Dimethylthiourea attenuates endotoxin-induced acute respiratory failure in pigs.
We hypothesized that toxic O2 radicals might be important mediators of endotoxin-induced acute respiratory failure in pigs. As a relatively specific scavenger of .OH, we infused dimethylthiourea (DMTU, 1 g/kg) before endotoxemia. Escherichia coli endotoxin (055-B5) was infused intravenously into anesthetized 10- to 14-wk-old pigs at 5 micrograms/kg the 1st h, followed by 2 micrograms.kg-1.h-1 for 3.5 h. During phase 1 (i.e., 0-2 h) and phase 2 (i.e., 2-4.5 h), endotoxin decreased cardiac index (CI) and increased mean pulmonary arterial pressure (Ppa), pulmonary vascular resistance (PVR), alveolar-arterial O2 gradient (AaDo2), and hematocrit (Hct). Endotoxemia also caused leukopenia and increased the postmortem bronchoalveolar lavage fluid (BALF) albumin concentration and wet weight-to-dry weight ratio of bloodless lung. Dimethylthiourea did not significantly modify the phase 1 response. However, during phase 2, DMTU attenuated the endotoxin-induced decrease in CI and increases in Ppa, PVR, Hct, AaDo2, lung water, and BALF albumin concentration. In separate groups of endotoxin- and DMTU + endotoxin-treated pigs, lung microvascular hydrostatic pressure was increased to approximately 16 Torr (by fluid overload) to assess alveolar-capillary membrane permeability. Under these conditions, DMTU markedly attenuated the endotoxin-induced increase in alveolar-capillary membrane permeability. Under these conditions, DMTU markedly attenuated the endotoxin-induced induced increase in alveolar-capillary membrane permeability. We conclude that .OH (and possibly H2O2) significantly contributes to endotoxin-induced lung injury in anesthetized pigs.
Olson
N C
NC
Department of Anatomy, Physiological Sciences and Radiology, School of Veterinary Medicine, North Carolina State University, Raleigh 27606.
Anderson
D L
DL
Grizzle
M K
MK
D000208:Acute Disease; D000818:Animals; D001784:Blood Gas Analysis; D001794:Blood Pressure; D004731:Endotoxins; D005609:Free Radicals; D006878:Hydroxides / Q000009:adverse effects*; D017665:Hydroxyl Radical; D011651:Pulmonary Artery / Q000502:physiology; D011659:Pulmonary Gas Exchange; D011669:Pulmonary Wedge Pressure; D012131:Respiratory Insufficiency / Q000209:etiology* / Q000628:therapy; D013552:Swine; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology
D004731:Endotoxins; D005609:Free Radicals; D006878:Hydroxides; D017665:Hydroxyl Radical; C038983:1,3-dimethylthiourea; D013890:Thiourea