Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0034063 (pulmonary edema)
 10,665 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interleukin-2 was recently shown to cause acute lung injury characterized by microvascular permeability defect, interstitial edema, and leukosequestration. Similar responses can also be produced by platelet activating factor (PAF). Thus, the present study aimed to examine whether PAF plays a key role in the development of IL-2-induced lung injury in the anesthetized rat. Intravenous infusion (60 min) of recombinant human IL-2 at 10(5)-10(6) U/rat (n = 7-9) dose-dependently elevated lung water content (27 +/- 1%, P less than 0.01), myeloperoxidase activity (+84 +/- 23%, P less than 0.05), and serum thromboxane B2 (990 +/- 70%, P less than 0.01), but failed to alter blood pressure, hematocrit, serum tumor necrosis factor-alpha, and circulating leukocytes and platelets. Pretreatment (-30 min) with a potent and specific PAF antagonist, BN 50739 (10 mg/kg, intraperitoneally, n = 6) prevented the pulmonary edema (P less than 0.05) and thromboxane B2 production (P less than 0.01), and attenuated the elevation of lung myeloperoxidase activity (+18 +/- 16%, P less than 0.05) induced by IL-2. These data suggest that PAF is involved in the pathophysiological processes leading to IL-2-induced lung injury, and point to the potential therapeutic capacity of PAF antagonists in preventing pulmonary edema during IL-2 therapy.
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PMID:Platelet activating factor mediates interleukin-2-induced lung injury in the rat. 131 53

The chest roentgenograms of 54 patients receiving high dose interleukin-2 with or without lymphokine-activated killer cell therapy for advanced cancer were retrospectively reviewed. Thirty-nine patients (72 percent) developed chest roentgenographic abnormalities consisting of pleural effusions, 28 (52 percent); diffuse infiltrates (pulmonary edema), 22 (41 percent); and focal infiltrates, 12 (22 percent). These abnormalities resolved in 30 of 39 (77 percent) patients by four weeks after therapy. Simple pleural effusions were the only residual roentgenographic abnormalities seen and were present primarily in patients receiving IL-2 by bolus intravenous injection (8 of 28) (29 percent) as compared to continuous intravenous infusion (1 of 24) (4 percent) (p = 0.03). Only roentgenographic evidence of pulmonary edema appeared to correlate with the degree of clinical pulmonary toxicity (p = 0.001). The development of chest roentgenographic abnormalities correlated with the administration of IL-2 solely by bolus intravenous injection (p = 0.04), a pretreatment FEV1 of less than 3 L (p = 0.04), and treatment associated bacteremia (p = 0.09), but not with prior therapy, the presence of pulmonary metastases or the degree of systemic capillary leak as measured by percentage of weight gain during therapy. Although the roentgenographic abnormalities did not relate to the number of LAK cells received, two patients developed sudden onset of dyspnea and chest roentgenographic evidence of pulmonary edema shortly after the first LAK cell administration, implying that a direct cause-and-effect relationship exists in some patients. Possible mechanisms for these IL-2 related chest roentgenographic abnormalities and pulmonary toxicity in general are discussed.
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PMID:Chest roentgenographic abnormalities in IL-2 recipients. Incidence and correlation with clinical parameters. 154 Nov 42

Patients injected systemically with recombinant human interleukin-2 (rhIL-2) for treatment of solid tumor develop a vascular leak syndrome (VLS), characterized mainly by pulmonary edema whose pathogenesis is unknown. We have examined the structure of pulmonary vessels in mice with severe VLS induced by systemic injections of rhIL-2 and recombinant human interferon-alpha-A/D (rhIFN-alpha), which has a synergistic effect with IL-2. The pulmonary edema was associated with lesions of venous and capillary endothelia, alveolar basement membrane, and type I epithelial cells. These changes were more severe and diffuse than those seen in mice systemically injected with rhIL-2 alone, and in beige mice (deficient in NK cells and certain enzymes of polymorphonuclear leukocytes) injected with rhIL-2 and rhIFN-alpha. The endothelial lesions were comparable to those seen when leukocytes activated by cytokines react with activated endothelial cells in vitro, or at the site of injection of cytokines in vivo. The observations are in agreement with the interpretation that the severe lesions occurring in mice systemically injected with rhIL-2 with rhIFN-alpha result from the interaction of leukocytes with the endothelium. The results confirm the validity of previous studies performed in vitro or in animals injected intradermally with cytokines and extend their significance.
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PMID:Morphological basis of pulmonary edema in mice with cytokine-induced vascular leak syndrome. 176 55

Fundamental analysis was conducted on the phenotype and function of autologous tumor-infiltrating lymphocytes (TIL) in terms of their role as effector cells in specific immunotherapy for malignant tumors. Their effects were further examined in a preliminary clinical study. Analysis of the phenotype of lymphocytes which infiltrate tumor tissue and proliferate in the presence of IL-2, by using cell-surface subset markers, revealed proliferation of two types of lymphocytes: CD8-positive cytotoxic/suppressor T-cells and CD4-positive helper/suppressor inducer T-cells. In vitro cytotoxicity tests on these lymphocytes for antitumor activity showed that only CD8-positive lymphocytes had a much stronger antitumor effect on autologous tumor cells than LAK cells. In contrast, they showed no antitumor effect on autologous normal cells or homologous tumor cells of the same histological type, indicating specificity of their antitumor activity. Furthermore, in vitro treatment of tumor cells with interferon was found to increase both expression of MHC class I antigens and sensitivity to TIL cytotoxicity. In vitro of the close relationship between induction of CD8-positive TIL and expression of HLA (A, B, C) antigens in tumor tissue, the above findings suggest that the presence or absence of expression of MHC class I antigens plays an important role in the efficacy of adoptive immunotherapy with TIL. Significant antitumor activity was observed in patients given CD8-positive cells in a preliminary clinical study, the same as in in vitro assay. No patient showed serious side effects such as the pulmonary edema or body fluid retention observed in LAK therapy. Specific immunotherapy using TIL seems to be a promising modality in multidisciplinary treatment of cancer. Further developments from research on this subject are expected.
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PMID:[Fundamental and clinical aspects of adoptive immunotherapy with tumor-infiltrating lymphocytes]. 247 59

We investigated the effect of IL-2 in the isolated guinea pig lung perfused with phosphate-buffered Ringer's solution (containing 0.5 g/100 ml albumin and 5.5 mM dextrose) to determine the mechanism of IL-2-induced pulmonary edema. IL-2 (0 to 10,000 U/ml) was added to the perfusate following a 10 min baseline steady-state period. Pulmonary arterial pressure (Ppa), pulmonary capillary pressure (Ppc), and change in lung weight (as a measure of developing pulmonary edema) were recorded at 0, 10, 30, 40, and 60 min. The capillary filtration coefficient (Kf.c), an index of vascular permeability to water, was measured at 30 and 60 min. Infusion of IL-2 increased Ppc (from 3.9 +/- 0.1 cm H2O at baseline to 8.8 +/- 1.1 cm H2O at 60 min for IL-2 at 2000 U/ml, p less than 0.01; and from 3.8 +/- 0.1 cm H2O at baseline to 8.9 +/- 0.6 cm H2O at 60 min for IL-2 at 10,000 U/ml, p less than 0.01. The lung weight also increased (32% at IL-2 concentration of 2000 U/ml, and 26% at IL-2 concentration of 10,000 U/ml) The capillary filtration coefficient did not change with IL-2 infusion. The IL-2 response was prevented using the pulmonary vasodilator, papaverine. The infusion of IL-2 was associated with the generation of thromboxane A2(TxA2) in the effluent perfusate. Inhibition of TxA2 synthetase using Dazoxiben prevented the pulmonary vasoconstriction and edema response to IL-2. In addition, IL-2 had no effect on the transendothelial clearance of 125I-albumin. The results indicate that IL-2 causes pulmonary edema secondary to an increase in Ppc. The response is mediated by IL-2 stimulation of TxA2 generation from the lung.
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PMID:IL-2 induces pulmonary edema and vasoconstriction independent of circulating lymphocytes. 278 41

A new approach to cancer treatment has been developed based on the adoptive transfer of activated lymphocytes into cancer patients. Lymphocytes harvested from patients by leukapheresis are converted into lymphokine-activated killer (LAK) cells by incubation with recombinant interleukin-2 (rIL-2). These LAK cells are then infused back into the patients in combination with intravenous IL-2. Among 25 patients treated with this form of adoptive immunotherapy there were 11 patients with measurable tumor reductions, including 1 complete responder. The majority of responses occurred in patients with metastatic renal cell carcinoma, melanoma and colorectal carcinoma. The toxicities of IL-2, including fluid retention and pulmonary edema, limit therapy, and laboratory investigation is now aimed toward understanding the mechanism of IL-2 toxicity. The use of LAK cells and IL-2 in cancer therapy is still in a developmental stage and needs to be refined before its role can be definitely established.
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PMID:Therapy of cancer using the adoptive transfer of activated killer cells and interleukin-2. 312 51

Four out of 23 consecutive patients treated with high-dose Ara-C for lymphomas in our institution developed a strikingly similar syndrome during the perfusion. It was characterized by the onset of fever, diarrhea, shock, pulmonary edema, acute renal failure, metabolic acidosis, weight gain and leukocytosis. Thorough bacteriological screening failed to provide evidence of infection. Sequential biological assays of IL-1, IL-2, TNF and PAF were performed during Ara-C infusion to ten patients, including the four who developed the syndrome. TNF and PAF activity was found in the serum of respectively two and four of the cases, but not in the six controls. As TNF and PAF are thought to be involved in the development of septic shock and adult respiratory distress syndrome, we hypothesize that high-dose Ara-C may be associated with cytokine release.
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PMID:Pulmonary edema and shock after high-dose aracytine-C for lymphoma; possible role of TNF-alpha and PAF. 831 74

Myeloablative chemo (+/- radio) therapy and rescue with ABMT has been used as final consolidation therapy in 18 patients with AML in first remission. In seven (6 autologous, 1 syngeneic) marrow reinfusion was followed by iv IL-2. One patient, who commenced IL-2 4 days after BMT, died from pulmonary oedema due to the capillary leak syndrome. Thereafter, treatment with IL-2 was delayed until the platelet count reached 30 x 10(9)/l. All patients developed reversible hypotension (treated with infusion of colloid), but treatment was otherwise well tolerated. With 21-58 months (median 32 months) from the time of ABMT there has been one relapse (actuarial risk 17%, 95% confidence intervals (CI) 3-31%). The disease-free survival is 71% (95% CI 38-100%). Eleven patients with comparable remission induction and consolidation therapy, and an identical interval between diagnosis and ABMT (5-11 months, median 6 months) received an autograft without immunotherapy. With 24-45 months (median 29 months) follow-up the actuarial disease-free survival is 36% (95% CI 8-64%), the actuarial relapse risk is 54% (95% CI 18-90%). We conclude that immunotherapy given after ABMT to patients with AML in first remission when the platelet count exceeds 30 x 10(9)/l is safe and may induce an immunological environment which results in the elimination of residual leukaemia.
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PMID:Immunotherapy with interleukin 2 after ABMT in AML. 850 74

Interleukin 12 (IL-12) enhances lysis mediated by NK- and lymphokine activated killer (LAK) cells. It also causes proliferation of IL-2 stimulated T and NK cells in vitro. For these IL-2 complementing properties murine pulmonary metastases of a coloncarcinoma line were treated with IL-12 and IL-2 or with the individual agents. Results were compared to sham treated controls. IL-2 alone mediated significant tumor reduction but provoked pulmonary edema and concomittand toxicity, graded in three steps. IL-12 combined with an IL-2 dose reduced by 81% still resulted in significant antitumoral activity. Toxicity, however, was not discernable from sham treated controls. IL-12 thus appears as an attractive cytokine for combination with IL-2 in antitumor therapy. Particularly treatment of tumors, like gastrointestinal tract cancers, so far mainly resistant to cell mediated antitumor therapy, might profit from this approach.
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PMID:Addition of interleukin 12 to low dose interleukin 2 treatment improves antitumor efficacy in vivo. 852 51

We tested whether treatment with an inhibitor of nitric oxide synthesis (Ng-methyl-L-arginine, MeArg) can ameliorate interleukin-2(IL-2)-therapy-induced capillary leak syndrome in healthy or tumor-bearing mice without compromising the antitumor effects of IL-2 therapy. Healthy or C3-L5-mammary-adenocarcinoma-bearing C3H/HeJ mice were treated with one or two rounds of various doses of IL-2 (ten injections, i. p., every 8 h) or MeArg (ten injections s. c., every 8 h) or their combination. In an additional experiment, MeArg was given chronically in the drinking water, rather than s. c. to healthy mice subjected to one round of therapy as above. Mice were killed 1 h after their last IL-2 injection to measure the water content of the lungs and pleural cavities (markers of capillary leakage), NO production (given by NO2- and NO3- levels in the serum and pleural effusion), as well as the effect of therapies on the primary tumor size and number of spontaneous lung metastatic nodules. Results revealed that all doses of IL-2 (7500-35000 Cetus U/injection), as well as both rounds of IL-2 therapy, caused capillary leakage. However, no pleural effusion was seen after the second round in any of the IL-2-treated groups. MeArg therapy, given subcutaneously (5-20 mgkg(-1) injection(-1) in healthy and 20 mgkg(-1) injection(-1) in tumor-bearing mice), did not ameliorate IL-2-induced capillary leakage in either group of mice, and did not compromise antitumor effects of IL-2. However, subcutaneous MeArg therapy alone reduced the growth of the primary tumors, the occurrence of lung metastases and the amount of tumor-induced pulmonary edema. When MeArg therapy was given orally (1 mg/ml drinking water), a substantial drop in NO production, as well as reduction in capillary leakage was noted in IL-2-treated healthy mice. These findings suggest that NO inhibitors could be a valuable adjunct to IL-2 therapy of cancer and infectious diseases.
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PMID:Effects of N(g)-methyl-L-arginine, an inhibitor of nitric oxide synthesis, on interleukin-2-induced capillary leakage and antitumor responses in healthy and tumor-bearing mice. 862 65


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