Prostaglandin E2 is a potent lipid mediator of inflammation that effects changes in cell functions through ligation of four distinct G protein-coupled receptors (E-prostanoid (EP)1, EP2, EP3, and EP4). During pneumonia, PGE2 production is enhanced. In the present study, we sought to assess the effect of endogenously produced and exogenously added PGE2 on FcRγ-mediated phagocytosis of bacterial pathogens by alveolar macrophages (AMs), which are critical participants in lung innate immunity. We also sought to characterize the EP receptor signaling pathways responsible for these effects. PGE2 (1–1000 nM) dose-dependently suppressed the phagocytosis by rat AMs of IgG-opsonized erythrocytes, immune serum-opsonized Klebsiella pneumoniae, and IgG-opsonized Escherichia coli. Conversely, phagocytosis was stimulated by pretreatment with the cyclooxygenase inhibitor indomethacin. PGE2 suppression of phagocytosis was associated with enhanced intracellular cAMP production. Experiments using both forskolin (adenylate cyclase activator) and rolipram (phosphodiesterase IV inhibitor) confirmed the inhibitory effect of cAMP stimulation. Immunoblot analysis of rat AMs identified expression of only EP2 and EP3 receptors. The selective EP2 agonist butaprost, but neither the EP1/EP3 agonist sulprostone nor the EP4-selective agonist ONO-AE1-329, mimicked the effects of PGE2 on phagocytosis and cAMP stimulation. Additionally, the EP2 antagonist AH-6809 abrogated the inhibitory effects of both PGE2 and butaprost. We confirmed the specificity of our results by showing that AMs from EP2-deficient mice were resistant to the inhibitory effects of PGE2. Our data support a negative regulatory role for PGE2 on the antimicrobial activity of AMs, which has important implications for future efforts to prevent and treat bacterial pneumonia.
Prostaglandin E2 (PGE2) inhibits fibroblast proliferation and collagen synthesis. In this study, we compared lung fibroblasts isolated from patients with idiopathic pulmonary fibrosis (F-IPF) and from patients undergoing resectional surgery for lung cancer (F-nl) with respect to their capacity for PGE2 synthesis and their expression and regulation of cyclooxygenase (COX)
The incidence of asthma has been positively associated with obesity. Asthma comprises diverse ''phenotypes'' reflecting heterogeneity in a number of characteristics, including response to therapy. The present authors examined whether body mass index (BMI) influenced the response to placebo, as well as to two asthma controller medications.A post hoc analysis was performed, pooling data from four double-blind, placebo-controlled studies randomising 3,073 moderate asthmatic adults to montelukast (n51,439), beclomethasone (n5894) or placebo (n5740). The primary end point was asthma control days; other end points were forced expiratory volume in one second, b-agonist use and nocturnal awakening. Analyses were conducted using BMI classification into normal (,25.0 kg?m ; 16%) categories, as well as BMI as a continuous variable.The treatment groups were balanced for BMI, demographic characteristics and parameters of asthma control. The placebo response for all end points was generally lower with increasing BMI. Similarly, the response to the inhaled corticosteroid decreased, whereas the response to the leukotriene antagonist remained stable.In conclusion, post hoc data from the present study suggested that body mass index may influence the natural history of asthma control (as reflected by response to placebo) and may differentially influence response to the two active agents, warranting explicit testing in future prospective studies.
Myofibroblasts, the hallmark of fibrotic disease, contribute to the pathology of fibrosis by secreting large amounts of extracellular matrix and contributing to alveolar contraction. Myofibroblasts are characterized by the expression of alpha-smooth muscle actin (alpha-SMA), a contractile protein normally associated with smooth muscle cells. Transforming growth factor-beta1 (TGF-beta1) is a well characterized profibrotic cytokine that induces myofibroblast transformation both in vitro and in vivo. We report here that the lipid mediator prostaglandin E2 (PGE2) inhibits TGF-beta1-induced expression of alpha-SMA in primary fetal and adult lung fibroblasts. This inhibition of alpha-SMA expression is associated with a reduction in the expression of collagen I. Inhibitory actions of PGE2 are mediated via E prostanoid receptor 2 (EP2) signaling, but not by EP3 signaling, and increases in cyclic adenosine monophosphate production. The inhibitory effects of PGE2 on TGF-beta1-induced alpha-SMA expression are mimicked by an EP2 selective agonist, butaprost, and by forskolin-induced direct activation of adenyl cyclase. An EP2 antagonist blocks the inhibitory effects of PGE2, and an EP3 agonist does not inhibit TGF-beta1-mediated increases in alpha-SMA expression. Our results demonstrate that PGE2 inhibits transition of fibroblasts to myofibroblasts by an EP2 receptor-activated pathway. Augmenting this pathway may serve as a potent antifibrotic therapeutic strategy.
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