Lower torso ischemia and reperfusion lead to respiratory dysfunction characterized by pulmonary hypertension and increased lung microvascular permeability. This is associated with lung leukose- questration and thromboxane (TX) generation. This study tests the role of elevated TX levels following muscle 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)-TXB2levels from 211 to 735 pg/ml (p<0.05), and at 30 minutes, lung lymph i-TXB2levels 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 (p<0.05). Lung lymph flow (QL) rose from 4.3 to 8.3 ml/30 min (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 min (p<0.05). Two hours after reperfusion, neutrophils were observed sequestered in lung capillaries and protemaceous exudates were found in alveoli in contrast to sham-operated animals (n=3). To maximize lung vascular surface area and acineve 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 (ód) of 0.72. During reperfusion the L/P ratio rose to 0.49 (p<0.05) and the ód decreased to 0.51 (p<0.05), documenting an increase in lung microvascular permeability. In contrast to untreated ischemk controls, ininbition of TX synthetase with OKY 046 (n=6) reduced plasma i-TXB2levels to 85 pg/ml (p<0.05) but also increased i-6-keto-PGF1αlevels 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 ischemic controls. Pretreatment with OKY 046 combined with ibuprofen (n=5) prevented the increase in i-6-keto-PGF1α(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 TXB, 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.