Acute respiratory inflammation, most commonly resulting from bacterial or viral infection, is one of the leading causes of death and disability worldwide. The inflammatory lipid mediator ...prostaglandin D2 (PGD2) and its rate-limiting enzyme, hematopoietic PGD synthase (hPGDS), are well-known drivers of allergic pulmonary inflammation. Here, we sought to investigate the source and role of hPGDS-derived PGD2 in acute pulmonary inflammation. Murine bronchoalveolar monocytes/macrophages from LPS- but not OVA-induced lung inflammation released significant amounts of PGD2. Accordingly, human monocyte-derived macrophages expressed high basal levels of hPGDS and released significant levels of PGD2 after LPS/IFN-γ, but not IL-4 stimulation. Human peripheral blood monocytes secreted significantly more PGD2 than monocyte-derived macrophages. Using human precision-cut lung slices (PCLS), we observed that LPS/IFN-γ but not IL-4/IL-13 drive PGD2 production in the lung. HPGDS inhibition prevented LPS-induced PGD2 release by human monocyte-derived macrophages and PCLS. As a result of hPGDS inhibition, less TNF-α, IL-6 and IL-10 could be determined in PCLS-conditioned medium. Collectively, this dataset reflects the time-dependent release of PGD2 by human phagocytes, highlights the importance of monocytes and macrophages as PGD2 sources and suggests that hPGDS inhibition might be a potential therapeutic option for acute, non-allergic lung inflammation.
Abstract Endothelial dysfunction is a hallmark of inflammatory conditions. We recently demonstrated that prostaglandin (PG)E2 enhances the resistance of pulmonary endothelium in vitro and counteracts ...lipopolysaccharide (LPS)-induced pulmonary inflammation in vivo via EP4 receptors. The aim of this study was to investigate the role of the EP1/EP3 receptor agonist 17-phenyl-trinor-(pt)-PGE2 on acute lung inflammation in a mouse model. In LPS-induced pulmonary inflammation in mice, 17-pt-PGE2 reduced neutrophil infiltration and inhibited vascular leakage. These effects were unaltered by an EP1 antagonist, but reversed by EP4 receptor antagonists. 17-pt-PGE2 increased the resistance of pulmonary microvascular endothelial cells and prevented thrombin-induced disruption of endothelial junctions. Again, these effects were not mediated via EP1 or EP3 but through activation of the EP4 receptor, as demonstrated by the lack of effect of more selective EP1 and EP3 receptor agonists, prevention of these effects by EP4 antagonists and EP4 receptor knock-down by siRNA. In contrast, the aggregation enhancing effect of 17-pt-PGE2 in human platelets was mediated via EP3 receptors. Our results demonstrate that 17-pt-PGE2 enhances the endothelial barrier in vitro on pulmonary microvascular endothelial cells, and accordingly ameliorates the recruitment of neutrophils, via EP4 receptors in vivo. This suggests a beneficial effect of 17-pt-PGE2 on pulmonary inflammatory diseases.
Idiopathic pulmonary fibrosis (IPF) is a disease with high 5-year mortality and few therapeutic options. Prostaglandin (PG) E2 exhibits antifibrotic properties and is reduced in bronchoalveolar ...lavage from patients with IPF. 15-Prostaglandin dehydrogenase (15-PGDH) is the key enzyme in PGE2 metabolism under the control of TGF-β and microRNA 218.
We sought to investigate the expression of 15-PGDH in IPF and the therapeutic potential of a specific inhibitor of this enzyme in a mouse model and human tissue.
In vitro studies, including fibrocyte differentiation, regulation of 15-PGDH, RT-PCR, and Western blot, were performed using peripheral blood from healthy donors and patients with IPF and A549 cells. Immunohistochemistry, immunofluorescence, 15-PGDH activity assays, and in situ hybridization as well as ex vivo IPF tissue culture experiments were done using healthy donor and IPF lungs. Therapeutic effects of 15-PGDH inhibition were studied in the bleomycin mouse model of pulmonary fibrosis.
We demonstrate that 15-PGDH shows areas of increased expression in patients with IPF. Inhibition of this enzyme increases PGE2 levels and reduces collagen production in IPF precision cut lung slices and in the bleomycin model. Inhibitor-treated mice show amelioration of lung function, decreased alveolar epithelial cell apoptosis, and fibroblast proliferation. Pulmonary fibrocyte accumulation is also decreased by inhibitor treatment in mice, similar to PGE2 that inhibits fibrocyte differentiation from blood of healthy donors and patients with IPF. Finally, microRNA 218-5p, which is downregulated in patients with IPF, suppressed 15-PGDH expression in vivo and in vitro.
These findings highlight the role of 15-PGDH in IPF and suggest 15-PGDH inhibition as a promising therapeutic approach.
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Endothelial dysfunction is a hallmark of inflammatory conditions. We recently demonstrated that prostaglandin (PG)E2 enhances the resistance of pulmonary endothelium in vitro and counteracts ...lipopolysaccharide (LPS)-induced pulmonary inflammation in vivo via EP4 receptors. The aim of this study was to investigate the role of the EP1/EP3 receptor agonist 17-phenyl-trinor-(pt)-PGE2 on acute lung inflammation in a mouse model. In LPS-induced pulmonary inflammation in mice, 17-pt-PGE2 reduced neutrophil infiltration and inhibited vascular leakage. These effects were unaltered by an EP1 antagonist, but reversed by EP4 receptor antagonists. 17-pt-PGE2 increased the resistance of pulmonary microvascular endothelial cells and prevented thrombin-induced disruption of endothelial junctions. Again, these effects were not mediated via EP1 or EP3 but through activation of the EP4 receptor, as demonstrated by the lack of effect of more selective EP1 and EP3 receptor agonists, prevention of these effects by EP4 antagonists and EP4 receptor knock-down by siRNA. In contrast, the aggregation enhancing effect of 17-pt-PGE2 in human platelets was mediated via EP3 receptors. Our results demonstrate that 17-pt-PGE2 enhances the endothelial barrier in vitro on pulmonary microvascular endothelial cells, and accordingly ameliorates the recruitment of neutrophils, via EP4 receptors in vivo. This suggests a beneficial effect of 17-pt-PGE2 on pulmonary inflammatory diseases.
Acute respiratory inflammation, most commonly resulting from bacterial or viral infection, is one of the leading causes of death and disability worldwide. The inflammatory lipid mediator ...prostaglandin D
(PGD
) and its rate-limiting enzyme, hematopoietic PGD synthase (hPGDS), are well-known drivers of allergic pulmonary inflammation. Here, we sought to investigate the source and role of hPGDS-derived PGD
in acute pulmonary inflammation. Murine bronchoalveolar monocytes/macrophages from LPS- but not OVA-induced lung inflammation released significant amounts of PGD
. Accordingly, human monocyte-derived macrophages expressed high basal levels of hPGDS and released significant levels of PGD
after LPS/IFN-γ, but not IL-4 stimulation. Human peripheral blood monocytes secreted significantly more PGD
than monocyte-derived macrophages. Using human precision-cut lung slices (PCLS), we observed that LPS/IFN-γ but not IL-4/IL-13 drive PGD
production in the lung. HPGDS inhibition prevented LPS-induced PGD
release by human monocyte-derived macrophages and PCLS. As a result of hPGDS inhibition, less TNF-α, IL-6 and IL-10 could be determined in PCLS-conditioned medium. Collectively, this dataset reflects the time-dependent release of PGD
by human phagocytes, highlights the importance of monocytes and macrophages as PGD
sources and suggests that hPGDS inhibition might be a potential therapeutic option for acute, non-allergic lung inflammation.
Histamine is known to cause edema and excitation of small-diameter primary afferent neurons. In the present study we wanted to investigate to which extent afferent neurons participate in ...histamine-induced edema and, subsequently, determine possible inhibitory effects of a tachykinin NK
1 receptor and CGRP receptor antagonist on the histamine response. Intraplantar injection of histamine (0.5 μmol) into the rat hind paw caused a 34% increase of paw volume. In capsaicin-denervated rats, this effect of histamine was nearly abolished. The calcitonin gene-related peptide (CGRP) receptor antagonist CGRP-(8-37), but not the tachykinin NK
1 receptor antagonist SR140333, caused significant inhibition of the edema response. Further indication that CGRP can promote the histamine action was obtained in capsaicin-denervated rats, where co-injection of CGRP (0.3 pmol) increased the edema response to intraplantar histamine. In additional experiments, plasma protein extravasation in the paw skin was evaluated after close arterial infusion of histamine. Also in these experiments CGRP-(8-37), but not SR140333, significantly reduced the histamine effect. The observation that in the rat hind paw a CGRP receptor antagonist, but not a tachykinin NK
1 receptor antagonist, attenuates histamine-induced vascular leakage raises the possibility that in some tissues CGRP receptor antagonists may be superior to tachykinin NK
1 receptor antagonists in reducing histamine-induced neurogenic inflammatory responses.
Intraplantar injection of mouse β (2.5S) nerve growth factor (NGF) caused thermal hyperalgesia and stimulated release of immunoreactive leukotriene B
4 from the rat paw skin. Both effects of NGF were ...prevented by the 5-lipoxygenase inhibitor, (
R)-2-4-quinolin-2-yl-methoxy)phenyl-2-cyclopentyl acetic acid (BAY X1005). BAY X1005 did not affect bradykinin-induced thermal hyperalgesia. These results suggest the participation of 5-lipoxygenase products of arachidonate in NGF-induced local thermal hyperalgesia.
Endothelial dysfunction is a hallmark of inflammatory conditions. We recently demonstrated that prostaglandin (PG)E
enhances the resistance of pulmonary endothelium in vitro and counteracts ...lipopolysaccharide (LPS)-induced pulmonary inflammation in vivo via EP4 receptors. The aim of this study was to investigate the role of the EP1/EP3 receptor agonist 17-phenyl-trinor-(pt)-PGE
on acute lung inflammation in a mouse model. In LPS-induced pulmonary inflammation in mice, 17-pt-PGE
reduced neutrophil infiltration and inhibited vascular leakage. These effects were unaltered by an EP1 antagonist, but reversed by EP4 receptor antagonists. 17-pt-PGE
increased the resistance of pulmonary microvascular endothelial cells and prevented thrombin-induced disruption of endothelial junctions. Again, these effects were not mediated via EP1 or EP3 but through activation of the EP4 receptor, as demonstrated by the lack of effect of more selective EP1 and EP3 receptor agonists, prevention of these effects by EP4 antagonists and EP4 receptor knock-down by siRNA. In contrast, the aggregation enhancing effect of 17-pt-PGE
in human platelets was mediated via EP3 receptors. Our results demonstrate that 17-pt-PGE
enhances the endothelial barrier in vitro on pulmonary microvascular endothelial cells, and accordingly ameliorates the recruitment of neutrophils, via EP4 receptors in vivo. This suggests a beneficial effect of 17-pt-PGE
on pulmonary inflammatory diseases.
Injection of carrageenan (1 mg) into the rat hind paw caused a time-dependent increase in paw volume that was maximal 3 h after injection. At this time, the concentration of nerve growth factor (NGF) ...in the skin of the inflamed paw was more than twofold higher than in the contralateral, non-inflamed paw. Treatment of rats with indomethacin reduced inflammatory oedema by 57%, morphine treatment attenuated oedema by 62%. While indomethacin had no statistically significant effect on the concentration of NGF in the skin of inflamed paws, morphine attenuated the NGF response by 24.2% in a naloxone reversible manner. These data suggest that drug-induced inhibition of inflammatory oedema is not predictive of its effect on an inflammation-induced rise in tissue NGF. Furthermore, our results confirm and extend previous observations suggesting an anti-inflammatory activity of morphine.
Hyperpolarized
C-MRI is an emerging tool for probing tissue metabolism by measuring
C-label exchange between intravenously injected hyperpolarized 1-
Cpyruvate and endogenous tissue lactate. Here, we ...demonstrate that hyperpolarized
C-MRI can be used to detect early response to neoadjuvant therapy in breast cancer. Seven patients underwent multiparametric
H-MRI and hyperpolarized
C-MRI before and 7-11 days after commencing treatment. An increase in the lactate-to-pyruvate ratio of approximately 20% identified three patients who, following 5-6 cycles of treatment, showed pathological complete response. This ratio correlated with gene expression of the pyruvate transporter
and lactate dehydrogenase A (
), the enzyme catalyzing label exchange between pyruvate and lactate. Analysis of approximately 2,000 breast tumors showed that overexpression of
and the hypoxia marker
was associated with reduced relapse-free and overall survival. Hyperpolarized
C-MRI represents a promising method for monitoring very early treatment response in breast cancer and has demonstrated prognostic potential. SIGNIFICANCE: Hyperpolarized carbon-13 MRI allows response assessment in patients with breast cancer after 7-11 days of neoadjuvant chemotherapy and outperformed state-of-the-art and research quantitative proton MRI techniques.
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