Skip to main content
NCBI home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1983 Jul;72(1):63–76. doi: 10.1172/JCI110985

Effects of cyclooxygenase inhibitors on the alterations in lung mechanics caused by endotoxemia in the unanesthetized sheep.

J R Snapper, A A Hutchison, M L Ogletree, K L Brigham
PMCID: PMC1129161  PMID: 6409930

Abstract

The effects of Escherichia coli endotoxin on lung mechanics, hemodynamics, gas exchange, and lung fluid and solute exchange were studied in 12 chronically instrumented unanesthetized sheep. A possible role for cyclooxygenase products of arachidonate metabolism as mediators of the endotoxin-induced alterations in lung mechanics was investigated by studying sheep before and after cyclooxygenase inhibition with sodium meclofenamate and ibuprofen. Sheep were studied three times in random order: (a) sodium meclofenamate (or ibuprofen) infusion alone; (b) E. coli endotoxin alone; and (c) meclofenamate (or ibuprofen) and endotoxin. Meclofenamate alone had no effect on any of the variables measured. Endotoxin alone caused early marked changes in lung mechanics: resistance to airflow across the lungs (RL) increased 10-fold, dynamic lung compliance (Cdyn) decreased 80% and functional residual capacity (FRC) decreased by greater than 30%. The alveolar-to-arterial oxygen difference (delta AaPO2) increased markedly following endotoxemia. In the presence of sufficient meclofenamate to inhibit accumulation of thromboxane-B2 and 6-keto-prostaglandin F1 alpha in lung lymph, endotoxin caused no increase in RL, Cdyn decreased by less than 40%, and FRC decreased by only 6%. Meclofenamate significantly attenuated the hypoxemia and early pulmonary hypertension caused by endotoxemia but had no effect on the late increases in lung fluid and solute exchange. Ibuprofen had similar effects to those observed with meclofenamate. We conclude that both the pulmonary hypertension and changes in lung mechanics observed after endotoxemia may be mediated, at least in part, by constrictor prostaglandins or thromboxanes and that gas exchange may be improved by preventing endogenous synthesis of these mediators.

Full text

PDF
63

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Ahmed T., Eyre P., Januszkiewicz A. J., Wanner A. Role of H1- and H2-receptors in airway reactions to histamine in conscious sheep. J Appl Physiol Respir Environ Exerc Physiol. 1980 Nov;49(5):826–833. doi: 10.1152/jappl.1980.49.5.826. [DOI] [PubMed] [Google Scholar]
  2. Allison R. C., Murphy T. L., Weisman I. M., McCaffree D. R., Gray B. A. Effect of methysergide on the acute lung mechanics response to endotoxin. J Appl Physiol Respir Environ Exerc Physiol. 1981 Jan;50(1):185–190. doi: 10.1152/jappl.1981.50.1.185. [DOI] [PubMed] [Google Scholar]
  3. Bland R. D., Demling R. H., Selinger S. L., Staub N. C. Effects of alveolar hypoxia on lung fluid and protein transport in unanesthetized sheep. Circ Res. 1977 Mar;40(3):269–274. doi: 10.1161/01.res.40.3.269. [DOI] [PubMed] [Google Scholar]
  4. Brigham K. L., Bowers R. E., McKeen C. R. Methylprednisolone prevention of increased lung vascular permeability following endotoxemia in sheep. J Clin Invest. 1981 Apr;67(4):1103–1110. doi: 10.1172/JCI110123. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Brigham K. L., Bowers R., Haynes J. Increased sheep lung vascular permeability caused by Escherichia coli endotoxin. Circ Res. 1979 Aug;45(2):292–297. doi: 10.1161/01.res.45.2.292. [DOI] [PubMed] [Google Scholar]
  6. DUBOIS A. B., BOTELHO S. Y., BEDELL G. N., MARSHALL R., COMROE J. H., Jr A rapid plethysmographic method for measuring thoracic gas volume: a comparison with a nitrogen washout method for measuring functional residual capacity in normal subjects. J Clin Invest. 1956 Mar;35(3):322–326. doi: 10.1172/JCI103281. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Drazen J. M., Loring S. H., Ingram R. H., Jr Distribution of pulmonary resistance: effects of gas density, viscosity, and flow rate. J Appl Physiol. 1976 Sep;41(3):388–395. doi: 10.1152/jappl.1976.41.3.388. [DOI] [PubMed] [Google Scholar]
  8. Heflin A. C., Jr, Brigham K. L. Prevention by granulocyte depletion of increased vascular permeability of sheep lung following endotoxemia. J Clin Invest. 1981 Nov;68(5):1253–1260. doi: 10.1172/JCI110371. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. McCaffree D. R., Gray B. A., Pennock B. E., Coalson J., Bridges C., Taylor F. B., Rogers R. M. Role of pulmonary edema in the acute pulmonary response to sepsis. J Appl Physiol Respir Environ Exerc Physiol. 1981 Jun;50(6):1198–1205. doi: 10.1152/jappl.1981.50.6.1198. [DOI] [PubMed] [Google Scholar]
  10. Ogletree M. L., Brigham K. L. Effects of cyclooxygenase inhibitors on pulmonary vascular responses to endotoxin in unanesthetized sheep. Prostaglandins Leukot Med. 1982 May;8(5):489–502. [PubMed] [Google Scholar]
  11. Ogletree M. L. Pharmacology of prostaglandins in the pulmonary microcirculation. Ann N Y Acad Sci. 1982;384:191–206. doi: 10.1111/j.1749-6632.1982.tb21372.x. [DOI] [PubMed] [Google Scholar]
  12. Staub N. C., Bland R. D., Brigham K. L., Demling R., Erdmann A. J., 3rd, Woolverton W. C. Preparation of chronic lung lymph fistulas in sheep. J Surg Res. 1975 Nov;19(5):315–320. doi: 10.1016/0022-4804(75)90056-6. [DOI] [PubMed] [Google Scholar]
  13. Wanner A., Reinhart M. E. Respiratory mechanics in conscious sheep: response to methacholine. J Appl Physiol Respir Environ Exerc Physiol. 1978 Mar;44(3):479–482. doi: 10.1152/jappl.1978.44.3.479. [DOI] [PubMed] [Google Scholar]
  14. Weir E. K., Mlczoch J., Reeves J. T., Grover R. F. Endotoxin and prevention of hypoxic pulmonary vasoconstriction. J Lab Clin Med. 1976 Dec;88(6):975–983. [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES