ABSTRACT
Aging is a major risk factor for Alzheimer's disease and the evidence suggests a role for cerebrovascular pathology in cognitive dysfunction. The hypothesis in this study is that aging is a significant risk factor in the effect of the Alzheimer peptide beta-amyloid on endothelium-dependent function of cerebral and peripheral vessels. The diameter response to acetylcholine, an endothelium-dependent vasodilator, was recorded in pressurized segments of rat posterior cerebral vessels from mature (3 months) and aged (20 months) rats. The threshold concentration of beta-amyloid for a significant decrease in the response to acetylcholine was lower in vessels from aged rats (10(-9) M) than in vessels from mature rats (10(-8) M). The threshold concentration of beta-amyloid for a significant decrease in the sensitivity to acetylcholine was lower for ring segments of aorta from aged rats (10(-10) M) than for aorta from mature rats (10(-8) M). Structural changes of the endothelium were first observed in electron micrographs of aorta from aged rats when the concentration of beta-amyloid was 10(-8) M, whereas structural changes in aorta from mature rats did not occur until the concentration of beta-amyloid was increased to 10(-7) M. The results suggest that aging increases the susceptibility of cerebral and peripheral blood vessels to beta-amyloid related dysfunction and that functional change precedes structural change.
Subject(s)
Aging , Amyloid beta-Peptides/toxicity , Cerebral Arteries , Cerebrovascular Disorders/chemically induced , Acetylcholine/pharmacology , Animals , Aorta/drug effects , Aorta/pathology , Aorta/ultrastructure , Blood Pressure/drug effects , Differential Threshold/drug effects , Dose-Response Relationship, Drug , Drug Interactions , Endothelial Cells/drug effects , Endothelial Cells/pathology , Endothelial Cells/ultrastructure , Microscopy, Electron/methods , Rats , Rats, Sprague-Dawley , Risk FactorsABSTRACT
Human lymphomas continue to represent a major challenge in oncology, and in particular occur at very high frequencies in AIDS patients. We report here the development of a CD30+ lymphoproliferative disease in mice lacking the proapoptotic transcription factor, interferon regulatory factor-1. These mice most closely represent a model of human anaplastic large-cell lymphoma (ALCL). This mouse model of lymphoma will likely be useful in understanding the development of ALCL and in understanding the development of other closely related CD30+ forms of lymphoma, such as CD30+ Hodgkin's disease and CD30+ cutaneous T-cell lymphoma. This mouse model will also be useful in testing therapies for different forms of CD30+ lymphoma, in particular anti-CD30-based therapies.
Subject(s)
DNA-Binding Proteins/genetics , Ki-1 Antigen/metabolism , Lymphoma, Large-Cell, Anaplastic/metabolism , Lymphoproliferative Disorders/genetics , Lymphoproliferative Disorders/metabolism , Phosphoproteins/genetics , Animals , Immunohistochemistry , Interferon Regulatory Factor-1 , Lymph Nodes/metabolism , Lymph Nodes/pathology , Lymphatic Diseases/metabolism , Lymphatic Diseases/pathology , Lymphoma, Large-Cell, Anaplastic/pathology , Lymphoma, Large-Cell, Anaplastic/ultrastructure , Lymphoproliferative Disorders/pathology , Mice , Mice, Knockout , Retinoblastoma Protein/genetics , Time Factors , Transcription Factors/geneticsABSTRACT
The pathophysiology of ischemia/reperfusion injury involves extravascular migration of leukocytes from the bloodstream to the site of injury. Leukocyte adhesion and intercellular adhesion molecule-1 (ICAM-1) play an important role in the recruitment of leukocytes to the site of injury. In this study, we evaluated the role of the ICAM-1 in spinal cord ischemia and the therapeutic effects of epidural ICAM-1 monoclonal antibody (Mab). The descending aorta was occluded below the renal artery with an aneurysm clip in rabbits anesthetized with halothane. The following variables were evaluated, in addition to ICAM-1 expression in the lumbar spinal cord, in animals receiving saline or ICAM-1 Mab via the epidural route: (1) leukocyte recruitment in the lumen of capillary vessels of the lumbar spinal cord (L6-7) at 8 h after 30 min of aortic occlusion and (2) neurological evaluation at 20 h after aortic occlusion of 10, 15, 17.5, 20, or 25 min. Paraplegia was graded with the following scale: Grade 0, no deficit; Grade 1, partial deficit; and Grade 2, complete paraplegia. Spinal cord ischemia increased the expression of ICAM-1 in the endothelium of spinal cord capillaries and led to capillary leukocyte recruitment and extravascular migration into the lumbar spinal cord parenchyma, which was ablated with epidural ICAM-1 Mab. Epidural ICAM-1 Mab reduced neurological deficits and offered neuroprotection. These findings demonstrate the involvement of the ICAM-1 pathway in spinal cord ischemia and the neuroprotective effects of epidural ICAM-1 Mab. Strategies to ameliorate spinal cord ischemia may entail the administration of leukocyte antiadhesion molecules into the neuraxial space.
