Effects of cyclooxygenase and lipoxygenase inhibition on lung fluid balance after thrombin

Abstract

We examined the roles of the cyclooxygenase and lipoxygenase pathways in the alterations in lung fluid and protein exchange after pulmonary microembolism. Infusion of alpha-thrombin (T) (55 +/- 13 U/kg) immediately increased mean pulmonary arterial pressure (Ppa) and mean pulmonary vascular resistance (PVR), but both Ppa and PVR waned with time after T. Cyclooxygenase inhibition with either indomethacin or ketoprofen produced sustained increases in Ppa and PVR. The initial increases in Ppa in the cyclooxygenase-inhibited groups (CI) were matched to the control group by administering greater amounts of T. In the control group, T rapidly increased pulmonary lymph flow (Qlym) by two- to threefold, and this was associated with a steady increase in lymph-to-plasma protein concentration ratio (L/P). In contrast, in cyclooxygenase-inhibited (CI) groups, Qlym increased gradually to greater levels than in the control group, and L/P did not change. The effect on lung vascular permeability was determined by inflating a left atrial balloon catheter to raise pulmonary capillary pressure (Pc). An increase in Pc after T in the control group further increased Qlym and did not change L/P, whereas the increase in Pc after T in CI groups further increased Qlym and decreased L/P, indicating that cyclooxygenase inhibition prevented the increase in permeability. We determined whether lipoxygenase activation contributed to the increase in Qlym in CI groups by examining the effects of BW755C, an inhibitor of both cyclooxygenase and lipoxygenase pathways. BW755C resulted in the same increase in Qlym after T as in the control group, but the increase in Qlym was associated with a decrease in L/P. Therefore, inhibition of both pathways prevented the permeability increase and the greater increase in Qlym. The results indicate that cyclooxygenase and lipoxygenase pathways contribute to the increases in pulmonary transvascular fluid and protein fluxes after thrombin.