The Hypoxia-Reoxygenation Injury Model

Abstract

Hypoxia-reoxygenation injury is a commonly used in vitro model of ischemia, which is useful to study the recovery processes following the hypoxic period. Hypoxia can be rapidly induced in vitro by replacing the culture atmosphere with hypoxic or anoxic gas mixture. Cellular injury mostly occurs as a result of energetic failure in this model: the lack of oxygen blocks the mitochondrial respiration and anaerobic metabolism becomes the major source of high-energy molecules in the cells. In the absence of glucose, glycolysis and pentose phosphate pathway fail to suffice the cellular energy prerequisite and longer periods of oxygen-glucose deprivation (OGD) can completely deplete the cellular NAD + and ATP pools. The lack of NAD + results in severe metabolic suppression and predisposes the cells to other injury types. This includes oxidant-induced damage, since oxidative stress activates poly(ADP-ribose) polymerase (PARP) that further depletes the cellular NAD + pool and leads to excessive cell death. The impaired mitochondrial respiration also leads to an increase in the mitochondrial membrane potential and augments the mitochondrial superoxide generation leading to oxidative stress. The above processes ultimately lead to necrotic cell death, but in certain cell types, mitochondrial damage can also trigger apoptosis.

Consecutive Hypoxia Decreases Expression of NOTCH3, HEY1, CC10, and FOXJ1 via NKX2-1 Downregulation and Intermittent Hypoxia-Reoxygenation Increases Expression of BMP4, NOTCH1, MKI67, OCT4, and MUC5AC via HIF1A Upregulation in Human Bronchial Epithelial Cells

“…Previous studies have demonstrated that the intracellular effects and cellular injury caused by hypoxia-reoxygenation (H/R) in vitro are similar to the responses induced by ischemia-reperfusion in vivo (Samaja and Milano, 2015;Gerõ, 2017). Under hypoxia, cells undergo energy depletion and transform from aerobic mitochondrial respiration into anaerobic metabolism, which induces intracellular acidosis via increasing intracellular concentrations of lactate and protons, and results in disequilibrium of the cytoplasmic concentrations of sodium and calcium ions (Gourdin and Dubois, 2017).…”

“…Under hypoxia, cells undergo energy depletion and transform from aerobic mitochondrial respiration into anaerobic metabolism, which induces intracellular acidosis via increasing intracellular concentrations of lactate and protons, and results in disequilibrium of the cytoplasmic concentrations of sodium and calcium ions (Gourdin and Dubois, 2017). Upon reperfusion or reoxygenation after a period of hypoxia, there will be intramitochondrial calcium overload and accumulation of reactive oxygen species (ROS) due to a sudden increase of intramitochondrial oxygen molecules and dramatic decrease of intracellular protons, and hence leading to opening of the mitochondrial permeability transition pore, which then induces cell apoptosis (Kalogeris et al, 2012;Gerõ, 2017). It has been reported that ischemia-reperfusion is a common hemorheological situation associated with solid organ transplantation, including lung transplantation (Fiser et al, 2002;de Perrot et al, 2003;Cicco et al, 2005;Kosieradzki and Rowinski, 2008;Lobo et al, 2014;Chen and Date, 2015;Laubach and Sharma, 2016), and that interruption of bronchial artery circulation during lung transplantation is highly associated with airway ischemia/hypoxia, pulmonary fibrosis, bronchiolitis obliterans syndrome, susceptibility to chronic rejection, and low long-term survival (Nicolls and Zamora, 2010;Wilkes, 2010;Tong et al, 2015).…”