Involvement of hypoxia-inducible factors in the dysregulation of oxygen homeostasis in sepsis

Kiichi Hirota, Kiichi Hirota

Abstract

Sepsis is a state of infection with serious systemic manifestations, and if severe enough, can be associated with multiple organ dysfunction and systemic hypotension, which can cause tissues to be hypoxic. Inflammation, as part of the multifaceted biological response to injurious stimuli, such as pathogens or damaged tissues and cells, underlies these biological processes. Prolonged and persistent inflammation, also known as chronic inflammation, results in progressive alteration in the various types of cells at the site of inflammation and is characterized by the simultaneous destruction and healing of tissue during the process. Tissue hypoxia during inflammation is not just a simple bystander process, but can considerably affect the development or attenuation of inflammation by causing the regulation of hypoxia-dependent gene expression. Indeed, the study of transcriptionally regulated tissue adaptation to hypoxia requires intense investigation to help control hypoxia-induced inflammation and organ failure. In this review, I have described the pathophysiology of sepsis with respect to oxygen metabolism and expression of hypoxia-inducible factor 1.

Figures

Fig. (1)
Fig. (1)
Regulation of oxygen delivery. In sepsis or a systemic inflammatory response, distribution of blood flow is largely abnormal. Moreover, tissues and organs fail to use oxygen. Responses to hypoxia induce dysregulation in organ function. Original plan of this figure was based on [5, 79].
Fig. (2)
Fig. (2)
Regulation of HIF-1 in sepsis. Under normoxic conditions, the prolyl hydroxylases (PHDs) hydroxylases hypoxia-inducible factor 1α (HIF-1α) usign molecular O2 at amino acid residues 402 and 564. Hydroxylated proryl residues are target for polyubiquitylation of the HIF1α protein by von Hippel–Lindau (VHL) tumor suppressor protein. The uniqutined HIF1α are transported to the proteasomes and degradated. The asparaginyl hydroxylase factor inhibiting HIF-1 (FIH-1; also known as HIF1AN) functions in conjunction with the prolyl hydroxylation. The asparagine residue is located in the HIF-1α carboxy-terminal domain, which serves as a strong transcription facilitator. As all of these post-translational events depend on intracellular oxygen, they are inhibited by intracellular oxygen deprivation. In addition to hypoxia, HIF-1 can be activated by a microenvironment affected by sepsis and systemic inflammation. HRE: hypoxia response element, PHD: prolyl hydroxylation domain, FIH-1: factor-inhibiting HIF-1, SNP: sodium nitroprusside, ROS: reactive oxygen species, LPS: lipopolysaccharide.
Fig. (3)
Fig. (3)
Interdependence of HIF-1 and NF-κB. The transcription factors HIF-1 and NF-κB interdependently act on each other involving in intracellular regulation of inflammation. Thus, the interaction between the transcription factors, which are under regulation by oxygen metabolism of the inflammation site, plays an essential role in the progress of sepsis. The evidence strongly suggests that the oxygen homeostasis can be a therapeutic target of sepsis.

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