Thromboxane A2 Mediates Increased Pulmonary Microvascular PermeabUity Following Limb Ischemia

Lower torso ischemia and reperfusion lead to respiratory dysfunction characterized by pulmonary hypertension and increased lung microvascular permeability. This is associated with lung leukosequestration and thromboxane (TX) generation. This study tests the role of elevated TX levels following musde ischemia in mediating remote lung injury. Anesthetized sheep prepared with chronic lung lymph fistulae underwent 2 hours of bilateral hind limb tourniquet ischemia. In untreated controls (n=7), 1 minute after reperfusion there was a transient increase in plasma immunoreactive (i)-TXRj levels from 211 to 735 pg/ml (p<0.05), and at 30 minutes, lung lymph i-TXBj levels rose from 400 to 1,005 pg/ml (p<0.05). At 1 minute, the mean pulmonary arterial pressure (MPAP) increased from 13 to 38 mm Hg (p<0.05) and pulmonary microvascular pressure (Pmv) from 7 to 18 mm Hg (/K0.05). Lung lymph flow (QL) rose from 4.3 to 8.3 ml/30 rnin (p<0.05), the lymph/plasma (L/P) protein ratio was unchanged from 0.6, and the lymph protein clearance increased from 2.6 to 4.6 ml/30 mm (p<0.05). Two hours after reperfusion, neutrophils were observed sequestered in lung capillaries and proteinaceous exudates were found in alveoli hi contrast to sham-operated animals ( R = 3 ) . TO maximize lung vascular surface area and achieve a pressure independent L/P protein ratio a left atrial balloon was inflated during one group of ischemia-reperfusion experiments (n=5). This resulted in a baseline rise in MPAP to 20 mm Hg (p<0.05); a 4.3-fold increase in QL (p<0.05), a decrease in the L/P ratio from 0.70 to 0.28 (p<0.05) and a protein reflection coefficient (<rd) of 0.72. During reperfusion the L/P ratio rose to 0.49 (p<0.05) and the ad decreased to 0.51 (p<0.05), documenting an increase in lung microvascular permeability. In contrast to untreated ischemk controls, inhibition of TX synthetase with OKY 046 (n=6) reduced plasma i-TXB, levels to 85 pg/ml (p<0.05) but also increased i-6-keto-PGFla levels to 78 pg/ml relative to 15 pg/ml in untreated controls (p<0.05). OKY 046 prevented the increase in MPAP, Pmv, QL, and lymph protein clearance (p<0.05). Lung histology was normal in distinction to the leukosequestration in untreated iscbemic controls. Pretreatment with OKY 046 combined with ibuprofen (n=5) prevented the increase in i-6-keto-PGFla (p<0.05) but still led to a response unchanged from OKY 046 treatment alone. Pretreatment with the TX receptor antagonist SQ 29,548 (n=5) did not affect the ischemia induced increases in TXBj levels in plasma and lung lymph to 702 and 789 pg/ml, respectively, but prevented the increase in MPAP, Pmv, QL, lymph protein clearance, and lung leukosequestration (p<0.05 for all). These data indicate that the increased lung permeability following lower torso ischemia and reperfusion may be mediated by TX. (Circulation Research 1989;64:1178-1189)