Antiinflammatory effects of the cyclopentenone isoprostane 15-A(2)-IsoP in human gestational tissues

Proinflammatory prostaglandins and cytokines are involved in the initiation of human labor and delivery. Although cyclopentenone prostaglandins regulate the formation of these prolabor mediators via nuclear factor-κB (NF-κB) and/or peroxisome proliferator-activated receptor-γ, recent evidence suggests that they do not exist in vivo. Cyclopentenone isoprostanes (IsoPs), which are highly reactive structural isomers of bioactive cyclopentenone prostaglandins, do exist physiologically and have been shown to inhibit the inflammatory response in macrophages. Therefore the aim of this study was to determine the effect of the synthetic cyclopentenone IosP 15-A₂-IsoP on the expression of prolabor mediators in human gestational tissues. Human placenta and gestational membranes (n = 5) were incubated in the absence or presence of 12.5, 25, and 50 μM 15-A₂-IsoP with 10 μg/ml lipopolysaccharide (LPS). Treatment of placenta and fetal membranes with 15-A₂-IsoP caused a dose-dependent decrease in LPS-stimulated release of the cytokines IL-1β, IL-6, IL-8, and TNF- and the prostaglandins PGE₂ and PGF₂. NF-κB p65 DNA binding activity was significantly inhibited by treatment with 50 μM 15-A₂-IsoP. Collectively, these data suggest that 15-A₂-IsoP exhibits antiinflammatory properties via antagonism of NF-κB activity. Cyclopentenone IsoPs may serve as negative feedback regulators of the inflammatory response in human gestational tissues.     

An IL-12-independent role for CD40-CD154 in mediating effector responses: studies in cell-mediated glomerulonephritis and dermal delayed-type hypersensitivity

Crescentic glomerulonephritis (GN) results from IL-12-driven Th1-directed cell-mediated responses (akin to delayed-type hypersensitivity (DTH)) directed against glomerular Ags. CD40-CD154 interactions are critical for IL-12 production and Th1 polarization of immune responses. Crescentic anti-glomerular basement membrane GN was induced in C57BL/6 (wild-type (WT)) mice (sensitized to sheep globulin) by planting this Ag (as sheep anti-mouse glomerular basement membrane globulin) in their glomeruli. Crescentic GN did not develop in CD40(-/-) mice due to significantly reduced nephritogenic Th1 responses. IL-12 was administered to CD40(-/-) mice with GN to dissect interactions between IL-12 and CD40 in inducing nephritogenic immunity and injury. Administration of IL-12 to CD40(-/-) mice restored Th cell IFN-gamma production, and up-regulated intrarenal chemokines and glomerular T cell and macrophage accumulation compared with WT control mice. Despite this, renal macrophages were not activated and renal injury and dermal DTH were not restored. Thus, CD40-directed IL-12 drives Th1 generation and effector cell recruitment but CD40 is required for activation. To test this hypothesis, activated OT-II OVA-specific CD4(+) cells and OVA(323-339)-loaded nonresponsive APCs were transferred into footpads of WT, CD40(-/-), and macrophage-depleted WT mice. WT mice developed significant DTH compared with CD40(-/-) and macrophage-depleted WT mice. This study demonstrated that CD40-induced IL-12 is required for generation of systemic Th1 immunity to nephritogenic Ags, and that IL-12 enhances Th1 effector cell recruitment to peripheral sites of Ag presentation via generation of local chemokines. Effector cell activation, renal DTH-like injury, and dermal DTH require direct Th1 CD154/macrophage CD40 interactions.     

Pulmonary aspiration in preschool children with cystic fibrosis

Pulmonary aspiration of gastric refluxate (PAGR) has been demonstrated in association with pulmonary inflammation in school aged children with Cystic Fibrosis (CF). We sought to determine if similar findings were present in preschool children. Pepsin was measured in Broncho-alveolar lavage (BAL) fluid collected from clinically stable preschool children with CF and controls. Elevated pepsin levels were found in a subgroup of children with CF, but this was not found to be associated with pulmonary infection, pulmonary inflammation or respiratory or gastrointestinal symptoms.     

Vitamin D3 and calcium absorption in the chick

1. An attempt has been made to locate the site of action of vitamin D(3) as it affects the translocation of calcium across the intestine. 2. Calcium appears to be pumped out of cells by a process dependent on energy from metabolism. 3. The effects of cold, inhibitors and vitamin D(3) on the translocation of calcium by everted sacs of intestine were studied and compared with results obtained in vivo. 4. A model was proposed to explain the results which suggests that vitamin D(3) inhibits a metabolically operated pump that returns calcium from the mucosal cell to the lumen. 5. Some observations on the effect of sodium lauryl sulphate on the translocation of calcium in vivo and in vitro are reported.