COMPLEMENT ACTIVATION AND CLEARANCE IN ACUTE ILLNESS AND INJURY - EVIDENCE FOR C5A AS A CELL-DIRECTED MEDIATOR OF THE ADULT RESPIRATORY-DISTRESS SYNDROME IN MAN

  • 1 January 1985
    • journal article
    • research article
    • Vol. 97  (6) , 668-678
Abstract
The appearance of the adult respiratory distress syndrome (ARDS) during the course of acute illness is believed to result, in part, from intrapulmonary neutrophil sequestration and degranulation induced by circulating inflammatory mediators. To evaluate the role of complement-neutrophil interactions in the pathogenesis of ARDS in man, 34 patients suffering from intra-abdominal sepsis (seven), multisystem trauma (15), or acute pancreatitis (12) were serially studied with regard to neutrophil migratory responses to C[complement]5a and F-Met-Leu-Phe (FMLP) lysosomal content of .beta.-glucuronidase and lysozyme and simultaneously obtained plasma levels of immunoreactive C3adesArg and C5adesArg. Nineteen patients developed ARDS. In these patients, plasma C3adesArg levels obtained within 72 h of admission to the hospital were elevated to 305 .+-. 35 ng/ml compared with 145 .+-. 16 ng/ml for patients who did not develop ARDS (P < 0.0005). C5adesArg levels were not elevated in either group. In vitro studies showed that neutrophils from normal persons were able to clear all of the C5a/C5adesArg generated in up to 5% zymosan-activated serum, while no clearance of C3adesArg was identified. Patient migratory responses could be divided into 3 groups based on their initial (< 72 h) samples: hyperresponsive to both FMLP and C5a, specifically deactivated to C5a and deactivated to both C5a amd FMLP. Patients in the latter 2 groups developed ARDS. Enzyme content of neutrophils from patients who developed ARDS showed a substantial fall in .beta.-glucuronidase and lysozyme levels. The finding of elevated C3a levels and deactivation of migratory response to C5a support the contention that complement activation had occurred in these patients and that their neutrophils had been exposed to C5a/C5adesArg in vivo. The finding of nonspecific migratory dysfunction associated with lysozymal enzyme loss, a circumstance not reproducible in vitro by C5a exposure, suggests that other stimuli produced degranulation of neutrophils made hyperresponsive by prior exposure to C5a.