Necrotizing enterocolitis (NEC) remains one of the most devastating diseases affecting premature babies and is the leading cause of intestinal failure in infancy, with currently no specific treatment available. Elucidating the mechanisms leading to NEC is essential so strategies that will improve the disease outcome can be designed in the future. We have evidence suggesting that nuclear factor-?B (NF-?B) and IKK? (the inhibitor of NF-?B (I?B) kinase), the critical upstream kinase activating NF-?B, mediate the bowel injury in a neonatal rat model of NEC. However, the specific requirement of NF-?B activation in individual cell types for bowel injury to occur is unknown. Our laboratory has recently developed and characterized a mouse model of NEC that will allow us to utilize transgenic mice to dissect the mechanism of NF-?B-dependent bowel injury in NEC in vivo. Using mice with deletion of IKK? in intestinal epithelial cells (IEC) or myeloid cells (MC), we have preliminary evidence that NF-?B in MC mediates the intestinal damage in a model of acute bowel injury. Furthermore, we also found that NF-?B in MC mediates the bowel injury in our neonatal mouse model of NEC. We believe that, in premature infants, perinatal stress and bacterial colonization initiate an increase in intestinal mucosal permeability at least in part through activation of NF-?B and production of downstream cytokines in IEC. However, the initial epithelial NF-?B activation alone does not lead to intestinal injury. We hypothesize that translocation of bacterial products to the lamina propria (LP) causes sustained activation of IKK? (inhibitor of NF-?B kinase) and NF-?B in the LP MC and subsequent production of large amounts of pro- inflammatory cytokines and chemokines (e.g., CXCL2). This in turn leads to the recruitment of neutrophils and production of reactive oxygen species. As a result, there is further intestinal epithelial damage, including apoptosis and mucosal necrosis, and NEC. Thus, NF-?B activation in intestinal MC is pivotal for the development of NEC. Therefore, to test this hypothesis using the neonatal mouse model of NEC that we have developed in our laboratory, we propose to: 1) Test the hypothesis that IKK? and NF-?B activation is required for NEC to develop;2) determine the requirement for MC IKK? activation in causing intestinal inflammation and injury;3) determine the role for IEC IKK? activation in the increase in intestinal permeability and in secondary mucosal cytokine and chemokine expression. By understanding the specific role of NF-?B in individual cell types such as IEC and MC in causing bowel injury in vivo, we will advance our knowledge of NEC, which will potentially lead to new therapeutic strategies.
This proposal aims at dissecting the mechanisms leading to necrotizing enterocolitis, a disease affecting premature babies with great morbidity and mortality. It uses genetically manipulated mice to study the role of a factor that regulates the gene transcription of inflammatory substances and contributes to intestinal injury.
|Bowker, Rakhee M; Yan, Xiaocai; Managlia, Elizabeth et al. (2018) Dimethyloxalylglycine preserves the intestinal microvasculature and protects against intestinal injury in a neonatal mouse NEC model: role of VEGF signaling. Pediatr Res 83:545-553|
|Liu, Fangyi; Bu, Heng-Fu; Geng, Hua et al. (2017) Sirtuin-6 preserves R-spondin-1 expression and increases resistance of intestinal epithelium to injury in mice. Mol Med 23:272-284|
|Wang, Xiao; Hao, Liangliang; Bu, Heng-Fu et al. (2016) Spherical nucleic acid targeting microRNA-99b enhances intestinal MFG-E8 gene expression and restores enterocyte migration in lipopolysaccharide-induced septic mice. Sci Rep 6:31687|
|Yan, Xiaocai; Managlia, Elizabeth; Liu, Shirley Xl et al. (2016) Lack of VEGFR2 signaling causes maldevelopment of the intestinal microvasculature and facilitates necrotizing enterocolitis in neonatal mice. Am J Physiol Gastrointest Liver Physiol 310:G716-25|
|Cohran, Valeria; Managlia, Elizabeth; Bradford, Emily M et al. (2016) Epithelial PIK3R1 (p85) and TP53 Regulate Survivin Expression during Adaptation to Ileocecal Resection. Am J Pathol 186:1837-1846|
|Wang, Xiao; Bu, Heng-Fu; Liu, Shirley X L et al. (2015) Molecular Mechanisms Underlying the Regulation of the MFG-E8 Gene Promoter Activity in Physiological and Inflammatory Conditions. J Cell Biochem 116:1867-79|
|Sabnis, Animesh; Carrasco, Rosa; Liu, Shirley X L et al. (2015) Intestinal vascular endothelial growth factor is decreased in necrotizing enterocolitis. Neonatology 107:191-8|
|Hunter, Catherine J; De Plaen, Isabelle G (2014) Inflammatory signaling in NEC: Role of NF-?B, cytokines and other inflammatory mediators. Pathophysiology 21:55-65|
|De Plaen, Isabelle G (2013) Inflammatory signaling in necrotizing enterocolitis. Clin Perinatol 40:109-24|
|Bergmann, Kelly R; Liu, Shirley X L; Tian, Runlan et al. (2013) Bifidobacteria stabilize claudins at tight junctions and prevent intestinal barrier dysfunction in mouse necrotizing enterocolitis. Am J Pathol 182:1595-606|
Showing the most recent 10 out of 11 publications