Prevention of granulocyte-mediated oxidant lung injury in rats by a hydroxyl radical scavenger, dimethylthiourea.
Toxic, partially reduced metabolites of oxygen (toxic oxygen radicals) are increasingly implicated in acute leukocyte-mediated tissue injury. To further probe the roles of oxygen radicals in acute lung edema, I studied the effects of a recently described and very potent oxygen radical scavenger, dimethylthiourea (DMTU) (Fox, R. B., R. N. Harada, R. M. Tate, and J. E. Repine, 1983, J. Appl. Physiol., 55:1456-1459) on polymorphonuclear leukocyte (PMN) oxidant function and on two types of lung injury mediated by oxygen radicals and PMN. DMTU (10 mM) blocked 79% of hydroxyl radical (OH) production by PMN in vitro without interfering with other PMN functions, such as O-2 production, myeloperoxidase activity, chemotaxis, degranulation, or aggregation. When isolated rat lung preparations were perfused with PMN activated to produce OH, lung weights were increased from 2.3 +/- 0.2 to 11.2 +/- 0.8 g. DMTU (10 mM) prevented 70% of these increases (lung weights, 5.0 +/- 1.1 g, P less than 0.005). Finally, when intact rats were exposed to 100% O2 for 66 h, lung weight:body weight ratios were increased from 5.78 +/- 0.33 to 8.87 +/- 0.16 g. DMTU (500 mg/kg) prevented 83% of this hyperoxia-induced lung edema in vivo (lung:body weight ratios, 6.05 +/- 0.21, P less than 0.001). Pharmacokinetic studies showed that DMTU diffused effectively into lung interstitial fluids and had a relatively long half-life (25-35 h) in the circulation. Because a variety of oxygen radicals, such as superoxide (O-2), hydrogen peroxide (H2O2), or OH are produced by PMN, there is usually some uncertainty about which one is responsible for injury. However, in these studies, DMTU did not scavenge O-2 and scavenged H2O2 only very slowly while scavenging OH very effectively. Therefore, DMTU may be useful in the investigation of the roles of oxygen radicals, especially OH, in acute granulocyte-mediated tissue injury.
D000818:Animals; D002449:Cell Aggregation / Q000187:drug effects; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D003594:Cytoplasmic Granules / Q000378:metabolism; D005609:Free Radicals; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D006878:Hydroxides / Q000096:biosynthesis / Q000097:blood / Q000378:metabolism*; D017665:Hydroxyl Radical; D066298:In Vitro Techniques; D007700:Kinetics; D008168:Lung / Q000378:metabolism; D055370:Lung Injury; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D010100:Oxygen / Q000633:toxicity*; D011654:Pulmonary Edema / Q000188:drug therapy; D051381:Rats; D011919:Rats, Inbred Strains; D013481:Superoxides / Q000378:metabolism; D013890:Thiourea / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use
D005609:Free Radicals; D006878:Hydroxides; D013481:Superoxides; D017665:Hydroxyl Radical; C038983:1,3-dimethylthiourea; D006861:Hydrogen Peroxide; D013890:Thiourea; D010100:Oxygen