In vivo effects of intravascularly applied Escherichia coli hemolysin: dissociation between induction of granulocytopenia and lethality in monkeys.
The effects of intravascular application of endotoxin-depleted Escherichia coli hemolysin (HlyA) was studied in rabbits and monkeys. In rabbits, bolus application of HlyA calculated to effect final blood levels of approximately 2-3 HU/ml (200-300 ng/ml) caused an acute fall of polymorphonuclear blood leukocytes to less than 20% of starting levels within 5 min. Additionally, platelet counts dropped to approximately 30% of starting levels, whereas lymphocyte counts varied considerably and seldom fell to less than 50%. Nine out ten animals that received 2-4 HU/ml toxin died within 90 min post application. These animals presented with signs of acute respiratory failure and post mortem inspection of the internal organs revealed hemorrhagic pulmonary edema. Other internal organs appeared unaffected. Application of less than 1 HU/ml HlyA was never fatal (n = 9), and only transient leukopenia was noted. Monkeys presented with a remarkable and different response. Two animals were repeatedly given HlyA at high doses ranging from 3 to 10 HU/ml. Both animals developed selective granulocytopenia, but following a short, transient drop in blood pressure they showed no severe clinical signs of cardiovascular or pulmonary malfunction. Histological examinations revealed accumulation of polymorphonuclear granulocytes in both animals in liver, lung and spleen. Very high leukocyte elastase levels were measured in one animal over a period of 1.5 h. The present results demonstrate a remarkable tolerance of monkeys towards the leukocidal effects of E. coli hemolysin. Lethality in rabbits must be due to additional effects of the toxin, possibly on cells in the pulmonary vasculature. Neither pulmonary sequestration of granulocytes nor massive release of elastase from these cells is in itself sufficient to provoke pulmonary dysfunction in monkeys.
Institute of Medical Microbiology, University of Mainz, Germany.
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D
Vagts
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Dienes
P J
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Barth
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Ronneberger
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KD
Hungerer
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Bhakdi
D000380:Agranulocytosis / Q000139:chemically induced*; D000818:Animals; D001426:Bacterial Proteins / Q000008:administration & dosage / Q000633:toxicity*; D001427:Bacterial Toxins / Q000008:administration & dosage / Q000633:toxicity*; D001772:Blood Cell Count / Q000187:drug effects; D001792:Blood Platelets / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D002196:Capillaries / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004926:Escherichia coli; D029968:Escherichia coli Proteins; D006098:Granulocytes / Q000187:drug effects; D006460:Hemolysin Proteins / Q000008:administration & dosage / Q000633:toxicity*; D007269:Injections, Intra-Arterial; D007275:Injections, Intravenous; D007928:Lethal Dose 50; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008168:Lung / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D008252:Macaca fascicularis; D010196:Pancreatic Elastase / Q000097:blood; D011654:Pulmonary Edema / Q000139:chemically induced; D011817:Rabbits; D013154:Spleen / Q000187:drug effects / Q000473:pathology
D001426:Bacterial Proteins; D001427:Bacterial Toxins; D029968:Escherichia coli Proteins; D006460:Hemolysin Proteins; C036507:Hlya protein, E coli; D010196:Pancreatic Elastase