Hyperoxic acute lung injury

Abstract

Prolonged breathing of very high F(IO(2)) (F(IO(2)) ≥ 0.9) uniformly causes severe hyperoxic acute lung injury (HALI) and, without a reduction of F(IO(2)), is usually fatal. The severity of HALI is directly proportional to P(O(2)) (particularly above 450 mm Hg, or an F(IO(2)) of 0.6) and exposure duration. Hyperoxia produces extraordinary amounts of reactive O(2) species that overwhelms natural anti-oxidant defenses and destroys cellular structures through several pathways. Genetic predisposition has been shown to play an important role in HALI among animals, and some genetics-based epidemiologic research suggests that this may be true for humans as well. Clinically, the risk of HALI likely occurs when F(IO(2)) exceeds 0.7, and may become problematic when F(IO(2)) exceeds 0.8 for an extended period of time. Both high-stretch mechanical ventilation and hyperoxia potentiate lung injury and may promote pulmonary infection. During the 1960s, confusion regarding the incidence and relevance of HALI largely reflected such issues as the primitive control of F(IO(2)), the absence of PEEP, and the fact that at the time both ALI and ventilator-induced lung injury were unknown. The advent of PEEP and precise control over F(IO(2)), as well as lung-protective ventilation, and other adjunctive therapies for severe hypoxemia, has greatly reduced the risk of HALI for the vast majority of patients requiring mechanical ventilation in the 21st century. However, a subset of patients with very severe ARDS requiring hyperoxic therapy is at substantial risk for developing HALI, therefore justifying the use of such adjunctive therapies.

Conflict of interest statement

The authors have disclosed no conflicts of interest.

Figures

Fig. 1

Mechanisms governing the initial burst in reactive oxygen species (ROS) in the primary target cell: the pulmonary capillary endothelium. 1: ROS generation is proportional to the PO2 during hyperoxia. 2: O2 molecules are reduced to form ROS by nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) oxidase (NOX) at the plasma membrane. 3: Damage to the plasma membrane lipid bilayer by ROS also generates additional ROS. 4: The primary sources of ROS production occur inside the mitochondria. Inadvertent electron leakage normally occurs at intermediate steps of energy transformation on the cytochrome chain (protein complexes I and III), but increases proportionally with the intensity of hyperoxia. Additional sources of ROS are generated from the interaction of O2 molecules with numerous mitochondrial enzymes, including cyclooxygenases, peroxidases, lipooxygenase, and cytochrome P450. 5: As the endothelium is a rich source of nitric oxide (NO), reactions with O2 molecules and superoxide anion produces nitrogen dioxide (NO2), a reactive nitrogen species, and peroxynitrite anion (ONOO−), respectively. Peroxynitrite anion reacts with carbon dioxide to form additional NO2.

Fig. 2

Mechanisms governing the secondary burst of reactive oxygen species (ROS) and basic pathways of cell death from hyperoxia. 1: Loss of plasma membrane integrity from lipid peroxidation by ROS. 2: ROS damage to the mitochondria membranes and deactivation of enzyme systems and cytochrome chain. 3: This results in the release of cytochrome c into the cytoplasm. 4: ROS damage to the nuclear membrane and fragmentation of DNA. 5: Evolving cell trauma from steps 1, 2, and 4 trigger the production and release of pro-inflammatory cytokines and chemokines into the extracellular space and circulation. 6: This attracts and activates platelets, neutrophils, and macrophages, resulting in a secondary burst of ROS from these inflammatory cells. Direct cell trauma results in necrosis or “unplanned” cell death. In addition, the release of cytochrome c into the cytoplasm (A-1) and damage to the plasma membrane (A-2) trigger other cellular processes that instruct the cell to essentially “commit suicide” through the process of apoptosis (programmed cell death).

Fig. 3

Superoxide dismutase (SOD) is the primary anti-oxidant defense system operating at the cell surface, inside the cytoplasm, and inside the mitochondria. Outside of the mitochondria this involves copper-zinc form (Cu-Zn) SOD, whereas inside the mitochondria it is manganese (Mn) SOD. Donated electrons (E*−) reduce O2 molecules to form the highly reactive superoxide anion (O2*−), which SOD converts to hydrogen peroxide (H2O2). Through a series of secondary reactions involving glutathione, catalase, N-acetylcysteine, and other agents, H2O2 is converted to H2O.