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Thoracic Diseases Research Unit, Division of Pulmonary, Critical Care and Internal Medicine, and
Department of Biochemistry and Molecular Biology, Mayo Clinic and Foundation, Rochester, MN 55905
Macrophage-induced lung inflammation contributes substantially to
respiratory failure during Pneumocystis carinii
pneumonia. We isolated a P. carinii cell wall fraction
rich in glucan carbohydrate, which potently induces TNF-
and
macrophage-inflammatory protein-2 generation from alveolar macrophages.
Instillation of this purified P. carinii carbohydrate
cell wall fraction into healthy rodents is accompanied by substantial
increases in whole lung TNF-
generation and is associated with
neutrophilic infiltration of the lungs. Digestion of the P.
carinii cell wall isolate with zymolyase, a preparation
containing predominantly ß-1,3 glucanase, substantially reduces the
ability of this P. carinii cell wall fraction to
activate alveolar macrophages, thus suggesting that ß-glucan
components of the P. carinii cell wall largely mediate
TNF-
release. Furthermore, the soluble carbohydrate ß-glucan
receptor antagonists laminariheptaose and laminarin also substantially
reduce the ability of the P. carinii cell wall isolate
to stimulate macrophage-inflammatory activation. In contrast, soluble
-mannan, a preparation that antagonizes macrophage mannose
receptors, had minimal effect on TNF-
release induced by the
P. carinii cell wall fraction. P. carinii
ß-glucan-induced TNF-
release from alveolar macrophages was also
inhibited by both dexamethasone and pentoxifylline, two pharmacological
agents with potential activity in controlling P.
carinii-induced lung inflammation. These data demonstrate that
P. carinii ß-glucan cell wall components can directly
stimulate alveolar macrophages to release proinflammatory cytokines
mainly through interaction with cognate ß-glucan receptors on the
phagocyte.
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