Hypoxia-dependent signaling in perioperative and critical care medicine

Abstract

A critical goal of patient management for anesthesiologists and intensivists is to maintain oxygen homeostasis in patients admitted to operation theaters and intensive care units. For this purpose, it is imperative to understand the strategies of the body against oxygen imbalance-especially oxygen deficiency (hypoxia). Adaptation to hypoxia and maintenance of oxygen homeostasis involve a wide range of responses that occur at different organizational levels in the body. These responses are greatly influenced by perioperative patient management including factors such as perioperative drugs. Herein, the influence of perioperative patient management on the body's response to oxygen imbalance was reviewed with a special emphasis on hypoxia-inducible factors (HIFs), transcription factors whose activity are regulated by the perturbation of oxygen metabolism. The 2019 Nobel Prize in Physiology or Medicine was awarded to three researchers who made outstanding achievements in this field. While previous studies have reported the effect of perioperatively used drugs on hypoxia-induced gene expression mediated by HIFs, this review focused on effects of subacute or chronic hypoxia changes in gene expression that are mediated by the transcriptional regulator HIFs. The clinical implications and perspectives of these findings also will be discussed. Understanding the basic biology of the transcription factor HIF can be informative for us since anesthesiologists manage patients during the perioperative period facing the imbalances the oxygen metabolism in organ and tissue. The clinical implications of hypoxia-dependent signaling in critical illness, including Coronavirus disease (COVID-19), in which disturbances in oxygen metabolism play a major role in its pathogenesis will also be discussed.

Keywords: Anesthesia; Hypoxia; Hypoxia-inducible factor; Oxygen metabolism; Perioperative care.

Fig. 1

Dysregulation of oxygen metabolism and hypoxia-inducible factors (HIFs). Oxygen acquired from the lungs is transported through the entire body by the blood stream. Impaired oxygenation due to lung injury, impaired transport due to anemia or thrombosis, and impaired transfer of oxygen from blood to cells in tissues due to edema of tissue interstitium can lead to tissue hypoxia. In addition, impaired oxygen metabolism due to inhibition of oxygen utilization by drug-induced mitochondrial suppression has the same effect on the body as hypoxia. Such disturbances in oxygen metabolism affect the activity of HIFs, and this activation is affected by perioperative drugs, including anesthetics

Fig. 2

Transcription factor networks and hypoxic response. Hypoxia-inducible factor-1 (HIF-1)-dependent gene response is an essential component of the hypoxia response in vivo and constitutes a network. The responses occur at the cellular, at the tissue and organ, and at the whole-body level. At each level, the hypoxia response appears as the sum of the reactions of individual cells. HIF-1 has been identified as a critical transcription factor in this network. HIF-1 is present in all nuclear cells, and its activation depends on the partial pressure of oxygen to which the cells are exposed, but its activation is also known to be modified by cell- and tissue-specific factors

Fig. 3

The central dogma of hypoxia-induced gene responses. The main route of hypoxia-inducible factor-1 (HIF-1) activation is hydroxylation by the prolyl hydroxylase domain (PHD) protein, an HIF-1α hydroxylase, and the factor inhibiting HIF-1 (FIH-1) protein. Oxygen is the substrate for this reaction. Reduced substrate concentration results in a reduced response, and HIF-1α protein accumulates in the cell as an activated transcription factor, leading to downstream gene expression. The intracellular processes affecting this response may be regulators of HIF-1 activity independent of oxygen partial pressure. Additionally, certain intracellular signals lead to enhanced translation of HIF-1α, leading to activation of HIF-1

Fig. 4

Impact of perioperative drugs on the regulation of hypoxia-inducible factor (HIF) activity. The effects of perioperative medicines, including anesthetics, narcotics, and vasoactive drugs on HIF-1 activity, are illustrated. Perioperative medications such as drugs that promote activation and drugs that inhibit activation exert various effects on HIF-1 activity

Fig. 5

Regulatory mechanism of EPO and iron metabolism-related genes in cells. HIF-PH inhibitors are already being prescribed in clinical practice for the treatment of renal anemia. The target organs of HIF-PH inhibitors include kidney, liver, and intestinal epithelial cells. HIF-2 rather than HIF-1 acts as a major factor in ameliorating anemia by inducing the expression of erythropoietic growth factors, including EPO, and various genes associated with improved iron metabolism. It is known that HIF-2 induces the expression of EPO in REP cells and inhibits the expression of hepcidin in the liver. EPO erythropoietin, HAMP: hepcidin, CYBRD1 Dcytb, TF transferin, FURIN furin