Prostaglandins potentiate U-46619-induced pulmonary microvascular dysfunction

Abstract

.-The induction of cyclooxygenase is an important event in the pathophysiology of acute lung injury. The purpose of this study was to examine the synergistic effects of various cyclooxygenase products (PGE 2 , PGI 2 , PGF 2␣ ) on thromboxane A 2 (TxA 2 )-mediated pulmonary microvascular dysfunction. The lungs of SpragueDawley rats were perfused ex vivo with Krebs-Henseleit buffer containing indomethacin and PGE 2 (5 ϫ 10 Ϫ8 to 1 ϫ 10 Ϫ7 M), PGF 2␣ (7 ϫ 10 Ϫ9 to 5 ϫ 10 Ϫ6 M), or PGI 2 (5 ϫ 10 Ϫ8 to 2 ϫ 10 Ϫ5 M). The TxA 2 -receptor agonist U-46619 (7 ϫ 10 Ϫ8 M) was then added to the perfusate, and then the capillary filtration coefficient (K f ), pulmonary arterial pressure (Ppa), and total pulmonary vascular resistance (RT) were determined. The K f of lungs perfused with U-46619 was twice that of lungs perfused with buffer alone (P ϭ 0.05). The presence of PGE 2 , PGF 2␣ , and PGI 2 within the perfusate of lungs exposed to U-46619 caused 118, 65, and 68% increases in K f , respectively, over that of lungs perfused with U-46619 alone (P Ͻ 0.03). The RT of lungs perfused with PGE 2 ϩ U-46619 was ϳ30% greater than that of lungs exposed to either U-46619 (P Ͻ 0.02) or PGE 2 (P Ͻ 0.01) alone. When paired measurements of RT taken before and then 15 min after the addition of U-46619 were compared, PGI 2 was found to attenuate U-46619-induced increases in RT (P Ͻ 0.01). These data suggest that PGE 2 , PGI 2 , and PGF 2␣ potentiate the effects of TxA 2 -receptor activation on pulmonary microvascular permeability.capillary filtration coefficient; pulmonary vascular resistance; isolated perfused lung model THROMBOXANE A 2 (TxA 2 ) has been incriminated as an important mediator of the pulmonary microvascular dysfunction that characterizes tissue ischemia and reperfusion injury (29), endotoxin exposure (9), and cutaneous thermal injury (14). In these conditions, as well as others, TxA 2 has been shown to cause vasoconstriction and enhanced microvascular permeability. Upregulation of cyclooxygenase is an important event in the generation of TxA 2 during acute inflammatory states. Cyclooxygenase catalyzes the incorporation of molecular oxygen into arachidonic acid, yielding a cyclic endoperoxide (PGG 2 ); subsequent peroxidation yields PGH 2 , the precursor for the synthesis of TxA 2 and PGE 2 , PGI 2 , and PGF 2␣ . In general, each of these cyclooxygenase products is released by the lung in response to a particular inflammatory stimulus, albeit in varying amounts (9,14).Despite their common origin, the physiological effects of these substances on the pulmonary microvasculature are diverse. For example, TxA 2 and PGF 2␣ are constrictors of the pulmonary vasculature in rats, whereas PGI 2 is a potent vasodilator (4, 5). Furthermore, TxA 2 profoundly increases microvascular permeability, whereas the other agents have little, if any, effect by themselves (20, 27). Several investigators have reported that PGE 2 and PGI 2 potentiate the effects of histamine, bradykinin, and interleukin-1 on microvascular permeability (2,34,35). Thi...