Lower Torso Ischemia-Induced Lung Injury Is Leukocyte Dependent

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Abstract
Lower torso ischemia leads on reperfusion to sequestration of polymorphonuclear leukocytes (PMN) in the lungs and increased permeability. This study tests the role of circulating leukocytes (WBC) in mediating this 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 were transient increases in mean pulmonary arterial pressure (MPAP) from 13 to 38 mmHg (p < 0.05) and pulmonary microvascular pressure (Pmv) from 7 to 18 mmHg (p < 0.05), changes temporally related to a rise in plasma thromboxane (Tx) B2 levels from 211 to 735 pg/ml (p < 0.05). Lung lymph TxB2 levels rose from 400 to 1005 pg/ml at 30 minutes (p < 0.05) and remained elevated longer than plasma levels. Lung lymph flow (.ovrhdot.QL) rose from 4.3 to 8.3 ml/30 minutes (p < 0.05) after 30 minutes of reperfusion and remained elevated for 2 hours. The lymph/plasma (L/P) protein ratio was unchanged from 0.6, while the lymph protein clearance increased from 2.6 to 4.6 ml/30 minutes (p < 0.05), suggesting increased microvascular permeability. WBC counts decreased within the first hour of reperfusion from 6853 to 3796/mm3 (p < 0.05), and lung histology after 2 hours showed proteinaceous exudates and leukosequestration of 62 PMN/10 high-powered fields (HPF), higher than the 22 PMN/10 HPF (p < 0.05) in sham animals (n = 3). Recruitment of the pulmonary vasculature by left atrial balloon inflation (n = 3) resulted in a rise in MPAP to 20 mmHg. After 3 hours of balloon inflation, .ovrhdot.QL stabilized at 9.8 ml/15 minutes, and a pressure-independent L/P protein ratio of 0.3 was achieved. During reperfusion, .ovrhdot.QL increased further to 11.2 ml/15 minutes, the L/P ratio rose to 0.56 and the calculated osmotic reflection coefficient decreased from 0.70 to 0.44, documenting an increase in lung microvascular permeability. In contrast to these untreated ischemic controls, sheep (n = 7) rendered leukopenic with hydroxyurea or nitrogen mustard and having a total WBC count of 760/mm3 and PMN count of 150/mm3 did not manifest reperfusion-induced increases in MPAP, Pmv, .ovrhdot.QL, lymph protein clearance, or lung lymph TxB2 levels (p < 0.05). Plasma TxB2 levels rose slightly at 30 minutes from 199 to 288 pg/ml (p < 0.05). Lung histology was normal. These data indicate that WBC mediate the ischemia-induced increase in pulmonary microvascular permeability.