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J Appl Physiol 84: 1610-1614, 1998;
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Vol. 84, Issue 5, 1610-1614, May 1998

Effect of platelet-activating factor-receptor antagonism on endotoxin-induced lung dysfunction in sheep

James R. Snapper, Weixuan Lu, Peter L. Lefferts, and John S. Thabes

Center for Lung Research, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232

    ABSTRACT
Top
Abstract
Introduction
Methods
Results
Discussion
References

To further define the role of platelet-activating factor (PAF) in endotoxin-induced lung dysfunction, we examined the effect of ABT-299, a specific and potent PAF-receptor antagonist, on the response to endotoxemia in six chronically instrumented awake sheep. We administered Escherichia coli endotoxin (0.5 µg/kg) intravenously with or without pretreatment with ABT-299 while monitoring mean pulmonary arterial pressure (Ppa), mean systemic arterial pressure (Psa), dynamic compliance of the lungs (Cdyn), and functional residual capacity (FRC). Endotoxin administration caused pulmonary hypertension, reduced Cdyn, leukopenia, and hypoxemia while having no significant effect on Psa or FRC. Administration of ABT-299 did not affect any of the measured variables at baseline. Pretreatment with ABT-299 attenuated the peak Ppa seen after endotoxin administration but had minimal effects on endotoxin-induced changes in Cdyn, white blood cell count, or alveolar-to-arterial oxygen difference. ABT-299 was shown to completely block the pulmonary hypertension and reduction in Cdyn seen after intravenous administration of exogenous PAF. We conclude that PAF does not play an essential role in the sheep's response to endotoxin.

bronchi; bronchial hyperreactivity; lung; pulmonary edema

    INTRODUCTION
Top
Abstract
Introduction
Methods
Results
Discussion
References

ADULT RESPIRATORY distress syndrome (ARDS) is a form of acute lung injury characterized by diffuse pulmonary infiltrates in the absence of left heart failure. Severe hypoxemia and diminished compliance of the lungs are observed. ARDS is not infrequently a sequela of endotoxemia (31). There is much evidence indicating an etiologic role for lipid mediators, including platelet-activating factor (PAF), in endotoxin-induced lung dysfunction. In the experiments reported in this study, we utilize ABT-299, a new potent and highly specific PAF-receptor antagonist (38), in chronically instrumented sheep to more clearly define the role of PAF in endotoxin-induced lung dysfunction.

PAF is produced after endotoxemia, and increased levels of PAF have been observed in humans with septicemia (17, 22). The administration of exogenous PAF to a variety of species, including sheep, mimics many of the effects seen as a result of endotoxemia (16, 36, 40). The administration of PAF to sheep causes marked pulmonary hypertension, alterations in lung mechanics, hypoxemia, and leukopenia (12, 15, 36). These changes are similar to those observed after endotoxemia in sheep. Endotoxin also causes an initial marked pulmonary hypertension, alterations in lung mechanics, hypoxemia, and leukopenia (8, 10, 11, 15, 24, 26, 27, 37).

Studies utilizing PAF-receptor antagonists in a variety of injury models (1-5, 29, 30, 42), including during endotoxemia in a variety of species (rats, pigs, sheep), have produced promising results (7, 13, 19, 28, 32, 34, 35). Christman et al. (15) used two different PAF-receptor antagonists, SRI-63-441 and WEB-2086, in sheep during endotoxemia. SRI-63-441 attenuated the early pulmonary hypertension and blocked the reduction in dynamic compliance of the lungs (Cdyn), late neutropenia, and increase in lung lymph flow seen after endotoxin administration (15). WEB-2086 had no significant effect on the early pulmonary hypertension or early changes in lung mechanics observed after endotoxin but did attenuate the late changes in Cdyn and lung lymph flow. These studies were limited by the quality of the PAF-receptor antagonists available at that time (15). SRI-63-441 and WEB-2086 were not potent compared with ABT-299. They had side effects at the higher doses required to block 10-µg bolus injections of PAF. They only partially blocked the in vivo effects of 25-µg bolus injections of exogenous PAF. ABT-299 in the present study, by comparison, abolished the effects of 300-µg bolus injections of PAF while having no direct effect on any of the outcome variables measured. SRI-63-441 and WEB-2086 may have had pharmacological actions unrelated to their ability to block PAF receptors (15).

ABT-299 is a prodrug that is rapidly converted in vivo to A-85783.0 in the presence of plasma esterases. ABT-299 is a highly potent, specific, competitive, reversible, and stereoselective PAF-receptor antagonist. ABT-299 is a potent inhibitor of [3H]PAF binding to receptors on rabbit platelet membranes (inhibitory binding constant = 3.8 nM). ABT-299 has been shown to block the lipopolysaccharide-induced systemic hypotension, vascular leak, disseminated intravascular coagulation, organ damage and/or failure, and high mortality in rats (38). The endotoxin model in sheep has proven to be useful for screening drugs for possible use in human sepsis and ARDS (10, 14, 41). To further study the role of PAF in endotoxin-induced lung dysfunction and to test for the possible utility of ABT-299 in human sepsis and ARDS, we examined the effects of ABT-299 pretreatment on the effects of endotoxin in six chronically instrumented awake sheep.

    METHODS
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Abstract
Introduction
Methods
Results
Discussion
References

Sheep preparation. Yearling sheep (25-35 kg) of both sexes were prepared surgically as previously described (8). Silastic envelopes attached to Silastic tubing were placed in the pleural cavity, and the tubing was externalized for the measurement of pleural pressure. Through a left thoracotomy, Silastic catheters were inserted directly into the main pulmonary artery and the left atrium. Vascular catheters were also inserted into the thoracic aorta and superior vena cava through cervical vessels. A tracheostomy was performed. The animals were allowed to recover for several days before investigation. A size-10 Shiley cuffed tracheostomy tube (Shiley, Irvine, CA) was inserted at the time of experimentation.

Lung mechanics. Sheep were studied unanesthetized while they stood in a whole body pressure-compensated integrated-flow plethysmograph. Ropes were used as passive restraints to prevent the sheep from lying down during the experiment. The sheep's tracheostomy tube was connected to an external valve via noncollapsible flexible tubing. A constant bias flow was used to reduce the effective dead space of the tubing. Tidal volume (VT) was measured by pressure compensating for the integrated signal from the plethysmographic pressure transducer. Flow was obtained by electronically differentiating the volume signal. Pleural pressure (Ppl) was measured directly from the Silastic catheter and envelope in the pleural space. Airway opening pressure (Pao) was measured by a multiple-side-hole catheter positioned 0.5 cm past the distal end of the tracheostomy tube. Transpulmonary pressure (Ptp) was the pressure difference between Ppl and Pao. All pressure signals were measured by using Validyne MP-45 pressure transducers and amplification equipment (Validyne Engineering, Northridge, CA). The signals from the pressure transducers, catheters, and Silastic envelopes were tuned to eliminate phasic distortion to 20 Hz. These methods have been described previously in detail (37).

Before each measurement of lung mechanics, the sheep's lungs were inflated to 40 cmH2O Pao by using the bias flow and an occluded airway. Simultaneous VT-flow and VT-Ptp curves were then recorded during spontaneous respiration on a Tektronix dual-beam storage oscilloscope (Tektronix, Beaverton, OR) and photographed for calculation of Cdyn. Cdyn was calculated as VT divided by Ptp at points of zero flow and expressed in liters per centimeter H2O at BTPS. Functional residual capacity (FRC) was measured by using the Boyle's law method of DuBois et al. (18). The airway was manually obstructed at end expiration. The sheep continued to make respiratory efforts against the obstruction for 1-3 breaths, and a graph of the change in plethysmographic volume against the change in Pao was traced on the oscilloscope and photographed for calculation of FRC.

Hemodynamics. We continuously recorded mean pulmonary artery pressure (Ppa) and mean systemic arterial pressure (Psa) by using fluid-filled pressure transducers (model 1208C, Hewlett-Packard, Palo Alto, CA). The level of the left atrium was the zero reference for all vascular pressure measurements.

Experimental protocol. To ensure that ABT-299 inhibited the action of PAF in sheep, we administered intravascular boluses of C-16 PAF (L-alpha -lecithin,beta -acetyl,gamma -O-alkyl, Calbiochem) with and without pretreatment with ABT-299 (loading dose of 1 mg/kg over 10 min followed by a continuous infusion of 0.6 mg · kg-1 · h-1). Ppa was continuously monitored, and lung mechanics were determined at 1-min intervals for the first 5 min after PAF administration and then every 15 min thereafter.

The effects of ABT-299 on the response to endotoxin were studied in six chronically instrumented awake sheep. Each sheep served as its own control and was studied three times: once with ABT-299 alone, once with endotoxin after ABT-299 pretreatment, and once with the vehicle for ABT-299 (0.9% NaCl) and endotoxin. A minimum of four days was allowed between endotoxin experiments. This protocol has previously been shown to cause reproducible responses to endotoxin (10, 11, 15, 24, 26, 27, 37, 41). The order of experimentation was varied to further exclude the possibility of sequential bias.

At the beginning of each experiment, the physiological measurements were recorded until a stable baseline was obtained for at least 1 h. ABT-299 was prepared by dissolving 203 mg of ABT-299 in 203 ml of sterile 0.9% NaCl. After baseline measurements were taken, infusion of ABT-299 (or an equal amount of vehicle) via the central venous catheter was started as a loading dose of 1 mg/kg over 10 min followed by a continuous infusion of 0.6 mg · kg-1 · h-1 through the remainder of the experiment. One hour after drug (or vehicle) infusion began, 0.5 µg/kg Escherichia coli endotoxin in sterile 0.9% NaCl (lipopolysaccharide E. coli O55:B5, Difco Laboratories, Detroit, MI) was infused over 15 min via the pulmonary artery catheter (average total volume 15 ml). Measurements were made for 5 h after the start of the endotoxin infusion.

Throughout the experiment, mean intravascular pressures were continuously recorded and averaged for intervals of 15 min. Lung mechanics were measured every 15 min throughout the experiment. Arterial blood was collected every 30 min for white blood cell (WBC) count and blood-gas determination.

Other methods. WBC were counted by using a Coulter counter (model ZBI, Fear Electronics, Hialeah, FL). Arterial gas tensions for oxygen and carbon dioxide and pH were determined by a Corning blood-gas analyzer (238 pH/blood-gas analyzer, Corning Medical and Scientific, Medfield, MA). The alveolar-arterial PO2 gradient {[Delta (A-a)PO2]} on room air was calculated by using the alveolar gas equation with a fixed respiratory exchange ratio of 0.8.

Statistics. The data were analyzed by using parametric repeated-measures analyses of variance with multiple comparisons by Newman-Keuls test (Statistica/W, StatSoft, Tulsa, OK). A value of P < 0.05 was considered significant.

    RESULTS
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Abstract
Introduction
Methods
Results
Discussion
References

PAF administration without and with ABT-299 pretreatment. Intravascular bolus administration of 3 µg PAF resulted in an acute nearly fourfold rise in Ppa, with return to baseline Ppa over the subsequent 15 min. The acute rise in Ppa was accompanied by a rapid 70% reduction in Cdyn, which also resolved within 15 min. Pretreatment with ABT-299 completely blocked the effects of 3-, 10-, 30-, 100-, and 300-µg bolus injections of PAF on Ppa and Cdyn. This effect was observed immediately after loading ABT-299, after a 6-h infusion of ABT-299, and after endotoxin.

Ppa. ABT-299 infusion alone did not significantly affect Ppa. As shown in Fig. 1, within 45 min after endotoxin infusion, Ppa increased from a baseline of 17.2 ± 1.7 cmH2O to a peak Ppa of 61.2 ± 4.3 cmH2O and then gradually declined toward baseline but remained significantly elevated for 5 h. After pretreatment with ABT-299, endotoxin administration resulted in an attenuated peak Ppa response, increasing from a baseline of 16.8 ± 0.9 cmH2O to a peak Ppa of 55.8 ± 6.1 cmH2O. Ppa remained significantly elevated from baseline at 1, 2, and 5 h after endotoxin and differed from the endotoxin alone experiments at peak Ppa only.


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  		Fig. 1.   Effect of ABT-299 on endotoxin (Endo)-induced changes in pulmonary arterial pressure (Ppa). Values are means ± SE; n = 6. ABT-299, platelet-activating factor (PAF)-receptor antagonist. open circle , Endotoxin alone; bullet , endotoxin+ABT-299; black-square, ABT-299 alone. The 1.5-h time point, peak value; 2-h time point, mean of data over 2nd hour. * Significantly different from baseline, P < 0.05. black-lozenge  Significantly different from time-matched endotoxin+ABT-299, P < 0.05.

Psa. ABT-299 infusion had no significant effect on Psa. Endotoxin infusion with or without pretreatment with ABT-299 did not cause any significant change in Psa during the observation period (Fig. 2).


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  		Fig. 2.   Effect of ABT-299 on endotoxin-induced changes in systemic arterial pressure (Psa). Values are means ± SE; n = 6. Symbols are defined as in Fig. 1.

Lung mechanics. As shown in Fig. 3, ABT-299 administration alone did not significantly affect Cdyn. Endotoxin infusion resulted in an acute decline in Cdyn to 30.6 ± 6% baseline within 30 min after endotoxin. Cdyn remained significantly below baseline measurements throughout the remainder of the observation period. Pretreatment with ABT-299 did not significantly affect the response to endotoxin administration with respect to Cdyn. Endotoxin infusion in the presence of ABT-299 resulted in an acute decline in Cdyn to 36.5 ± 8.1% of baseline followed by a gradual return toward baseline, remaining significantly reduced from baseline throughout the remainder of the observation period. There were no statistically significant changes in FRC from baseline values in any of the experimental groups during the course of the experiments (data not shown).


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  		Fig. 3.   Effect of ABT-299 on endotoxin-induced changes in lung dynamic compliance (Cdyn). Values are means ± SE; n = 6. Time point significance and symbols are defined as in Fig. 1. * Significantly different from baseline, P < 0.05.

Delta (A-a)PO2. As shown in Fig. 4, ABT-299 infusion alone did not significantly affect Delta (A-a)PO2. Endotoxin infusion resulted in an increase in Delta (A-a)PO2 from a baseline of 26.1 ± 1.6 Torr to a maximum of 44.6 ± 5.7 Torr at 2 h after endotoxin infusion before slowly returning to baseline. Pretreatment with ABT-299 did not significantly alter the effect of endotoxin on Delta (A-a)PO2.


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  		Fig. 4.   Effect of ABT-299 on endotoxin-induced changes in alveolar-arterial PO2 gradient ([Delta (A-a)PO2]). Values are means ± SE; n = 6. Symbols are defined as in Fig. 1. * Significantly different from baseline, P < 0.05.

WBC. ABT-299 administration alone did not significantly affect WBC (see Fig. 5). Endotoxin infusion resulted in a decline in WBC from a baseline of 8,863 ± 673 to a nadir of 3,049 ± 870 cells/mm3 at 2 h after endotoxin administration before gradually increasing, but the number remained significantly reduced with respect to baseline throughout the remainder of the observation period. Pretreatment with ABT-299 did not significantly alter the leukopenia observed after endotoxin administration.


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  		Fig. 5.   Effect of ABT-299 on endotoxin-induced changes in white blood cell (WBC) count. Values are means ± SE; n = 6. Symbols are defined as in Fig. 1. * Significantly different from baseline, P < 0.05.

    DISCUSSION
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Abstract
Introduction
Methods
Results
Discussion
References

The rationale for believing that PAF is involved in the response to endotoxin is based on the following: 1) PAF levels are elevated after endotoxin administration (12); 2) exogenously administered PAF induces physiological and biochemical responses that are qualitatively similar to those seen after endotoxin administration (16, 33, 36, 40); and 3) PAF-receptor antagonists have attenuated the physiological and biochemical responses to endotoxin administration in several animal models (6, 7, 12, 13, 19-21, 25, 28, 32, 34, 35).

In the experiments reported in this study, ABT-299 had minimal effects on the response to endotoxin administration in chronically instrumented awake sheep. ABT-299 pretreatment reduced the peak Ppa seen after endotoxin administration. ABT-299 had no effect on the response to endotoxin with respect to Psa, Cdyn, FRC, Delta (A-a)PO2, or WBC. ABT-299 clearly was effective in blocking the changes in Ppa and Cdyn elicited by exogenous PAF administration in this animal model (ABT-299 completely blocked the effects of a 2-log-greater dose of exogenous PAF that was nearly lethal in untreated animals), and no untoward effects were apparent during the drug's administration.

The results reported here contradict those of previously published experiments in which other PAF antagonists (WEB-2086, SRI-63-441, SDZ-64-688, BN-52021) were utilized. ABT-299 is a more potent (38) and specific PAF-receptor antagonist than those previously mentioned (15) and is therefore potentially a better experimental tool. It is possible that some of the beneficial effects during endotoxemia reported with other PAF antagonists were the result of unforeseen properties of the drugs that are not associated with the antagonism of PAF receptors per se (15).

The literature contains results from studies with a variety of PAF-receptor antagonists, species, and lung-injury models (7, 13, 15, 19, 27, 32, 34, 35). Differences between the results of these studies and the present work with ABT-299 in the sheep endotoxin model may be the results of non-PAF-receptor-blocking actions of drugs used in the earlier studies, differences between species, or differences between details of the actual models studied. Because ABT-299 attenuates endotoxin-induced injury in rats (37) and pigs (23) but does not have comparable effects in sheep, the role of PAF in endotoxin-induced injury probably varies among species. ABT-299 was highly potent in sheep (blocking the effects of 300-µg bolus injections of PAF) and had no direct effects of its own. The results obtained with ABT-299 in the present study suggest that PAF is not an important mediator of endotoxin-induced lung dysfunction in sheep.

Although these negative results neither will nor should prevent further investigations into the role of PAF in endotoxin-induced lung injury, an argument can be made, on the basis of these results, that it is highly unlikely that PAF-receptor antagonists by themselves will prove beneficial in human sepsis or ARDS. The sheep endotoxin model has proven to be useful for screening drugs for possible use in human sepsis and ARDS. The sheep endotoxin model has proven to be effective in supporting further study in humans (cyclooxygenase inhibitors) (10) or in anticipating negative results in human studies (anti-endotoxin antibodies and steroids) (8, 9, 41). In a situation where bringing new drugs into human use for any indication is exceedingly expensive, we believe that the sheep endotoxin model is a useful tool to employ for making the decision about whether to go ahead with drug development in humans for sepsis and ARDS. ABT-299 did not prove efficacious in the sheep endotoxin model.

In summary, pretreatment with ABT-299 resulted in a small reduction in the peak Ppa seen after endotoxin administration but had no significant effects on any other variables measured. We conclude that PAF does not play an essential role in the sheep's response to endotoxin.

    ACKNOWLEDGEMENTS

The authors thank Tamara Lasakow for assistance in preparing the manuscript.

    FOOTNOTES

This work was supported by National Heart, Lung, and Blood Institute Grants HL-27274, HL-46971, and HL-07123.

Address for reprint requests: J. R. Snapper, T1217, Medical Center North, Vanderbilt Univ. Medical Center, Nashville, TN 37232-2650.

Received 9 September 1997; accepted in final form 30 December 1997.

    REFERENCES
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Abstract
Introduction
Methods
Results
Discussion
References

1.   Abu-Zidan, F. M., and S. Walther. Platelet activating factor antagonism improves cardiovascular function in non-hypotensive sepsis in pigs. Eur. J. Surg. 162: 499-504, 1996[Medline].

2.   Abu-Zidan, F. M., S. Walther, and S. Lennquist. Role of platelet-activating factor antagonism in haemorrhagic shock in pigs. Eur. Surg. Res. 27: 379-388, 1995[Medline].

3.   Abu-Zidan, F. M., S. Walther, and S. Lennquist. Role of platelet-activating factor antagonism in posthemorrhage septic shock in pigs. J. Trauma 41: 634-640, 1996[Medline].

4.   Abu-Zidan, F. M., S. Walther, and S. Lennquist. Role of platelet-activating factor on cardiovascular dysfunction in postischemic shock in pigs. Eur. Surg. Res. 29: 133-141, 1997[Medline].

5.   Ayala, A., and I. H. Chaudry. Platelet activating factor and its role in trauma, shock, and sepsis. New Horizons 4: 265-275, 1996[Medline].

6.   Bahrami, S., H. Redl, M. Thurnher, C. Vogl, E. Paul, A. Schieber, and G. Schlag. Effect of PAF-antagonists in endotoxin shock-ovine and rat experiments. Prog. Clin. Biol. Res. 308: 931-936, 1989[Medline].

7.   Baum, T. D., S. O. Heard, H. S. Feldman, C. A. Latka, and M. P. Fink. Endotoxin-induced myocardial depression in rats: effect of ibuprofen and SDZ 64-688, a platelet activating factor receptor antagonist. J. Surg. Res. 48: 629-634, 1990[Medline].

8.   Begley, C. J., M. L. Ogletree, B. O. Meyrick, and K. L. Brigham. Modification of pulmonary responses to endotoxemia in awake sheep by steroidal and nonsteroidal anti-inflammatory agents. Am. Rev. Respir. Dis. 130: 1140-1146, 1984[Medline].

9.   Bernard, G. R., J. M. Luce, C. L. Sprung, J. E. Rinaldo, R. M. Tate, W. J. Sibbald, K. Kariman, S. Higgins, R. Bradley, C. A. Metz, and T. R. Harris. High-dose corticosteroids in patients with the adult respiratory distress syndrome. N. Engl. J. Med. 317: 1565-1570, 1987[Abstract].

10.   Brigham, K. L., R. E. Bowers, and C. R. McKeen. Methylprednisolone prevention of increased lung vascular permeability following endotoxemia in sheep. J. Clin. Invest. 67: 1103-1110, 1981.

11.   Brigham, K. L., and B. Meyrick. Endotoxin and lung injury. Am. Rev. Respir. Dis. 133: 913-927, 1986[Medline].

12.   Chang, S., C. O. Feddersen, P. M. Henson, and N. F. Voelkel. Platelet-activating factor mediates hemodynamic changes and lung injury in endotoxin-treated rats. J. Clin. Invest. 79: 1498-1509, 1987.

13.   Chang, S., S. Fernyak, and N. F. Voelkel. Beneficial effect of a platelet-activating factor antagonist, WEB 2086, on endotoxin-induced lung injury. Am. J. Physiol. 258 (Heart Circ. Physiol. 27): H153-H158, 1990[Abstract/Free Full Text].

14.   Chen, T. Y., W. M. Zapol, and E. Greene. Protective effects of E5, an antiendotoxin monoclonal antibody, in the ovine pulmonary circulation. J. Appl. Physiol. 75: 233-239, 1993[Abstract/Free Full Text].

15.   Christman, B. W., P. L. Lefferts, I. A. Blair, and J. R. Snapper. Effect of platelet-activating factor receptor antagonism on endotoxin-induced lung dysfunction in awake sheep. Am. Rev. Respir. Dis. 142: 1272-1278, 1990[Medline].

16.   Christman, B. W., P. L. Lefferts, G. A. King, and J. R. Snapper. Role of circulating platelets and granulocytes in PAF-induced pulmonary dysfunction in awake sheep. J. Appl. Physiol. 64: 2033-2041, 1988[Abstract/Free Full Text].

17.   Diez, F. L., M. L. Nieto, S. Fernandez-Gallardo, M. A. Gijon, and M. S. Crespo. Occupancy of platelet receptors for platelet-activating factor in patients with septicemia. J. Clin. Invest. 83: 1733-1740, 1989.

18.   DuBois, A. B., S. Y. Bothelho, G. N. Bedell, R. Marshall, and J. H. Comroe. A rapid plethysmographic method measuring thoracic gas volume: a comparison with a nitrogen washout method for measuring functional residual capacity in normal subjects. J. Clin. Med. 35: 322-326, 1956.

19.   Fletcher, J. R., A. G. DiSimone, and M. A. Earnest. Platelet activating factor receptor antagonist improves survival and attenuates eicosanoid release in severe endotoxemia. Ann. Surg. 211: 312-316, 1990[Medline].

20.   Heuer, H., and J. Casals-Stenzel. The pathophysiological role of PAF in anaphylactic lung reaction in the guinea pig and in endotoxin shock evidenced by the specific PAF-antagonist WEB 2086. Prog. Clin. Biol. Res. 308: 925-930, 1989[Medline].

21.   Heuer, H. O. Involvement of platelet-activating factor (PAF) in septic shock and priming as indicated by the effect of hetrazepinoic PAF antagonists. Lipids 26: 1369-1373, 1991[Medline].

22.   Heuer, H. O., H. Darius, H. F. Lohmann, J. Meyer, M. Schierenberg, and N. Treese. Platelet-activating factor type activity in plasma from patients with septicemia and other diseases. Lipids 26: 1381-1385, 1991[Medline].

23.   Kruse-Elliott, K. T., D. H. Albert, J. B. Summers, G. W. Carter, and J. J. Zimmerman. Attenuation of endotoxin-induced pathophysiology by a new potent PAF receptor antagonist. Shock 5: 265-273, 1996[Medline].

24.   Kuhl, P. G., J. M. Bolds, J. E. Loyd, J. R. Snapper, and G. A. FitzGerald. Thromboxane receptor-mediated bronchial and hemodynamic responses in ovine endotoxemia. Am. J. Physiol. 254 (Regulatory Integrative Comp. Physiol. 23): R310-R319, 1988[Abstract/Free Full Text].

25.   Lantz, R. C., G. E. Keller III, and R. Burrell. The role of platelet-activating factor in the pulmonary response to inhaled bacterial endotoxin. Am. Rev. Respir. Dis. 144: 167-172, 1991[Medline].

26.   Ogletree, M. L., C. J. Begley, G. A. King, and K. L. Brigham. Influence of steroidal and nonsteroidal anti-inflammatory agents on the accumulation of arachidonic acid metabolites in plasma and lung lymph after endotoxemia in awake sheep. Measurements of prostacyclin and thromboxane metabolites and 12-HETE. Am. Rev. Respir. Dis. 133: 55-61, 1986[Medline].

27.   Ogletree, M. L., and K. L. Brigham. Effects of cyclooxygenase inhibitors on pulmonary vascular responses to endotoxin in unanesthetized sheep. Prostaglandins Leukot. Med. 8: 489-502, 1982[Medline].

28.   Olson, N. C., P. B. Joyce, and L. N. Fleisher. Role of platelet-activating factor and eicosanoids during endotoxin-induced lung injury in pigs. Am. J. Physiol. 258 (Heart Circ. Physiol. 27): H1674-H1686, 1990[Abstract/Free Full Text].

29.   Ono, S., H. Mochizuki, and S. Tamakuma. A clinical study on the significance of platelet-activating factor in the pathophysiology of septic disseminated intravascular coagulation in surgery. Am. J. Surg. 171: 409-415, 1996[Medline].

30.   Ono, S., S. Tamakuma, H. Mochizuki, M. Kinoshita, Y. Ohkusa, S. Aosasa, Y. Oda, and H. Ohe. Clinical and experimental studies on the role of platelet-activating factor (PAF) in the pathogenesis of septic DIC. Surg. Today 23: 228-233, 1993[Medline].

31.   Parsons, P. E., G. S. Worthen, E. E. Moore, R. M. Tate, and P. M. Henson. The association of circulating endotoxin with the development of the adult respiratory distress syndrome. Am. Rev. Respir. Dis. 140: 294-301, 1989[Medline].

32.   Qi, M., and S. B. Jones. Contribution of platelet activating factor to hemodynamic and sympathetic responses to bacterial endotoxin in conscious rats. Circulatory Shock 32: 153-163, 1990[Medline].

33.   Salari, H., M. Demos, and A. Wong. Comparative hemodynamics and cardiovascular effect of endotoxin and platelet-activating factor in rat. Circulatory Shock 32: 189-207, 1990[Medline].

34.   Sessler, C. N., F. L. Glauser, D. Davis, and A. A. Fowler III. Effects of platelet-activating factor antagonist SRI 63-411 on endotoxemia in sheep. J. Appl. Physiol. 65: 2624-2631, 1988[Abstract/Free Full Text].

35.   Siebeck, M., J. Weipert, C. Keser, J. Kohl, M. Spannagl, W. Machleidt, and L. Schweiberer. A triazolodiazepine platelet activating factor receptor antagonist (WEB 2086) reduces pulmonary dysfunction during endotoxin shock in swine. J. Trauma 31: 942-950, 1991[Medline].

36.   Smallbone, B. W., N. E. Taylor, and J. W. D. McDonald. Effects of L-652,731, a platelet-activating factor (PAF) receptor antagonist, on PAF- and complement-induced pulmonary hypertension in sheep. J. Pharmacol. Exp. Ther. 242: 1035-1040, 1987[Abstract/Free Full Text].

37.   Snapper, J. R., A. A. Hutchison, M. L. Ogletree, and K. L. Brigham. Effects of cyclooxygenase inhibitors on the alterations in lung mechanics caused by endotoxemia in unanesthetized sheep. J. Clin. Invest. 72: 63-76, 1983.

38.   Summers, J. B., D. H. Albert, S. K. Davidsen, R. G. Conway, J. H. Holms, T. J. Magoc, G. Luo, P. Tapang, D. A. Rhein, and G. W. Carter. ABT-299, a potent antagonist of platelet activating factor. Adv. Prostaglandin Thromboxane Leukot. Res. 23: 475-477, 1995[Medline].

39.   The Veterans Administration Systemic Sepsis Cooperative Study Group. Effect of high-dose glucocorticoid therapy on mortality in patients with clinical signs of systemic sepsis. N. Engl. J. Med. 317: 659-665, 1987[Abstract].

40.   Trochtenberg, D. S., P. L. Lefferts, G. A. King, Y. S. Hwang, B. W. Christman, and J. R. Snapper. Effects of thromboxane synthase and cyclooxygenase inhibition on PAF-induced changes in lung function and arachidonic acid metabolism. Prostaglandins 44: 555-557, 1992[Medline].

41.   Wheeler, A. P., W. D. Hardie, and G. Bernard. Studies of an antiendotoxin antibody in preventing the physiologic changes of endotoxemia in awake sheep. Am. Rev. Respir. Dis. 142: 775-781, 1990[Medline].

42.   Zehr, K. J., R. S. Poston, P. C. Lee, K. Uthoff, P. Kumar, P. W. Cho, A. M. Gillinov, J. M. Redmond, J. A. Winkelstein, A. Herskowitz, and D. E. Cameron. Platelet activating factor inhibition reduces lung injury after cardiopulmonary bypass [see comments]. Ann. Thorac. Surg. 59: 328-335, 1995[Abstract/Free Full Text].

J APPL PHYSIOL 84(5):1610-1614
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