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Anesth Analg 2002;94:943-947
© 2002 International Anesthesia Research Society

CRITICAL CARE AND TRAUMA

Halothane Potentiation of Hydrogen Peroxide-Induced Inhibition of Surfactant Synthesis: The Role of Type II Cell Energy Status

Alka B. Patel, MD, PhD{dagger}, June Sokolowski, BS*, Bruce A. Davidson, BS{ddagger}, Paul R. Knight, MD, PhD{ddagger}§, and Bruce A. Holm, PhD*{dagger}

Departments of *Pediatrics, {dagger}Pharmacology, {ddagger}Anesthesiology, and §Microbiology, State University of New York at Buffalo, School of Medicine and Biomedical Sciences, Buffalo, New York

Address correspondence and reprint requests to Dr. Bruce A. Holm, Office of the Dean, 128 Biomedical Education Building, School of Medicine & Biomedical Sciences, State University of New York at Buffalo, Buffalo, New York 14214. Address e-mail to baholm{at}buffalo.edu


   Abstract
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 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Small concentrations of inhaled anesthetics can affect Type II cell surfactant production and exacerbate oxidant-mediated lung injury. We hypothesized that inhaled anesthetics augment oxidant-induced Type II pneumocyte dysfunction related to their different effects on cellular adenosine triphosphate (ATP) status. Freshly isolated Type II cells were exposed to different concentrations of hydrogen peroxide (H2O2) in the presence or absence of an in vitro halothane exposure. Cells exposed to 100 µM H2O2 alone demonstrated a 23% decrease in ATP levels and a 32% decrease in phosphatidylcholine (PC) synthesis compared with controls. Halothane alone decreased PC synthesis by only 12% and reduced ATP levels by 20%. However, when exposed to both halothane and H2O2 together, ATP levels decreased by 40%, and PC synthesis rates decreased by 51%. Pretreatment of cells with nicotinamide, an inhibitor of poly adenosine diphosphate ribose polymerase, completely prevented the ATP loss and PC synthesis decline caused by H2O2 alone, but it had no effect on the halothane-augmented portion of the cell injury. These data suggest that the ability of halothane to enhance oxidative damage may be related to its own specific effects on cell energetics that may not be amenable to the same treatments used to mitigate other cellular mechanisms of oxidative stress.

IMPLICATIONS: A mediator of inflammation (hydrogen peroxide) and an inhaled anesthetic (halothane) interact to decrease cell energy and secretion of a substance (surfactant) required for healthy lung function from cells that line gas-exchange compartments. This interaction represents a possible mechanism by which inflammatory lung disease may become more severe intraoperatively.


   Introduction
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 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Patients may develop an acute inflammatory process in the lung before or during anesthesia and surgery. Previously we have demonstrated, in experimental animals, that in the presence of an acute neutrophilic lung injury, exposure to halothane, enflurane, or isoflurane resulted in an increase in markers of lung injury (1). Because neutrophils elaborate a number of toxic products, including reactive species of oxygen, we have postulated that there could be a toxic interaction between the volatile anesthetics and these chemical inflammatory effectors. In vitro we have been able to show that cellular injury is increased after exposure to either halothane or isoflurane in co-cultures of phorbol myristate acetate-activated neutrophils or in response to exogenously added hydrogen peroxide (H2O2) (2).

Alterations in the pulmonary surfactant system contribute significantly to the pathophysiology of various acute lung injuries (3–7). One common factor in many of these injuries is the presence of increased oxidant stress on the lung. In vivo studies with hyperoxia have demonstrated that the functional or quantitative pulmonary surfactant alterations occurred secondarily to changes in the Type II cell metabolic function (5,8). Correspondingly, in vitro studies have shown that, regardless of the oxidant stress-generating system, Type II pneumocyte surfactant synthesis, as assessed by labeled lipid precursor incorporation into phosphatidylcholine (PC) and dipalmitoyl PC, decreased without a corresponding reduction in cell viability (9–14).

Depletion of adenosine triphosphate (ATP), a cofactor essential to surfactant phospholipid biosynthesis, seems to be an important mechanism through which oxidant stress affects Type II pneumocyte surfactant synthesis (12–15). By use of 300 µM H2O2, Hudak et al. (16) observed decreases in ATP, nicotinamide adenine dinucleotide (NAD), and reduced NAD (NADH) levels coupled with activation of poly adenosine diphosphate ribose polymerase (PARP) and inhibition of surfactant synthesis in Type II pneumocytes. Pretreatment of cells with 3-aminobenzamide or nicotinamide prevented both depletion of cellular energy stores and activation of PARP, as well as the inhibition of surfactant synthesis, thus demonstrating a causal relationship between in vitro H2O2 exposure, activation of PARP, depletion of cellular ATP stores, and inhibition of surfactant synthesis. In addition, inhibition of glycolysis by pretreatment of Type II cells with 2-deoxyglucose resulted in a decrease in cellular ATP levels and surfactant synthesis, suggesting that nonoxidant-mediated ATP depletion also affects PC synthesis (14).

These studies raise the interesting question of whether Type II cell ATP depletion by different mechanistic pathways may lead to a potentiation of surfactant synthesis inhibition and, hence, acute lung injury. One such clinical situation in which this may occur is during the use of volatile anesthetics, such as halothane, when preexisting lung injury is present. Clinically relevant concentrations of halothane inhibit Type II cell PC synthesis (17). In addition, halothane limits liver ATP synthesis through inhibition of the electron transport chain and uncoupling of oxidative phosphorylation (18–21).

Hence, the purpose of this study was to determine the effects of halothane in combination with H2O2 on rabbit alveolar Type II cell metabolic function and cellular energetics. It is hypothesized that halothane further depletes cellular ATP, resulting in potentiation of the surfactant synthesis inhibition associated with H2O2, and this potentiation occurs through a different mechanistic depletion of ATP.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
All animal experiments were reviewed and approved by the Institutional Animal Care and Use Committee of the State University of New York at Buffalo in accordance with AALAC and federal guidelines. Type II cells were isolated from adult New Zealand white rabbits, as described by Finkelstein and Shapiro (22) and Finkelstein et al. (23). Briefly, rabbits were killed and the lungs removed and incubated with a protease cocktail consisting of 0.10 mg/mL DNase I, 0.18 mg/mL trypsin, and 1.3 U/mL elastase. After incubation for 35 min at 37°C, the tissue was minced with microdissecting scissors. The retained media was added to the minced tissue, and the suspension was stirred for 20 min at room temperature. The tissue suspension was filtered and Type II cells isolated by centrifugation of a discontinuous Percoll density. Cell counts were determined by a hemocytometer, and viability was assessed by trypan blue exclusion. This isolation technique resulted in Type II cell purity of >90% and >95% viability.

The rate of incorporation of (methyl-[3H]) choline (75 µCi/mmol) was used to measure PC synthesis in Type II cells as described by Finkelstein et al. (22). After incubation with 2 µCi/mL (methyl-[3H]) choline for 60 min at 37°C, samples were removed at 0, 30, and 60 min after equilibration. The phospholipids were then extracted from the pelted cells by using the method of Bligh and Dyer (24) and isolated by thin layer chromatography (25). The separated phospholipids were visualized by using rhodamine, and the PC spot was identified and radioactivity determined.

By use of a modified version of the firefly luciferin/luciferase assay, intracellular ATP levels were assessed (26). Pelleted, resuspended cells were incubated with 2% trichloroacetic acid with 2 mM EDTA for 10 min. Luciferin/luciferase (BioOrbit, Turku, Finland) and Tris acetate buffer were then added, and light emission was determined with a luminometer (model 1250; BioOrbit) and compared with a known internal ATP standard.

Cultures of Type II cells were exposed for 20 min to 2.5% halothane at room temperature, as previously described (1). This concentration of anesthetic was chosen on the basis of these previous studies. Respiratory epithelium may be exposed to this anesthetic level in vivo during induction or at other times when rapid increases in anesthetic depth may be required. For choline incorporation studies, exposure occurred during the final 20 min of the equilibration period. For ATP studies, 2 x 106 cells/mL minimum essential medium were simply exposed to halothane for 20 min in the absence of radiolabeled choline.

Type II cells were exposed to either 100 or 300 µM H2O2. For choline incorporation studies, H2O2 was added to the cells after the 60-min equilibration period with radiolabeled choline (16,27). For ATP studies, H2O2 was added to the cell suspension for a 30-min incubation period, as previously described (16,27). In both cases, exposure to H2O2 occurred during a 37°C incubation and did not cause cell death.

The concentration of H2O2 was verified spectrophotometrically by determining the horseradish peroxidase-mediated oxidation of phenol in the presence of 15 mM aminoantipyrene at 510 nm and comparing the results with an H2O2 stock solution (27). In selected experiments, the PARP inhibitor nicotinamide (5 mM) was added to the cells 15 min before the addition of H2O2.

Results for all experiments are expressed as means ± SEM. All groups were equally weighed statistically; significant differences among groups were assessed by Student’s t-test with a Bonferroni modification for multiple-group analysis. In all cases, P < 0.05 was considered significant.


   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Exposure of cells to 2.5% halothane resulted in a PC synthesis rate of 0.464 ± 0.13 nmol/106 cells per hour compared with 0.530 ± 0.062 nmol/106 cells per hour in control cells (P = 0.15), as shown in Figure 1A. Exposure to 100 µM H2O2 alone resulted in a PC synthesis rate of 0.360 ± 0.02 nmol/106 cells per hour (P = 0.016 compared with control), whereas exposure to 300 µM H2O2 reduced PC synthesis to 0.259 ± 0.01 nmol/106 cells per hour (P = 0.008 compared with control) (Fig. 1A).



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  		Figure 1. (A) Effects of 2.5% halothane and hydrogen peroxide (H2O2) on phosphatidylcholine (PC) synthesis rates in Type II pneumocytes. Cells were incubated with halothane 20 min before exposure to 30 min of H2O2. *P < 0.02 compared with controls; +P < 0.02 compared with H2O2; n = 6. (B) Effects of 2.5% halothane and H2O2 on adenosine triphosphate (ATP) levels in Type II pneumocytes. Cells were incubated with halothane 20 min before exposure to 30 min of H2O2. *P < 0.02 compared with controls; +P < 0.02 compared with H2O2; n = 6.

 
The data in Figure 1A also show that exposure to both halothane and 100 µM H2O2 resulted in a Type II cell PC synthesis rate of 0.261 ± 0.025 nmol/106 cells per hour (P = 0.008 compared with control; P = 0.024 compared with 100 µM H2O2 alone). In contrast, cells exposed to 300 µM H2O2 plus halothane exhibited a PC synthesis rate of 0.249 ± 0.04 nmol/106 cells per hour (P = 0.01 compared with control; P = 0.82 compared with 300 µM H2O2 alone).

Figure 1B shows the effects of halothane and H2O2 on Type II cell ATP levels. Halothane decreased Type II pneumocyte ATP levels by 20% (P = 0.004). H2O2 treatment alone resulted in dose-dependent reductions in ATP levels compared with controls; 100 µM H2O2 decreased ATP levels by 23% (P < 0.001), whereas 300 µM H2O2 treatment decreased intracellular ATP levels by 41% (P = 0.03). After pretreatment with halothane, ATP levels in cells exposed to 100 µM H2O2 or to 300 µM H2O2 were 62% (P < 0.001) and 49% (P < 0.001) of control levels, respectively, as shown in Figure 1B.



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  		Figure 2. (A) Effects of pretreatment with nicotinamide on halothane/hydrogen peroxide (H2O2) reduction of phosphatidylcholine (PC) synthesis in Type II pneumocytes. Cells were incubated with halothane and 5 mM nicotinamide 15 min before exposure to 30 min of H2O2. PC synthesis in Type II pneumocytes was then determined. *P < 0.00016 compared with controls; n = 8. (B) Effects of pretreatment with nicotinamide on halothane/H2O2 reduction of adenosine triphosphate (ATP) in Type II pneumocytes. Cells were incubated with halothane and 5 mM nicotinamide 15 min before exposure to 30 min of H2O2. ATP levels in Type II pneumocytes were then determined. *P = 0.0007 compared with controls; n = 6.

 
The data in Figure 2B demonstrate that after treatment with nicotinamide, cellular ATP levels in Type II cells exposed to 2.5% halothane and 100 µM H2O2 were 83.1% ± 4.7% of control (P = 0.126). ATP levels in Type II cells treated with nicotinamide and exposed to 100 µM H2O2 alone were 95% ± 5% of control (Fig. 2B). Nicotinamide treatment blocked the decrease in PC synthesis caused by 100 µM H2O2, but it only partially protected PC synthesis rates in cells exposed to 2.5% halothane plus 100 µM H2O2 (Fig. 2A).


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
Our studies support previous observations that exposure to the volatile anesthetics (halothane, enflurane, or isoflurane) increases inflammatory lung injury in vivo as well as oxidant-induced cell injury in vitro (1,2). These experiments also provide further support for the hypothesis that cellular ATP depletion is an important mechanism of Type II pneumocyte metabolic dysfunction and suggest that volatile anesthetics may also increase cellular injury by this mechanism. Exposure of Type II pneumocytes in vitro to concentrations of halothane that the respiratory epithelium may clinically experience significantly decreased ATP levels. Similarly, in vitro exposure of Type II pneumocytes to H2O2 caused dose-dependent decreases in both cellular ATP levels and the rate of PC synthesis. Halothane exposure before H2O2 treatment augmented the cellular ATP reduction of both 100 µM H2O2 and 300 µM H2O2. Halothane also enhanced the inhibition of PC synthesis by 100 µM H2O2, such that the rates were similar to cells exposed to 300 µM H2O2 alone. However, exposure of cells to both halothane and 300 µM H2O2 did not reduce PC synthesis rates any further, suggesting a limit to the halothane interaction. Pretreatment of halothane-exposed cells with the PARP inhibitor nicotinamide partially protected both cellular ATP levels and PC synthesis rates after 100 µM H2O2 exposure.

These results provide further support for the study of Molliex et al. (17), which demonstrated that clinically relevant concentrations of halothane are capable of causing Type II pneumocyte metabolic dysfunction. These investigators demonstrated that a four-hour exposure to 2% halothane decreased the rate of PC synthesis in cultured Type II pneumocytes by 24%. In this study, a 20-minute exposure to 2.5% halothane alone caused a smaller change in the rate of PC synthesis but resulted in a 20% decrease in ATP levels compared with controls.

Molliex et al. (17) also found that halothane induced a dose-dependent decrease in cellular ATP levels, but they found statistical significance only at 8% halothane. Because of the lack of statistical significance at smaller halothane concentrations, these authors concluded that ATP depletion did not play a major role in the halothane-mediated reduction of PC synthesis. Our results suggest otherwise. Halothane was clearly capable of enhancing the H2O2-mediated depletion of ATP levels and reduction of PC synthesis. In the case of choline incorporation into PC, there seemed to be a limit to the extent of potentiation, because halothane did not enhance the effects of 300 µM H2O2 on PC synthesis, despite further decreasing ATP levels.

We have previously shown that inhibitors of poly adenosine diphosphate ribosylation can protect both Type II cell energetics and surfactant metabolism after oxidant stress (16), a finding that was repeated in this study with 100 µM H2O2. In contrast, pretreatment of halothane-exposed cells with PARP inhibitors only partially restored the rates of PC synthesis and ATP levels during exposure to H2O2. These results suggest that the reduction of cellular ATP elicited by halothane and H2O2 is mechanistically different.

There is significant literature demonstrating that halothane, as well as other volatile anesthetics, alters ATP synthesis through interactions with the mitochondria. Specifically, halothane inhibits the passage of electrons through Complex I (NADH dehydrogenase to ubiquinone) of the electron transport chain and acts as an atypical uncoupler of oxidative phosphorylation (18–20). Exposure of Type II pneumocytes to increasing concentrations of halothane resulted in decreased ATP levels accompanied by increased glycolysis and lactate production (17). Whether the increase in glycolytic metabolism caused or was the result of ATP depletion is unclear. Regardless, these studies suggest that whereas H2O2 depletes ATP stores through PARP activation (16), halothane may reduce cellular ATP levels through interactions with electron transport and oxidative phosphorylation (18–20). The ability of PARP inhibitors to only partially restore cellular ATP levels after combined exposure to halothane and H2O2 supports this theory. Similarly, the inability of PARP inhibitors to restore choline incorporation rates to normal after combined halothane-oxidant exposure supports the hypothesis that cellular ATP levels affect surfactant synthesis.

It is difficult to make in vivo predictions on the basis of in vitro results. This is particularly true when reactive species of oxygen are involved, because interactions with other chemical effectors, such as proteinases or nitric oxide, may affect the outcome. However, these findings do suggest a mechanism to account for our observations that halothane, enflurane, or isoflurane exacerbate acute inflammatory lung injury in a rodent model (1). Our results suggest that halothane can potentially exacerbate inflammatory lung injury through interactions with the Type II pneumocyte. Mechanistically, this may occur as a result of the combined and distinct effects of oxidants and volatile anesthetics on cellular energetics. The decrease in energy status in vivo after oxidant stress is similar to the decrease observed in vitro in this study (28). These findings may have important clinical implications. Patients who undergo surgery and, thus, anesthesia may intraoperatively develop (i.e., gastric aspiration) or already have preexisting inflammatory lung pathology (i.e., acute exacerbation of underlying chronic obstructive pulmonary disease) that is, in part, mediated by the generation of oxidants. Volatile anesthetics may serve to aggravate the existing pathophysiology. Unfortunately, patient studies to detect an interaction between volatile anesthetics with active oxidant-mediated pulmonary disease may be difficult because the role of oxidants in any acute inflammatory processes is somewhat unpredictable. Furthermore, it is not ethical to standardize an inflammatory lung injury in patients.


   Acknowledgments
 
This study was supported by National Institutes of Health Grants HL48889 (PRK) and HL56176 (BAH).


   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication December 4, 2001.





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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 2002 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press