Granulocyte oxygen radicals as potential suppressors of hemopoiesis: potentiating roles of lactoferrin and elastase; inhibitory role of oxygen radical scavengers.
In vitro studies suggest intact endothelial cells and their released growth factors are required for optimal growth and differentiation of hematopoietic cells in culture. Conversely, processes that damage endothelium might, therefore, suppress hematopoiesis. We have studied mechanisms by which stimulated inflammatory cells, particularly granulocytes, damage endothelium and suggest these studies may provide new insights into the hematopoietic suppression of inflammatory diseases. We demonstrate that the granulocyte lysosomal constituent, lactoferrin, which has independently been shown to inhibit in-vitro hematopoiesis, may act by amplifying granulocyte-mediated toxic oxidant damage to endothelium. Its deleterious effects are twofold: 1) it releases iron that catalyses the Haber-Weiss reaction, thereby producing highly toxic hydroxyl radicals; and 2) its highly positive charge facilitates its absorption to target membranes that traffics oxygen-radical damage directly to endothelium. In addition, we demonstrate that another granulocyte lysosomal component, elastase, also perturbs endothelium--not so much by direct lytic effect, but by proteolysing matrix proteins that serve to attach endothelium to its substratum. Thus, elastase promotes endothelial lift-off. Plasma alpha-1-antiproteinase, a potent antielastase, should be protective, but is inactivated by the same granulocyte oxidants that directly lyse endothelial cells. However, antielastase activity can be preserved by antioxidants and a novel, innocuous one--methionine--is described. It is oxidized as a surrogate for the critical-site methionine of alpha-1-proteinase inhibitor, preserving in the process antielastase activity. Our results suggest that strategies to reduce production of inflammatory cell toxic oxygen radicals with reagents such as antilactoferrin antibody or iron chelators might be useful adjuncts in maintaining in vitro hematopoiesis.(ABSTRACT TRUNCATED AT 250 WORDS)
Vercellotti
G
G
Division of Hematology/Oncology, University of Minnesota Medical School, Minneapolis 55455.
Stroncek
D
D
Jacob
H S
HS
D000975:Antioxidants / Q000494:pharmacology*; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000502:physiology*; D005109:Extracellular Matrix / Q000502:physiology; D005609:Free Radicals; D006098:Granulocytes / Q000502:physiology*; D006410:Hematopoiesis / Q000187:drug effects*; D006801:Humans; D007231:Infant, Newborn; D007781:Lactoferrin / Q000502:physiology*; D007782:Lactoglobulins / Q000502:physiology*; D010100:Oxygen / Q000494:pharmacology*; D010196:Pancreatic Elastase / Q000502:physiology*; D000515:alpha 1-Antitrypsin / Q000502:physiology
D000975:Antioxidants; D005609:Free Radicals; D007782:Lactoglobulins; D000515:alpha 1-Antitrypsin; D007781:Lactoferrin; D010196:Pancreatic Elastase; D010100:Oxygen