Plasma metabolomic profile in fibrosing pulmonary sarcoidosis.

BACKGROUND: There is no known marker to screen patients with sarcoidosis to determine the risk of progression to pulmonary fibrosis. We aimed to identify potential noninvasive biomarkers for early detection of pulmonary fibrosing sarcoidosis. METHODS: A case-control study was performed on African Americans with confirmed sarcoidosis included 31 subjects with pulmonary fibrosis vs. 36 without pulmonary fibrosis. Plasma samples were analyzed by liquid chromatography-mass spectrum. Multivariate statistical analysis models were developed in a training set based on 50 age- and sex-matched samples to identify metabolites involved in the discrimination. Principal component analysis and orthogonal partial least squares-discriminant (OPLS) analysis coupled to the most influential variables were used to derive significant metabolic discriminations. RESULTS: Of the datasets from 171 feature peaks, 14 features including p-coumaroylagmatine and palmitoylcarnitine showed significant differences between fibrosing and non-fibrosing pulmonary sarcoidosis (p = 0.001). OPLS analysis presented clear separation between two groups with an acceptable goodness of fit (R(2) = 0.522) and predictive power (Q(2)=0.322). Discriminating metabolites involved collagen pathway metabolites especially those in the arginine-proline pathway. CONCLUSIONS: Metabolomics can provide a useful tool to detect pulmonary fibrosis in patients with sarcoidosis. Two discriminating metabolites, p-coumaroylagmatine and palmitoylcarnitine may be potential markers for fibrosing pulmonary sarcoidosis.

Sphingosine-1-phosphate, FTY720, and sphingosine-1-phosphate receptors in the pathobiology of acute lung injury.

Acute lung injury (ALI) attributable to sepsis or mechanical ventilation and subacute lung injury because of ionizing radiation (RILI) share profound increases in vascular permeability as a key element and a common pathway driving increased morbidity and mortality. Unfortunately, despite advances in the understanding of lung pathophysiology, specific therapies do not yet exist for the treatment of ALI or RILI, or for the alleviation of unremitting pulmonary leakage, which serves as a defining feature of the illness. A critical need exists for new mechanistic insights that can lead to novel strategies, biomarkers, and therapies to reduce lung injury. Sphingosine 1-phosphate (S1P) is a naturally occurring bioactive sphingolipid that acts extracellularly via its G protein-coupled S1P1-5 as well as intracellularly on various targets. S1P-mediated cellular responses are regulated by the synthesis of S1P, catalyzed by sphingosine kinases 1 and 2, and by the degradation of S1P mediated by lipid phosphate phosphatases, S1P phosphatases, and S1P lyase. We and others have demonstrated that S1P is a potent angiogenic factor that enhances lung endothelial cell integrity and an inhibitor of vascular permeability and alveolar flooding in preclinical animal models of ALI. In addition to S1P, S1P analogues such as 2-amino-2-(2-[4-octylphenyl]ethyl)-1,3-propanediol (FTY720), FTY720 phosphate, and FTY720 phosphonates offer therapeutic potential in murine models of lung injury. This translational review summarizes the roles of S1P, S1P analogues, S1P-metabolizing enzymes, and S1P receptors in the pathophysiology of lung injury, with particular emphasis on the development of potential novel biomarkers and S1P-based therapies for ALI and RILI.