Defective apoptotic cell phagocytosis attenuates prostaglandin E2 and 15-hydroxyeicosatetraenoic acid in severe asthma alveolar macrophages.

Abstract

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 (AMphis) 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:

AMphis 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, AMphis 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 alpha 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 AMphis 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.

• Authors: Mai-Lan N Huynh, Kenneth C Malcolm, Chakradhar Kotaru, John A Tilstra, Jay Y Westcott, Valerie A Fadok, Sally E Wenzel
• Journal: American journal of respiratory and critical care medicine (Am J Respir Crit Care Med) Vol. 172 Issue 8 Pg. 972-9 (Oct 15 2005) ISSN: 1073-449X [Print] United States
• PMID: 16040786 (Publication Type: Journal Article)

Chemical References

• Anti-Inflammatory Agents
• Hydroxyeicosatetraenoic Acids
• Tumor Necrosis Factor-alpha
• Dexamethasone
• 15-hydroxyeicosatrienoic acid
• Granulocyte-Macrophage Colony-Stimulating Factor
• Dinoprostone

Topics

• Adult
• Analysis of Variance
• Anti-Inflammatory Agents (immunology, therapeutic use)
• Apoptosis (immunology)
• Asthma (classification, diagnosis, immunology)
• Bronchoalveolar Lavage Fluid
• Case-Control Studies
• Cell Survival
• Chronic Disease
• Dexamethasone (immunology, therapeutic use)
• Dinoprostone (analysis, immunology)
• Female
• Forced Expiratory Volume
• Granulocyte-Macrophage Colony-Stimulating Factor (immunology)
• Humans
• Hydroxyeicosatetraenoic Acids (analysis, immunology)
• Inflammation
• Jurkat Cells
• Macrophages, Alveolar (immunology)
• Male
• Phagocytosis (immunology)
• Severity of Illness Index
• Tumor Necrosis Factor-alpha (immunology)
• Vital Capacity