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Ann Thorac Surg 1996;61:1453-1457
© 1996 The Society of Thoracic Surgeons

Original Articles: General Thoracic

Thromboxane Receptor Blockade Improves Oxygenation in an Experimental Model of Acute Lung Injury

Steven D. Thies, MD, R. Scott Corbin, MD, Charles D. Goff, MD, Oliver A. R. Binns, MD, Scott A. Buchanan, MD, Kimberly S. Shockey, MS, Henry F. Frierson, Jr, MD, Jeffrey S. Young, MD, Curtis G. Tribble, MD, Irving L. Kron, MD

Department of Surgery, University of Virginia, Charlottesville, Virginia


   Abstract
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 Abstract
Introduction
 Materials and Methods
 Results
 Comment
 Acknowledgments
 References
 
Background. Adult respiratory distress syndrome remains a major cause of morbidity and mortality. We investigated the role of thromboxane receptor antagonism in an experimental model of acute lung injury that mimics adult respiratory distress syndrome.

Methods. Three groups of rabbit heart-lung preparations were studied for 30 minutes in an ex vivo blood perfusion/ventilation system. Saline control (SC) lungs received saline solution during the first 20 minutes of study. Injury control (IC) lungs received an oleic acid-ethanol solution during the first 20 minutes. Thromboxane receptor blockade (TRB) lungs received the same injury as IC lungs, but a thromboxane receptor antagonist (SQ30741) was added to the blood perfusate just prior to study. Blood gases were obtained at 10-minute intervals, and tidal volume, pulmonary artery pressure, and lung weight were continuously recorded. Oxygenation was assessed by measuring the percent change in oxygen tension over the 30-minute study period. Tissue samples were collected from all lungs for histologic evaluation.

Results. Significant differences were found between SC and IC lungs as well as TRB and IC lungs when comparing pulmonary artery pressure (SC = 33.1 ± 2.2 mm Hg, TRB = 35.4 ± 2.1 mm Hg, IC = 60.4 ± 11.1 mm Hg; p < 0.02) and percent change in oxygenation (SC = -20.6% ± 10.3%, TRB = -24.2% ± 9.5%, IC = -57.1% ± 6.2%; p < 0.03). None of the other variables demonstrated significant differences.

Conclusions. Thromboxane receptor blockade prevents the pulmonary hypertension and the decline in oxygenation seen in an experimental model of acute lung injury that mimics adult respiratory distress syndrome.


   Introduction
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 Abstract
 Introduction
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See also page 1457.

Adult respiratory distress syndrome (ARDS) remains a devastating form of respiratory failure among critically ill patients. The mortality rate for patients with ARDS alone is approximately 50%, a figure that increases dramatically as other organ systems fail [1, 2]. Respiratory failure in ARDS is progressive and stems from pathologic changes at the alveolar-capillary membrane. Understanding how such changes are mediated at the cellular level is essential if effective treatment strategies are to be devised.

A variety of physiologically active substances are present within the microenvironment of acute lung injury. Of note among these are the eicosanoids, which have a myriad of effects on both healthy and injured lung tissues. We chose to study a single eicosanoid, thromboxane, in an isolated rabbit lung model of acute lung injury. Thromboxane has been implicated as a mediator of deleterious physiologic changes that promote pulmonary failure after acute lung injury. Its active form, thromboxane A2 (TXA2), is produced by thromboxane synthetase in the cyclooxygenase pathway of arachidonic acid metabolism. Thromboxane A2 is a potent but unstable eicosanoid with a half-life of only 30 seconds. Degradation leads to the stable, inactive thromboxane B2, whose measurement provides a useful inference of TXA2 levels. By using a selective TXA2 receptor antagonist, we hoped to elucidate the contributions of thromboxane to the pathologic changes seen in acute lung injury.


   Materials and Methods
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We studied a series of lung preparations using an isolated, blood-perfused rabbit lung model. Our protocol was approved by the university's institutional review board, and all animals were cared for in accordance with institutional guidelines as well as those set forth by the National Institutes of Health.

New Zealand White rabbits, each weighing 3 to 4 kg, were anesthetized with intramuscular injections of xylazine (20 mg) and ketamine hydrochloride (200 mg). After a tracheostomy, animals were mechanically ventilated. A median sternotomy was performed, and systemic anticoagulation was achieved with 1,000 units of intravenous heparin sodium. The heart and great vessels were then isolated, cannulated, and flushed with saline solution. The entire heart-lung preparation was explanted en bloc and placed immediately into our ex vivo system for study.

The isolated lungs were continuously ventilated by a pressure-controlled small-animal ventilator (Kent Scientific) at a rate of 20 breaths/min and an inspired oxygen fraction of 21%. Continuous blood perfusion was achieved with a Masterflex roller pump (Cole Parmer Instruments) at a rate of 60 mL/min. Blood was recirculated through a 200-mL reservoir filled with heparinized blood (1,000 units) collected from separate donor rabbits at the time of lung harvest. Perfusate hematocrit was maintained at 25% to 30% for each trial. Infusions entered the circuit through a side port in the inflow channel and were controlled by a Harvard pump infusion system.

This circuit allowed for direct measurement of tidal volume (mL), pulmonary artery pressure (PAP) (mm Hg), and lung weight (g) at 15-second intervals. Pulmonary venous pressure (mm Hg) was also measured but was fixed at 5 mm Hg based on the height of the outflow channel. Calculated variables included pulmonary vascular resistance (dynes•s/cm5) and dynamic pulmonary compliance. All variables were continuously recorded by computer and displayed on an adjacent monitor. These data were later used to calculate dynamic pulmonary compliance as well as percent changes in tidal volume, lung weight, PAP, and pulmonary vascular resistance. In addition, a separate reservoir of fresh venous blood was used to obtain outflow blood gases at baseline and at 10-minute intervals. These values along with blood gases obtained simultaneously from the venous reservoir were used to determine changes in the capacity of the lungs to oxygenate. Measurement of oxygenation capacity was calculated as follows:



where AVO2 = arteriovenous oxygen, PO2 = oxygen tension, and 0` and 30` = 0 and 30 minutes.

After ventilation and perfusion had begun, the lung preparations were monitored for a period of 2 to 5 minutes. If tidal volume, PAP, and weight remained constant, the preparations were considered stable, and further study was undertaken. All lung preparations were assigned to one of three study groups and studied for a period of 30 minutes (Fig 1Go). All variables were recorded as already described, and blood gases were obtained at time 0, 10, 20, and 30 minutes. On completion of the study, tissue samples were taken from all lungs for histologic evaluation.



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  		Fig 1. . Study protocol: After stabilization, each group was perfused for 30 minutes. The saline control lungs received normal saline solution (NS) for the first 20 minutes, and the injury control and thromboxane A2 (TXA) blockade groups each received oleic acid-ethanol (OA/EtOH) infusion for the first 20 minutes. The TXA blockade group was perfused with blood pretreated with TXA receptor antagonist. The arteriovenous oxygen (AVO2) difference was calculated at 10-minute intervals. (TRB = thromboxane receptor blockade.)

 
Saline control (SC) lungs received a continuous infusion of normal saline solution that began at time 0 and continued at 0.06 mL/min for 20 minutes, for a total infusion volume of 1.2 mL. Injury control (IC) lungs received a continuous infusion of an oleic acid (OA)-ethanol solution that began at time 0 and continued at 0.06 mL/min for 20 minutes, for a total infusion volume of 1.2 mL. Ethanol solubilized the OA to provide a diffuse injury. Previous controls demonstrated no hemodynamic or histologic change when ethanol alone was used at these volumes. Thromboxane receptor blockade (TRB) lungs received the same OA injury as IC lungs, but 6 mg of TXA2 receptor antagonist (SQ30741, Bristol Myers Squibb) was added to the blood perfusate just before study.


   Results
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 Footnotes
 Abstract
 Introduction
 Materials and Methods
 Results
Comment
 Acknowledgments
 References
 
All data from the three study groups were analyzed using analysis of variance. When significant differences existed between groups, Tukey's honestly significant difference test was employed to determine where the difference existed. The study groups had the following number of preparations: SC, 9; TRB, 8; and IC, 9.

Significant differences between groups were found when evaluating both oxygenation data and PAP data. Oxygenation was assessed by measuring the percent change in oxygen tension over the 30-minute study period. Injured lungs experienced dramatic changes in oxygenation capacity, whereas SC and TXA2 receptor antagonist-treated lungs fared significantly better (Fig 2Go). Analysis of variance demonstrated significant differences between SC and IC lungs (uninjured and injured controls, respectively) as well as between TRB and IC lungs (treatment and injury controls, respectively) at a p value of less than 0.03. Importantly, no significant difference existed between SC lungs and TRB lungs.



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  		Fig 2. . Percent change in oxygenation. The injury control (IC) lungs showed a significantly greater decline than either the saline vehicle control (SC) or thromboxane receptor blockade (TRB) lungs (p < 0.03). (AVO2 = arteriovenous oxygen.)

 
Pulmonary artery pressures were monitored throughout the study period, and the mean PAP was then calculated. A progressive pulmonary hypertension was noted in those lungs that were injured by OA but not in those receiving saline solution or TXA2 receptor antagonist (Fig 3Go). Analysis of variance demonstrated significant differences between SC and IC lungs (uninjured and injured controls) as well as TRB and IC lungs (treatment and injury controls) at a p value of less than 0.02. Importantly, no significant difference existed between SC lungs and TRB lungs.



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  		Fig 3. . Pulmonary artery pressure (PAP) in saline vehicle control (SC) lungs, injury control (IC) lungs, and thromboxane receptor blockade (TRB) lungs. Mean PAP was significantly higher in the IC lungs than in the SVC and TRB groups (p < 0.02).

 
Because pulmonary venous pressure and cardiac output (60 mL/min) were fixed in this model, pulmonary vascular resistance varied directly with PAP and therefore was not subjected to further analysis. Percent changes in weight and tidal volume were also analyzed, as was dynamic pulmonary compliance. None of these variables demonstrated significant differences. Lung weights generally increased 30% to 50% during the initial reperfusion/stabilization period, but no significant differences were seen between the study groups thereafter. Tidal volumes remained fairly constant throughout, and compliance generally fell by 10% to 20% in all groups.

On completion of physiologic studies, tissue samples were collected from each lung preparation for histologic evaluation. All samples were examined microscopically for evidence of parenchymal injury as manifested by edema, thrombi, hemorrhage, or a combination of these (Table 1Go). Using {chi}2 testing for tables, a significant difference was demonstrated between the study groups for edema formation (p < 0.005). Given the low percentages in these categories, statistical analysis was not very reliable, but the trends seem clear. Thromboxane A2 receptor antagonism appears to minimize the parenchymal injury created by OA.


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  		Table 1. . Results of Histologic Evaluationa-c
 

   Comment
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 Abstract
 Introduction
 Materials and Methods
 Results
 Comment
Acknowledgments
 References
 
Originally used to study fat embolism, OA infusion has become a widely used and well-accepted model of acute lung injury for the study of ARDS. As Schuster [3] pointed out, OA injury is not necessarily an accurate model for the causes of ARDS, but it does reproduce the effects of ARDS.

Oleic acid-injured lungs demonstrate markedly increased vascular permeability, a hallmark of ARDS. How OA, an unsaturated fatty acid, actually achieves this increase in permeability has long been the subject of investigation [4]. The preponderant cause, however, appears to be a direct injury to the alveolar epithelial lining that leads to alveolar-capillary disruption, interstitial edema, and alveolar flooding [5]. These parenchymal changes generate a variety of local and systemic responses that are comparable to ARDS [6]. It is these responses that we sought to evaluate with our model.

Oleic acid-induced acute lung injury has been studied in a variety of species as both in vivo and ex vivo systems. In vivo models are useful for evaluating systemic physiologic responses to acute lung injury. Ex vivo models, on the other hand, eliminate all systemic variables and focus instead on local pulmonary responses. Most ex vivo systems have used crystalloid preparations such as Krebs-Henseleit solution for lung perfusion. Our model, however, uses blood perfusion at a constant hematocrit with all normal blood components present. This more closely represents normal conditions and enables us to assess dynamic changes in the oxygenation capacity of the lungs. In addition, OA injury in our model occurs after the lungs have been harvested, thus removing any confounding effects of systemic OA injury. Therefore, we believe our model is a valuable one for studying pulmonary responses to acute lung injury.

Many of the major physiologic changes seen in OA-induced acute lung injury are thought to be mediated by vasoactive eicosanoids. Some investigators have found increased levels of eicosanoids and their metabolites after OA injury. Others have noted a lessening of injury after treatment with inhibitors or antagonists of specific eicosanoids. Efforts to determine which of these molecules is most responsible for the profound physiologic changes seen in acute lung injury have been underway for several years. We did not directly assay for any of these molecules in our study but concentrated instead on dynamic physiologic measurements.

Thromboxane A2 is a potent by-product of the cyclooxygenase pathway. Its major effect is vasoconstriction, but it also promotes platelet aggregation and increases airway resistance. Significantly increased levels of circulating thromboxane B2, the stable metabolite of TXA2, have been documented in models of OA-induced acute lung injury [7–9]. Elevated thromboxane B2 levels have also been found in lung tissues injured by OA [10, 11].

Using positron emission tomography, Stephenson and colleagues [10, 11] examined the effects of cyclooxygenase inhibitors and TXA2 receptor agonists on the perfusion of OA-injured lungs. The group concluded that the spontaneous perfusion redistribution that occurs after OA injury is due primarily to increased levels of TXA2. This conclusion in conjunction with the ubiquitous elevations in TXA2 levels seen by other investigators supports TXA2 as the preponderant eicosanoid in OA-induced acute lung injury.

Our study demonstrated significant differences in PAP when OA-injured lungs were compared with SC lungs and TRB lungs (see Fig 3Go). Treatment with SQ30741, a TXA2 receptor antagonist, kept the PAP of OA-injured lungs at levels not significantly different from SC lungs. Thus, we conclude that TXA2 is an important mediator of pulmonary hypertension in acute lung injury, a finding consistent with other studies. Acute lung injury models using staphylococcal toxin [12], ischemia-reperfusion [13], hydrogen peroxide [14], and arachidonic acid induction [15] all demonstrate significant links between high PAP and increased TXA2 levels. These studies also demonstrate a return of PAP to baseline (uninjured) levels when TXA2 antagonists are employed.

The biochemical basis of pulmonary artery contractions is addressed by Buzzard and associates [16] in a study of isolated segments of rabbit pulmonary artery. Thromboxane A2 appears to be the primary mediator of pulmonary artery contraction in their model. Endothelial cells were found not to possess thromboxane synthase, a finding implying that TXA2 is not of endothelial origin. However, the endothelium in this study was not injured.

In a model of ischemia-reperfusion injury, Zamora and associates [13] promoted macrophages, platelets, and types I and II pneumonocytes as likely sources of TXA2. Because their model was perfused with a cell-free, balanced salt solution, any TXA2 generated must have arisen from within the lung. Our model, on the other hand, was perfused with fresh whole blood. It is possible that in the injured lung, platelets or cellular aggregates could be deposited within the pulmonary capillary bed. A small number of our OA-injury controls (2/9) did demonstrate thrombus formation on histologic evaluation, but this was not significant. Interestingly, another blood-perfused model [17] discounted the effects of platelet aggregates on pulmonary vascular resistance and attributed increases in resistance solely to TXA2 and prostacyclin levels. Determining the true effect that platelets have on PAP in this model will require sophisticated TXA2 assay schemes. After endothelial injury, there seems to be a surge in TXA2 that tends to elevate PAP. This TXA2 appears to arise primarily from endogenous pulmonary cells, namely, pneumonocytes and macrophages.

Our study demonstrated significant differences in oxygenation when OA-injured lungs were compared with SC lungs and TRB lungs (see Fig 2Go). Treatment with SQ30741 provided OA-injured lungs protection against the oxygenation losses sustained by untreated injured lungs. This protection was rather dramatic. Though all groups experienced a decline in oxygenation, no significant differences existed between SC lungs and injured SQ30741-treated lungs. As discussed already, the elevated PAP seen in OA-injury was also negated by treatment with SQ30741. It appears therefore that the pulmonary hypertension seen in OA injury mediates a decline in oxygenation. This decline is prevented by TXA2 receptor blockade.

The end effects of OA injury are similar to those of ARDS. The ultimate deficit in both conditions is a deteriorating capacity to oxygenate the bloodstream. Oxygenation requires, first and foremost, a functional alveolar-capillary interface. Damage to this interface by OA leads to transcapillary protein leak with subsequent interstitial and intraalveolar edema [5, 18]. This edema can impair gas exchange, worsen compliance, and create large pulmonary shunt fractions. Such effects are seen in in vivo models of OA injury and contribute to hypoxia [6]. Most ex vivo models, however, are not blood perfused and are therefore unable to assess changes in oxygenation.

Our study groups did demonstrate a significant difference in edema formation when lung samples were examined microscopically. Percent gains in lung weight, however, were not significantly different. It is possible that this edema, which was present on a microscopic level, would have generated increased lung weights if our perfusion time had been greater. Furthermore, it is reasonable to expect compliance to decline as injury led to interstitial edema, but we found no significant difference in dynamic pulmonary compliance between study groups. These findings are probably related to our relatively short study period and do not accurately reflect injury severity. Indeed, newer data from our apparatus show a gradually worsening compliance curve when lungs are studied for longer periods under similar conditions.

The importance of interstitial edema and intraalveolar edema as impediments to oxygenation is well addressed by Schuster and associates [11]. Using a TXA2 agonist, they generated significant increases in edema and pulmonary shunting, which greatly reduced oxygenation. Regression analysis indicated that more than 60% of this reduction in oxygenation could be predicted by measurements of edema and shunting. Thromboxane A2 receptor blockade should minimize these changes and improve oxygenation.

In summary, our model of acute lung injury provides a useful method by which to study the end effects of ARDS. Oleic acid injury produces significant pulmonary hypertension, which is mediated chiefly by TXA2. This hypertension generates parenchymal lung injury, which is due mostly to elevated hydrostatic pressure. As this injury progresses, oxygenation becomes gradually more impaired. On the basis of these observations, we conclude that TXA2 receptor blockade improves oxygenation in our model by reducing PAPs to uninjured levels.


   Acknowledgments
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 Abstract
 Introduction
 Materials and Methods
 Results
 Comment
 Acknowledgments
References
 
Funded in part by the National Institutes of Health under National Research Service Award Fellowships 5F32 HL 08940 and 1F32 HL 09115 as well as R01 HL 48242.

We gratefully acknowledge Mr Anthony Herring, whose expert technical assistance was invaluable during completion of this study.


   Footnotes
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Abstract
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Presented at the Forty-second Annual Meeting of the Southern Thoracic Surgical Association, San Antonio, TX, Nov 9–11, 1995.

Address reprint requests to Dr Kron, Department of Surgery, University of Virginia Health Sciences Center, Box 310, Charlottesville, VA 22908.


   References
Top
 Footnotes
 Abstract
 Introduction
 Materials and Methods
 Results
 Comment
 Acknowledgments
 References
 

  1. Taylor RW, Norwood SH. The adult respiratory distress syndrome. In: Civetta JM, ed. Critical care. Philadelphia: JB Lippincott, 1992:1237.
  2. Rochon RB, Rice CL, Carrico CJ. Adult respiratory distress syndrome. In: Shields TW, ed. General thoracic surgery. 4th ed. Baltimore: Williams & Wilkins, 1994:788.
  3. Schuster DP. ARDS: clinical lessons from the oleic acid model of acute lung injury. Am J Respir Crit Care Med 1994;149:245–60.[Medline]
  4. Peltier LF. The toxic properties of neutral fat and free fatty acids. Surgery 1956;40:665–70.[Medline]
  5. Montaner JSG, Tsang J, Evans KG, et al. Alveolar epithelial damage. A critical difference between high pressure and oleic acid-induced low pressure pulmonary edema. J Clin Invest 1986;77:1786–96.
  6. Sum-Ping ST, Symreng T, Jebson P, Kamal GD. Stable and reproducible porcine model of acute lung injury induced by oleic acid. Crit Care Med 1991;19:405–8.[Medline]
  7. Katz SA, Halushka PV, Wise WC, Cook JA. Oleic acid induces pulmonary injury independent of eicosanoids in the isolated, perfused rabbit lung. Circ Shock 1987;22:221–30.[Medline]
  8. Olanoff LS, Reines HD, Spicer KM, Halushka PV. Effects of oleic acid on pulmonary capillary leak and thromboxanes. J Surg Res 1984;36:597–605.[Medline]
  9. Tachmes L, Adler H, Wolozsyn TT, et al. Role of arachidonic acid metabolites in oleic acid-induced pulmonary injury in a canine model: effect of ketoconazole (thromboxane synthetase inhibitor). Am Surg 1991;3:171–7.
  10. Stephenson AH, Lonigro AJ, Holmberg SW, Schuster DP. Eicosanoid balance and perfusion redistribution of oleic acid-induced acute lung injury. J Appl Physiol 1992;73: 2126–34.[Abstract/Free Full Text]
  11. Schuster DP, Sandiford P, Stephenson AH. Thromboxane receptor stimulation/inhibition and perfusion redistribution after acute lung injury. J Appl Physiol 1993;75:2069–78.[Abstract/Free Full Text]
  12. Seeger W, Bauer M, Bhakdi S. Staphylococcal alpha-toxin elicits hypertension in isolated rabbit lungs. J Clin Invest 1984;74:849–58.
  13. Zamora CA, Baron DA, Heffner JE. Thromboxane contributes to pulmonary hypertension in ischemia-reperfusion lung injury. J Appl Physiol 1993;74:224–9.[Abstract/Free Full Text]
  14. Corten I, Peeters FAM, Rampart M, Bult H, Buyssens N, Herman AG. Ridogrel prevents the thromboxane-mediated pressor response and oedema induced by hydrogen peroxide in isolated rabbit lungs. Eur J Pharmacol 1991;201:83–90.[Medline]
  15. Littner MR, Lott FD. Edema from cyclooxygenase products of endogenous arachidonic acid in isolated lung. J Appl Physiol 1989;67:846–55.[Abstract/Free Full Text]
  16. Buzzard CJ, Pfister SL, Campbell WB. Endothelium-dependent contractions in rabbit pulmonary artery are mediated by thromboxane A2. Circ Res 1993;72:1023–34.[Abstract/Free Full Text]
  17. Barnard JW, Ward RA, Adkins WK, Taylor AE. Characterization of thromboxane and prostacyclin effects on pulmonary vascular resistance. J Appl Physiol 1992;72:1845–53.[Abstract/Free Full Text]
  18. Sugerman HJ, Strash AM, Hirsch JI, et al. Sensitivity of scintigraphy for detection of pulmonary capillary albumin leak in canine oleic acid ARDS. J Trauma 1981;21:520–5.[Medline]

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