Cardiovascular and pulmonary effects of human recombinant tumor necrosis factor in the conscious rat.
The purpose of this study was to examine the dose response to a highly purified human recombinant tumor necrosis factor (TNF alpha) preparation (1-2 x 10(7) U/mg; less than 0.05 ng endotoxin/mg TNF alpha) in the conscious rat. Rats received intravenous bolus injections of 0.3 mg/kg (n = 6), 1.0 mg/kg (n = 17), 3.0 mg/kg (n = 11), or 10 mg/kg (n = 15) of TNF alpha, 30 mg/kg (n = 7) Salmonella enteritidis endotoxin (LPS), or isotonic saline (n = 11). Upon termination of the experiment, the lungs were removed for lavage or histology. Survival was 0% 24 hr after the injection of LPS and 83, 59, 73, and 73% after the lowest to highest doses of TNF alpha, respectively. As with endotoxin, TNF alpha caused a dose-dependent increase in heart rate (HR) (P less than 0.05) within 0.5 hr of administration, which remained elevated throughout the 24 hr period. TNF alpha had no effect on mean arterial blood pressure (MABP) acutely, but it caused a 15-20% decrease in MABP 24 hr post exposure (P less than 0.05). TNF alpha increased hematocrit within 0.5 to 3 hr in all dose groups by 10-15%. Furthermore, TNF alpha produced a thrombocytopenia in all dose groups, although the decrease in platelet count was less than that produced by endotoxin. TNF alpha doses of 1-10 mg/kg caused leukopenia within 0.5 hr (P less than 0.05). Lavage and histology revealed no changes in the number of pulmonary neutrophils. These results suggest that TNF alpha stimulated dose-dependent responses, which were consistent with those produced by LPS. However, these responses to TNF alpha were appreciably smaller than those reported for either LPS or for TNF alpha from other sources.
Turner
C R
CR
Smith Kline and French Laboratories, Department of Experimental Pathology, King of Prussia, Pennsylvania 19406-0939.
Esser
K M
KM
Wheeldon
E B
EB
Slivjak
M
M
Smith
E F
EF
D000818:Animals; D001772:Blood Cell Count; D001794:Blood Pressure / Q000187:drug effects*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology*; D004305:Dose-Response Relationship, Drug; D004731:Endotoxins / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects*; D006400:Hematocrit; D006801:Humans; D008168:Lung / Q000187:drug effects*; D008214:Lymphocytes / Q000166:cytology; D008264:Macrophages / Q000166:cytology; D008297:Male; D009504:Neutrophils / Q000166:cytology; D051381:Rats; D011919:Rats, Inbred Strains; D011994:Recombinant Proteins; D012477:Salmonella enteritidis; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D004731:Endotoxins; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha