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Published ahead of print on July 22, 2005, doi:10.1164/rccm.200501-035OC

Am. J. Respir. Crit. Care Med., Volume 172, Number 8, October 2005, 972-979

A more recent version of this article appeared on October 15, 2005
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Submitted on January 10, 2005
Accepted on July 19, 2005

Defective Apoptotic Cell Phagocytosis Attenuates PGE2 and 15-HETE in Severe Asthma Alveolar Macrophages

Mai-Lan N Huynh1*, Kenneth C Malcolm2, Chakradhar Kotaru3, John A Tilstra2, Jay Y Westcott2, Valerie A Fadok1, and Sally E Wenzel1

1 Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Denver, CO, USA; Department of Pulmonary Medicine, National Jewish Medical and Research Center, Denver, CO, USA, 2 Department of Pulmonary Medicine, National Jewish Medical and Research Center, Denver, CO, USA, 3 Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Denver, CO, USA

* To whom correspondence should be addressed. 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 anti-inflammatory/anti-fibrotic mediators. Methods: Human bronchoalveolar lavage macrophages (AM{phi}s) from normal control, mild-moderate or severe asthmatic subjects were examined in vitro for phagocytosis of apoptotic human T-cell line Jurkats and secretion of inflammatory mediators. Measurements and Main Results: AM{phi}s from normal and mild-moderate asthmatic subjects were able to phagocytose apoptotic cells in response to lipopolysaccharide, resulting in an induction of the anti-fibrotic and/or anti-inflammatory eicosanoids, PGE2 and 15-HETE. In contrast, severe asthmatic AM{phi}s had defective lipopolysaccharide-stimulated uptake of apoptotic cells, with associated failure to induce PGE2 and 15-HETE. In addition, lipopolysaccharide-stimulated basal levels of TNF{alpha} and GM-CSF were reduced in all asthmatics, while PGE2 and 15-HETE were reduced only in severe asthmatics. Dexamethasone enhanced specific uptake of apoptotic cells in all subjects, while suppressing inflammatory mediator secretion. Conclusions: A decrease in AM{phi}s lipopolysaccharide-responsiveness in severe asthma is manifested by defective apoptotic cell uptake and reduced secretion of inflammatory mediators. This may contribute to the chronicity of inflammation and remodeling in asthmatic lungs.
Key words: Asthma, alveolar macrophages, phagocytosis, PGE2, lipopolysaccharide




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