ABSTRACT
Recombinant human granulocyte colony-stimulating factor (rhG-CSF) is widely used to promote granulocyte recovery from a variety of pathologic states. Recombinant human interleukin-11 (rhIL-11) has recently become available clinically as a platelet restorative agent after myelosuppressive chemotherapy. Preclinical data has shown that rhIL-11 limits mucosal injury after chemotherapy and attenuates the proinflammatory cytokine response. The potential efficacy of combination therapy with recombinant human forms of rhIL-11 and rhG-CSF was studied in a neutropenic rat model of Pseudomonas aeruginosa sepsis. At the onset of neutropenia, animals were randomly assigned to receive either rhG-CSF at a dose of 200 micrograms/kg subcutaneously every 24 hours for 7 days; rhIL-11 at 200 micrograms/kg subcutaneously every 24 hours for 7 days; the combination of both rhG-CSF and rhIL-11; or saline control. Animals were orally colonized with Pseudomonas aeruginosa 12.4.4 and then given a myelosuppressive dose of cyclophosphamide. rhG-CSF resulted in a slight increase in absolute neutrophil counts (ANC), but did not provide a survival advantage (0 of 12, 0% survival) compared with the placebo group (1 of 12, 8% survival). rhIL-11 was partially protective (4 of 10, 40% survival); the combination of rhG-CSF and rhIL-11 resulted in a survival rate of 80% (16 of 20; P <.001). rhIL-11 alone or in combination with rhG-CSF resulted in preservation of gastrointestinal mucosal integrity (P <.001), lower circulating endotoxin levels (P <.01), and reduced quantitative levels of P. aeruginosa in quantitative organ cultures. These results indicate that the combination of rhIL-11 and rhG-CSF is additive as a treatment strategy in the prevention and treatment of experimental Gram-negative sepsis in immunocompromised animals. This combination may prove to be efficacious in the prevention of severe sepsis in neutropenic patients.
Subject(s)
Bacteremia/therapy , Granulocyte Colony-Stimulating Factor/therapeutic use , Interleukin-11/therapeutic use , Pseudomonas Infections/therapy , Animals , Bacteremia/pathology , Cyclophosphamide/pharmacology , Granulocyte Colony-Stimulating Factor/administration & dosage , Humans , Immunosuppressive Agents/pharmacology , Inflammation , Injections, Subcutaneous , Interleukin-11/administration & dosage , Intestinal Mucosa/pathology , Intestine, Small/pathology , Neutropenia/complications , Pseudomonas Infections/pathology , Pseudomonas aeruginosa , Rats , Rats, Sprague-Dawley , Recombinant Proteins/administration & dosage , Recombinant Proteins/therapeutic use , SurvivalABSTRACT
The therapeutic potential of recombinant human interleukin-11 (rhIL-11) was tested in a neutropenic rat model that mimics the clinical consequences of myelosuppressive chemotherapy complicated by Pseudomonas aeruginosa sepsis. rhIL-11-treated animals (150 micrograms/kg intravenously every 24 h for 3 days) had reduced endotoxin levels (P < .05) and less pulmonary edema fluid (P < .001) and were protected (P < .01) against thinning and necrosis of the intestinal mucosa compared with the control group. The survival rate in rhIL-11-treated animals was 40% (19/47), whereas it was 0 (0 of 19) in the control group (P < .01). The addition of ciprofloxacin (10 mg/kg every 12 h) resulted in a survival rate of 9 (60%) of 15, while the combination of rhIL-11 and ciprofloxacin resulted in 100% survival (15/15; P < .05). These results indicate that rhIL-11 supports mucous membrane integrity of the alimentary tract and decreases the systemic inflammatory response to experimental gram-negative infection in immunocompromised animals.
Subject(s)
Immunocompromised Host , Interleukin-11/therapeutic use , Pseudomonas Infections/drug therapy , Sepsis/drug therapy , Animals , Anti-Infective Agents/therapeutic use , Bacteremia/drug therapy , Bacteremia/mortality , Ciprofloxacin/therapeutic use , Disease Models, Animal , Drug Therapy, Combination , Humans , Neutropenia , Pseudomonas Infections/mortality , Rats , Rats, Sprague-Dawley , Recombinant Proteins/therapeutic useABSTRACT
Using an actual infection model of Pseudomonas aeruginosa sepsis in neutropenic rats, the potential utility of a combination anticytokine approach for the treatment of sepsis was tested. A dimeric tumor necrosis factor binding protein (TNF-BP) consisting of two soluble recombinant human TNF type 1 receptors linked with polyethylene glycol was used with recombinant human interleukin-1 receptor antagonist (IL-1ra). Despite having levels of bacteremia and endotoxemia similar to the control group (survivors, 0/18), 30% of IL-1ra-treated animals survived (P < .05); 31% of TNF-BP-treated animals survived (P < .01). Unexpectedly, the combination of IL-1ra plus TNF-BP proved to be uniformly fatal (survivors, 0/20). Endotoxin (P < .0001) and bacteremia (P < .01) levels were >10-fold higher than levels in animals treated with IL-1ra alone, TNF-BP alone, or placebo. Disseminated microabscesses in major organs were found in animals treated with combination immunotherapy. Combination anticytokine therapy may exacerbate systemic infection and worsen outcome in experimental sepsis.
Subject(s)
Carrier Proteins/adverse effects , Pseudomonas Infections/therapy , Receptors, Tumor Necrosis Factor , Shock, Septic/therapy , Sialoglycoproteins/adverse effects , Animals , Bacteremia/blood , Carrier Proteins/chemistry , Carrier Proteins/therapeutic use , Colony Count, Microbial , Cyclophosphamide/pharmacology , Drug Therapy, Combination , Endotoxins/blood , Humans , Immunosuppressive Agents/pharmacology , Immunotherapy/adverse effects , Interleukin 1 Receptor Antagonist Protein , Interleukin-1 , Neutropenia/chemically induced , Polyethylene Glycols/chemistry , Pseudomonas Infections/pathology , Pseudomonas aeruginosa/growth & development , Rats , Receptors, Tumor Necrosis Factor, Type I , Recombinant Proteins/adverse effects , Shock, Septic/pathology , Sialoglycoproteins/therapeutic use , Tumor Necrosis Factor Decoy Receptors , Tumor Necrosis Factor-alpha/analysisABSTRACT
A chimeric protein consisting of the N-terminal domain of lipopolysaccharide-binding protein and the C-terminal domain of bactericidal/permeability-increasing protein demonstrated a dose-dependent survival benefit (P = 0.001) and reduced endotoxin levels (P < 0.01) in neutropenic rats with Pseudomonas aeruginosa sepsis. This lipopolysaccharide-binding protein-bactericidal/ permeability-increasing peptide has favorable pharmacokinetics and antiendotoxin properties which may be of value for human sepsis.
Subject(s)
Acute-Phase Proteins , Blood Proteins/therapeutic use , Carrier Proteins/therapeutic use , Membrane Glycoproteins , Membrane Proteins , Pseudomonas Infections/drug therapy , Sepsis/drug therapy , Animals , Antimicrobial Cationic Peptides , Blood Proteins/pharmacokinetics , Carrier Proteins/pharmacokinetics , Cell Membrane/metabolism , Colony Count, Microbial , Endotoxins/analysis , Female , Limulus Test , Neutropenia/complications , Pseudomonas Infections/microbiology , Pseudomonas aeruginosa/drug effects , Rats , Rats, Sprague-Dawley , Recombinant Fusion Proteins/pharmacokinetics , Recombinant Fusion Proteins/therapeutic use , Sepsis/metabolism , Sepsis/microbiologyABSTRACT
Epithelial hemangioendothelioma (EH), originally termed intravascular sclerosing bronchioloalveolar tumor (IVBAT), is a rare pulmonary vascular neoplasm usually associated with an indolent but slowly progressive clinical course. We describe a patient with EH who presented with alveolar hemorrhage and died within 8 wk. This report extends the clinical spectrum of epithelial hemangioendothelioma to include this aggressive form. EH should be considered in the differential diagnosis of alveolar hemorrhage syndrome.
Subject(s)
Hemangioendothelioma/complications , Hemoptysis/etiology , Lung Neoplasms/complications , Aged , Hemangioendothelioma/diagnostic imaging , Hemangioendothelioma/pathology , Humans , Lung/diagnostic imaging , Lung/pathology , Lung Neoplasms/diagnostic imaging , Lung Neoplasms/pathology , Male , RadiographyABSTRACT
This article documents a case of recurrence in Hodgkin's disease, lymphocyte depletion type, 29 years after remission. This is the longest remission reported in the literature.
Subject(s)
Hodgkin Disease/pathology , Aged , Hodgkin Disease/blood , Humans , Male , Recurrence , Time FactorsABSTRACT
We report a case of massive and fatal intraperitoneal hemorrhage from ruptured superior mesenteric varices secondary to portal hypertension and hepatic cirrhosis and proved by postmortem angioradiography. To our knowledge, this is the second case in the English language literature. Although very rare, this possibility should be borne in mind when one attempts to locate hemorrhagic complications of portal hypertension.
Subject(s)
Hemoperitoneum/etiology , Liver Cirrhosis, Alcoholic/complications , Mesenteric Veins/diagnostic imaging , Varicose Veins/complications , Autopsy , Female , Humans , Hypertension, Portal/complications , Liver Cirrhosis, Alcoholic/pathology , Mesenteric Veins/pathology , Middle Aged , Radiography , Rupture, Spontaneous , Varicose Veins/pathologyABSTRACT
Melanin pigment in liver and heart tissue, obtained at autopsy from patients, was isolated and quantified. The quantity of melanin extracted was directly proportional to lipofuscin granule counts. Infrared and electron spin resonance spectographs of the isolated pigments from liver and heart showed absorption characteristics identical to those of known melanins. The pigment was absent in fetal and neonatal life, increased in brown atrophy of the heart and liver, and diminished in livers with fatty metamorphosis.