Comprehensive Physiology Wiley Online Library

Oxygen Utilization and Toxicity in the Lungs

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Abstract

The sections in this article are:

1 Bioenergetics
1.1 General Concepts
1.2 Lung Bioenergetics
2 Oxygen‐Dependent Metabolic Reactions
2.1 Pathways of O2 Utilization
2.2 Pulmonary O2‐Dependent Metabolic Reactions
2.3 Inactivation of Vasoactive Amines
3 Oxygen Toxicity
3.1 Pathological Effects of O2
3.2 Mechanisms of O2 Toxicity
3.3 Antioxidant Defenses
4 Conclusion
Figure 1. Figure 1.

Scheme for mitochondrial electron‐transport chain showing pathway for electrons from substrate (NADH, fatty acyl‐CoA, or succinate) to O2. Components are shown with their midpoint redox potentials in parentheses. Components of complexes are grouped together. Arrows, direction of electron flow between complexes. Left, scales for redox potential (Em) and relative standard free‐energy changes (ΔGO). Right, summation of energy (ΔGO) available per phosphorylation site. Energy available at each site exceeds the ΔGO required for ATP synthesis (7 kcal/mol); ΔGO required for ATP synthesis under physiological conditions exceeds the ΔGO by ∼50%. Heavy bars, sites of inhibition by electron‐transport inhibitors. IS, iron‐sulfur center; ttfa, thenoyltrifluoroacetone.

Figure 2. Figure 2.

Postulated scheme for ubiquinone (Q) cycle, indicating movements of electrons and protons across mitochondrial inner membrane in cyclic reduction and oxidation of ubiquinone. Associated components of electron‐transport chain are shown with midpoint potentials (in mV) in parentheses. Scheme provides both a mechanism for involvement of ubiquinone in electron‐transport chain and movement of protons from mitochondrial matrix through inner membrane into intermembrane space.

Figure 3. Figure 3.

O2 uptake of lung slices from different species plotted as a function of body weight. Closed circles, results for mouse, rat, guinea pig, rabbit, cat, dog, sheep, cow, and horse. Open circles, results for mouse, rat, cat, rabbit, and dog. Line, least mean square regression for a second‐degree polynomial (r = 0.936).

Closed circles, data from Krebs . Open circles, data from Massaro et al.
Figure 4. Figure 4.

Relationship between alveolar Po2 and glycolytic activity of the isolated perfused rat lung. Lactate (L) production and lactate to pyruvate (P) ratios are plotted as a function of log Po2. Arrows, approximate values for alveolar Po2 of 10 mmHg, 1 mmHg, and 0.05 mmHg.

Data from Fisher and Dodia
Figure 5. Figure 5.

Relationship between alveolar Po2 and ATP content of isolated perfused rat lung. Effect of hypoxia on lung ATP content occurs well below the physiological range of alveolar Po2.

Data from Fisher and Dodia
Figure 6. Figure 6.

Relationship between concentration of free Ca2+ in incubation medium and rate of glycerol 3‐phosphate oxidation by isolated rat lung mitochondria. Glycerol 3‐phosphate concentration was 3 mM. Free Ca2+ is plotted as minus log free Ca2+ (p Ca++).

From Fisher et al. . Copyright 1973 American Chemical Society
Figure 7. Figure 7.

Scheme for mixed‐function oxidation by cytochrome P‐450 system. Flow of electrons from NADPH to O2 and an organic substrate (AH2) through the NADPH‐cytochrome P‐450 reductase‐cytochrome P‐450 complex.

Figure 8. Figure 8.

Relationships of active O2 species formed from reduction of molecular O2. Electrons, if added one at a time, result in sequential formation of superoxide (), hydrogen peroxide (H2O2), hydroxyl radical () and finally H2O. Addition of 22 kcal of energy to O2 (e.g., through photoactivation with methylene blue) can form metastable singlet oxygen (). Not shown are protonation of to form hydroperoxy radical () or addition of 37 kcal to O2 to form a higher but very labile state.

Figure 9. Figure 9.

Postulated metabolic events accompanying exposure to elevated partial pressures of O2. Primary event is an increased rate of generation of superoxide anion, H2O2, and possibly and HO•. These and perhaps other agents form tissue pool of oxidants. Interaction of these oxidants with tissue components may oxidize tissue proteins and lipids, resulting in damage to cell membranes and intracellular enzymes. Interaction of quenchers with oxidizing agents and with tissue‐oxidized components decreases size of tissue oxidant pool and terminates free‐radical chain reactions. Oxidized tissue components (including H2O2 and oxidized quenchers) can be reduced through action of glutathione system, which in turn is in equilibrium with cytoplasmic NADP+/NADPH. In the lung, NADPH is generated primarily through activity of pentose shunt pathway of glucose metabolism. Degree of lung damage during O2 exposure may depend on outcome of interaction between radical‐generating and radical‐quenching pathways and tissue‐damaging and tissue‐repairing processes. Increased oxidation of tissue components may become manifest by damage to tissue membranes and depression of tissue metabolism due to inactivation of enzymes. This process may eventuate in pulmonary edema, but the precise mechanisms remain to be defined. GSH, reduced glutathione; GSSG, oxidized glutathione; SOD, superoxide dismutase.

From Fisher, Bassett, and Forman


Figure 1.

Scheme for mitochondrial electron‐transport chain showing pathway for electrons from substrate (NADH, fatty acyl‐CoA, or succinate) to O2. Components are shown with their midpoint redox potentials in parentheses. Components of complexes are grouped together. Arrows, direction of electron flow between complexes. Left, scales for redox potential (Em) and relative standard free‐energy changes (ΔGO). Right, summation of energy (ΔGO) available per phosphorylation site. Energy available at each site exceeds the ΔGO required for ATP synthesis (7 kcal/mol); ΔGO required for ATP synthesis under physiological conditions exceeds the ΔGO by ∼50%. Heavy bars, sites of inhibition by electron‐transport inhibitors. IS, iron‐sulfur center; ttfa, thenoyltrifluoroacetone.



Figure 2.

Postulated scheme for ubiquinone (Q) cycle, indicating movements of electrons and protons across mitochondrial inner membrane in cyclic reduction and oxidation of ubiquinone. Associated components of electron‐transport chain are shown with midpoint potentials (in mV) in parentheses. Scheme provides both a mechanism for involvement of ubiquinone in electron‐transport chain and movement of protons from mitochondrial matrix through inner membrane into intermembrane space.



Figure 3.

O2 uptake of lung slices from different species plotted as a function of body weight. Closed circles, results for mouse, rat, guinea pig, rabbit, cat, dog, sheep, cow, and horse. Open circles, results for mouse, rat, cat, rabbit, and dog. Line, least mean square regression for a second‐degree polynomial (r = 0.936).

Closed circles, data from Krebs . Open circles, data from Massaro et al.


Figure 4.

Relationship between alveolar Po2 and glycolytic activity of the isolated perfused rat lung. Lactate (L) production and lactate to pyruvate (P) ratios are plotted as a function of log Po2. Arrows, approximate values for alveolar Po2 of 10 mmHg, 1 mmHg, and 0.05 mmHg.

Data from Fisher and Dodia


Figure 5.

Relationship between alveolar Po2 and ATP content of isolated perfused rat lung. Effect of hypoxia on lung ATP content occurs well below the physiological range of alveolar Po2.

Data from Fisher and Dodia


Figure 6.

Relationship between concentration of free Ca2+ in incubation medium and rate of glycerol 3‐phosphate oxidation by isolated rat lung mitochondria. Glycerol 3‐phosphate concentration was 3 mM. Free Ca2+ is plotted as minus log free Ca2+ (p Ca++).

From Fisher et al. . Copyright 1973 American Chemical Society


Figure 7.

Scheme for mixed‐function oxidation by cytochrome P‐450 system. Flow of electrons from NADPH to O2 and an organic substrate (AH2) through the NADPH‐cytochrome P‐450 reductase‐cytochrome P‐450 complex.



Figure 8.

Relationships of active O2 species formed from reduction of molecular O2. Electrons, if added one at a time, result in sequential formation of superoxide (), hydrogen peroxide (H2O2), hydroxyl radical () and finally H2O. Addition of 22 kcal of energy to O2 (e.g., through photoactivation with methylene blue) can form metastable singlet oxygen (). Not shown are protonation of to form hydroperoxy radical () or addition of 37 kcal to O2 to form a higher but very labile state.



Figure 9.

Postulated metabolic events accompanying exposure to elevated partial pressures of O2. Primary event is an increased rate of generation of superoxide anion, H2O2, and possibly and HO•. These and perhaps other agents form tissue pool of oxidants. Interaction of these oxidants with tissue components may oxidize tissue proteins and lipids, resulting in damage to cell membranes and intracellular enzymes. Interaction of quenchers with oxidizing agents and with tissue‐oxidized components decreases size of tissue oxidant pool and terminates free‐radical chain reactions. Oxidized tissue components (including H2O2 and oxidized quenchers) can be reduced through action of glutathione system, which in turn is in equilibrium with cytoplasmic NADP+/NADPH. In the lung, NADPH is generated primarily through activity of pentose shunt pathway of glucose metabolism. Degree of lung damage during O2 exposure may depend on outcome of interaction between radical‐generating and radical‐quenching pathways and tissue‐damaging and tissue‐repairing processes. Increased oxidation of tissue components may become manifest by damage to tissue membranes and depression of tissue metabolism due to inactivation of enzymes. This process may eventuate in pulmonary edema, but the precise mechanisms remain to be defined. GSH, reduced glutathione; GSSG, oxidized glutathione; SOD, superoxide dismutase.

From Fisher, Bassett, and Forman
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Aron B. Fisher, Henry J. Forman. Oxygen Utilization and Toxicity in the Lungs. Compr Physiol 2011, Supplement 10: Handbook of Physiology, The Respiratory System, Circulation and Nonrespiratory Functions: 231-254. First published in print 1985. doi: 10.1002/cphy.cp030105