Transcription of liver X receptor is down-regulated by 15-deoxy-Δ12,14-prostaglandin J2 through oxidative stress in human neutrophils

Liver X receptors (LXRs) are ligand-activated transcription factors of the nuclear receptor superfamily. They play important roles in controlling cholesterol homeostasis and as regulators of inflammatory gene expression and innate immunity, by blunting the induction of classical pro-inflammatory genes. However, opposite data have also been reported on the consequences of LXR activation by oxysterols, resulting in the specific production of potent pro-inflammatory cytokines and reactive oxygen species (ROS). The effect of the inflammatory state on the expression of LXRs has not been studied in human cells, and constitutes the main aim of the present work. Our data show that when human neutrophils are triggered with synthetic ligands, the synthesis of LXRα mRNA became activated together with transcription of the LXR target genes ABCA1, ABCG1 and SREBP1c. An inflammatory mediator, 15-deoxy-Δ12,14-prostaglandin J2 (15dPGJ2), hindered T0901317-promoted induction of LXRα mRNA expression together with transcription of its target genes in both neutrophils and human macrophages. This down-regulatory effect was dependent on the release of reactive oxygen species elicited by 15dPGJ2, since it was enhanced by pro-oxidant treatment and reversed by antioxidants, and was also mediated by ERK1/2 activation. Present data also support that the 15dPGJ2-induced serine phosphorylation of the LXRα molecule is mediated by ERK1/2. These results allow to postulate that down-regulation of LXR cellular levels by pro-inflammatory stimuli might be involved in the development of different vascular diseases, such as atherosclerosis.

Control of ion transport in mammalian airways by protease activated receptors type 2 (PAR-2)

Protease-activated receptors (PARs) are widely distributed in human airways. They couple to G-proteins and are activated after proteolytic cleavage of the N terminus of the receptor. Evidence is growing that PAR subtype 2 plays a pivotal role in inflammatory airway diseases, such as allergic asthma or bronchitis. However, nothing is known about the effects of PAR-2 on electrolyte transport in the native airways. PAR-2 is expressed in airway epithelial cells, where they are activated by mast cell tryptase, neutrophil proteinase 3, or trypsin. Recent studies produced conflicting results about the functional consequence of PAR-2 stimulation. Here we report that stimulation of PAR-2 receptors in mouse and human airways leads to a change in electrolyte transport and a shift from absorption to secretion. Although PAR-2 appears to be expressed on both sides of the epithelium, only basolateral stimulation results in inhibition of amiloride sensitive Na+ conductance and stimulation of both luminal Cl- channels and basolateral K+ channels. The present data indicate that these changes occur through activation of phospholipase C and increase in intracellular Ca2+, which activates basolateral SK4 K+ channels and luminal Ca2+-dependent Cl- channels. In addition, the present data suggest a PAR-2 mediated release of prostaglandin E2, which may contribute to the secretory response. In conclusion, these results provide further evidence for a role of PAR-2 in inflammatory airway disease: stimulation of these receptors may cause accumulation of airway surface liquid, which, however, may help to flush noxious stimuli away from the affected airways. ©2005 FASEB

Inhibitors of cyclo-oxygenase-2 and secretory phospholipase A2 preserve bone architecture following ovariectomy in adult rats

Epidemiological evidence and in vitro data suggest that COX-2 is a key regulator of accelerated remodeling. Accelerated states of osteoblast and osteoclast activity are regulated by prostaglandins in vitro, but experimental evidence for specific roles of cyclooxygenase-2 (COX-2) and secretory phospholipase A(2) (sPLA(2)) in activated states of remodeling in vivo is lacking. The aim of this study was to determine the effect of specific inhibitors of sPLA(2)-IIa and COX-2 on bone remodeling activated by estrogen deficiency in adult female rats. One hundred and twenty-four adult female Wistar rats were ovariectomized (OVX) or sham-operated. Rats commenced treatment 14 days after surgery with either vehicle, a COX-2 inhibitor (DFU at 0.02 mg/kg/day and 2.0 mg/kg/day) or a sPLA(2)-group-IIa inhibitor (KH064 at 0.4 mg/kg/day and 4.0 mg/kg/day). Treatment continued daily until rats were sacrificed at 70 days or 98 days post-OVX. The right tibiae were harvested, fixed and embedded in methylmethacrylate for structural histomorphometric bone analysis at the proximal tibial metaphysis. The specific COX-2 or sPLA(2) inhibitors prevented ovariectomy-induced (OVX-induced) decreases in trabecular connectivity (P < 0.05); suppressed the acceleration of bone resorption; and maintained bone turnover at SHAM levels following OVX in the rat. The sPLA2 inhibitor significantly suppressed increases in osteoclast surface induced by OVX (P < 0.05), while the effect of COX-2 inhibition was less marked. These findings demonstrate that inhibitors of COX-2 and sPLA(2)-IIa can effectively suppress OVX-induced bone loss in the adult rat by conserving trabecular bone mass and architecture through reduced bone remodeling and decreased resorptive activity. Moreover, we report an important role of sPLA(2)-IIa in osteoclastogenesis that may be independent of the COX-2 metabolic pathway in the OVX rat in vivo. (c) 2006 Elsevier Inc. All rights reserved.

Regulation of bone biology by prostaglandin endoperoxide H synthases (PGHS): A rose by any other name...

It is well established that prostaglandins are essential mediators of bone resorption and formation. In the early 1990s, it was discovered that enzymatic reactions producing prostaglandins were regulated by two cyclooxygenase enzymes, one producing prostaglandins constitutively in tissues like the stomach, prostaglandin endoperoxide H synthase-1 (PGHS-1 or COX-1), and another induced by mitogens or inflammatory mediators (PGHS-2 or COX-2). This neat distinction has not been maintained because both enzymes act in different cell systems to provide physiological signaling, constitutively or by induction under certain conditions. For example, the regulation patterns of PGHS-1 and PGHS-2 are distinct, but the evidence shows that PGHS-2 functions constitutively in the skeleton. PGHS-2 hits quickly been established, therefore, as a key regulator of bone biology, capable of rapid and transient expression in bone cells, and mediating osteoclastogenesis, mechanotransduction, bone formation and fracture repair. The goal of this review is to Summarize the current state of our knowledge of PGHS regulation of bone metabolism and to identify some of the key unresolved challenges and questions that require further study. (c) 2006 Elsevier Ltd. All rights reserved.

Usability of prostaglandin monotherapy eye droppers

AIM: To determine the force needed to extract a drop from a range of current prostaglandin monotherapy eye droppers and how this related to the comfortable and maximum pressure subjects could exert. METHODS: The comfortable and maximum pressure subjects could apply to an eye dropper constructed around a set of cantilevered pressure sensors and mounted above their eye was assessed in 102 subjects (mean 51.2±18.7 years), repeated three times. A load cell amplifier, mounted on a stepper motor controlled linear slide, was constructed and calibrated to test the force required to extract the first three drops from 13 multidose or unidose latanoprost medication eye droppers. RESULTS: The pressure that could be exerted on a dropper comfortably (25.9±17.7 Newtons, range 1.2-87.4) could be exceeded with effort (to 64.8±27.1 Newtons, range 19.9-157.8; F=19.045, p<0.001), and did not differ between repeats (F=0.609, p=0.545). Comfortable and maximum pressures exerted were correlated (r=0.618, p<0.001), neither were influenced strongly by age (r=0.138, p=0.168; r=-0.118, p=0237, respectively), but were lower in women than in men (F=12.757, p=0.001). The force required to expel a drop differed between dropper designs (F=22.528, p<0.001), ranging from 6.4 Newtons to 23.4 Newtons. The force needed to exert successive drops increased (F=36.373, p<0.001) and storing droppers in the fridge further increased the force required (F=7.987, p=0.009). CONCLUSIONS: Prostaglandin monotherapy droppers for glaucoma treatment vary in their resistance to extract a drop and with some a drop could not be comfortably achieved by half the population, which may affect compliance and efficacy.

The administration of exogenous prostaglandin may improve ovulation in pacu (Piaractus mesopotamicus)

Based on the reports of unsuccessful ovulation in pacu (Piaractus mesopotamicus) by fish farmers and researchers undertaking artificial reproduction programs, we evaluated the use of prostaglandin F (PGF) to improve pacu ovulation. This study was conducted during two spawning seasons (2009/2010 and 2010/2011) with two samplings in the first season and one sampling in the second season. A total of 45 females was sampled in this study. The control group was injected with carp pituitary extract (crude extract, 6 mg/kg), and the treatment group received PGF (2 mL per fish in the 2009/2010 season and 5 mL per fish in the 2010/2011 season) in addition to the crude extract. In both seasons, 100% (N = 4, 2009/2010 first sampling; N = 5, 2009/2010 second sampling; and N = 3, 2010/2011) of the PGF-treated fish spawned. In contrast, 53.0% (N = 9) and 83.3% (N = 10) of the control fish spawned in the first and second samplings of the 2009/2010 season, respectively, and only 25.0% (N = 1) spawned in the 2010/2011 season. Fecundity, fertility, and hatching rates did not differ (P > 0.05) between the treated and control fish. Based on oocyte volume frequency analysis, ovaries of the control fish had more (P < 0.05) vitellogenic oocytes with germinal vesicle breakdown that remained unovulated after spawning, whereas more (P < 0.05) of previtellogenic oocytes were present in the ovaries of the PGF-treated fish. In conclusion, administration of exogenous prostaglandin may improve the outcome of hormonally induced spawning in tropical migratory fish. (C) 2012 Elsevier B.V. All rights reserved.