Fatty Acid-binding Protein 4 Expression in Tumor Cells as a Potential Marker for Anaplastic Meningiomas.

Meningiomas are highly vascularized tumors originating from arachnoid cap cells of the leptomeninges. The majority of meningiomas are classified as World Health Organization (WHO) grade I and display a benign clinical course with a low risk of recurrence. In contrast, WHO grade III meningiomas carry a high risk of recurrence and poor prognosis. However, it is commonly recognized that histopathologic grading does not always reliably predict recurrence or progression of meningiomas. Fatty acid-binding protein 4 (FABP4) is a small molecular weight lipid chaperone that plays a proangiogenic role in vascular endothelial cells. FABP4 is not expressed in normal brain vasculature but is detected in some glioblastoma and arteriovenous malformations. The expression pattern of FABP4 in meningiomas have not been reported to date. We analyzed FABP4 expression in a cohort of paraffin-embedded meningioma specimens by immunohistochemistry and double immunofluorescence analyses. FABP4 expression was detected in a subset of endothelial cells in 47 of 48 meningioma samples analyzed. Interestingly, tumor cell-FABP4 expression was also detected in only 1 of 22 grade I, none of grade II, but 10 of 12 grade III meningiomas (P<0.0001). These results demonstrate that FABP4 is commonly expressed in meningioma vascular endothelial cells while tumor cell expression of FABP4 is primarily observed in anaplastic meningiomas. A combination of FABP4 immunostaining with histopathologic grading might provide a more accurate prediction of the biological behavior of meningiomas than histopathologic grading alone.

Airway epithelial cell PPARγ modulates cigarette smoke-induced chemokine expression and emphysema susceptibility in mice.

Chronic obstructive pulmonary disease (COPD) is a highly prevalent, chronic inflammatory lung disease with limited existing therapeutic options. While modulation of peroxisome proliferator-activating receptor (PPAR)-γ activity can modify inflammatory responses in several models of lung injury, the relevance of the PPARG pathway in COPD pathogenesis has not been previously explored. Mice lacking Pparg specifically in airway epithelial cells displayed increased susceptibility to chronic cigarette smoke (CS)-induced emphysema, with excessive macrophage accumulation associated with increased expression of chemokines, Ccl5, Cxcl10, and Cxcl15. Conversely, treatment of mice with a pharmacological PPARγ activator attenuated Cxcl10 and Cxcl15 expression and macrophage accumulation in response to CS. In vitro, CS increased lung epithelial cell chemokine expression in a PPARγ activation-dependent fashion. The ability of PPARγ to regulate CS-induced chemokine expression in vitro was not specifically associated with peroxisome proliferator response element (PPRE)-mediated transactivation activity but was correlated with PPARγ-mediated transrepression of NF-κB activity. Pharmacological or genetic activation of PPARγ activity abrogated CS-dependent induction of NF-κB activity. Regulation of NF-κB activity involved direct PPARγ-NF-κB interaction and PPARγ-mediated effects on IKK activation, IκBα degradation, and nuclear translocation of p65. Our data indicate that PPARG represents a disease-relevant pathophysiological and pharmacological target in COPD. Its activation state likely contributes to NF-κB-dependent, CS-induced chemokine-mediated regulation of inflammatory cell accumulation.

Epithelial cell PPAR[gamma] contributes to normal lung maturation.

Peroxisome proliferator-activated receptor (PPAR)-gamma is a member of the nuclear hormone receptor superfamily that can promote cellular differentiation and organ development. PPARgamma expression has been reported in a number of pulmonary cell types, including inflammatory, mesenchymal, and epithelial cells. We find that PPARgamma is prominently expressed in the airway epithelium in the mouse lung. In an effort to define the physiological role of PPARgamma within the lung, we have ablated PPARgamma using a novel line of mice capable of specifically targeting the airway epithelium. Airway epithelial cell PPARgamma-targeted mice display enlarged airspaces resulting from insufficient postnatal lung maturation. The increase in airspace size is accompanied by alterations in lung physiology, including increased lung volumes and decreased tissue resistance. Genome-wide expression profiling reveals a reduction in structural extracellular matrix (ECM) gene expression in conditionally targeted mice, suggesting a disruption in epithelial-mesenchymal interactions necessary for the establishment of normal lung structure. Expression profiling of airway epithelial cells isolated from conditionally targeted mice indicates PPARgamma regulates genes encoding known PPARgamma targets, additional lipid metabolism enzymes, and markers of cellular differentiation. These data reveal airway epithelial cell PPARgamma is necessary for normal lung structure and function.

Induction of macrophage elastase (MMP-12) gene expression by statins.

The statins (including mevastatin and lovastatin) are a widely prescribed class of serum-cholesterol lowering drugs that function by inhibiting 3-hydroxymethylglutaryl coenzyme A (HMG CoA) reductase activity and cellular sterol synthesis. Statins are also widely being appreciated for their inhibitory effects upon inflammation, primarily mediated through direct regulation of inflammatory gene expression. Here we report that statins are also capable of increasing the expression of macrophage elastase (MMP-12). The induction of MMP-12 in mouse macrophages by statins is specific for HMG CoA reductase inhibition, rescued by mevalonate and not observed after inhibition of subsequent steps in the cholesterol biosynthetic pathway. Modulation of cholesterol metabolism may lead to changes in MMP-12 expression and subsequent impacts during physiological and pathophysiological states. We conclude that statins, in addition to their previously described anti-inflammatory properties, may promote the production of some proteinases from activated macrophages.