In spite of the development of various
antibiotics, management of elderly patients with
pneumonia remains an important problem. It is suggested that
adult respiratory distress syndrome (ARDS) and
disseminated intravascular coagulation (
DIC) often occur in elderly patients with
pneumonia. Although neutrophils are suggested to be involved in the genesis of these conditions, details remain unknown. We demonstrated that a highly cytotoxic substance,
9,10-epoxy-12-octadecenoate, is biosynthesized from
linoleate by human neutrophils, thus it was named
leukotoxin.
Leukotoxin was detected in lung lavages from patients with ARDS. In these lung lavages, increases in
albumin concentration and
angiotensin converting enzyme (ACE) activity were also observed. Similar results were observed in lung lavages from rats after exposure to
hyperoxia for 60 hours in an experimental model of ARDS.
Intravenous administration of
leukotoxin (100 mumol/kg) caused lung
edema.
Albumin concentration and ACE activity were increased in lung lavages of rats receiving
leukotoxin. In contrast, these changes were not observed in rats administered with
linoleate. Furthermore, administration of
leukotoxin (100 mumol/kg) caused coagulation abnormality, i.e., increase in
fibrin-fibrinogen degradation products, decrease in
fibrinogen, and prolongation of activated partial thromboplastin time and prothrombin time. Administration of
linoleate did not induce these changes. It is indicated that O2- was produced by respiratory burst
enzyme located in neutrophil plasma membrane, and that
hydroxyl radicals derived from O2- by Fenton reaction were responsible for
leukotoxin synthesis. From our results,
leukotoxin, a product of
hydroxyl radicals and
linoleate, might be responsible for the genesis of ARDS and
DIC.