Pulmonary Leukosequestration Induced by Hind Limb Ischemia

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Abstract
Lower torso ischemia leads to acute respiratory failure, an event associated with the accumulation of inflammatory cells in the lungs. This study tests whether ischemia-induced eicosanoid synthesis leads to polymorphonuclear leukocyte (PMN) accumulation in the lungs. Anesthetized rats (N = 51) were randomized into five groups: nonischemic sham rats (N = 10); the remaining four groups were rats made ischemic for 4 hours with bilateral thigh tourniquets treated just before tourniquet release with saline vehicle (N = 17): the thromboxane (Tx) synthase inhibitor OKY-046 (Ono Pharmaceutica, Osaka, Japan) 2 mg/kg intravenously every 2 hours (N = 8); the lipoxygenase inhibitor diethylcarbamazine (DEC) (Sigma, St. Louis, MO) 0.2 mg/kg/min intravenously (N = 8); the platelet-activating factor receptor antagonist SRI (Sandoz Inc., East Hanover, NJ) 63–072 3 mg/kg intravenously every 30 minutes (N = 8). Four hours after ischemia, plasma TxB2 levels in the ischemic placebo-treated group was 3570 ± 695 pg/mL, compared with 495 ± 73 pg/mL in sham rats (p < 0.001). Lung microscopy showed foci of proteinaceous exudate in alveoli and 121 ± 10 PMN/20 high power fields (HPF) compared with 59 ± 9 PMN/20 HPF in the sham group (p < 0.001). One day after ischemia PMN accumulations remained elevated at 119 PMN/20 HPF. Pretreatment with OKY-046 led to reduced TxB2 levels of 149 ± 17 pg/mL, normal lung histology, and 83 ± 13 PMN/20 HPF, a value similar to that of the sham group and lower than that of the placebo-treated group (p < 0. 05). Treatment with DEC yielded TxB2 levels of 1419 ± 492 pg/mL, which was lower than that of the placebo group (p < 0.05) but higher than that of the sham group (p < 0.05). Microscopy showed normal lungs with 79 ± 7 PMN/20 HPF lower than the placebo group (p < 0. 05). SRI 63–072 did not inhibit Tx synthesis or leukosequestration in the lungs. Platelet counts decreased in all groups relative to sham animals (p < 0.05). The results indicate that Tx synthesis induced by ischemia moderates PMN accumulations in the lungs. Inhibition of lipoxygenase is believed to prevent PMN accumulations both by limiting leukotriene-induced Tx synthesis as well as by limiting production of chemoattractants.

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