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We previously reported that alveolar macrophages from patients with chronic obstructive pulmonary disease (COPD) are defective in their ability to phagocytose apoptotic cells, with a similar defect in response to cigarette smoke. The exact mechanisms for this defect are unknown. Sphingolipids including ceramide, sphingosine and sphingosine-1-phosphate (S1P) are involved in diverse cellular processes and we hypothesised that a comprehensive analysis of this system in alveolar macrophages in COPD may help to delineate the reasons for defective phagocytic function.    Methods  We compared mRNA expression of sphingosine kinases ( SPHK1/2 ), S1P receptors  (S1PR1-5)  and S1P-degrading enzymes ( SGPP1 ,  SGPP2 ,  SGPL1 ) in bronchoalveolar lavage-derived alveolar macrophages from 10 healthy controls, 7 healthy smokers and 20 COPD patients (10 current- and 10 ex-smokers) using Real-Time PCR. Phagocytosis of apoptotic cells was investigated using flow cytometry. Functional associations were assessed between sphingosine signalling system components and alveolar macrophage phagocytic ability in COPD. To elucidate functional effects of increased  S1PR5  on macrophage phagocytic ability, we performed the phagocytosis assay in the presence of varying concentrations of suramin, an antagonist of  S1PR3  and  S1PR5 . The effects of cigarette smoking on the S1P system were investigated using a THP-1 macrophage cell line model.    Results  We found significant increases in  SPHK1/2  (3.4- and 2.1-fold increases respectively),  S1PR2  and  5  (4.3- and 14.6-fold increases respectively), and  SGPL1  (4.5-fold increase) in COPD vs. controls.  S1PR5  and  SGPL1  expression was unaffected by smoking status, suggesting a COPD “disease effect” rather than smoke effect  per se . Significant associations were noted between  S1PR5  and both lung function and phagocytosis. Cigarette smoke extract significantly increased mRNA expression of  SPHK1 ,  SPHK2 ,  S1PR2  and  S1PR5  by THP-1 macrophages, confirming the results in patient-derived macrophages. Antagonising  SIPR5  significantly improved phagocytosis.    Conclusion  Our results suggest a potential link between the S1P signalling system and defective macrophage phagocytic function in COPD and advise therapeutic targets.

plos one

Potential Link between the Sphingosine-1-Phosphate (S1P) System and Defective Alveolar Macrophage Phagocytic Function in Chronic Obstructive Pulmonary Disease (COPD)