Activation of macrophages in vivo and in vitro. Correlation between hydrogen peroxide release and killing of Trypanosoma cruzi.

Abstract

As reported previously, mouse peritoneal macrophages could be activated to kill intracellular trypomastigotes of Trypanosoma cruzi, the agent of Chagas' disease, in either of two ways: by immunizing and boosting the mice (3), or by culturing resident or inflammatory macrophages in spleen cell factor(s) (SCF) in vitro (2). Macrophages activated in vivo became less trypanocidal with time in culture, and cells activated in vitro lost trypanocidal capacity when CSF was removed (2). In the present study, the ability of macrophages to release H2O2 in response to phorbol myristate acetate (PMA) could be induced in vivo and in vitro, and reversed in vitro, in a manner correlating closely with changes in trypanocidal activity. Macrophages could be activated in vitro with SCF in a time-dependent and dose-dependent fashion, so that they released as much H2O2 as macrophages activated in vivo. The sensitivity of epimastigotes and trypomastigotes to enzymatically generated H2O2 suggested that the generation of H2O2 by activated macrophages could be plausible explanation for their trypanocidal activity. Of the biochemical correlates of macrophage activation reported to date, increased ability to release H2O2 seems most closely allied to enhanced capacity to kill an intracellular pathogen.

Immunization with recombinant paraflagellar rod protein induces protective immunity against Trypanosoma cruzi infection

“…An important function of IFN-␥ in PFR-immune mice is likely activation of infected macrophages to produce nitric oxide and reactive oxygen species known to be effective against T. cruzi [11,31]. Interestingly, the selective depletion of macrophages results in increased cardiac pathology in the rat model, suggesting a direct role for macrophages in protection against Chagas' disease pathology [12].…”

Failure to trigger the oxidative metabolic burst by normal macrophages: possible mechanism for survival of intracellular pathogens.

“…Previous studies of the role of oxidative metabolism in the microbicidal activity of macrophages have shown that activated macrophages, which have increased antimi-crobial activity, generate increased amounts of reactive oxygen metabolites when triggered by particulate and chemical agents such as zymosan and phorbol myristate acetate (3)(4)(5)36). This suggests that differences in maximum oxidative metabolic response between mononuclear phagocytes of different types or of different degrees of activation to such general triggering agents may be causally related to differences in antimicrobial activity.…”

Electron transport chain ofSaccharomyces cerevisiaemitochondria is inhibited by H2O2at succinate-cytochromecoxidoreductase level without lipid peroxidation involvement

“…In addition, activation of NADPH oxidases on immune cells (e.g. macrophages) increase cellular levels of H 2 O 2 [40], supporting the rationale of using this oxidant as an oxidative stress inducer. H 2 O 2 decreases oxygen consumption rate in all the respiratory states (Figure 1), even in the lowest concentration used (0.125 μM).…”