Gene/Protein Disease Symptom Drug Enzyme Compound
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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

Interleukin-2 is a glycoprotein physiologically produced by human lymphocytes which is capable of mediating some still unknown immunologic reactions. In vitro, interleukin-2 was seen to induce a lytic reaction against tumor cells through the activation of a cytolytic system of natural killer cells. If administered to man in heavy doses, it causes a clinical response in the treatment of metastases from melanoma and renal cell carcinoma in 20-40% of cases. However, the clinical use of the drug, in therapeutic doses, is prevented by the occurrence of several side-effects, the major one being increased permeability of alveolar vessels with capillary leak and interstitial pulmonary edema (Vascular Leak Syndrome in the English literature). Thus, this work was aimed at evaluating chest radiographs during interleukin-2 treatment to detect, in the pulmonary district, the early stages of the vascular leak syndrome--i.e., pulmonary edema, pleural and pericardial effusions. Forty-three patients had been treated for metastases from renal cell carcinoma and melanoma November 1989 through September 1991: standard chest radiographs demonstrated 26 cases (60%) of pulmonary edema, 14 cases (32%) of bilateral pleural effusions and 12 cases (27%) of pericardial effusions. Daily chest films of the patients undergoing interleukin-2 therapy allowed the early stage of the vascular leak syndrome to be depicted, thus enabling the physician to use the highest tolerated doses and eventually to stop infusion before marked respiratory distress develops.
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PMID:[Radiologic characteristics of the thorax during therapy with interleukin-2]. 145 17

The most serious side effects of recombinant interleukin-2 (rIL-2) and recombinant interferon-alpha (rIFN alpha) immunotherapy are cardiovascular disturbances, including systemic hypotension, left-ventricular dysfunction and pulmonary edema. We present a 25-year-old female who developed reversible cardiogenic shock during intermediate dose rIL-2 and low dose rIFN alpha therapy. Rapid clinical improvement occurred after intravenous fluid and dopamine support. A serial echocardiographic evaluation, which has not been described previously in this setting, is reported.
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PMID:Recombinant interleukin-2 and interferon alpha immunotherapy following autologous bone marrow transplantation. A case report of cardiovascular toxicity with serial echocardiographic evaluation. 151 64

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

Interleukin-2 (IL-2), an agent known to activate neutrophils (PMN) with thromboxane (Tx)B2 release, produces pulmonary edema within 6 hours of intravenous infusion. This study tests the role of PMN in mediating the edema. Anesthetized rats received 10(6)U recombinant human IL-2 (n = 15) or vehicle (n = 14) as a constant intravenous infusion during a period of 1 hour. At this time there was leukopenia 3.63 +/- 0.43 (x10(3)/mm3) relative to vehicle-infused control rats 6.12 +/- 0.86 and a decline in PMN, 2.19 +/- 0.14 relative to control value of 3.33 +/- 0.05 (both p less than 0.05). After 6 hours edema, as measured by increase in the wet to dry weight (W/d) ratio, was present in the lungs (4.93 +/- 0.20 relative to control 4.06 +/- 0.10), heart (4.09 +/- 0.11 versus 3.76 +/- 0.08), liver (3.50 +/- 0.10 versus 3.18 +/- 0.10), and kidney (4.25 +/- 0.07 versus 4.00 +/- 0.07) (all p less than 0.05). There was increased lung permeability demonstrated by bronchoalveolar lavage fluid protein concentration of 1970 +/- 210 micrograms/mL relative to control 460 +/- 90 micrograms/mL (p less than 0.05). Interleukin-2 resulted in lung PMN sequestration of 53 +/- 7 PMN/10 high-power fields (HPF) relative to 23 +/- 2 PMN/10 HPF in controls (p less than 0.05) and increased plasma TxB2 levels to 1290 +/- 245 pg/mL relative to control 481 +/- 93 pg/mL (p less than 0.05). Pretreatment of other rats (n = 8) with selective anti-rat neutrophil antiserum 18 hours before the experiment led to a peripheral PMN count 10% of baseline and prevented edema in the lungs (W/d ratio 4.20 +/- 0.16) and heart (3.67 +/- 0.07) (both p less than 0.05) but not liver or kidney. Protein in lung lavage was reduced to 760 +/- 220 micrograms/mL (p less than 0.05). The protection afforded by leukopenia was associated with lack of PMN sequestration and prevention of the increase in plasma Tx levels (484 +/- 120 pg/mL, p less than 0.05). These data indicate that the rapid induction of lung and heart edema with a 1-hour infusion of IL-2 in the rat is mediated, in large part, by activated PMNs.
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PMID:Interleukin-2 induces early multisystem organ edema mediated by neutrophils. 186 24

The pathogenesis of pulmonary edema that occurs during interleukin-2 therapy has often been attributed to an increase in pulmonary capillary permeability. However, renal insufficiency, fluid overload, and hypotension also develop in many patients. These manifestations of systemic toxicity may contribute to the development of pulmonary edema during therapy. Understanding the cause of pulmonary edema during interleukin-2 therapy could directly affect patients' care. Therefore, we reviewed the chest radiographs and clinical course of 54 patients who received high-dose interleukin-2 therapy and lymphokine-activated killer cells for advanced carcinoma. The type, frequency, and course over time of pulmonary abnormalities were recorded and correlated with clinical measures of renal function, fluid status, and blood pressure. Focal or diffuse parenchymal lung opacities were found on radiographs in 43 (80%) of 54 patients. Findings of interstitial pulmonary edema were most common, occurring in 76% of patients. Weight gain, hypotension, and elevation of the serum creatinine level were not associated statistically with interstitial edema. Diffuse air-space disease developed in 20% of patients. Focal consolidation, which was associated with positive central venous catheter cultures (p less than .03), developed in 28% of patients. Pleural effusion occurred in 48% of patients and was associated with all types of parenchymal disease. These data suggest that the frequent development of pulmonary edema during interleukin-2 therapy is not due to renal insufficiency, fluid overload, or hypotension, but is more likely the result of an interleukin-2-related increase in pulmonary capillary permeability.
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PMID:Pathogenesis of pulmonary edema during interleukin-2 therapy: correlation of chest radiographic and clinical findings in 54 patients. 189 99

Human recombinant interleukin-2 (rIL-2), with or without lymphokine-activated killer cells, has been shown to mediate tumor regressions in animals and in humans. A well-recognized adverse effect of rIL-2 is the development of a generalized vascular leak syndrome that involves the pulmonary microvasculature. We present a rabbit model for the study of rIL-2 pulmonary toxicity that closely reflects the human situation. Rabbits were treated with rIL-2 (Cetus) by two dose/schedule schemata. Separate control groups received rIL-2 excipient (Cetus) or 5% dextrose in water (D5W). In a short-term model, animals were treated with 10(6) Cetus units of rIL-2 in five bolus injections of 200,000 Cetus units each. In a long-term model, rabbits were treated with 3 (x) 10(6) Cetus units/kg of rIL-2 daily in three divided doses every 8 h for 9-11 doses (a schedule analogous to one used in human trials). Following treatment, animals were killed and examined for evidence of pulmonary toxicity. Among the treatment and control groups, there was no evidence of pulmonary leukostasis as determined by mean alveolar septal wall granulocytes per high power field or mean lung myeloperoxidase activity per gram of tissue. While there were no differences among the three treatment groups with regard to pulmonary edema formation (wet/dry weights), there was a tendency toward statistically significant differences between the rIL-2 and control groups. Pulmonary vascular permeability was assessed using i.v.-administered [125I]rabbit serum albumin (RSA) and expressed as mean bronchoalveolar lavage fluid/plasma [125I]RSA ratios. The rIL-2-treated animals had significantly increased pulmonary extravasation of [125I]RSA compared to controls, but there were no differences between the excipient- and D5W-treated controls. Lungs from rIL-2-treated (but not controls) animals displayed marked ultrastructural changes by electron microscopy in the arteriolar segment to include intracellular and subcellular blebs throughout the arteriole with separation of endothelial cells from basement membrane, interstitial edema, endothelial adhesion, and transmigration of lymphocytes into interstitium. Immunoperoxidase stains using an antirabbit T-cell monoclonal antibody demonstrated significant T-cell infiltration into the pulmonary interstitium of rIL-2-treated animals compared to controls. The long-term treatment model described appears to be highly suited for studies of rIL-2-induced pulmonary toxicity.
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PMID:Human recombinant interleukin-2 provokes acute pulmonary vascular endothelial injury in rabbits. 216 May 20

Adoptive immunotherapy with tumor-infiltrating lymphocytes (TIL) and interleukin-2 (IL-2) is currently being investigated in the treatment of chemoresistant cancers. In protocols using high dosages of IL-2 and adoptive transfers of lymphokine-activated killer (LAK) cells, severe pulmonary toxicities, including pulmonary edema and respiratory failure, are regularly observed. Serial measurements of pulmonary function in patients receiving TIL and continuous infusions of moderate dosages of IL-2 showed the development of mild obstructive and restrictive defects. Partial reversibility of the FEV1 with bronchodilators was observed, suggesting the development of hyperreactive airways. Decreases in lung volumes, DLCO, and gas exchange occurred and may reflect pulmonary infiltration by inflammatory cells, increased lung water, or diminished chest wall function. We conclude that adoptive immunotherapy with TIL and IL-2 produces changes in systemic immune response that may contribute to abnormal pulmonary physiology.
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PMID:Alterations in pulmonary function in cancer patients receiving adoptive immunotherapy with tumor-infiltrating lymphocytes and interleukin-2. 229 77

Lymphokine-activated killer (LAK) cells combined with recombinant interleukin-2 (rIL-2) can produce tumor regression in murine models and in patients with pulmonary metastatic disease. However, the dose escalations of rIL-2 required for optimal therapeutic effect often result in increased vascular permeability ("vascular leak syndrome") and other toxic systemic consequences. To avoid systemic distribution, lung perfusion was used to administer LAK and rIL-2 locally. Preliminary to using these agents to treat tumor-bearing lungs, we used a nonblood-perfused isolated rat lung model to study the localization of radiolabeled rIL-2 and LAK and to characterize effects on normal lung tissue of increasing dosages and exposure times of rIL-2 and LAK cells, individually and combined. Lung function or permeability was assessed by measuring lung weight gain and pulmonary arterial pressure during the perfusion, extravascular lung water by double indicator dilution techniques, and wet weight to dry weight ratio. After perfusion for 1 hour using 200,000 U (1,300 U/ml) rIL-2, injury was detected as visible pulmonary edema, weight gain and increases in wet to dry weight ratio, and extravascular lung water; no injury was detected at lower, clinically appropriate dosages. When 1 X 10(8) LAK cells combined with 100,000 U rIL-2 (666 U/ml) were perfused for up to 2 hours, no injury was ascertained. Uptake and distribution of the radiolabeled rIL-2 or LAK was uniform to all lung lobes and corresponded to the decrease of 12% of the rIL-2 or 50% of the LAK from the perfusate after 1-hour perfusion.
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PMID:Lymphokine-activated killer cells with interleukin-2: dose toxicity and localization in isolated perfused rat lungs. 233 37


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