Table 1.
Agent Types, General Behaviors, and Functions Included in the Necrotizing Enterocolitis Agent-Based Model
| Agent | Description | Functions |
|---|---|---|
| NGECs | Agents that perform basic metabolic functions; secrete inflammatory mediators; regulate cell death pathways | • Cellular respiration: Nutrient consumption that leads to generation of ROS • ROS clearance: Decreases total ROS within each agent • Tight junction formation: Prevents interaction of bacteria with cells • Apoptosis: Programmed cell death without spillover of cell contents • Inflammation: Activation leads to production of mediators (TNF-α and NO·), which are both secreted. • Necrosis: Cell death by excessive inflammatory signaling with spillover of cell contents (i.e., DAMPs) |
| Goblet cells | Agents with ability to create protective mucus barrier for NGECs | • Same cellular and metabolic processes as NGECs • Secretion of mucus, which prevents interaction between NGECs and bacteria |
| Bacteria | Agents with ability to activate inflammatory pathways in NGECs through interaction with TLR-4 | • Generation of PAMPs, which activate NF-κB in NGECs via TLR-4 • Interaction with NGECs is inhibited by tight junctions and mucus |
| Reactive oxygen species | Produced by cells as part of metabolism secondary to consumption of nutrients | • Low amounts cause generation of p53 • Large amounts cause generation of free NF-κB |
| p53 | Generated by cells depending on amount of ROS; initial effector of apoptosis | • Generation of cytochrome c, which activates caspases to effect apoptosis |
| Nuclear factor-κB | Principal pro-inflammatory signaling molecule for cells | • Leads to generation of TNF-α and NO • Presence initiates production of I-κB, its inhibitor |
| Nitric oxide | Product of NF-κB inflammatory pathway | • Inhibits production of tight junction proteins • Secreted and absorbed by cells • Incorporated into total ROS |
| Tumor necrosis factor-α | Product of NF-κB inflammatory pathway | • Secreted and absorbed by cells • Activates NF-κB • Activates RIP kinase |
| RIP kinase | TNF-α receptor-mediated inflammatory pathway | • Leads to necrotic cell death • Spillover of NO and TNF-α to surrounding cells • Release of DAMPs |
| TLR-4 | Receptor that recognizes DAMPs and PAMPs | • Activates NF-κB |
| PAMPs | Secreted products of bacteria | • Activates NF-κB |
| Mucus | Secreted product of goblet cells | • Prevents interaction between PAMPs and TLR-4 |
DAMP=damage-associated molecular pattern; I-κB=nuclear factor kappa-beta inhibitor; NF=nuclear factor; NF-κB=nuclear factor kappa-beta; NO·=nitric oxide; NGEC=neonatal gut epithelial cells; PAMP=pathogen-associated molecular pattern; RIP=receptor-interacting protein; ROS=reactive oxygen species; TLR=Toll-like receptor; TNF-α=tumor necrosis factor-alpha.