title: Interleukin-2-induced lung injury is mediated by oxygen free radicals.
abstract: Interleukin-2 therapy leads to respiratory dysfunction caused by increased vascular permeability. This study examines the role of oxygen-derived free radicals (OFR). Sheep (n = 6) with chronic lung lymph fistulae were given interleukin-2, 10(5) units/kg, as an intravenous bolus. The mean pulmonary artery pressure rose from 13 to 23 mm Hg (p less than 0.05) at 1 hour and remained elevated for 4 hours, although the pulmonary artery wedge pressure was unchanged at 4 mm Hg. Arterial oxygen tension fell from 88 to 77 mm Hg (p less than 0.05). Lung lymph flow rose from 2.2 to 6.4 ml/30 min (p less than 0.05) at 3 hours. This rise coincided with an increase in the lymph/plasma protein ratio from 0.67 to 0.77 (p less than 0.05) and lymph protein clearance from 1.5 to 4.4 ml/30 min (p less than 0.05), indicating increased lung microvascular permeability. Interleukin-2 led to transient increases in plasma thromboxane B2 from 168 to 388 pg/ml (p less than 0.05) and lung lymph thromboxane B2 from 235 to 694 pg/ml (p less than 0.05). The leukocyte count fell from 8156 to 4375/mm3 (p less than 0.05) primarily caused by a 78% drop in lymphocyte count. Platelet count declined from 292 to 184 X 10(3)/mm3 (p less than 0.05). Pretreatment with the hydroxyl radical scavenger dimethylthiourea, 1 gm/kg, intravenously, (n = 6) prevented the interleukin-2-induced increase in mean pulmonary artery pressure, lung lymph flow, lymph/plasma protein ration, lymph protein clearance, and thromboxane B2 levels in plasma and lung lymph. The arterial oxygen tension decreased from 85 to 80 mm Hg (p less than 0.05). The leukocyte count declined from 7854 to 6229/mm3 (p less than 0.05), but this was not as low nor as prolonged as the interleukin-2 group. Further, the decrease in platelet count was prevented (p less than 0.05). Interleukin-2 incubated with sheep or human leukocytes led to a dose-dependent increase in intracellular hydrogen peroxide production by neutrophils as measured by flow cytometry of dichlorofluorescein oxidation. These data indicate that interleukin-2 stimulates OFR generation and that OFR moderate the interleukin-2-induced increased lung permeability.
authors.affiliation: Department of Surgery, Brigham & Women's Hospital, Boston, Mass.
authors.forename: J M
authors.initials: JM
authors.lastname: Klausner
authors.forename: I S
authors.initials: IS
authors.lastname: Paterson
authors.forename: G
authors.initials: G
authors.lastname: Goldman
authors.forename: L
authors.initials: L
authors.lastname: Kobzik
authors.forename: S
authors.initials: S
authors.lastname: Lelcuk
authors.forename: Y
authors.initials: Y
authors.lastname: Skornick
authors.forename: T
authors.initials: T
authors.lastname: Eberlein
authors.forename: C R
authors.initials: CR
authors.lastname: Valeri
authors.forename: D
authors.initials: D
authors.lastname: Shepro
authors.forename: H B
authors.initials: HB
authors.lastname: Hechtman
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D005260:Female; D016166:Free Radical Scavengers; D005609:Free Radicals; D006861:Hydrogen Peroxide / Q000378:metabolism*; D006976:Hypertension, Pulmonary / Q000517:prevention & control; D007376:Interleukin-2 / Q000633:toxicity*; D007970:Leukopenia / Q000139:chemically induced / Q000517:prevention & control; D008168:Lung / Q000187:drug effects / Q000473:pathology* / Q000502:physiology; D008196:Lymph / Q000187:drug effects / Q000502:physiology; D010100:Oxygen; D010976:Platelet Count / Q000187:drug effects; D011651:Pulmonary Artery / Q000187:drug effects; D011994:Recombinant Proteins / Q000633:toxicity; D012756:Sheep; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology; D013929:Thromboxane B2 / Q000097:blood
chemical_list: D016166:Free Radical Scavengers; D005609:Free Radicals; D007376:Interleukin-2; D011994:Recombinant Proteins; D013929:Thromboxane B2; C038983:1,3-dimethylthiourea; D006861:Hydrogen Peroxide; D013890:Thiourea; D010100:Oxygen