Top

Published in:

Open Access 01-12-2022 | Brain Tumor | Research

DMBT1 expression and neutrophil-to-lymphocyte ratio during necrotizing enterocolitis are influenced by impaired perfusion due to cardiac anomalies

Authors: Sonja Diez, Manuel Besendörfer, Veronika Weyerer, Arndt Hartmann, Julia Moosmann, Christel Weiss, Marcus Renner, Hanna Müller

Published in: Molecular and Cellular Pediatrics | Issue 1/2022

Abstract

Background

Deleted in malignant brain tumors 1 (DMBT1) is involved in innate immunity and epithelial differentiation. It has been proven to play a role in various states of inflammation or hypoxia of fetal gastrointestinal and pulmonary diseases. Discrimination of pathogenesis in necrotizing enterocolitis (NEC) based on cardiac status improves the understanding of NEC in different patient subgroups. We aimed at examining DMBT1 expressions regarding their association with cardiac status leading to impaired intestinal perfusion, intraoperative bacteria proof, and a fulminant course of NEC.

Methods

Twenty-eight patients with NEC were treated surgically between 2010 and 2019 at our institution. DMBT1 expression was examined in intestinal sections using immunohistochemistry to detect DMBT1 protein. Associations of clinical parameters and DMBT1 expression were analyzed.

Results

We examined DMBT1 levels in 10 patients without cardiac defects and 18 patients with persisting ductus arteriosus (PDA) and congenital heart defects (CHD). Compared to patients without cardiac malformations, DMBT1 levels tended to score higher in patients with PDA/CHD (p = 0.2113) and were negatively correlated with C-reactive protein in these infants (p = 0.0172; r = − 0.5533). The number of DMBT1-expressing macrophages was elevated in the PDA/CHD-subgroup (p = 0.0399). Ratios of neutrophils and monocytes to lymphocytes were significantly higher in infants with PDA/CHD (p = 0.0319 and 0.0493). DMBT1 expression was significantly associated with positive bacterial culture of intraoperative swabs (p = 0.0252) and DMBT1 expression of the serosa was associated with a fulminant course of NEC (p = 0.0239).

Conclusions

This study demonstrates that DMBT1 expression may be influenced by cardiac anomalies with an impaired intestinal perfusion in the neonatal intestine. NEC in PDA/CHD infants is associated with more DMBT1-positive macrophages and a significantly elevated neutrophil-to-lymphocyte ratio.

Fitzgibbons SC, Ching Y, Yu D, Carpenter J, Kenny M, Weldon C, Lillehei C, Valim C, Horbar JD, Jaksic T (2009) Mortality of necrotizing enterocolitis expressed by birth weight categories. J Pediatr Surg 44:1072–1075. https://doi.org/10.1016/j.jpedsurg.2009.02.013 discussion 1075-1076CrossRefPubMed

Velazco CS, Fullerton BS, Hong CR, Morrow KA, Edwards EM, Soll RF, Jaksic T, Horbar JD, Modi BP (2017) Morbidity and mortality among “big” babies who develop necrotizing enterocolitis: a prospective multicenter cohort analysis. J Pediatr Surg. https://doi.org/10.1016/j.jpedsurg.2017.10.028

Giannone PJ, Luce WA, Nankervis CA, Hoffman TM, Wold LE (2008) Necrotizing enterocolitis in neonates with congenital heart disease. Life Sci 82:341–347. https://doi.org/10.1016/j.lfs.2007.09.036CrossRefPubMed

Maheshwari A (2015) Immunologic and hematological abnormalities in necrotizing enterocolitis. Clin Perinatol 42:567–585. https://doi.org/10.1016/j.clp.2015.04.014CrossRefPubMedPubMedCentral

Denning TL, Bhatia AM, Kane AF, Patel RM, Denning PW (2017) Pathogenesis of NEC: role of the innate and adaptive immune response. Semin Perinatol 41:15–28. https://doi.org/10.1053/j.semperi.2016.09.014CrossRefPubMed

Giannone PJ, Schanbacher BL, Bauer JA, Reber KM (2006) Effects of prenatal lipopolysaccharide exposure on epithelial development and function in newborn rat intestine. J Pediatr Gastroenterol Nutr 43:284–290. https://doi.org/10.1097/01.mpg.0000232572.56397.d6CrossRefPubMed

Hodzic Z, Bolock AM, Good M (2017) The role of mucosal immunity in the pathogenesis of necrotizing enterocolitis. Front Pediatr 5:40. https://doi.org/10.3389/fped.2017.00040CrossRefPubMedPubMedCentral

Siano E, Lauriti G, Ceccanti S, Zani A (2019) Cardiogenic necrotizing enterocolitis: a clinically distinct entity from classical necrotizing enterocolitis. Eur J Pediatr Surg 29:14–22. https://doi.org/10.1055/s-0038-1668144CrossRefPubMed

Bubberman JM, van Zoonen A, Bruggink JLM, van der Heide M, Berger RMF, Bos AF, Kooi EMW, Hulscher JBF (2018) Necrotizing enterocolitis associated with congenital heart disease: a different entity? J Pediatr Surg. https://doi.org/10.1016/j.jpedsurg.2018.11.012

10.

Kessler U, Hau EM, Kordasz M, Haefeli S, Tsai C, Klimek P, Cholewa D, Nelle M, Pavlovic M, Berger S (2018) Congenital heart disease increases mortality in neonates with necrotizing enterocolitis. Front Pediatr 6:312. https://doi.org/10.3389/fped.2018.00312CrossRefPubMedPubMedCentral

11.

Diez S, Tielesch L, Weiss C, Halbfass J, Müller H, Besendörfer M (2020) Clinical characteristics of necrotizing enterocolitis in preterm patients with and without persistent ductus arteriosus and in patients with congenital heart disease. Front Pediatr 8:257. https://doi.org/10.3389/fped.2020.00257CrossRefPubMedPubMedCentral

12.

Neu J (2020) Necrotizing enterocolitis: the future. Neonatology 117:240–244. https://doi.org/10.1159/000506866CrossRefPubMed

13.

Klinke M, Wiskemann H, Bay B, Schäfer HJ, Pagerols Raluy L, Reinshagen K, Vincent D, Boettcher M (2020) Cardiac and inflammatory necrotizing enterocolitis in newborns are not the same entity. Front Pediatr 8:593926. https://doi.org/10.3389/fped.2020.593926CrossRefPubMed

14.

Mollenhauer J, Herbertz S, Holmskov U, Tolnay M, Krebs I, Merlo A, Schrøder HD, Maier D, Breitling F, Wiemann S, Gröne HJ, Poustka A (2000) DMBT1 encodes a protein involved in the immune defense and in epithelial differentiation and is highly unstable in cancer. Cancer Res 60:1704–1710PubMed

15.

Madsen J, Tornøe I, Nielsen O, Lausen M, Krebs I, Mollenhauer J, Kollender G, Poustka A, Skjødt K, Holmskov U (2003) CRP-ductin, the mouse homologue of gp-340/deleted in malignant brain tumors 1 (DMBT1), binds gram-positive and gram-negative bacteria and interacts with lung surfactant protein D. Eur J Immunol 33:2327–2336. https://doi.org/10.1002/eji.200323972CrossRefPubMed

16.

Müller H, End C, Weiss C, Renner M, Bhandiwad A, Helmke BM, Gassler N, Hafner M, Poustka A, Mollenhauer J, Poeschl J (2008) Respiratory deleted in malignant brain tumours 1 (DMBT1) levels increase during lung maturation and infection. Clin Exp Immunol 151:123–129. https://doi.org/10.1111/j.1365-2249.2007.03528.xCrossRefPubMedPubMedCentral

17.

Muller H, Renner M, Helmke BM, Mollenhauer J, Felderhoff-Muser U (2016) Elevated DMBT1 levels in neonatal gastrointestinal diseases. Histochem Cell Biol 145:227–237. https://doi.org/10.1007/s00418-015-1381-8CrossRefPubMed

18.

Müller H, Schmiedl A, Weiss C, Ai M, Jung S, Renner M (2020) DMBT1 is upregulated in lung epithelial cells after hypoxia and changes surfactant ultrastructure. Pediatr Pulmonol. https://doi.org/10.1002/ppul.25018

19.

Bell MJ, Ternberg JL, Feigin RD, Keating JP, Marshall R, Barton L, Brotherton T (1978) Neonatal necrotizing enterocolitis. Therapeutic decisions based upon clinical staging. Ann Surg 187:1–7. https://doi.org/10.1097/00000658-197801000-00001CrossRefPubMedPubMedCentral

20.

AWMF-Guidelines (2017) Nekrotisierende Enterokolitis. AWMF-Leitlinien-Register Nr. 024/009. Site visited 01/01/21

21.

Müller H, End C, Renner M, Helmke BM, Gassler N, Weiss C, Hartl D, Griese M, Hafner M, Poustka A, Mollenhauer J, Poeschl J (2007) Deleted in malignant brain tumors 1 (DMBT1) is present in hyaline membranes and modulates surface tension of surfactant. Respir Res 8:69. https://doi.org/10.1186/1465-9921-8-69CrossRefPubMedPubMedCentral

22.

Muller H, Weiss C, Renner M, Felderhoff-Muser U, Mollenhauer J (2017) DMBT1 promotes basal and meconium-induced nitric oxide production in human lung epithelial cells in vitro. Histochem Cell Biol 147:389–397. https://doi.org/10.1007/s00418-016-1493-9CrossRefPubMed

23.

Renner M, Bergmann G, Krebs I, End C, Lyer S, Hilberg F, Helmke B, Gassler N, Autschbach F, Bikker F, Strobel-Freidekind O, Gronert-Sum S, Benner A, Blaich S, Wittig R, Hudler M, Ligtenberg AJ, Madsen J, Holmskov U, Annese V, Latiano A, Schirmacher P, Amerongen AVN, D’Amato M, Kioschis P, Hafner M, Poustka A, Mollenhauer J (2007) DMBT1 confers mucosal protection in vivo and a deletion variant is associated with Crohn’s disease. Gastroenterology 133:1499–1509. https://doi.org/10.1053/j.gastro.2007.08.007CrossRefPubMed

24.

Madsen J, Mollenhauer J, Holmskov U (2010) Review: Gp-340/DMBT1 in mucosal innate immunity. Innate Immun 16:160–167. https://doi.org/10.1177/1753425910368447CrossRefPubMed

25.

Bikker FJ, Ligtenberg AJ, End C, Renner M, Blaich S, Lyer S, Wittig R, van’t Hof W, Veerman EC, Nazmi K, de Blieck-Hogervorst JM, Kioschis P, Nieuw Amerongen AV, Poustka A, Mollenhauer J (2004) Bacteria binding by DMBT1/SAG/gp-340 is confined to the VEVLXXXXW motif in its scavenger receptor cysteine-rich domains. J Biol Chem 279:47699–47703. https://doi.org/10.1074/jbc.M406095200CrossRefPubMed

26.

Braegger CP, Spencer J, MacDonald TT (1992) Ontogenetic aspects of the intestinal immune system in man. Int J Clin Lab Res 22:1–4CrossRef

27.

MacDonald TT (1996) Accessory cells in the human gastrointestinal tract. Histopathology 29:89–92. https://doi.org/10.1046/j.1365-2559.1996.d01-488.xCrossRefPubMed

28.

Rognum TO, Thrane S, Stoltenberg L, Vege A, Brandtzaeg P (1992) Development of intestinal mucosal immunity in fetal life and the first postnatal months. Pediatr Res 32:145–149. https://doi.org/10.1203/00006450-199208000-00003CrossRefPubMed

29.

MohanKumar K, Kaza N, Jagadeeswaran R, Garzon SA, Bansal A, Kurundkar AR, Namachivayam K, Remon JI, Bandepalli CR, Feng X, Weitkamp JH, Maheshwari A (2012) Gut mucosal injury in neonates is marked by macrophage infiltration in contrast to pleomorphic infiltrates in adult: evidence from an animal model. Am J Physiol Gastrointest Liver Physiol 303:G93–G102. https://doi.org/10.1152/ajpgi.00016.2012CrossRefPubMedPubMedCentral

30.

Maheshwari A, Kurundkar AR, Shaik SS, Kelly DR, Hartman Y, Zhang W, Dimmitt R, Saeed S, Randolph DA, Aprahamian C, Datta G, Ohls RK (2009) Epithelial cells in fetal intestine produce chemerin to recruit macrophages. Am J Physiol Gastrointest Liver Physiol 297:G1–g10. https://doi.org/10.1152/ajpgi.90730.2008CrossRefPubMedPubMedCentral

31.

Smythies LE, Maheshwari A, Clements R, Eckhoff D, Novak L, Vu HL, Mosteller-Barnum LM, Sellers M, Smith PD (2006) Mucosal IL-8 and TGF-beta recruit blood monocytes: evidence for cross-talk between the lamina propria stroma and myeloid cells. J Leukoc Biol 80:492–499. https://doi.org/10.1189/jlb.1005566CrossRefPubMed

32.

Djordjevic D, Rondovic G, Surbatovic M, Stanojevic I, Udovicic I, Andjelic T, Zeba S, Milosavljevic S, Stankovic N, Abazovic D, Jevdjic J, Vojvodic D (2018) Neutrophil-to-lymphocyte ratio, monocyte-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and mean platelet volume-to-platelet count ratio as biomarkers in critically ill and injured patients: which ratio to choose to predict outcome and nature of bacteremia? Mediators Inflamm 2018:3758068. https://doi.org/10.1155/2018/3758068CrossRefPubMedPubMedCentral

33.

Forget P, Khalifa C, Defour JP, Latinne D, Van Pel MC, De Kock M (2017) What is the normal value of the neutrophil-to-lymphocyte ratio? BMC Res Notes 10:12. https://doi.org/10.1186/s13104-016-2335-5CrossRefPubMedPubMedCentral

34.

Yang Y, Cao ZL, Zhou XY, Chen XQ, Pan JJ, Cheng R (2019) Does neutrophil/lymphocyte ratio have good diagnostic value in neonatal necrotizing colitis? J Matern Fetal Neonatal Med 32:3026–3033. https://doi.org/10.1080/14767058.2018.1455182CrossRefPubMed

35.

Cho SX, Berger PJ, Nold-Petry CA, Nold MF (2016) The immunological landscape in necrotising enterocolitis. Expert Rev Mol Med 18:e12. https://doi.org/10.1017/erm.2016.13CrossRefPubMedPubMedCentral

36.

Müller H, Nagel C, Weiss C, Mollenhauer J, Poeschl J (2015) Deleted in malignant brain tumors 1 (DMBT1) elicits increased VEGF and decreased IL-6 production in type II lung epithelial cells. BMC Pulm Med 15:32. https://doi.org/10.1186/s12890-015-0027-xCrossRefPubMedPubMedCentral

Title: DMBT1 expression and neutrophil-to-lymphocyte ratio during necrotizing enterocolitis are influenced by impaired perfusion due to cardiac anomalies
Authors: Sonja Diez
Manuel Besendörfer
Veronika Weyerer
Arndt Hartmann
Julia Moosmann
Christel Weiss
Marcus Renner
Hanna Müller
Publication date: 01-12-2022
Publisher: Springer Berlin Heidelberg
Keyword: Brain Tumor
Published in: Molecular and Cellular Pediatrics / Issue 1/2022
Electronic ISSN: 2194-7791
DOI: https://doi.org/10.1186/s40348-021-00133-9

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

DMBT1 expression and neutrophil-to-lymphocyte ratio during necrotizing enterocolitis are influenced by impaired perfusion due to cardiac anomalies

Abstract

Background

Methods

Results

Conclusions

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2022

High-resolution label-free mapping of murine kidney vasculature by raster-scanning optoacoustic mesoscopy: an ex vivo study

DMBT1 is upregulated in cystic fibrosis, affects ciliary motility, and is reduced by acetylcysteine

PTEN hamartoma tumor syndrome in childhood and adolescence—a comprehensive review and presentation of the German pediatric guideline

Evaluation of phenotypic and genotypic patterns of aminoglycoside resistance in the Gram-negative bacteria isolates collected from pediatric and general hospitals

Adsorption of insulin onto neonatal infusion sets: should intravenous administration of insulin to treat hyperglycemia in preterm babies on the NICU be proceeded by priming of the intravenous system, adding of albumin, or non-priming to get to a stable insulin dose?

When inflammation meets lung development—an update on the pathogenesis of bronchopulmonary dysplasia