Mechanism of phosgene-induced lung toxicity: Role of arachidonate mediators

Y. L. Guo, T. P. Kennedy, J. R. Michael, A. M. Sciuto, A. J. Ghio, N. F. Adkinson, G. H. Gurtner

Research output: Contribution to journalArticle

Abstract

We have previously shown that phosgene markedly increases lung weight gain and pulmonary vascular permeability in rabbits. The current experiments were designed to determine whether cyclooxygenase- and lipoxygenase-derived mediators contribute to the phosgene-induced lung injury. We exposed rabbits to phosgene (1,500 ppm/min), killed the animals 30 min later, and then perfused the lungs with a saline buffer for 90 min. Phosgene markedly increased lung weight gain, did not appear to increase the synthesis of cyclooxygenase metabolites, but increased 10-fold the synthesis of lipoxygenase products. Pre- or posttreatment with indomethacin decreased thromboxane and prostacyclin levels without affecting leukotriene synthesis and partially reduced the lung weight gain caused by phosgene. Methylprednisolone pretreatment completely blocked the increase in leukotriene synthesis and lung weight gain. Posttreatment with 5,8,11,14-eicosatetraynoic acid (ETYA), a nonmetabolized competitive inhibitor of arachidonic acid metabolism, or the leukotriene receptor blockers, FPL 55712 and LY 171883, also dramatically reduced the lung weight gain caused by phosgene. These results suggest that lipoxygenase products contribute to the phosgene-induced lung damage. Because phosgene exposure did not increase cyclooxygenase synthesis or pulmonary arterial pressure, we tested whether phosgene affects the lung's ability to generate or to react to thromboxane. Infusing arachidonic acid increased thromboxane synthesis to the same extent in phosgene-exposed lungs as in control lungs; however, phosgene exposure significantly reduced pulmonary vascular reactivity to thromboxane but not to angiotensin II and KCl.

Original languageEnglish (US)
Pages (from-to)1615-1622
Number of pages8
JournalJournal of applied physiology
Volume69
Issue number5
StatePublished - Dec 1 1990
Externally publishedYes

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Keywords

  • FPL 55712
  • LY 171883
  • corticosteroids
  • indomethacin
  • leukotrienes
  • thromboxane

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

Cite this

Guo, Y. L., Kennedy, T. P., Michael, J. R., Sciuto, A. M., Ghio, A. J., Adkinson, N. F., & Gurtner, G. H. (1990). Mechanism of phosgene-induced lung toxicity: Role of arachidonate mediators. Journal of applied physiology, 69(5), 1615-1622.