title: Immunoregulatory protein profiles of necrotizing enterocolitis versus spontaneous intestinal perforation in preterm infants.
abstract: Necrotizing enterocolitis (NEC) and spontaneous intestinal perforation (SIP) are the most common acute surgical emergencies associated with high morbidity and mortality in preterm infants. We aimed to compare the profiles of immunoregulatory proteins and identify novel mediators in plasma of NEC and SIP infants. We also investigated the expression of target genes in resected intestinal tissues and an enterocyte cell line. Using Cytokine Antibody Array assay, we reported the first comparative profiles of immunoregulatory proteins in plasma of NEC and SIP infants, and showed that dysregulated proteins belonged to functionally diversified categories, including pro- and anti-inflammation, angiogenesis, cell growth, wound healing, anti-apoptosis, cell adhesion and extracellular matrix reorganization. Validation by ELISA confirmed significantly higher concentrations of interleukin (IL)-6, angiopoietin (Ang)-2, soluble type II interleukin-1 receptor (sIL-1RII), and soluble urokinase-type plasminogen activator receptor (suPAR) in NEC infants compared with gestational age-matched control, and a lower level of an epidermal growth factor receptor, secreted form of receptor tyrosine-protein kinase ErbB3 (sErbB3), compared with SIP infants. mRNA expressions of IL1-RII and uPAR were up-regulated in resected bowel tissues from NEC infants, indicating that immunoregulation also occurred at the cellular level. In FHs-74 Int cells, Ang-2, IL1-RII and uPAR mRNA expressions were significantly induced by the combined treatment with lipopolysaccharide (LPS) and platelet activating factor (PAF). Our study provided plasmatic signatures of immunoregulatory proteins in NEC and SIP infants, and demonstrated involvement of multiple functional pathways. The magnitude of changes in these proteins was significantly more extensive in NEC infants, reflecting the different nature of injury and/or severity of inflammation. We speculate that dysregulation of IL-6, Ang-2, IL-1RII and uPAR occurred at both systemic and cellular levels, and probably mediated via LPS and endogeneous PAF signals. Such exaggerated immunologic responses may account for the high morbidity and mortality in NEC compared with SIP patients.
authors.affiliation: Department of Paediatrics, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong.
authors.forename: Kathy Yuen Yee
authors.initials: KY
authors.lastname: Chan
authors.forename: Fiona Wan Lun
authors.initials: FW
authors.lastname: Leung
authors.forename: Hugh Simon
authors.initials: HS
authors.lastname: Lam
authors.forename: Yuk Him
authors.initials: YH
authors.lastname: Tam
authors.forename: Ka Fai
authors.initials: KF
authors.lastname: To
authors.forename: Hon Ming
authors.initials: HM
authors.lastname: Cheung
authors.forename: Kam Tong
authors.initials: KT
authors.lastname: Leung
authors.forename: Terence Chuen Wai
authors.initials: TC
authors.lastname: Poon
authors.forename: Kim Hung
authors.initials: KH
authors.lastname: Lee
authors.forename: Karen
authors.initials: K
authors.lastname: Li
authors.forename: Tai Fai
authors.initials: TF
authors.lastname: Fok
authors.forename: Pak Cheung
authors.initials: PC
authors.lastname: Ng
mesh_terms: D042702:Angiopoietin-2 / Q000235:genetics / Q000378:metabolism; D016022:Case-Control Studies; D002460:Cell Line; D016207:Cytokines / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D020345:Enterocolitis, Necrotizing / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007234:Infant, Premature; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D007416:Intestinal Perforation / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D008297:Male; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020893:Receptor, ErbB-3 / Q000235:genetics / Q000378:metabolism; D053574:Receptors, Interleukin-1 Type II / Q000235:genetics / Q000378:metabolism; D055293:Receptors, Urokinase Plasminogen Activator / Q000235:genetics / Q000378:metabolism
chemical_list: D042702:Angiopoietin-2; D016207:Cytokines; C508592:IL1R2 protein, human; C508600:IL6 protein, human; D015850:Interleukin-6; D012333:RNA, Messenger; D053574:Receptors, Interleukin-1 Type II; D055293:Receptors, Urokinase Plasminogen Activator; D020893:Receptor, ErbB-3