Engraftment syndrome following hematopoietic stem cell transplantation.
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During neutrophil recovery following hematopoietic stem cell transplantation, a constellation of symptoms and signs including fever, erythrodermatous skin rash, and noncardiogenic pulmonary edema often occur. These clinical findings have usually been referred to as engraftment syndrome, or, reflecting the manifestations of increased capillary permeability, capillary leak syndrome. While described most often following autologous stem cell transplantation, a similar clinical syndrome has been observed followed allogeneic stem cell transplantation. Distinction from graft-versus-host disease in the allogeneic setting however, has been difficult. Recent experience with non-myeloablative conditioning for stem cell transplantation, however, reveals that an engraftment syndrome independent of GVHD may occur. In some cases, this engraftment syndrome may be a manifestation of a host-versus-graft reaction (graft rejection). While cellular and cytokine interactions are believed to be responsible for these clinical findings, a distinct effector cell population and cytokine profile have not been defined. Engraftment syndromes are likely associated with an increased transplant-related mortality, mostly from pulmonary and associated multi-organ failure. Corticosteroid therapy is often dramatically effective for engraftment syndrome, particularly for the treatment of the pulmonary manifestations. A proposal for a more uniform definition of engraftment syndrome has been developed in order to allow for a reproducible method of reporting of this complication and for evaluating prophylactic and therapeutic strategies. (+info)
Life-threatening capillary leak syndrome after G-CSF mobilization and collection of peripheral blood progenitor cells for allogeneic transplantation.
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We report a case of capillary leak syndrome in a 37-year-old female PBPC donor who received G-CSF 900 microg/day for 4 days and underwent leukapheresis. This lady had remained well and stable despite marked leukocytosis during G-CSF treatment, but developed hypotension during leukapheresis, quickly followed by hypoxemia, ascites, pericardial and pleural effusion, shock, edema, neurologic changes and hepatocellular injury. Upon G-CSF withdrawal, dopamine and crystalloid infusion, methylprednisolone treatment and suspension of apheresis, the clinical situation fully reversed. We hypothesize that leukapheresis, in the presence of marked leukocytosis and high doses of G-CSF, may have triggered neutrophil activation and the release of inflammatory mediators, resulting in tissue damage and systemic manifestations of increased capillary permeability. (+info)
Increased and prolonged inflammation and angiogenesis in delayed-type hypersensitivity reactions elicited in the skin of thrombospondin-2--deficient mice.
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Angiogenesis and enhanced microvascular permeability are hallmarks of a large number of inflammatory diseases. Although up-regulation of proangiogenic factors such as vascular endothelial growth factor and interleukin-8 have been previously reported in inflamed tissue, the biologic role of endogenous inhibitors of angiogenesis in inflammation has remained unclear. To investigate the biologic role of the potent angiogenesis inhibitor thrombospondin-2 (TSP-2) in the control of cutaneous inflammation, delayed-type hypersensitivity reactions were elicited in the ear skin of wild-type and TSP-2-deficient mice by topical sensitization and challenge with oxazolone. Cutaneous TSP-2 expression was up-regulated in the inflamed skin of wild-type mice, predominantly in dermal fibroblasts and microvessels. Lack of TSP-2 resulted in a significantly enhanced inflammatory response with increased angiogenesis, edema formation, and inflammatory infiltration. Ear swelling and inflammation persisted for more than 2 weeks in TSP-2-deficient mice, as compared with 1 week in wild-type mice. Although baseline vascular permeability was unchanged, significantly enhanced microvascular leakage was found in the inflamed skin of TSP-2-deficient mice. Moreover, the fraction of rolling leukocytes was significantly increased in the untreated skin of TSP-2-deficient mice. These results reveal an important role of TSP-2 in limiting the extent and the duration of edema formation, angiogenesis, and inflammatory cell infiltration during acute and chronic inflammation. (+info)
Systemic capillary leak syndrome (SCLS) is a rare disorder with a high mortality rate, characterized by rapidly developing edema, weight gain and hypotension, hemoconcentration and hypoproteinemia. This syndrome is caused by sudden, reversible capillary hyperpermeability with a rapid extravasation of plasma from the intravascular to the interstitial space. Even though SCLS has been suggested to be the pathogenic mechanism for the pulmonary toxicity of gemcitabine (GCB), a new deoxycytidine analogue with structural similarities to cytosine arabinoside, a direct correlation between GCB and SCLS has never been reported. We describe a case of repeated SCLS after GCB administration in a 51-year-old male with locally-advanced non-small-cell lung cancer treated with a combination of cisplatin and GCB. The detection of GCB-induced SCLS supports the hypothesis that SCLS could be the pathogenic way of GCB pulmonary toxicity. This finding can help to better understand and treat the potentially deadly GCB-related acute respiratory distress syndrome that is being recognized. (+info)
Systemic capillary leak syndrome.
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A 40-year-old woman was referred to our hospital with severe hypovolemic shock and anasarca. The laboratory findings showed marked hemoconcentration and a decrease in total serum protein with the presence of monoclonal IgG-lambda. She had had a similar episode of generalized edema 2 years previously. We diagnosed the patient as having typical systemic capillary leak syndrome (SCLS) and she improved gradually after infusion of albumin-containing fluid. SCLS is a very rare condition caused by unexplained episodic capillary hyperpermeability. Its treatment has remained largely supportive and the prognosis is generally poor. Awareness of SCLS is necessary for improvement of the outcome. (+info)
Differential effects of FR900482 and FK317 on apoptosis, IL-2 gene expression, and induction of vascular leak syndrome.
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Vascular leak syndrome (VLS) is a harmful side effect that resulted in withdrawal of the antitumor drug FR900482, but not FK317, from clinical trials. Here we present chromatin immunoprecipitation data showing that FK317, like FR900482, crosslinks minor-groove binding proteins to DNA in vivo. However, these drugs differ in how they induce cell death. We demonstrate that, whereas FR900482 induces necrosis, FK317 induces a necrosis-to-apoptosis switch that is drug concentration dependent. Northern blot analyses of drug-treated cells suggest that this "switch" is mediated, at least in part, by modulation of the expression levels of Bcl-2. Additionally, FR900482, in contrast to FK317, induces the expression of known elicitors of both Bcl-2 gene expression and VLS. These findings provide plausible explanations for why these structurally similar drugs have different biological effects, especially with respect to VLS. (+info)
Effects of hypothermia and rewarming on the mucosal villus microcirculation and survival after rat intestinal ischemia-reperfusion injury.
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OBJECTIVE: To determine the effects of hypothermia and rewarming on changes in the villus microcirculation induced by intestinal ischemia-reperfusion (I/R). SUMMARY BACKGROUND DATA: The small intestine is extremely sensitive to I/R injury, and although hypothermia can reduce cellular injury, its capacity to influence the villous microcirculation after intestinal I/R is unclear, especially after the return to normothermic conditions. METHODS: Core body temperature of PVG rats was maintained at either 36 degrees to 38 degrees C (n = 12) or 30 degrees to 32 degrees C (n = 24) and then subjected to 30 minutes of intestinal ischemia. A subgroup of hypothermic animals (n = 12) were returned to normothermic conditions 120 minutes after clamp removal. The mucosal surface was visualized in an exteriorized ileal segment and macromolecular leak (MML) and leukocyte adhesion were monitored using in vivo microscopy (n = 6 in each group). MML from individual villi and numbers of adherent leukocytes within villi were determined for 2 to 4 hours after clamp removal. Heart rate and mean blood pressure were monitored in all animals. Control animals underwent sham surgery (n = 12). RESULTS: Ten of 12 normothermic animals failed to survive the reperfusion period, whereas all hypothermic animals and 11 of 12 of the hypothermic animals that were returned to normothermic conditions survived. MML was significantly increased in all animals subjected to I/R, although leakage was more marked in animals subjected to continuous normothermia. Enhanced leukocyte adhesion and decreased blood flow were observed only in normothermic animals. CONCLUSIONS: Hypothermia might prove to be an effective strategy for preventing adverse side effects in clinical settings in which intestinal I/R can be predicted. (+info)
Intracellular signalling involved in modulating human endothelial barrier function.
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The endothelium dynamically regulates the extravasation of hormones, macromolecules and other solutes. In pathological conditions, endothelial hyperpermeability can be induced by vasoactive agents, which induce tiny leakage sites between the cells, and by cytokines, in particular vascular endothelial growth factor, which increase the exchange of plasma proteins by vesicles and intracellular pores. It is generally believed that the interaction of actin and non-muscle myosin in the periphery of the endothelial cell, and the destabilization of endothelial junctions, are required for endothelial hyperpermeability induced by vasoactive agents. Transient short-term hyperpermeability induced by histamine involves Ca2+/calmodulin-dependent activation of the myosin light chain (MLC) kinase. Prolonged elevated permeability induced by thrombin in addition involves activation of the small GTPase RhoA and Rho kinase, which inhibits dephosphorylation of MLC. It also involves the action of other protein kinases. Several mechanisms can increase endothelial barrier function, depending on the tissue affected and the cause of hyperpermeability. They include blockage of specific receptors, and elevation of cyclic AMP by agents such as beta2-adrenergic agents. Depending on the vascular bed, nitric oxide and cyclic GMP can counteract or aggravate endothelial hyperpermeability. Finally, inhibitors of RhoA activation and Rho kinase represent a potentially valuable group of agents with endothelial hyperpermeability-reducing properties. (+info)