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Enhanced microvascular permeability of PMA-induced acute lung injury is not mediated by cyclooxygenase products
M M Wurtz1, A H Stephenson, R S Sprague
1Department of Internal Medicine, St. Louis University School of Medicine, Missouri 63104.
Abstract:
Products of cyclooxygenase activity have been proposed to mediate the pulmonary hypertension and increased microvascular permeability associated with phorbol myristate acetate- (PMA) induced acute lung injury. Previously, we reported that thromboxane (Tx) does not mediate PMA-induced pulmonary hypertension in intact anesthetized dogs. In the present study, PMA was administered to isolated canine lungs perfused with autologous blood at constant flow to investigate a possible role for Tx in the PMA-induced increase in microvascular permeability. Changes in permeability were assessed by determining changes in the capillary filtration coefficient (Kfc). In lobes pretreated with papaverine to prevent PMA-induced increases in pulmonary vascular resistance, Kfc increased from a baseline value of 0.2 +/- 0.03 to 1.5 +/- 0.29 ml.min-1.cmH2O-1.100 g wet lobe wt-1 (P < 0.01) 30 min after PMA (5.8 x 10(-8) M, n = 10). Concomitantly, TxB2, the stable metabolite of TxA2, increased from 138 +/- 44 to 1,498 +/- 505 pg/ml (P < 0.05) in the blood. Both the selective Tx synthase inhibitor, OKY-046 (7 x 10(-4) M, n = 6), and the cyclooxygenase inhibitor, indomethacin (10(-4) M, n = 7), prevented the PMA-induced increase in TxB2, but neither compound attenuated the PMA-induced increase in Kfc. ONO-3708 (10(-6) M), a selective prostaglandin (PG) H2/TxA2 receptor antagonist, prevented the vasoconstriction resulting from administration of U-46619, a stable PGH2/TxA2 receptor agonist, but it did not prevent the PMA-induced increases in Kfc (n = 6).(ABSTRACT TRUNCATED AT 250 WORDS)
Insights
Thromboxane (Tx) does not mediate increased microvascular permeability in acute lung injury. Inhibiting Tx production or blocking Tx receptors did not alter permeability changes induced by phorbol myristate acetate (PMA).
Area of Science:
- Pulmonary Medicine
- Cardiovascular Research
- Inflammation and Immunology
Background:
- Cyclooxygenase (COX) products are implicated in acute lung injury (ALI) pathogenesis, specifically pulmonary hypertension and increased microvascular permeability.
- Previous studies indicated thromboxane (Tx) does not mediate phorbol myristate acetate (PMA)-induced pulmonary hypertension in vivo.
- The role of Tx in PMA-induced microvascular permeability in ALI remains unclear.
Purpose of the Study:
- To investigate the role of thromboxane (Tx) in mediating increased microvascular permeability in isolated canine lungs exposed to phorbol myristate acetate (PMA).
- To assess the effects of Tx synthase inhibition, COX inhibition, and Tx receptor antagonism on PMA-induced changes in microvascular permeability.
Main Methods:
- Isolated canine lungs were perfused with autologous blood at a constant flow rate.
- Phorbol myristate acetate (PMA) was administered to induce acute lung injury.
- Capillary filtration coefficient (Kfc) was measured to assess microvascular permeability.
- Thromboxane B2 (TxB2) levels were measured in perfusate.
- Drugs tested included a Tx synthase inhibitor (OKY-046), a COX inhibitor (indomethacin), and a Tx receptor antagonist (ONO-3708).
Main Results:
- PMA administration significantly increased microvascular permeability (Kfc) and TxB2 levels in isolated canine lungs.
- Both OKY-046 and indomethacin successfully inhibited the PMA-induced increase in TxB2.
- Neither Tx synthase inhibition nor COX inhibition attenuated the PMA-induced increase in Kfc.
- The Tx receptor antagonist ONO-3708 blocked U-46619-induced vasoconstriction but did not prevent PMA-induced increases in Kfc.
Conclusions:
- Thromboxane (Tx) does not appear to mediate the increased microvascular permeability associated with phorbol myristate acetate (PMA)-induced acute lung injury in isolated canine lungs.
- The cyclooxygenase (COX) pathway leading to Tx production is not responsible for the observed permeability changes.
- These findings suggest that other mediators, independent of thromboxane, are involved in PMA-induced pulmonary microvascular leakage.