Letters to the Editor

	ABSTRACT

Top Abstract Letter References

The following is the abstract of the article discussed in the subsequent letter:

Steudel, Wolfgang, Hans-Joachim Krämer, Daniela Degner, Simone Rosseau, Hartwig Schütte, Dieter Walmrath, and Werner Seeger. Endotoxin priming of thromboxane-related vasoconstrictor responses in perfused rabbit lungs. J. Appl. Physiol. 83(1): 18-24, 1997.In prior studies of perfused lungs, endotoxin priming markedly enhanced thromboxane (Tx) generation and Tx-mediated vasoconstriction in response to secondarily applied bacterial exotoxins. The present study addressed this aspect in more detail by employing precursor and intermediates of prostanoid synthesis and performing functional testing of vasoreactivity and measurement of product formation. Rabbit lungs were buffer perfused in the absence or presence of 10 ng/ml endotoxin. Repetitive intravascular bolus applications of free arachidonic acid provoked constant pulmonary arterial pressor responses and constant release reactions of TxA₂ and prostaglandin (PG) I₂ in nonprimed lungs. Within 60-90 min of endotoxin recirculation, which provoked progressive liberation of tumor necrosis factor- but did not effect any hemodynamic changes by itself, both pressor responses and prostanoid release markedly increased, and both events were fully blocked by cyclooxygenase (Cyclo) inhibition with acetylsalicylic acid (ASA). The unstable intermediate PGG₂ provoked moderate pressor responses, again enhanced by preceding endotoxin priming and fully suppressed by ASA. Vasoconstriction also occurred in response to the direct Cyclo product PGH₂, again amplified after endotoxin pretreatment, together with markedly enhanced liberation of TxA₂ and PGI₂. In the presence of ASA, the priming-related increase in pressor responses and the prostanoid formation were blocked, but baseline vasoconstrictor responses corresponding to those in nonprimed lungs were maintained. Pressor responses to the stable Tx analog U-46619 were not significantly increased by endotoxin pretreatment, but some generation of TxA₂ and PGI₂ was also noted under these conditions. We conclude that endotoxin priming exerts profound effects on the lung vascular prostanoid metabolism, increasing the readiness to react with Tx-mediated vasoconstrictor responses to various stimuli, suggesting that enhanced Cyclo activity is an important underlying event.

	LETTER

Top Abstract Letter References

Endotoxemia affects lung vascular prostanoid metabolism in rabbits

To the Editor: The recent demonstration by Steudel et al. (3) that endotoxin pretreatment amplifies thromboxane-related vasoconstrictor responses in isolated buffer-perfused rabbit lungs contributes significantly to the interpretation of the findings that we obtained in 10 endotoxin-treated, artificially ventilated rabbits (1, 2).

Specifically:
  1) In our animals, the first infusion of endotoxin (0.46 mg/kg Escherichia coli-derived lipopolysaccharide, serotype 0111:B4; Sigma Chemical, Deisenhofen, Germany) led to a transient pulmonary hypertension (up to 25 mmHg), followed by a breakdown of pulmonary arterial pressure (PAP). Then, PAP recovered to baseline values of ~14 mmHg. Intriguingly, additional infusions of endotoxin, applied by the hour, did not reproduce such increases in PAP but reduced arterial PO₂ (Pa_O2) more and more to minimal values of Pa_O2 = 48 ± 3.4 (SD) Torr. Furthermore, we determined pulmonary diffusing capacity for nitric oxide (DL_NO) and found a decline in DL_NO values by 20 ± 5.5% of baseline until the experiments were concluded (2). In view of the results reported by Steudel et al. (3), such endotoxin-induced changes in PAP, Pa_O2, and DL_NO values compare reliably with an endotoxin priming of vasoconstrictor responses. The permanent impairment of pulmonary gas exchange without a persisting pulmonary hypertension strongly indicates that hypoxemia was associated with severe ventilation-perfusion mismatching.
  2) In one further endotoxin-treated rabbit, we infused intravenously prostacyclin (150 ng/kg Flolan, Wellcome, London, UK) (1). By contrast to the absence of a therapeutic benefit from insufflating nitric oxide [NO; 3-50 parts/million for 6-8 min (2)], the five intravenous applications of prostacyclin transiently improved Pa_O2 for ~10 min by 15 ± 10 Torr, although mechanical ventilation remained unchanged (1). Because prostacyclin is the antagonist of thromboxane, this observation is in agreement with the conclusion of Steudel et al. (3) that endotoxin priming of vasoconstrictor responses is thromboxane related.

	REFERENCES

Top Abstract Letter References

1.   Heller, H., G. Hoffmann, W. Schobersberger, and K.-D. Schuster. Does inhaled nitric oxide and intravenous prostacyclin improve endotoxin-induced hypoxemia (Abstract). Pflügers Arch. 431: R125, 1995.

2.   Heller, H., G. Hoffmann, W. Schobersberger, and K.-D. Schuster. Effect of inhaled nitric oxide on endotoxin-induced hypoxaemia in rabbits. Acta Physiol. Scand. 161: 311-315, 1997[Medline].

3.   Steudel, W., H.-J. Krämer, D. Degner, S. Rosseau, H. Schütte, D. Walmrath, and W. Seeger. Endotoxin priming of thromboxane-related vasoconstrictor responses in perfused rabbit lungs. J. Appl. Physiol. 83: 18-24, 1997[Abstract/Free Full Text].

					Hartmut Heller Georg Hoffmann Klaus-Dieter Schuster Department of Physiology University of Bonn 53115 Bonn, Germany
					Wolfgang Schobersberger Division for General and Surgical   Intensive Care Medicine University of Innsbruck 6020 Innsbruck, Austria

	REPLY

Top Abstract Letter References

To the Editor: We thank Dr. Heller and his colleagues for their interest in our report and welcome the opportunity to respond to their comments.
  1) Heller and co-authors suggest that initial reversible pulmonary hypertension and the lack of PAP responses after repetitive endotoxin challenges in intact rabbits are caused by endotoxin priming of vasoconstrictor responses, as we have recently reported in isolated rabbit lungs (8). Reversible pulmonary hypertension and the release of cyclooxygenase metabolites have been described in high-dose endotoxemia (2). Endotoxin priming in our study, however, refers to the administration of a very low dose of endotoxin (10 ng/ml perfusate), applied during bloodless perfusion. It did not cause pulmonary hypertension per se but increased cyclooxygenase activity within 90 min. Priming caused increasing pulmonary artery pressor responses and prostanoid formation in response to subsequent arachidonic acid (AA) injections. Endotoxin also enhanced secondary AA release and prostanoid formation after stimulation of the thromboxane/prostaglandin H₂ receptor. As recently reported (3), endotoxin priming in isolated lungs can be inhibited with a selective cyclooxygenase-2 inhibitor.

The lack of pulmonary artery pressor responses after repetitive endotoxin doses, however, cannot be explained by our data. In contrast, a decrease of prostanoid formation associated with attenuation of pulmonary artery pressor responses after repetitive endotoxin doses has been reported (2). Therefore, the following hypotheses should be tested to explain the attenuated pressor responses. 1) An initial endotoxin dose triggers maximal prostanoid formation and temporarily depletes AA pools. 2) Endotoxin-binding proteins and cellular receptors are fully occupied with the initial endotoxin dose and not further stimulated by additional doses. 3) Prostacyclin formation and subsequent vasodilation override the effects of thromboxane formation with prolonged endotoxemia.

Hypoxemia and severe ventilation-perfusion disturbances are a known pattern in high-dose endotoxemic lung injury (5). These are due to endothelial damage, pulmonary edema, and right-to-left shunt. Pulmonary hypertension does not necessarily occur or persist. In contrast, low doses of endotoxin did not change ventilation-perfusion characteristics of isolated perfused rabbit lungs (9).
  2) Inhaled NO causes pulmonary vasodilation and improvement of ventilation-perfusion matching and Pa_O2 in lung injury (1, 7). In the absence of pulmonary hypertension (4), no pulmonary vasodilator effect should be expected. In a porcine model of septic lung injury, NO inhalation attenuated hypoxemia and ventilation-perfusion mismatching (5). The lack of NO effects on pulmonary gas exchange (4) may be due to severe pulmonary edema and inadequate NO delivery to pulmonary vessels, as indicated by the decreased NO diffusion capacity.

Prostacyclin and thromboxane exert opposite physiological effects but do not fullfill agonist/antagonist criteria (6). It has been recently reported that aerosolized prostacyclin improves pulmonary gas exchange and ventilation-perfusion matching in severe lung injury (10). The finding that systemically infused prostacyclin improves oxygenation should be further evaluated, since it is not supported by the literature (7).

	REFERENCES

Top Abstract Letter References

1.   Dellinger, R. P., J. L. Zimmerman, R. W. Taylor, R. C. Straube, D. L. Hauser, G. J. Criner, K. J. Davis, T. M. Hyers, and P. Papadakos. Effects of inhaled nitric oxide in patients with acute respiratory distress syndrome: results of a randomized phase II trial. Crit. Care Med. 26: 15-23, 1998[Medline].

2.   Demling, R. H., C. C. Lalonde, L. J. Jin, J. Albes, and N. Fiori. The pulmonary and systemic response to recurrent endotoxemia in the adult sheep. Surgery 100: 876-883, 1986[Medline].

3.   Ermert, L., M. Ermert, A. Althoff, F. Grimminger, and W. Seeger. COX-2 inhibition eliminates thromboxane-related vasoconstrictor responses in isolated perfused rat lungs (Abstract). Am. J. Respir. Crit. Care Med. 155: A618, 1997.

4.   Heller, H., G. Hoffman, W. Schobersberger, and D. K. Schuster. Effect of inhaled nitric oxide on endotoxin-induced hypoxaemia in rabbits. Acta Physiol. Scand. 161: 311-315, 1997.

5.   Ogura, H., W. G. Cioffi, P. J. Offner, B. S. Jordan, A. A. Johnson, and B. A. Pruitt, Jr. Effect of inhaled nitric oxide on pulmonary function after sepsis in a swine model. Surgery 116: 313-321, 1994[Medline].

6.   Ross, E. M. Pharmacodynamics: mechanisms of drug action and the relationship between drug concentration and effect. In: The Pharmacological Basis of Therapeutics, edited by A. Goodman Gilman, T. W. Rall, A. S. Nies, and P. Taylor. New York: Pergamon, 1991, p. 33-48.

7.   Rossaint, R., K. J. Falke, F. Lopez, K. Slama, U. Pison, and W. M. Zapol. Inhaled nitric oxide for the adult respiratory distress syndrome. N. Engl. J. Med. 328: 399-405, 1993[Abstract/Free Full Text].

8.   Steudel, W., H. J. Krämer, D. Degner, S. Rosseau, H. Schütte, D. Walmrath, and W. Seeger. Endotoxin priming of thromboxane-related vasoconstrictor responses in perfused rabbit lungs. J. Appl. Physiol. 83: 18-24, 1997.

9.   Walmrath, D., J. Pilch, M. Scharmann, F. Grimminger, and W. Seeger. Severe A/ mismatch in perfused lungs evoked by sequential challenge with endotoxin and E. coli hemolysin. J. Appl. Physiol. 76: 1020-1030, 1994[Abstract/Free Full Text].

10.   Walmrath, D., T. Schneider, R. Schermuly, H. Olschewski, F. Grimminger, and W. Seeger. Direct comparison of inhaled nitric oxide and aerosolized prostacyclin in acute respiratory distress syndrome. Am. J. Respir. Crit. Care. Med. 153: 991-996, 1996[Abstract].

					Wolfgang Steudel Department of Anesthesia   and Critical Care Massachusetts General Hospital Harvard Medical School Boston, Massachusetts 02114
					Werner Seeger Department of Internal Medicine Justus-Liebig University 35292 Giessen, Germany