Oxygen-independent killing by alveolar macrophages.

Abstract

Alveolar macrophages play a key role in defense of the host against pulmonary infection (1-6). Their clinical importance is emphasized by the high incidence of life-threatening pneumonia (7,8) in patients with abnormal macrophage function (6) or impaired ceU-mediated immunity (6-9). However, the mechanisms by which alveolar macrophages kill microorganisms are poorly understood.We recently examined the mechanism by which human alveolar macrophages kill the intracellular parasite, Toxoplasma gondii (10). We chose this organism because it causes pneumonia in immunosuppressed patients (11-14) but not in healthy individuals (11), and because macrophages play an important part in the host's resistance to this organism (5,(15)(16)(17). Our studies showed that killing of T. gondii by human alveolar macrophages occurred without involvement of toxic metabolites of oxygen (Catterall, J. R., and J. S. Remington, manuscript in preparation). This suggested that previous studies of intracellular killing by normal macrophages might have limitations as models for the human alveolar macrophage, since most of them (18-20, and reviewed in 21), including all those that employed T. gondii (18-23), have emphasized the overriding importance of oxidative killing mechanisms. Nonoxidative antimicrobial activity has been shown in subcellular macrophage fragments (21, 24) and in oxidatively deficient cells (19,(21)(22)(23)25), but in none of the previously described models using normal intact macrophages has the killing of intracellular parasites been reported as nonoxidative.To facilitate the study of nonoxidative killing by alveolar macrophages, we have sought a laboratory animal model relevant to the human alveolar macrophage. Since rats more closely resemble human subjects in their resistance to T. gondii than many other animals (26, 27), we have examined the interaction between T. gondii and rat alveolar macrophages in vitro. The studies reported here indicate that rat alveolar macrophages, like those from human subjects, also kill T. gondii, and by nonoxidative mechanisms. They suggest that nonoxidative antimicrobial mechanisms may be important in alveolar macrophages, and they provide a convenient model for the study of such mechanisms.

Cytotoxic activity of monocytes againstToxoplasma gondii in acute, chronic and reactivated murine toxoplasmosis

“…Normal rat and human alveolar macrophages, however, kill intracellular toxoplasma by a mechanism that does not involve toxic oxygen metabolites but probably involves phagosome formation. This antimicrobial mechanism is not present in resident murine alveolar and peritoneal macrophages [3]. There is a large body of data suggesting that oxygen-independent mechanisms of intraceUular killing by phagocytic cells are impor-tant.…”

In-vitro toxoplasmacidal activity of cationic electron carriers

“…Scavengers of oxygen intermediates (Catterall, Sharma & Remington, 1986) were obtained from Sigma GmbH, Deisenhofen, West Germany, and used at the concentrations shown. Superoxide dismutase, 3000 U/mg (2-5 mg/ml) was used for superoxide anion; catalase from bovine liver recrystallized twice (2-5 mg/ml) for hydrogen peroxide; and histidinc (10 mM) and diazabicyclooctane (1 ITLM) for singlet oxygen radicals.…”

Macrophage responses to Toxoplasma antigens in vitro: a possible role in inflammatory lesions in toxoplasmosis.

“…46,47 Macrophages (human and rat alveolar and peritoneal) possess oxygen-dependent and oxygen-independent anti-microbial activities, both of which are active in unstimulated and activated cells. Studies by Catterall and others 48,49 and Chang and Pechere 50 demonstrated that intracellular killing of T. gondii by human and rat alveolar and peritoneal macrophages was by a non-oxidative mechanism, with no oxidative burst being triggered in these cells. Catteral and others 48 also investigated the roles of oxygen scavengers and found that these metabolites had no effect on the toxoplasmicidal activities of human and rat macrophages.…”

“…Studies by Catterall and others 48,49 and Chang and Pechere 50 demonstrated that intracellular killing of T. gondii by human and rat alveolar and peritoneal macrophages was by a non-oxidative mechanism, with no oxidative burst being triggered in these cells. Catteral and others 48 also investigated the roles of oxygen scavengers and found that these metabolites had no effect on the toxoplasmicidal activities of human and rat macrophages. This suggests that the intracellular killing of T. gondii in these cells does not involve toxic oxygen metabolites.…”