title: Isolated Pneumocystis carinii cell wall glucan provokes lower respiratory tract inflammatory responses.
abstract: 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-alpha 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-alpha generation and is associated with neutrophilic infiltration of the lungs. Digestion of the P. carinii cell wall isolate with zymolyase, a preparation containing predominantly beta-1,3 glucanase, substantially reduces the ability of this P. carinii cell wall fraction to activate alveolar macrophages, thus suggesting that beta-glucan components of the P. carinii cell wall largely mediate TNF-alpha release. Furthermore, the soluble carbohydrate beta-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 alpha-mannan, a preparation that antagonizes macrophage mannose receptors, had minimal effect on TNF-alpha release induced by the P. carinii cell wall fraction. P. carinii beta-glucan-induced TNF-alpha 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 beta-glucan cell wall components can directly stimulate alveolar macrophages to release proinflammatory cytokines mainly through interaction with cognate beta-glucan receptors on the phagocyte.
authors.affiliation: Thoracic Diseases Research Unit, Division of Pulmonary Medicine, Department of Biochemistry, Mayo Clinic and Foundation, Rochester, MN 55905, USA.
authors.forename: R
authors.initials: R
authors.lastname: Vassallo
authors.forename: J E
authors.initials: JE
authors.lastname: Standing
authors.forename: A H
authors.initials: AH
authors.lastname: Limper
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001667:Binding, Competitive / Q000276:immunology; D002473:Cell Wall / Q000737:chemistry / Q000201:enzymology / Q000276:immunology; D002478:Cells, Cultured; D054426:Chemokine CXCL2; D018925:Chemokines / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D005260:Female; D004693:Glucan Endo-1,3-beta-D-Glucosidase / Q000378:metabolism; D005936:Glucans / Q000008:administration & dosage / Q000276:immunology* / Q000302:isolation & purification* / Q000378:metabolism; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D007442:Intubation, Intratracheal; D037181:Lectins, C-Type; D008168:Lung / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008358:Mannose / Q000378:metabolism; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D010431:Pentoxifylline / Q000494:pharmacology; D011010:Pneumocystis / Q000737:chemistry / Q000201:enzymology / Q000276:immunology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors; D012995:Solubility; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D054426:Chemokine CXCL2; D018925:Chemokines; C404915:Cxcl2 protein, mouse; D005936:Glucans; D037181:Lectins, C-Type; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D014409:Tumor Necrosis Factor-alpha; C045268:beta-glucan receptor; D003907:Dexamethasone; D004693:Glucan Endo-1,3-beta-D-Glucosidase; D008358:Mannose; D010431:Pentoxifylline