Release Of Reactive Oxygen Metabolites Research Articles

The respiratory burst in activated macrophages: studies of its molecular basis and evidence for downregulation in chronic infection.

Macrophages (Ko) elicited by injection of inflammatory agents or obtained from animals infected with intracellular parasites are primed so that they respond to phagocytosis or exposure to phorbol myristate acetate (PMA) with a marked increase in the respiratory burst (1). Unstimulated Mo release little if any reactive oxygen metabolites; stimulation is required to demonstrate the primed state. This capacity for an increased stimulated release of reactive oxygen metabolites appears to play an essential role in the increased microhicidal capacity of activated Mo (2–4). Priming is a manifestation of Mo activation, but it is not the same as activation; i.e., priming may not always reflect the fully activated state (5).

Mycobacterial growth inhibition by interferon-gamma-activated bone marrow macrophages and differential susceptibility among strains of Mycobacterium tuberculosis.

Growth inhibition of the intracellular bacterial pathogens Mycobacterium bovis and M. tuberculosis by lymphokine-activated murine bone marrow macrophages was studied. Mycobacterial growth was assessed by the uptake of 3H-uracil or by determination of colony-forming units. Stimulation of macrophages with recombinant interferon-gamma (r-IFN-gamma) or with IFN-gamma-containing supernatants from antigen- or mitogen-stimulated T cells markedly reduced growth of M. bovis strain BCG Phipps or M. tuberculosis strain H37Rv. In contrast, M. tuberculosis strain Middelburg proved resistant to lymphokine-stimulated macrophages, suggesting heterogeneous susceptibility toward lymphokine-activated macrophages among different M. tuberculosis strains. Stimulation could be blocked by anti-IFN-gamma antiserum, indicating that IFN-gamma was capable of activating antimycobacterial macrophage functions. Stimulation with r-IFN-gamma and subsequent phagocytosis of M. bovis did not lead to increased chemiluminescence responses by bone marrow macrophages, suggesting that mycobacterial growth inhibition was not paralleled by the release of reactive oxygen metabolites. We conclude that IFN-gamma-mediated macrophage activation represents a major step in acquired resistance against tuberculosis and that evasion from this mechanism contributes to mycobacterial virulence.

Modulation of the macrophage oxidative burst by Histoplasma capsulatum.

The production of reactive oxygen species by phagocytic cells is an important host defense against invading microorganisms. Because pathogens that achieve intracellular survival escape destruction by reactive oxidants, we investigated the relationship between the intracellular survival of H. capsulatum and the macrophage oxidative burst. H. capsulatum yeast failed to stimulate the release of reactive oxygen metabolites in unprimed murine macrophages despite extensive phagocytosis of the microorganisms. This effect was observed with live as well as heat-killed fungi over a wide range of yeast-to-macrophage ratios. Preincubation of murine macrophages with heat-killed H. capsulatum (but not with latex spheres), followed by incubation with unopsonized zymosan, resulted in inhibition of oxidative burst triggering without inhibition of zymosan phagocytosis. Ingestion of H. capsulatum yeast opsonized with the cognate mouse antibody resulted in significant oxidant release, suggesting that suppression of the respiratory burst may be circumvented through Fc-mediated phagocytosis.