Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024312 (lymphopenia)
 4,859 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Current strategies for the treatment of ARDS have been unsuccessful in reducing mortality. In the present study, we have evaluated the role of cyclooxygenase (CO) products in a rat model of ARDS by testing naproxen, indomethacin, ibuprofen, and a thromboxane A2 (TXA2) receptor antagonist (SK&F 96148). Rats were treated 1 hr prior to endotoxin (LPS) exposure and 24 hr later, survival, body weight changes, wet/dry lung weight (W/D), total protein content (TP) of the bronchoalveolar lavage (BAL) fluid, and total erythrocyte and differential leukocyte counts of the BAL fluid were measured. In addition, the following hematologic measurements were taken: hemoglobin (Hb), hematocrit (Hct), circulating erythrocyte, differential leukocyte, and platelet counts. Treatment with the TXA2 receptor antagonist reduced mortality to zero after 24 hr after LPS administration. Other compounds had no significant effect on LPS-induced mortality. Pretreatment with CO inhibitors or the TXA2 receptor antagonist attenuated the LPS-induced increase in TP and W/D. Although all compounds tended to reduce the LPS-induced increase in BAL erythrocytes, only the TXA2 receptor antagonist did so significantly. The LPS-induced increase in BAL neutrophil counts was significantly reduced by 30 mg/kg ibuprofen, but not by the other compounds. In fact, the TXA2 receptor antagonist actually exacerbated BAL neutrophil counts, but diminished the peripheral neutrophilia and lymphopenia induced by LPS. None of the CO inhibitors tested significantly affected LPS-induced hematologic responses. We conclude that by virtue of its protection against LPS-induced mortality, the TXA2 receptor antagonist was the most effective compound in this model. However, it did cause certain negative side effects such as increased pulmonary inflammation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Therapeutic intervention in a rat model of adult respiratory distress syndrome: III. Cyclooxygenase pathway inhibition. 193 28

The protective effects of altered arachidonic acid metabolism, using either methylprednisolone or a dual cyclooxygenase and 5-lipoxygenase inhibitor (SK&F 86002), were compared in a rat model of adult respiratory distress syndrome (ARDS). Rats were either unexposed (n = 9) or pretreated with vehicle (n = 25), 100 mg/kg SK&F 86002 (n = 8) or 30 mg/kg methylprednisolone (MP, n = 7) 1 h prior to the intratracheal administration of 7 mg/kg aerosolized endotoxin (LPS) or phosphate buffered saline (PBS). Twenty-four hours later, blood samples were collected and the rats were anesthetized and exsanguinated. The lungs were surgically removed, weighed and bronchoalveolar lavage (BAL) was performed. LPS caused 30-35% mortality and induced significant differences in body weight, BAL erythrocyte and neutrophil counts, lung wet/dry weight ratio (W/D), total BAL protein (TP), hemoglobin (Hb), hematocrit (HCT), and circulating leukocyte and platelet counts as compared with controls. Pretreatment with MP reduced mortality to zero and also attenuated the LPS-induced alterations in body weight, W/D, TP, BAL erythrocyte count, and circulating platelet count. However, MP exacerbated LPS-induced increases in Hb, HCT and circulating neutrophil counts while enhancing lymphopenia. Pretreatment with SK&F 86002 also reduced mortality to zero and attenuated LPS-induced alterations in W/D, TP, HCT and circulating platelet count. Like MP, SK&F 86002 exacerbated the LPS-induced lymphopenia, and increased circulating neutrophils above baseline values. We conclude that both MP and SK&F 86002 provided protection against LPS-induced responses in this model of ARDS. Mechanistically, this indicates the critical role of eicosanoid mediators in this model. Therapeutically, SK&F 86002, or a similar compound, may be beneficial in preventing the acute phase responses so harmful to ARDS patients.
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PMID:Therapeutic intervention in a rat model of ARDS: I. Dual inhibition of arachidonic acid metabolism. 212 22

We have documented in previous studies that local irradiation therapy for breast cancer caused severe lymphopenia with reduction of both T and non-T lymphocytes. Non-T cells were relatively more depressed but recovered within six months. The recovery of T cells, on the other hand, remained incomplete 10-11 years after irradiation. Several lymphocyte functions were also severely impaired. An association was found between prognosis and postirradiation mitogen reactivity of lymphocytes from these patients. Mortality up to eight years after irradiation was significantly higher in patients with low postirradiation phytohemagglutinin and PPD reactivity. The radiation induced decrease in mitogenic response seemed mainly to be caused by immunosuppressive monocytes, which suggests that the underlying mechanism might be mediated by increased production of prostaglandins by monocytes. For this reason we examined the effect of some cyclooxygenase products on different lymphocyte functions and found that prostaglandins A2, D2, and E2 inhibited phytohemagglutinin response in vitro. Natural killer cell activity was also reduced by prostaglandins D2 and E2. The next step was to examine various inhibitors of cyclooxygenase in respect to their capacity to revert irradiation-induced suppression of in vitro mitogen response in lymphocytes from breast cancer patients. It was demonstrated that Diclofenac Na (Voltaren), Meclofenamic acid, Indomethacin, and lysin-mono-acetylsalicylate (Aspisol) could enhance mitogen responses both before and after radiation therapy. This effect was most pronounced at completion of irradiation. On a molar basis, Diclofenac Na was most effective followed by Indomethacin, Meclofenamic acid, and lysin-monoacetylsalicylate. The clinically beneficial effects of irradiation might be overshadowed by its effects on the immune system. If true, the value of treatment could be improved if radiation-induced suppression of lymphocyte response, which correlates inversely to survival, is reduced. Since such an effect can be achieved in these patients with cyclooxygenase inhibitors in vitro it is possible that it can be achieved also in vivo.
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PMID:Immunosuppression in irradiated breast cancer patients: in vitro effect of cyclooxygenase inhibitors. 251 94

Human recombinant interleukins 1 alpha and 1 beta (rIL-1 alpha and -1 beta) both induced monophasic peripheral neutrophilia and lymphopenia in Lewis rats 1.5 hr after i.v. injection. The kinetics of rIL-1 alpha- and -1 beta-induced neutrophilia were similar to those induced by human monocyte-derived IL-1, IL-1 alpha, and IL-1 beta, and the peripheral neutrophilia was accompanied by a marked decrease in marrow neutrophils. Arachidonic acid metabolites are implicated as biochemical intermediates in the production of the neutrophilia but not lymphopenia, since indomethacin and dexamethasone both completely abrogated IL-1-induced neutrophilia but did not affect the IL-1-induced lymphopenia. Acetylsalicylic acid, a cyclooxygenase inhibitor, did not inhibit IL-1-induced neutrophilia, suggesting that products of the lipoxygenase rather than the cyclooxygenase pathway of arachidonate metabolism may contribute to the neutrophilia. Human recombinant tumor necrosis factor-alpha (rTNF) administered i.v. to Lewis rats induced peripheral neutropenia, two peaks of neutrophilia, and lymphopenia. A wide range of doses of rTNF resulted in an initial neutropenia at 0.5 hr after injection followed by a first peak of neutrophilia at 1.5 hr and a second peak of neutrophilia at 6 hr. The initial neutropenia and the first peak of neutrophilia were not inhibited by pretreatment of rats with dexamethasone, indomethacin, or aspirin. The second peak of neutrophilia was inhibited by both dexamethasone and indomethacin, but was not at all inhibited by aspirin, suggesting that the second peak of neutrophilia is mediated by the release of endogenous cytokines, especially by IL-1, since exogenous IL-1-induced neutrophilia is also completely inhibited by dexamethasone and indomethacin but not by aspirin. The TNF-induced peripheral neutrophilia is also accompanied by a significant depletion of bone marrow neutrophils, indicating that the source of increased circulating neutrophils is, at least in part, via recruitment of marrow neutrophils. Systemic blood pressure was not affected by IL-1 or rTNF at the dosages employed, showing that the changes in circulating leukocyte subsets were not attributable to hemodynamic changes nor to the hemodynamic change-related release of adrenal hormones. Adrenalectomy did not alter the IL-1- or rTNF-induced neutrophilia or lymphopenia, also demonstrating that neither monokine mediates its hematologic effects on peripheral blood leukocytes via the release of adrenal hormones.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Kinetics and mechanisms of recombinant human interleukin 1 and tumor necrosis factor-alpha-induced changes in circulating numbers of neutrophils and lymphocytes. 331 83