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Serum activity of platelet-activating factor acetylhydrolase is a potential clinical marker for leptospirosis pulmonary hemorrhage.

ABSTRACT: Pulmonary hemorrhage has been recognized as a major, often lethal, manifestation of severe leptospirosis albeit the pathogenesis remains unclear. The Leptospira interrogans virulent serogroup Icterohaemorrhagiae serovar Lai encodes a protein (LA2144), which exhibited the platelet-activating factor acetylhydrolase (PAF-AH) activity in vitro similar to that of human serum with respect to its substrate affinity and specificity and thus designated L-PAF-AH. On the other hand, the primary amino acid sequence of L-PAF-AH is homologous to the alpha1-subunit of the bovine brain PAF-AH isoform I. The L-PAF-AH was proven to be an intracellular protein, which was encoded unanimously and expressed similarly in either pathogenic or saprophytic leptospires. Mongolian gerbil is an appropriate experimental model to study the PAF-AH level in serum with its basal activity level comparable to that of human while elevated directly associated with the course of pulmonary hemorrhage during severe leptospirosis. Mortality occurred around the peak of pulmonary hemorrhage, along with the transition of the PAF-AH activity level in serum, from the increasing phase to the final decreasing phase. Limited clinical data indicated that the serum activity of PAF-AH was likely to be elevated in the patients infected by L. interrogans serogroup Icterohaemorrhagiae, but not in those infected by other less severe serogroups. Although L-PAF-AH might be released into the micro-environment via cell lysis, its PAF-AH activity apparently contributed little to this elevation. Therefore, the change of PAF-AH in serum not only may be influential for pulmonary hemorrhage, but also seems suitable for disease monitoring to ensure prompt clinical treatment, which is critical for reducing the mortality of severe leptospirosis.

SUBMITTER: Yang J

PROVIDER: S-EPMC2615213 | biostudies-literature | 2009

REPOSITORIES: biostudies-literature

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Serum activity of platelet-activating factor acetylhydrolase is a potential clinical marker for leptospirosis pulmonary hemorrhage.

Yang Junwei J Zhang Yixuan Y Xu Jing J Geng Yan Y Chen Xiaoying X Yang Hongliang H Wang Shengnian S Wang Hengan H Jiang Xucheng X Guo Xiaokui X Zhao Guoping G

PloS one 20090115 1

Pulmonary hemorrhage has been recognized as a major, often lethal, manifestation of severe leptospirosis albeit the pathogenesis remains unclear. The Leptospira interrogans virulent serogroup Icterohaemorrhagiae serovar Lai encodes a protein (LA2144), which exhibited the platelet-activating factor acetylhydrolase (PAF-AH) activity in vitro similar to that of human serum with respect to its substrate affinity and specificity and thus designated L-PAF-AH. On the other hand, the primary amino acid ...[more]

PMID: 19145243

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Project description:Aberrantly activated Wnt/β-catenin signaling pathway, as well as platelet-activating factor (PAF), contribute to cancer progression and metastasis of many cancer entities. Nonetheless, the role of the degradation enzyme named platelet-activating factor acetylhydrolase (PLA2G7/PAF-AH) in ovarian cancer etiology is still unclear. This study investigated the functional impact of platelet-activating factor acetylhydrolase on BRCA1 mutant ovarian cancer biology and its crosstalk with the Wnt signaling pathway. PAF-AH, pGSK3β, and β-catenin expressions were analyzed in 156 ovarian cancer specimens by immunohistochemistry. PAF-AH expression was investigated in ovarian cancer tissue, serum of BRCA1-mutated patients, and in vitro in four ovarian cancer cell lines. Functional assays were performed after PLA2G7 silencing. The association of PAF-AH and β-catenin was examined by immunocytochemistry. In an established ovarian carcinoma collective, we identified PAF-AH as an independent positive prognostic factor for overall survival (median 59.9 vs. 27.4 months; p = 0.016). PAF-AH correlated strongly with the Wnt signaling proteins pGSK3β (Y216; nuclear: cc = 0.494, p < 0.001; cytoplasmic: cc = 0.488, p < 0.001) and β-catenin (nuclear: cc = 0.267, p = 0.001; cytoplasmic: cc = 0.291, p < 0.001). In particular, high levels of PAF-AH were found in tumor tissue and in the serum of BRCA1 mutation carriers. By in vitro expression analysis, a relevant gene and protein expression of PLA2G7/PAF-AH was detected exclusively in the BRCA1-negative ovarian cancer cell line UWB1.289 (p < 0.05). Functional assays showed enhanced viability, proliferation, and motility of UWB1.289 cells when PLA2G7/PAF-AH was downregulated, which underlines its protective character. Interestingly, by siRNA knockdown of PLA2G7/PAF-AH, the immunocytochemistry staining pattern of β-catenin changed from a predominantly membranous expression to a nuclear one, suggesting a negative regulatory role of PAF-AH on the Wnt/β-catenin pathway. Our data provide evidence that PAF-AH is a positive prognostic factor with functional impact, which seems particularly relevant in BRCA1 mutant ovarian cancer. For the first time, we show that its protective character may be mediated by a negative regulation of the Wnt/β-catenin pathway. Further studies need to specify this effect. Potential use of PAF-AH as a biomarker for predicting the disease risk of BRCA1 mutation carriers and for the prognosis of patients with BRCA1-negative ovarian cancer should be explored.

Dataset Information

Serum activity of platelet-activating factor acetylhydrolase is a potential clinical marker for leptospirosis pulmonary hemorrhage.

Publications

Serum activity of platelet-activating factor acetylhydrolase is a potential clinical marker for leptospirosis pulmonary hemorrhage.

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