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Reversal of Ischemia/Reperfusion Lung Injury by Inhibition of Polymorphonuclear Leukocytes^*

^* From Otsuka America Pharmaceuticals Inc (Dr. Barnard and Messrs. Shappell and Yoshitake), Rockville, MD; and Rush Medical College (Dr. Barnard), Chicago, IL.

Correspondence to: Joseph W. Barnard, PhD, Maryland Research Laboratories, 9900 Medical Center Dr, Rockville, MD 20850

Because polymorphonuclear leukocytes (PMNs) have been shown to mediate ischemia/reperfusion lung injury, we hypothesized that their inhibition by the agent OPC-6535, which blocks PMN adherence and superoxide production, would reverse ischemia/reperfusion injury in the isolated rat lung.

Lungs were isolated from rats using our established techniques, perfused with Earl's balanced salt solution at 0.03 mL/g of body weight, and ventilated with air/5% CO₂ except during ischemia (45 min) when flow was also stopped. Permeability was assessed by the filtration coefficient (Kf,c) and increased after 30 min of reperfusion (from 0.47 ± 0.08 to 1.27 ± 0.29 mL/min/cm H₂O/100 g [p < 0.05]) and 90 min of reperfusion (1.77 ± 0.44 [p < 0.05] [n = 8]) resulting in severe edema (final wet weight, 4.24 ± 1.07 g [p < 0.05]). Treatment with 10 µM isoproterenol after 30 min of reperfusion reversed the increase (30 min of reperfusion increased Kf,c from 0.22 ± 0.02 to 0.41 ± 0.14), which was reversed by isoproterenol (back to 0.21 ± 0.06 at 90 min of reperfusion; final wet weight, 2.55 ± 1.27 g) as we have previously shown.

OPC-6535 (27 µM) also reversed reperfusion injury (Kf,c rose from 0.43 ± 0.09 at baseline to 0.97 ± 0.38 at 30 min of reperfusion, which decreased after 45 min of OPC-6535 to 0.62 ± 0.2; final wet weight, 3.18 ± 0.82 g). Kf,c in control lungs did not change (baseline 0.33 ± 0.04 to 0.21 ± 0.04 at the same time as 30 min of reperfusion to 0.21 ± 0.04 at 90 min [n = 9]). As was true for isoproterenol, OPC-6535 decreased lung myeloperoxidase (from reperfusion control values of 11,154 U/g dry lung tissue to 7,395 ± 2,303 with OPC-6535 posttreatment). These data suggest that OPC-6535 may hold promise in the treatment of acute lung injury.

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