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Defective Apoptotic Cell Phagocytosis Attenuates Prostaglandin E₂ and 15-Hydroxyeicosatetraenoic Acid in Severe Asthma Alveolar Macrophages

Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center; and Division of Pulmonary Medicine, National Jewish Medical and Research Center, Denver, Colorado

Correspondence and requests for reprints should be addressed to Mai-Lan N. Huynh, M.D., Assistant Professor, University of Colorado Health Sciences Center, Division of Pulmonary Sciences and Critical Care Medicine, National Jewish Medical and Research Center, 1400 Jackson Street, D210, Denver, CO 80206. E-mail: huynhm{at}njc.org

Rationale: Clearance of apoptotic cells is crucial to the resolution of inflammation and development of fibrosis, but the process is not well understood in normal or diseased human lungs.

Objectives: To determine phagocytosis of apoptotic cells by primary human alveolar macrophages and whether defects in uptake of apoptotic cells are associated with decreases in antiinflammatory/antifibrotic mediators.

Methods: Human bronchoalveolar lavage macrophages (AMs) from normal control subjects and subjects with mild-moderate or severe asthma were examined in vitro for phagocytosis of apoptotic human T-cell line Jurkats and secretion of inflammatory mediators.

Measurements and Main Results: AMs from normal subjects and patients with mild-moderate asthma were able to phagocytose apoptotic cells in response to LPS, resulting in an induction of the antifibrotic and/or antiinflammatory eicosanoids, prostaglandin E₂ (PGE₂) and 15-hydroxyeicosatetraenoic acid (HETE). In contrast, AMs from patients with severe asthma had defective LPS-stimulated uptake of apoptotic cells, with associated failure to induce PGE₂ and 15-HETE. In addition, LPS-stimulated basal levels of tumor necrosis factor and granulocyte-macrophage colony–stimulating factor were reduced in all patients with asthma, whereas PGE₂ and 15-HETE were reduced only in patients with severe asthma. Dexamethasone enhanced specific uptake of apoptotic cells in all subjects, while suppressing inflammatory mediator secretion.

Conclusions: A decrease in AMs LPS-responsiveness in severe asthma is manifested by defective apoptotic cell uptake and reduces secretion of inflammatory mediators. This may contribute to the chronicity of inflammation and remodeling in lungs of patients with asthma.

Key Words: alveolar macrophages • asthma • lipopolysaccharide • phagocytosis • prostaglandin E₂

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