The Mechanisms of Action of Hyperbaric Oxygen in Restoring Host Homeostasis during Sepsis

Abstract

The perception of sepsis has shifted over time; however, it remains a leading cause of death worldwide. Sepsis is now recognized as an imbalance in host cellular functions triggered by the invading pathogens, both related to immune cells, endothelial function, glucose and oxygen metabolism, tissue repair and restoration. Many of these key mechanisms in sepsis are also targets of hyperbaric oxygen (HBO₂) treatment. HBO₂ treatment has been shown to improve survival in clinical studies on patients with necrotizing soft tissue infections as well as experimental sepsis models. High tissue oxygen tension during HBO₂ treatment may affect oxidative phosphorylation in mitochondria. Oxygen is converted to energy, and, as a natural byproduct, reactive oxygen species are produced. Reactive oxygen species can act as mediators, and both these and the HBO₂-mediated increase in oxygen supply have the potential to influence the cellular processes involved in sepsis. The pathophysiology of sepsis can be explained comprehensively through resistance and tolerance to infection. We argue that HBO₂ treatment may protect the host from collateral tissue damage during resistance by reducing neutrophil extracellular traps, inhibiting neutrophil adhesion to vascular endothelium, reducing proinflammatory cytokines, and halting the Warburg effect, while also assisting the host in tolerance to infection by reducing iron-mediated injury and upregulating anti-inflammatory measures. Finally, we show how inflammation and oxygen-sensing pathways are connected on the cellular level in a self-reinforcing and detrimental manner in inflammatory conditions, and with support from a substantial body of studies from the literature, we conclude by demonstrating that HBO₂ treatment can intervene to maintain homeostasis.

Keywords: host immune response; hyperbaric oxygen treatment; hypoxia; hypoxia-inducible factor 1-alpha; inflammation; nuclear factor kappa-light-chain-enhancer of activated B cells; oxygen; sepsis; systemic infectious diseases; tolerance to infection.

Figure 1

The division of host defense mechanisms in infection resistance and tolerance. Host resistance effector mechanisms that restrict and contain invading pathogens may be self-harming. Disease tolerance is defined as the host’s ability to limit damage and maintain health in the face of increasing pathogen burden. The tolerance curve: in this linear relationship, hosts with steep negative slopes lose health as pathogen loads increase, whereas hosts with shallow slopes maintain relatively higher levels of health even as pathogen burden increases. We propose that HBO₂ treatment can help the host immune system by increasing tolerance and preventing self-damage during resistance.

Figure 2

Schematic illustration of the link between the inflammatory NF-κB and hypoxic HIF pathways. During inflammation, a self-perpetuating cycle occurs, in which the host immune balance shifts to a proinflammatory hypoxic state, as seen in sepsis. HIF-1α stimulates the activation of NF-κB genes, resulting in the transcription of inflammation-related genes. Before and during inflammation, NF-κB is a critical transcriptional activator of HIF-1α. High levels of HIF-1α and its constitutively expressed β-subunit are translocated to the nucleus in the absence of oxygen, where they bind as heterodimers to HRE, causing transcription of hypoxia responsive genes, including those coding for NF-κB. A loop by which hypoxia and inflammation reinforce one another is established (red arrow). This maladaptive response is interrupted by intervention with HBO₂. The high levels of dissolved O₂ during HBO₂ treatment will activate cellular O₂-sensing causing hydroxylation and hence proteasomal degradation of HIF-1α and inhibition of IKKβ-mediated tyrosine phosphorylation of IκBα, which keeps it bound to NF-κB in plasma, thereby preventing NF-κB pathway activation (blue arrows). HIF-1α = Hypoxia-Inducing Factor 1-alpha; HIF-1ß = Hypoxia-Inducing Factor 1-beta; HRE = hypoxia response promotor; NF-κB = Nuclear factor kappa-light-chain-enhancer of activated B cells; IκBα = nuclear factor of kappa light polypeptide gene-enhancer in B-cells inhibitor, alpha; PHD = prolyl hydroxylase domain; FIH = Factor Inhibiting HIF-1α; IK-Bα = IkappaB kinase, alpha; OH = Hydroxylation; P = phosphorylation.