A. Dwenger

Effect of ascorbic acid on neutrophil functions and hypoxanthine/xanthine oxidase-generated, oxygen-derived radicals.

The chemiluminescence of isolated neutrophils, stimulated with N-formyl-L-methionyl-L-leucyl-L-phenylalanine, latex, lipopolysaccharide from Escherichia coli, zymosan A, or 4 beta-phorbol 12 beta-myristate 13 alpha-acetate was inhibited up to 99% by the dose-dependent oxygen radical scavenging activity of 6 mmol/l ascorbic acid. The chemiluminescence of neutrophils in blood, stimulated with 4 beta-phorbol 12 beta-myristate 13 alpha-acetate, or with zymosan A was inhibited 35% or 48%, respectively, by 6 mmol/l ascorbic acid. Ascorbic acid, up to 6 mmol/l, did not inhibit the release of beta-N-acetylglucosaminidase and elastase from isolated neutrophils activated by the above stimulatory agents. During neutrophil/nylon fibre interaction ascorbic acid reduced the oxygen radical production dose-dependently (77% inhibition of the chemiluminescence response at 6 mmol/l ascorbic acid), whereas the adherence was unaffected. Hypoxanthine/xanthine oxidase-generated oxygen radicals were scavenged by ascorbic acid in a dose-dependent manner (99% inhibition of the chemiluminescence response at 100 mumol/l ascorbic acid). From these results, ascorbic acid can highly be recommended for animal experiments and clinical studies in patients with trauma, shock and sepsis and for studies to prevent or reduce reperfusion injuries.

Alveolar cell pattern and chemiluminescence response of blood neutrophils and alveolar macrophages in sheep after endotoxin injection.

In order to study the pathomechanisms of the Adult Respiratory Distress Syndrome in an acute animal model, we monitored the alveolar cell pattern and the stimulatory chemiluminescence responses of blood neutrophils and alveolar macrophages in sheep after Escherichia coli endotoxin injection (2 micrograms/kg of body weight). Using appropriate bronchoalveolar lavage techniques, thereby avoiding local inflammation, it was demonstrated that endotoxin injection did not cause any recruitment of neutrophils into the alveoli for a period of up to 24 hours. Following endotoxin injection, blood neutrophils showed a maximal stimulatory response after 5 minutes, and alveolar macrophages after 4 hours. It is concluded that if neutrophils are responsible for initiating the increase in microvascular permeability, then this action must be purely intravascular.

Suppression of the neutrophil chemiluminescence response in blood of multiply traumatized patients with and without the adult respiratory distress syndrome (ARDS)

ConclusionsFrom the results, alterations of humoral and cellular components of the nonspecific immune system were supposed to be involved in the ARDS pathogenesis. Concerning the intravascular compartment, a plasma opsonin defect could be observed, especially for group C patients with a later EVLW increase. Furthermore, these patients demonstrated a continuous synthesis of a trauma factor that suppressed CL responses and presumably also phagocytosis/killing functions of PMNL in blood, hereby predisposing this patient group to sepsis and sepsis-amplified ARDS development. Such an inhibition factor has been described by Lanser et al. [5] in septic patients, but our results demonstrated that this factor seemed always to be synthetized after a traumatic event irrespective of septicemia. As a consequence, the increased endogenous respiratory burst potential of neutrophils, especially of patients with a later EVLW increase, becomes effective after the neutrophil has left the capillary and entered the alveolar space, no longer being kept in check by the trauma factor and then liberating the complete set of inflammation mediators for lung structure damage.

Prostaglandin E1 Inhibits the Stimulation of Neutrophils In Vitro and In Vivo and Improves Cardio-Respiratory Functions in Multiply Traumatized Patients at Risk of Adult Respiratory Distress Syndrome

The trauma-induced activation of granulocytes (PMN) and their functional alterations (increase in adherence, extracellular release of reactive oxygen derived agents and lysosomal enzymes) are believed to play a central role in the initiation and amplification of capillary endothelial cell (EC) damage and organ failure such as that in adult respiratory distress syndrome (ARDS) [1]. Prostaglandin E1 (PGE1) is known to inhibit several PMN functions involved in these processes. Because of this and its vasodilating actions, the immunomodulator PGE1 seems a promising agent for the treatment of ARDS patients. Clinical trials were therefore started in recent years; however, the expected beneficial effects were not observed, presumably because of beginning the PGE1 treatment only after the diagnosis of ARDS [2, 3]. Our study design called for treating patients at risk of ARDS before the onset of the disease to prevent or minimize very initial pathogenetic reactions of activated granulocytes by early PGE1 infusion therapy. Additionally, the effects of PGE1 on essential functions of granulocytes (adherence, oxygen radical production, enzyme release) and on EC/PMN interactions were investigated to enable a uniform and critical judgement about the proposed therapeutic approach and underlying patho-mechanisms.

Die Wirkung von Ascorbinsäure auf Neutrophilen-Funktionen und auf Sauerstoffradikale aus der Xanthinoxidase-Reaktion — ein Therapieprinzip?

Neutrophilen-Dysfunktionen (Freisetzung lysosomaler Enzyme, Bildung von Sauerstoffradikalen, Chemotaxis, Adharenz) sowie die vermehrte Sauerstoffradikal-Bildung durch das (Hypo)Xanthin/Xanthinoxidase-System gelten als Ausloser fur Mono- und Multiples Organversagen [1, 2]. Ziel dieser Untersuchung war es, die Wirksamkeit des extrem gut wasserloslichen Antioxidans Ascorbinsaure auf diese Pathomechanismen, insbesondere sein Neutralisationsvermogen fur reaktive Sauerstoff-Metabolite, zu untersuchen. Hiermit im Zusammenhang steht die Frage, ob die Zufuhr hoher Ascorbinsaure-Konzentrationen bei oxidativem Stres (Trauma, Schock, Sepsis) den im Verlauf der Evolution aufgetretenen Gendefekt der L-Gulonolactonoxidase ausgleichen und somit fur eine fruhe Therapie derartiger Zustande empfohlen werden kann.