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Erschienen in: Digestive Diseases and Sciences 3/2022

18.03.2021 | Original Article

Galectin-4 as a Novel Biomarker of Neonatal Intestinal Injury

verfasst von: Jennifer B. Fundora, Jie Zhu, Lisa R. Yanek, Mitzi Go, Fauzia Shakeel, Sandra S. Brooks, Jun Yang, David J. Hackam, Allen D. Everett, Darla R. Shores

Erschienen in: Digestive Diseases and Sciences | Ausgabe 3/2022

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Abstract

Background

Neonates are at risk of gastrointestinal emergencies including necrotizing enterocolitis (NEC) and spontaneous intestinal perforation (SIP). Identifying biomarkers to aid in diagnosis is imperative. We hypothesized that circulating intestinal-specific protein concentrations would distinguish infants with intestinal injury from controls.

Aims

To identify serum concentrations of intestinal-specific protein(s) in infants with intestinal injury and controls.

Methods

We used an in silico approach to identify intestinal-specific proteins. We collected serum from control infants and infants with NEC or SIP and measured protein concentrations using ELISA. If baseline concentrations were near the detection limit in initial control assays, we proceeded to assess concentrations in a larger cohort of controls and infants with injury. Control infants were frequency matched to infants with injury and compared with nonparametric and mixed-effects models analysis.

Results

We evaluated four proteins with high intestinal expression: Galectin-4 (Gal-4), S100G, Trefoil Factor-3, and alanyl aminopeptidase. Only Gal-4 demonstrated consistent results near the lower limit of quantification in controls and was studied in the larger cohorts. Gal-4 concentration was low in 111 control infants (median 0.012 ng/ml). By contrast, Gal-4 was significantly increased at diagnosis in infants with surgical NEC and SIP (n = 14, p ≤ 0.001 and n = 8, p = 0.031) compared to matched controls, but not in infants with medical NEC (n = 32, p = 0.10).

Conclusions

Of the intestinal-specific proteins evaluated, circulating Gal-4 concentrations were at the assay detection limit in control infants. Gal-4 concentrations were significantly elevated in infants with surgical NEC or SIP, suggesting that Gal-4 may serve as a biomarker for neonatal intestinal injury.
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Literatur
1.
Zurück zum Zitat Wang K, Tao G, Sun Z, Sylvester KG. Recent potential noninvasive biomarkers in necrotizing enterocolitis. Gastroenterol Res Pract. 2019;2019:1–9. Wang K, Tao G, Sun Z, Sylvester KG. Recent potential noninvasive biomarkers in necrotizing enterocolitis. Gastroenterol Res Pract. 2019;2019:1–9.
2.
Zurück zum Zitat Goldstein GP, Sylvester KG. Biomarker discovery and utility in necrotizing enterocolitis. Clin Perinatol. 2019;46:1–17.CrossRef Goldstein GP, Sylvester KG. Biomarker discovery and utility in necrotizing enterocolitis. Clin Perinatol. 2019;46:1–17.CrossRef
3.
Zurück zum Zitat Kasivajjula H, Maheshwari A. Pathophysiology and current management of necrotizing enterocolitis. Indian J Pediatr. 2014;81:489–497.CrossRef Kasivajjula H, Maheshwari A. Pathophysiology and current management of necrotizing enterocolitis. Indian J Pediatr. 2014;81:489–497.CrossRef
4.
Zurück zum Zitat Rich BS, Dolgin SE. Necrotizing enterocolitis. Pediatr Rev. 2017;38:552–559.CrossRef Rich BS, Dolgin SE. Necrotizing enterocolitis. Pediatr Rev. 2017;38:552–559.CrossRef
5.
Zurück zum Zitat Bazacliu C, Neu J. Pathophysiology of necrotizing enterocolitis: an update. Curr Pediatr Rev. 2019;15:68–87.CrossRef Bazacliu C, Neu J. Pathophysiology of necrotizing enterocolitis: an update. Curr Pediatr Rev. 2019;15:68–87.CrossRef
6.
Zurück zum Zitat Vongbhavit K, Underwood MA. Intestinal perforation in the premature infant. J Neonatal Perinat Med. 2017;10:281–289.CrossRef Vongbhavit K, Underwood MA. Intestinal perforation in the premature infant. J Neonatal Perinat Med. 2017;10:281–289.CrossRef
7.
Zurück zum Zitat Neu J. Necrotizing enterocolitis: the future. Neonatology. 2020;117:1–5.CrossRef Neu J. Necrotizing enterocolitis: the future. Neonatology. 2020;117:1–5.CrossRef
8.
Zurück zum Zitat Pumberger W, Mayr M, Kohlhauser C, Weninger M. Spontaneous localized intestinal perforation in very-low-birth-weight infants. J Am Coll Surg. 2002;195:796–803.CrossRef Pumberger W, Mayr M, Kohlhauser C, Weninger M. Spontaneous localized intestinal perforation in very-low-birth-weight infants. J Am Coll Surg. 2002;195:796–803.CrossRef
9.
Zurück zum Zitat Pontén F, Jirström K, Uhlen M. The human protein atlas—a tool for pathology. J Pathol. 2008;216:387–393.CrossRef Pontén F, Jirström K, Uhlen M. The human protein atlas—a tool for pathology. J Pathol. 2008;216:387–393.CrossRef
10.
Zurück zum Zitat Shores DR, Fundora J, Go M et al. Normative values for circulating intestinal fatty acid binding protein and calprotectin across gestational ages. BMC Pediatr. 2020;20:1–7.CrossRef Shores DR, Fundora J, Go M et al. Normative values for circulating intestinal fatty acid binding protein and calprotectin across gestational ages. BMC Pediatr. 2020;20:1–7.CrossRef
11.
Zurück zum Zitat Llanos AR, Moss ME, Pinzòn MC, Dye T, Sinkin RA, Kendig JW. Epidemiology of neonatal necrotising enterocolitis: a population-based study. Paediatr Perinat Epidemiol. 2002;16:342–349.CrossRef Llanos AR, Moss ME, Pinzòn MC, Dye T, Sinkin RA, Kendig JW. Epidemiology of neonatal necrotising enterocolitis: a population-based study. Paediatr Perinat Epidemiol. 2002;16:342–349.CrossRef
12.
Zurück zum Zitat Bell MJ, Ternberg JL, Feigin RD et al. Neonatal necrotizing enterocolitis. Therapeutic decisions based upon clinical staging. Ann Surg. 1978;187:1–7.CrossRef Bell MJ, Ternberg JL, Feigin RD et al. Neonatal necrotizing enterocolitis. Therapeutic decisions based upon clinical staging. Ann Surg. 1978;187:1–7.CrossRef
13.
Zurück zum Zitat Walsh M, Kliegman R. Necrotizing enterocolitis: treatment based on staging criteria. Pediatr Clin N Am. 1986;33:179–201.CrossRef Walsh M, Kliegman R. Necrotizing enterocolitis: treatment based on staging criteria. Pediatr Clin N Am. 1986;33:179–201.CrossRef
14.
Zurück zum Zitat Johannes L, Jacob R, Leffler H. Galectins at a glance. J Cell Sci. 2018;1:131. Johannes L, Jacob R, Leffler H. Galectins at a glance. J Cell Sci. 2018;1:131.
15.
Zurück zum Zitat Huflejt ME, Leffler H. Galectin-4 in normal tissues and cancer. Glycoconj J. 2003;20:247–255.CrossRef Huflejt ME, Leffler H. Galectin-4 in normal tissues and cancer. Glycoconj J. 2003;20:247–255.CrossRef
16.
Zurück zum Zitat Brewer CF, Miceli MC, Baum LG. Clusters, bundles, arrays and lattices: novel mechanisms for lectin-saccharide-mediated cellular interactions. Curr Opin Struct Biol. 2002;12:616–623.CrossRef Brewer CF, Miceli MC, Baum LG. Clusters, bundles, arrays and lattices: novel mechanisms for lectin-saccharide-mediated cellular interactions. Curr Opin Struct Biol. 2002;12:616–623.CrossRef
17.
Zurück zum Zitat Danielsen EM, Hansen GH. Lipid raft organization and function in the small intestinal brush border. J Physiol Biochem. 2008;64:377–382.CrossRef Danielsen EM, Hansen GH. Lipid raft organization and function in the small intestinal brush border. J Physiol Biochem. 2008;64:377–382.CrossRef
18.
Zurück zum Zitat Stechly L, Morelle W, Dessein A-F et al. Galectin-4-regulated delivery of glycoproteins to the brush border membrane of enterocyte-like cells. Traffic. 2009;10:438–450.CrossRef Stechly L, Morelle W, Dessein A-F et al. Galectin-4-regulated delivery of glycoproteins to the brush border membrane of enterocyte-like cells. Traffic. 2009;10:438–450.CrossRef
19.
Zurück zum Zitat Cao Z-Q, Guo X-L. The role of galectin-4 in physiology and diseases. Protein Cell. 2016;7:314–324.CrossRef Cao Z-Q, Guo X-L. The role of galectin-4 in physiology and diseases. Protein Cell. 2016;7:314–324.CrossRef
20.
Zurück zum Zitat Huflejt ME, Jordan ET, Gitt MA, Barondes SH, Leffler H. Strikingly different localization of galectin-3 and galectin-4 in human colon adenocarcinoma T84 cells. J Biol Chem. 1997;272:14294–14303.CrossRef Huflejt ME, Jordan ET, Gitt MA, Barondes SH, Leffler H. Strikingly different localization of galectin-3 and galectin-4 in human colon adenocarcinoma T84 cells. J Biol Chem. 1997;272:14294–14303.CrossRef
21.
Zurück zum Zitat Watanabe M, Takemasa I, Kaneko N et al. Clinical significance of circulating galectins as colorectal cancer markers. Oncol Rep. 2011;25:1217–1226.PubMed Watanabe M, Takemasa I, Kaneko N et al. Clinical significance of circulating galectins as colorectal cancer markers. Oncol Rep. 2011;25:1217–1226.PubMed
22.
Zurück zum Zitat Rechreche H, Mallo GV, Montalto G, Dagorn JC, Iovanna JL. Cloning and expression of the mRNA of human galectin-4, an S-type lectin down-regulated in colorectal cancer. Eur J Biochem. 1997;248:225–230.CrossRef Rechreche H, Mallo GV, Montalto G, Dagorn JC, Iovanna JL. Cloning and expression of the mRNA of human galectin-4, an S-type lectin down-regulated in colorectal cancer. Eur J Biochem. 1997;248:225–230.CrossRef
23.
Zurück zum Zitat Barrow H, Guo X, Wandall HH et al. Serum galectin-2, -4, and -8 are greatly increased in colon and breast cancer patients and promote cancer cell adhesion to blood vascular endothelium. Clin Cancer Res. 2011;17:7035–7046.CrossRef Barrow H, Guo X, Wandall HH et al. Serum galectin-2, -4, and -8 are greatly increased in colon and breast cancer patients and promote cancer cell adhesion to blood vascular endothelium. Clin Cancer Res. 2011;17:7035–7046.CrossRef
24.
Zurück zum Zitat Papa Gobbi R, De Francesco N, Bondar C et al. A galectin-specific signature in the gut delineates Crohn’s disease and ulcerative colitis from other human inflammatory intestinal disorders. Biofactors. 2016;42:93–105.PubMed Papa Gobbi R, De Francesco N, Bondar C et al. A galectin-specific signature in the gut delineates Crohn’s disease and ulcerative colitis from other human inflammatory intestinal disorders. Biofactors. 2016;42:93–105.PubMed
25.
Zurück zum Zitat Yu TB, Dodd S, Yu LG, Subramanian S. Serum galectins as potential biomarkers of inflammatory bowel diseases. PLoS ONE. 2020;15:e0227306.CrossRef Yu TB, Dodd S, Yu LG, Subramanian S. Serum galectins as potential biomarkers of inflammatory bowel diseases. PLoS ONE. 2020;15:e0227306.CrossRef
26.
Zurück zum Zitat Hokama A, Mizoguchi E, Mizoguchi A. Roles of galectins in inflammatory bowel disease. World J Gastroenterol. 2008;14:5133–5137.CrossRef Hokama A, Mizoguchi E, Mizoguchi A. Roles of galectins in inflammatory bowel disease. World J Gastroenterol. 2008;14:5133–5137.CrossRef
27.
Zurück zum Zitat Hokama A, Mizoguchi E, Sugimoto K et al. Induced reactivity of intestinal CD4(+) T cells with an epithelial cell lectin, galectin-4, contributes to exacerbation of intestinal inflammation. Immunity. 2004;20:681–693.CrossRef Hokama A, Mizoguchi E, Sugimoto K et al. Induced reactivity of intestinal CD4(+) T cells with an epithelial cell lectin, galectin-4, contributes to exacerbation of intestinal inflammation. Immunity. 2004;20:681–693.CrossRef
28.
Zurück zum Zitat Paclik D, Danese S, Berndt U, Wiedenmann B, Dignass A, Sturm A. Galectin-4 controls intestinal inflammation by selective regulation of peripheral and mucosal T cell apoptosis and cell cycle. PLoS ONE. 2008;3:e2629.CrossRef Paclik D, Danese S, Berndt U, Wiedenmann B, Dignass A, Sturm A. Galectin-4 controls intestinal inflammation by selective regulation of peripheral and mucosal T cell apoptosis and cell cycle. PLoS ONE. 2008;3:e2629.CrossRef
29.
Zurück zum Zitat Kubota A, Yamanaka H, Okuyama H et al. Focal intestinal perforation in extremely-low-birth-weight neonates: etiological consideration from histological findings. Pediatr Surg Int. 2007;23:997–1000.CrossRef Kubota A, Yamanaka H, Okuyama H et al. Focal intestinal perforation in extremely-low-birth-weight neonates: etiological consideration from histological findings. Pediatr Surg Int. 2007;23:997–1000.CrossRef
30.
Zurück zum Zitat Paclik D, Lohse K, Wiedenmann B, Dignass AU, Sturm A. Galectin-2 and -4, but not galectin-1, promote intestinal epithelial wound healing in vitro through a TGF-beta-independent mechanism. Inflamm Bowel Dis. 2008;14:1366–1372.CrossRef Paclik D, Lohse K, Wiedenmann B, Dignass AU, Sturm A. Galectin-2 and -4, but not galectin-1, promote intestinal epithelial wound healing in vitro through a TGF-beta-independent mechanism. Inflamm Bowel Dis. 2008;14:1366–1372.CrossRef
31.
Zurück zum Zitat Terrin G, Stronati L, Cucchiara S, De Curtis M. Serum markers of necrotizing enterocolitis: a systematic review. J Pediatr Gastroenterol Nutr. 2017;65:e120–e132.CrossRef Terrin G, Stronati L, Cucchiara S, De Curtis M. Serum markers of necrotizing enterocolitis: a systematic review. J Pediatr Gastroenterol Nutr. 2017;65:e120–e132.CrossRef
32.
Zurück zum Zitat Yang G, Wang Y, Jiang X. Diagnostic value of intestinal fatty-acid-binding protein in necrotizing enterocolitis: a systematic review and meta-analysis. Indian J Pediatr. 2016;83:1410–1419.CrossRef Yang G, Wang Y, Jiang X. Diagnostic value of intestinal fatty-acid-binding protein in necrotizing enterocolitis: a systematic review and meta-analysis. Indian J Pediatr. 2016;83:1410–1419.CrossRef
33.
Zurück zum Zitat Kuik SJ, Kalteren WS, Mebius MJ, Bos AF, Hulscher JBF, Kooi EMW. Predicting intestinal recovery after necrotizing enterocolitis in preterm infants. Pediatr Res. 2020;87:903–909.CrossRef Kuik SJ, Kalteren WS, Mebius MJ, Bos AF, Hulscher JBF, Kooi EMW. Predicting intestinal recovery after necrotizing enterocolitis in preterm infants. Pediatr Res. 2020;87:903–909.CrossRef
Metadaten
Titel
Galectin-4 as a Novel Biomarker of Neonatal Intestinal Injury
verfasst von
Jennifer B. Fundora
Jie Zhu
Lisa R. Yanek
Mitzi Go
Fauzia Shakeel
Sandra S. Brooks
Jun Yang
David J. Hackam
Allen D. Everett
Darla R. Shores
Publikationsdatum
18.03.2021
Verlag
Springer US
Erschienen in
Digestive Diseases and Sciences / Ausgabe 3/2022
Print ISSN: 0163-2116
Elektronische ISSN: 1573-2568
DOI
https://doi.org/10.1007/s10620-021-06929-z

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