Mechanism of phosgene-induced lung toxicity: role of arachidonate mediators.

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 angiotension II and KCl.

• Authors: Y L Guo, T P Kennedy, J R Michael, A M Sciuto, A J Ghio, N F Adkinson Jr, G H Gurtner
• Journal: Journal of applied physiology (Bethesda, Md. : 1985) (J Appl Physiol (1985)) Vol. 69 Issue 5 Pg. 1615-22 (Nov 1990) ISSN: 8750-7587 [Print] United States
• PMID: 2125593 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Acetophenones
• Arachidonic Acids
• Chromones
• SRS-A
• Tetrazoles
• Angiotensin II
• Phosgene
• 5,8,11,14-Eicosatetraynoic Acid
• Arachidonic Acid
• Potassium Chloride
• LY 171883
• FPL 55712
• Methylprednisolone
• Indomethacin

Topics

• 5,8,11,14-Eicosatetraynoic Acid (pharmacology)
• Acetophenones (pharmacology)
• Angiotensin II (pharmacology)
• Animals
• Arachidonic Acid
• Arachidonic Acids (pharmacology, physiology)
• Chromones (pharmacology)
• Indomethacin (pharmacology)
• Lung (drug effects)
• Male
• Methylprednisolone (pharmacology)
• Phosgene (poisoning)
• Potassium Chloride (pharmacology)
• Pulmonary Circulation (drug effects)
• Rabbits
• SRS-A (antagonists & inhibitors)
• Tetrazoles (pharmacology)