant.

Müller H, End C, Renner M, Helmke BM, Gassler N, Weiss C, Hartl D, Griese M, Hafner M, Poustka A, Mollenhauer J, Poeschl J - Respir. Res. (2007)

DMBT1 expression in hyaline membranes. Analysis of DMBT1 expression in post-mortem lung sections of preterm infants. Binding of anti-DMBT1p84 displayed as red staining (arrows). (A) Lung section of a preterm infant born at 23 weeks of gestation without infection, who died at the same day because of primary surfactant deficiency and shock after resuscitation, illustrating respiratory DMBT1 expression in hyaline membranes. (B) Lung section of a neonate with primary surfactant deficiency born at 28 weeks and dying on day 2 without infection, which demonstrates DMBT1 expression in hyaline membranes. (C) Higher lung magnification of (B). (D) Lung tissue of a preterm infant with pneumonia born at 27 weeks who died at a gestational age of 28 weeks. (E, F) mRNA in situ hybridization of lung section (D) confirmed the results obtained from immunohistochemical analyses.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2164949&req=5

Figure 1: DMBT1 expression in hyaline membranes. Analysis of DMBT1 expression in post-mortem lung sections of preterm infants. Binding of anti-DMBT1p84 displayed as red staining (arrows). (A) Lung section of a preterm infant born at 23 weeks of gestation without infection, who died at the same day because of primary surfactant deficiency and shock after resuscitation, illustrating respiratory DMBT1 expression in hyaline membranes. (B) Lung section of a neonate with primary surfactant deficiency born at 28 weeks and dying on day 2 without infection, which demonstrates DMBT1 expression in hyaline membranes. (C) Higher lung magnification of (B). (D) Lung tissue of a preterm infant with pneumonia born at 27 weeks who died at a gestational age of 28 weeks. (E, F) mRNA in situ hybridization of lung section (D) confirmed the results obtained from immunohistochemical analyses.
Mentions: The expression of DMBT1 was analyzed in postmortem lung sections of preterm and term infants by immunohistochemistry. DMBT1 expression was found in alveolar epithelial and glandular cells as well as in hyaline membranes of preterm infants with respiratory distress syndrome (RDS) and acute shock lung, and in hyaline membranes of term infants with acute shock lungs. Parallel treatments of consecutive lung sections with a DMBT1-specific monoclonal antibody (anti-DMBT1h12) and a DMBT1-specific polyclonal antiserum (anti-DMBT1p84) revealed similar staining patterns of respiratory epithelia cells and glands. The monoclonal antibody anti-DMBT1h12 gave stronger staining signals in epithelial cells, whereas the usage of anti-DMBT1p84 resulted in stronger staining signals of respiratory glands and mucus. In situ hybridizations confirmed the observed expression patterns. DMBT1 mainly localize on the cell surface, i.e. below/above the surfactant layer. Figure 1, panels A, B and C, show lung sections of two preterm infants (no. 1; no. 4 of table 1) who died from severe hyaline membrane disease without infection. DMBT1 expression was found in the hyaline membranes illustrated in the lung section of a preterm infant with primary surfactant deficiency and shock (Fig. 1A) as well as in the lung sections of a preterm infant with RDS caused by primary surfactant deficiency (Fig. 1B, 1C). Figure 1D presents a lung section of a preterm infant born at 27 weeks of gestation (no. 2 of table 1). The infant developed severe bronchopneumonia, surfactant deficiency, and formation of hyaline membranes. The infant received eleven doses of natural bovine surfactant preparation (Alveofact®), but died after 8 days due to bronchopneumonia and pulmonary interstitial emphysema with concomitant respiratory failure. The hyaline membranes stained strongly for DMBT1, which was confirmed by mRNA in situ hybridization revealing corresponding signals in the underlying cells (Fig. 1D – F). In Figure 2 the time course of mechanical ventilation of this preterm infant (no. 2 of table 1) with high DMBT1 levels is presented. High mean airway pressures and different forms of mechanical ventilation (synchronized intermittent mechanical ventilation, high-frequency ventilation) had to be used to reach sufficient oxygenation (Fig. 2). This was accompanied by multiple pneumothoraces and by interstitial emphysema. Multiple applications of surfactant and inhalation of nitric oxide were not able to change this fatal situation. At day 8 the preterm infant died as a consequence of insufficient oxygenation.

Bottom Line: The effect of human recombinant DMBT1 on the function of bovine and porcine surfactant was measured by a capillary surfactometer.In vitro addition of human recombinant DMBT1 to the surfactants increased surface tension in a dose-dependent manner.The DMBT1-mediated effect was reverted by the addition of calcium depending on the surfactant preparation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Neonatology, Department of Pediatrics, University of Heidelberg, Im Neuenheimer Feld 153, 69120 Heidelberg, Germany. Hanna.Mueller@med.uni-heidelberg.de

ABSTRACT

Background: Deleted in Malignant Brain Tumors 1 (DMBT1) is a secreted scavenger receptor cysteine-rich protein that binds various bacteria and is thought to participate in innate pulmonary host defense. We hypothesized that pulmonary DMBT1 could contribute to respiratory distress syndrome in neonates by modulating surfactant function.

Methods: DMBT1 expression was studied by immunohistochemistry and mRNA in situ hybridization in post-mortem lungs of preterm and full-term neonates with pulmonary hyaline membranes. The effect of human recombinant DMBT1 on the function of bovine and porcine surfactant was measured by a capillary surfactometer. DMBT1-levels in tracheal aspirates of ventilated preterm and term infants were determined by ELISA.

Results: Pulmonary DMBT1 was localized in hyaline membranes during respiratory distress syndrome. In vitro addition of human recombinant DMBT1 to the surfactants increased surface tension in a dose-dependent manner. The DMBT1-mediated effect was reverted by the addition of calcium depending on the surfactant preparation.

Conclusion: Our data showed pulmonary DMBT1 expression in hyaline membranes during respiratory distress syndrome and demonstrated that DMBT1 increases lung surface tension in vitro. This raises the possibility that DMBT1 could antagonize surfactant supplementation in respiratory distress syndrome and could represent a candidate target molecule for therapeutic intervention in neonatal lung disease.

Show MeSH
Related in: MedlinePlus