Gamma-glutamyl transferase: a novel cardiovascular risk biomarker.

Gamma-glutamyl transferase (GGT) is a second-generation enzymatic liver function test available for several decades, initially used as a sensitive indicator of alcohol ingestion, hepatic inflammation, fatty liver disease, and hepatitis. Longitudinal and cross-sectional investigational studies since 1990 have associated GGT with an increase in all-cause mortality, as well as chronic heart disease events such as congestive heart failure and components of the metabolic syndrome (abnormal body mass index and levels of high-density lipoprotein cholesterol, glucose, triglycerides, and systolic and diastolic blood pressure). In the upper reference range, GGT was found to be an independent biomarker of the metabolic syndrome, with a 20% per GGT quartile trend rise. Additionally, GGT was positively correlated with an 18% per quartile risk of cardiovascular events and a 26% per quartile increased risk of all-cause mortality. Furthermore, it may be considered a biomarker for "oxidative stress" associated with glutathione metabolism and possibly a "proatherogenic" marker because of its indirect relationship in the biochemical steps to low-density lipoprotein cholesterol oxidation. GGT is becoming an important addition to the multimarker approach to cardiovascular risk evaluation. It should be considered a valuable adjunct in stratifying patient risk and in assessing the aggressiveness of appropriate treatment, with hopes of preventing unnecessary cardiac events and deaths in future years.

Crystalline and amorphous silica differentially regulate the cyclooxygenase-prostaglandin pathway in pulmonary fibroblasts: implications for pulmonary fibrosis.

Inhalation of crystalline (CS) and amorphous silica (AS) results in human pulmonary inflammation. However, silicosis develops only following CS exposure, and the pathogenic mechanisms are poorly understood. This report describes the differential abilities of CS and AS to directly upregulate the early inflammatory mediator COX-2, the recently identified prostaglandin E (PGE) synthase and the downstream mediator PGE2 in primary human lung fibroblasts. Increased cyclooxygenase (COX)-2 gene transcription and protein production were demonstrated by ribonuclease protection assay, Western blot analysis, and immunocytochemistry. In each case the ability of AS to induce COX-2 exceeded that of CS. Similarly, downstream of COX-2, production of the antifibrotic prostaglandin PGE2 was induced in a dose-dependent fashion, but AS was significantly more potent (maximal production: CS = 4,710 pg/ml and AS = 7,651 pg/ml). These increases in COX-2 and PGE2 were preceded by induction of the PGE2 synthase protein, demonstrating the potential role of this novel molecule in silica-mediated inflammation. There was specificity of induction of prostaglandins, as PGF2alpha, but not PGD2, was induced. Using specific COX-2 inhibitors, we showed increased PG production to be dependent on the COX-2 enzyme. Furthermore, stimulation of fibroblasts was particle specific, as silica but not carbon black resulted in fibroblast activation. These results demonstrate that silica can directly stimulate human lung fibroblasts to produce key inflammatory enzymes and prostaglandins. Moreover, they suggest a mechanism to explain the differing fibrogenic potential of CS and AS. The molecules COX-2, PGE synthase, and PGE2 are identified as effectors in silicosis.