Fig. 2

CHD-induced activation of HIF-1α and NF-κB. Hypoxia and inflammation induced activation of HIF-1α and NF-κB pathways leads to intestinal barrier dysfunction and systemic inflammation. Hypoxia with reduced cardiac output induces selection of pro-inflammatory bacteria activating NK and T cells yielding increased production of IFN-γ. IFN-γ signals activation of NF-κB transcription factors and subsequent activation of the HIF-1α pathway intestinal epithelial cells. HIF-1α activates pro-inflammatory cytokines leading to intestinal barrier dysfunction and permeability of bacteria, toxins, and cytokines into systemic circulation. Hypoxia also induces LPS producing bacterial leading to immune cell activation and subsequent inflammatory cytokine cascade. This induces intestinal barrier dysfunction leading to systemic inflammation. Hypoxia also leads to increase pattern recognition receptors on intestinal epithelial cells which bind to pro-inflammatory microbe ligands activating the HIF-1α pathway and NF-κB transcription factors. This induces a pro-inflammatory cell response as well as host protective measures including anti-apoptosis, anti-oxidant, and anti-microbial peptides. This feeds back to inhibit the barrier disruption and cytokine activation. When patients undergo CPB, this increased systemic inflammation induces significant reactive oxygen species and cytokine activation leading to severe barrier dysfunction and exacerbating the systemic inflammatory process following surgery with CPB. CPB, cardiopulmonary bypass; CO, cardiac output; EBD, epithelial barrier dysfunction; HIF, hypoxia-inducible factor; IEC, intestinal epithelial cell;  IFN-γ, interferon gamma; LPS, lipopolysaccharide; NF-κB, nuclear factor kappa B cells; NK, natural killer; ROS, reactive oxygen species