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Reduction of polymorphonuclear leukocyte accumulations by inhibition of cyclooxygenase and thromboxane syntase in the rabbit
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status, and the degree of injury have been related to the severity of the immunosuppression that occurs, the physiologic alterations leading to immunosuppression are not well defined. We hypothesized that changes in the endogenous opiate peptides, such as B-endorphin, might contribute to changes in the immune system following injury, Levels of circulating/~-endorphin, responsiveness to the mitogen PHA, and the frequency of circulating TI I, T4, and T8 cells were measured in trauma patients hospitalized in a surgical intensive care unit. •-endorphin levels were elevated during the first 4 days after trauma (134.1 ± 22.5 vs. 49.3 ± 4.3 pg/ml, mean ± S.E., pa'~ient vs. control; p < 9.001). During the same time period patient PHA response (10,852 ± 3,775 vs. 28,147 ± 12,078; p < 0,05), and the per cent of T4 positive (3t.2 ± 2.6 vs. 47.0 ± 1.4; p < 0.0017 cells were lower than controls. These parameters were not significantly different from control values when measured at later times. Thus we conclude there is a temporal association of depressed immune parameters and elevated/~-endorphin levels after traumatic injury. (Reprinted with permission,)
Reduction of Polymorphonuclear Leukocyte Accumulations by Inhibition of Cyelooxygenese and Thromboxane Syntese in the Rabbit./'alder SB, Huval W. Lelcuk S, etal. Surgery
99:72, 1986. Thromboxane (Tx) inhibition prevents puhnonary leukostasis after acid aspiration. This observation prompted study of polymorphonuclear leukocyte (PMN) accumulations and products of cyclooxygenase. Experiments were conducted with a skin abrasion preparation. Five groups of six rabbits were pretreated intravenously with: (I) placebo, (2) ibuprofen, (3) imidazole and two other Tx syntase inhibitors, (4) OKY 1555, or (5) OKY 046. Zymosan-activated serum (ZAS) and leukotriene B4 were used as chemotaxins and balanced salt solution as control. After pretreatment with placebo, PMN accumulation in leukotriene B4 sites was 2130 ± 874 P M N / m m 3 (mean ± SD). Pretreatment with ibuprofen, imidazole, or OKY 046 decreased (p < 0.05) accumulations to 205 ± 139 P M N / m m J, 485 _+ 387 P M N / m m 3, and 504 ± 260 P M N / m m 3, respectively. In ZAS sites, placebo pretreatment led to 2006 _+ 866 P M N / m m ~, while the ibuprofen, imidazole, and OKY 046 groups had decreased (p < 0.05) responses of 295 ± 218 P M N / m m 3, 444 ± 477 P M N / m m J, and 386 ± 151 P M N / m m 3, respectively. Protreatment with OKY 1555 did not produce significant reductions in response. Six animals in each group received intradermal injections of the two chemotaxins or Hank's balanced salt solution. Reduction in PMN accumulations after cyclooxygenase and Tx inhibition were similar to those observed in the skin abrasion preparation. Pretreatment with either ibuprofen, imidazole, or OKY 046 resulted in a decreased concentration of Tx in abrasion fluid exudate in response to leukotriene B4, 275 ± 164 pg/ml, 460 ± 144 pg/ml, and 440 ± 260 pg/mt, respectively, as compared with 1168 ± 380 pg/ml in the placebo group. The reduced responses were not the result of a decrease in regional perfusion as measured by t33Xe washout. The in vitro themetactic response of PMN to leukotriene B4 and ZAS was unchanged after incubation in either ibuprofen, imidazole. OKY 1555, or OKY 046. These data show that cyclooxygen-
ABSTRACTS
ase and Tx syntase are integrally associated with PMN aocumulations. (Reprinted with permission.) Postburn Immunosuppression in an Animal Model. IV. Improved Resistance to Septic Challenge With Immunemodulating Drugs. Zapata-Sirvent RL, Hansbrough JF,
Bender EM. et al. Surgery 99:53, 1986. We have previously demonstrated that certain pharmacologic agents administered to burned mice will restore cellmediated immunity, as evidenced by measurement of delayed hypersensitivity responses and determination of splenic helper/suppressor lymphocyte ratios. These drugs are systemic cimetidine, ibuprofen, cyclophosphamide, and topical cerium nitrate. In the studies reported here we performed cecal ligation and puncture (CLP) in burned mice as a measure of resistance to infectious challenge. Survival after CLP with a 23-gauge needle used for puncture was markedly decreased when performed on the tenth postburn day (normal 63.7%, 10 days postburn 20.0%; p < 0.00t), but survival was not decreased when CLP was performed on the fifth (60.0%; p not significant) or twenty-first postburn day (65.3%; p not significant). Animals were then treated with the four agents in carefully defined dosage regimens, and survival was again determined on the tenth postburn day. Survival figures with p values compared to burned, untreated animals: burn plus cimetidine 62.5%, p < 0.0005; burn plus: ibuprofen 64.7% p < 0.0003; burn plus cyclophosphamide 68.2%, p < 0.000l; burn plus cerium nitrate 54.1%, p < 0,004. Specific pharmacologic therapy in burned mice in dosage regimens that have been shown to improve cell-mediated immunity is also able to significantly improve resistance to subsequent infectious challenge. (Reprinted with permission.) Susceptibility to Bacterial Sepsis. Accurate Measurement by the Delayed-Type Hypersensitivity Skin Test Score.
Tchervenkov JI, Diane E, Meakins JL, et el. Arch Surg 121:37, 1986. To test the hypothesis that any alteration in the delayedtype hypersensitivity (DTH) skin test response (not necessarily total anergy) reflects increased susceptibility to bacterial sepsis, male Sprague-Dawley rats prescnsitized to keyhole-limpet hemocyanin were subjected to a 30% fullthickness scald burn. Susceptibility to bacteria was assessed by the intradermal injection of Staphylococcus aureus 502A. The DTltt response decreased following burn injury from 6.6 to 3.9 mm on days 2 and 8. Skin abscess size increased from 5.8 to 9.3 mm on day 2 and 8.9 mm on day 8. There was a significant inverse correlation between DTH skin test score and abscess size. Histologically there was no difference in the overall leukocyte accumulation in the abscess or the DTH reaction between the two groups, yet the overall size of the abscess was greater and the swelling of the dermis in the DTH response was less in the burned rats. (Reprinted with permission.) Thermal Injury Promotes Bacterial Translocation From the Gastrointestinal Tract in Mice With Impaired T-CeilMediated Immunity. Deitch E/l, Winterton J, Berg R. Arch
Surg 121:97, 1986. We have shown previously that after thermal trauma viable bacteria will cross the intact gastrointestinal mucosa
status, and the degree of injury have been related to the severity of the immunosuppression that occurs, the physiologic alterations leading to immunosuppression are not well defined. We hypothesized that changes in the endogenous opiate peptides, such as B-endorphin, might contribute to changes in the immune system following injury, Levels of circulating/~-endorphin, responsiveness to the mitogen PHA, and the frequency of circulating TI I, T4, and T8 cells were measured in trauma patients hospitalized in a surgical intensive care unit. •-endorphin levels were elevated during the first 4 days after trauma (134.1 ± 22.5 vs. 49.3 ± 4.3 pg/ml, mean ± S.E., pa'~ient vs. control; p < 9.001). During the same time period patient PHA response (10,852 ± 3,775 vs. 28,147 ± 12,078; p < 0,05), and the per cent of T4 positive (3t.2 ± 2.6 vs. 47.0 ± 1.4; p < 0.0017 cells were lower than controls. These parameters were not significantly different from control values when measured at later times. Thus we conclude there is a temporal association of depressed immune parameters and elevated/~-endorphin levels after traumatic injury. (Reprinted with permission,)
Reduction of Polymorphonuclear Leukocyte Accumulations by Inhibition of Cyelooxygenese and Thromboxane Syntese in the Rabbit./'alder SB, Huval W. Lelcuk S, etal. Surgery
99:72, 1986. Thromboxane (Tx) inhibition prevents puhnonary leukostasis after acid aspiration. This observation prompted study of polymorphonuclear leukocyte (PMN) accumulations and products of cyclooxygenase. Experiments were conducted with a skin abrasion preparation. Five groups of six rabbits were pretreated intravenously with: (I) placebo, (2) ibuprofen, (3) imidazole and two other Tx syntase inhibitors, (4) OKY 1555, or (5) OKY 046. Zymosan-activated serum (ZAS) and leukotriene B4 were used as chemotaxins and balanced salt solution as control. After pretreatment with placebo, PMN accumulation in leukotriene B4 sites was 2130 ± 874 P M N / m m 3 (mean ± SD). Pretreatment with ibuprofen, imidazole, or OKY 046 decreased (p < 0.05) accumulations to 205 ± 139 P M N / m m J, 485 _+ 387 P M N / m m 3, and 504 ± 260 P M N / m m 3, respectively. In ZAS sites, placebo pretreatment led to 2006 _+ 866 P M N / m m ~, while the ibuprofen, imidazole, and OKY 046 groups had decreased (p < 0.05) responses of 295 ± 218 P M N / m m 3, 444 ± 477 P M N / m m J, and 386 ± 151 P M N / m m 3, respectively. Protreatment with OKY 1555 did not produce significant reductions in response. Six animals in each group received intradermal injections of the two chemotaxins or Hank's balanced salt solution. Reduction in PMN accumulations after cyclooxygenase and Tx inhibition were similar to those observed in the skin abrasion preparation. Pretreatment with either ibuprofen, imidazole, or OKY 046 resulted in a decreased concentration of Tx in abrasion fluid exudate in response to leukotriene B4, 275 ± 164 pg/ml, 460 ± 144 pg/ml, and 440 ± 260 pg/mt, respectively, as compared with 1168 ± 380 pg/ml in the placebo group. The reduced responses were not the result of a decrease in regional perfusion as measured by t33Xe washout. The in vitro themetactic response of PMN to leukotriene B4 and ZAS was unchanged after incubation in either ibuprofen, imidazole. OKY 1555, or OKY 046. These data show that cyclooxygen-
ABSTRACTS
ase and Tx syntase are integrally associated with PMN aocumulations. (Reprinted with permission.) Postburn Immunosuppression in an Animal Model. IV. Improved Resistance to Septic Challenge With Immunemodulating Drugs. Zapata-Sirvent RL, Hansbrough JF,
Bender EM. et al. Surgery 99:53, 1986. We have previously demonstrated that certain pharmacologic agents administered to burned mice will restore cellmediated immunity, as evidenced by measurement of delayed hypersensitivity responses and determination of splenic helper/suppressor lymphocyte ratios. These drugs are systemic cimetidine, ibuprofen, cyclophosphamide, and topical cerium nitrate. In the studies reported here we performed cecal ligation and puncture (CLP) in burned mice as a measure of resistance to infectious challenge. Survival after CLP with a 23-gauge needle used for puncture was markedly decreased when performed on the tenth postburn day (normal 63.7%, 10 days postburn 20.0%; p < 0.00t), but survival was not decreased when CLP was performed on the fifth (60.0%; p not significant) or twenty-first postburn day (65.3%; p not significant). Animals were then treated with the four agents in carefully defined dosage regimens, and survival was again determined on the tenth postburn day. Survival figures with p values compared to burned, untreated animals: burn plus cimetidine 62.5%, p < 0.0005; burn plus: ibuprofen 64.7% p < 0.0003; burn plus cyclophosphamide 68.2%, p < 0.000l; burn plus cerium nitrate 54.1%, p < 0,004. Specific pharmacologic therapy in burned mice in dosage regimens that have been shown to improve cell-mediated immunity is also able to significantly improve resistance to subsequent infectious challenge. (Reprinted with permission.) Susceptibility to Bacterial Sepsis. Accurate Measurement by the Delayed-Type Hypersensitivity Skin Test Score.
Tchervenkov JI, Diane E, Meakins JL, et el. Arch Surg 121:37, 1986. To test the hypothesis that any alteration in the delayedtype hypersensitivity (DTH) skin test response (not necessarily total anergy) reflects increased susceptibility to bacterial sepsis, male Sprague-Dawley rats prescnsitized to keyhole-limpet hemocyanin were subjected to a 30% fullthickness scald burn. Susceptibility to bacteria was assessed by the intradermal injection of Staphylococcus aureus 502A. The DTltt response decreased following burn injury from 6.6 to 3.9 mm on days 2 and 8. Skin abscess size increased from 5.8 to 9.3 mm on day 2 and 8.9 mm on day 8. There was a significant inverse correlation between DTH skin test score and abscess size. Histologically there was no difference in the overall leukocyte accumulation in the abscess or the DTH reaction between the two groups, yet the overall size of the abscess was greater and the swelling of the dermis in the DTH response was less in the burned rats. (Reprinted with permission.) Thermal Injury Promotes Bacterial Translocation From the Gastrointestinal Tract in Mice With Impaired T-CeilMediated Immunity. Deitch E/l, Winterton J, Berg R. Arch
Surg 121:97, 1986. We have shown previously that after thermal trauma viable bacteria will cross the intact gastrointestinal mucosa