Identification Of Triptolide, A Natural Diterpenoid Compound, As An Inhibitor Of Lung Inflammation

Hoyle, Gary W.; Hoyle, Christine I.; Chen, Jing; Chang, Weiyuan; Rt, Williams; Rando, Roy J.

doi:10.1164/ajrccm-conference.2010.181.1_meetingabstracts.a1370

Cited by 11 publications

(15 citation statements)

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“…Ascorbate may also have a role in down-regulating hypoxia-inducible transcription factor (HIF)-1a protein levels (35). Ascorbate inhibits endothelial cell nicotinamide adenine dinucleotide phosphatereduced oxidase (36), and decreases the lipid peroxidation that leads to the initiation of local and systemic inflammation (37)(38)(39). Deferoxamine alone is used clinically in chronic iron overload (37) and as an antidote in acute iron poisoning (40), and it was found to decrease protein tyrosine nitration (41).…”

Section: Discussionmentioning

confidence: 99%

Post-Exposure Antioxidant Treatment in Rats Decreases Airway Hyperplasia and Hyperreactivity Due to Chlorine Inhalation

Fanucchi¹,

Bracher

Doran

et al. 2012

Am J Respir Cell Mol Biol

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We assessed the safety and efficacy of combined intravenous and aerosolized antioxidant administration to attenuate chlorine gasinduced airway alterations when administered after exposure. Adult male Sprague-Dawley rats were exposed to air or 400 parts per million (ppm) chlorine (a concentration likely to be encountered in the vicinity of industrial accidents) in environmental chambers for 30 minutes, and returned to room air, and they then received a single intravenous injection of ascorbic acid and deferoxamine or saline. At 1 hour and 15 hours after chlorine exposure, the rats were treated with aerosolized ascorbate and deferoxamine or vehicle. Lung antioxidant profiles, plasma ascorbate concentrations, airway morphology, and airway reactivity were evaluated at 24 hours and 7 days after chlorine exposure. At 24 hours after exposure, chlorine-exposed rats had significantly lower pulmonary ascorbate and reduced glutathione concentrations. Treatment with antioxidants restored depleted ascorbate in lungs and plasma. At 7 days after exposure, in chlorineexposed, vehicle-treated rats, the thickness of the proximal airways was 60% greater than in control rats, with twice the amount of mucosubstances. Airway resistance in response to methacholine challenge was also significantly elevated. Combined treatment with intravenous and aerosolized antioxidants restored airway morphology, the amount of airway mucosubstances, and airway reactivity to control levels by 7 days after chlorine exposure. Our results demonstrate for the first time, to the best of our knowledge, that severe injury to major airways in rats exposed to chlorine, as characterized by epithelial hyperplasia, mucus accumulation, and airway hyperreactivity, can be reversed in a safe and efficacious manner by the postexposure administration of ascorbate and deferoxamine.Keywords: epithelial injury; epithelial repair; mucosubstances; ascorbate; deferoxamine; aerosol Chlorine is essential to global industry and to global public health. According to the World Chlorine Council (http://www. worldchlorine.org), 14.4 million metric tons were produced in North America in 2008, and 62.8 million metric tons were produced globally. Water treatment makes up only 5% of the world's use of chlorine. The majority of chlorine is used in the production of plastics such as polyvinyl chloride (1). It is also used as a bleaching agent for pulp and paper production, as feedstock in the production of chlorinated solvents used in metalworking, in dry cleaning, in electronics, and in pharmaceutical production (1-6).Only 20 American states contain facilities that produce chlorine, but every American state has facilities that use chlorine. This results in the shipping of chlorine by railcar, and increases the potential for large-scale accidents. According to the Environmental Protection Agency, chlorine gas was related to 518 serious accidents over a 5-year period during the 1990s (1). Multiple-casualty exposures to chlorine have resulted from industrial accidents involving chlorine ta...

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Section: Discussionmentioning

confidence: 99%

Post-Exposure Antioxidant Treatment in Rats Decreases Airway Hyperplasia and Hyperreactivity Due to Chlorine Inhalation

Fanucchi¹,

Bracher

Doran

et al. 2012

Am J Respir Cell Mol Biol

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“…T. wilfordii contains >100 bioactive compounds and triptolide is one of the major biologically active components. In vivo and in vitro experiments have demonstrated that triptolide has a role in numerous immune disorders, including multiple sclerosis, colitis, lupus nephritis and transplant rejection (6,15,16). The anti-inflammatory activity of triptolide not only activates immune cells, such as T cells and monocytes, Anti-inflammatory effects of triptolide by inhibiting the NF-κB signalling pathway in LPS-induced acute lung injury in a murine model but also resident tissue cells (17,18).…”

Section: Introductionmentioning

confidence: 99%

Anti-inflammatory effects of triptolide by inhibiting the NF-κB signalling pathway in LPS-induced acute lung injury in a murine model

Xian

Zhang

Duan

et al. 2014

Molecular Medicine Reports

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Abstract.Triptolide is one of the main active components in the Chinese herb Tripterygium wilfordii Hook F, which has been demonstrated to possess anti-inflammatory properties. The aim of this study was to investigate the effects of triptolide on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice and to explore the possible mechanisms. Mice were administered LPS intranasally to induce lung injury, and triptolide was administered intraperitoneally 1 h prior to the LPS challenge. Triptolide-treated mice exhibited significantly reduced levels of leukocytes, myeloperoxidase activity and edema of the lung, as well as tumour necrosis factor-α, interleukin (IL)-1β and IL-6 production in the bronchoalveolar lavage fluid compared with LPS-treated mice. Additionally, western blot analysis showed that triptolide inhibited the LPS-induced phosphorylation of nuclear factor of κ light polypeptide gene enhancer in B cells inhibitor-α and nuclear factor κ-light-chain-enhancer of activated B cells-p65 (NF-κB p65) and the expression of Toll-like receptor 4 (TLR4). In conclusion, the results from the present study suggest that the anti-inflammatory effect of triptolide against LPS-induced ALI may be due to its ability to inhibit the TLR4-mediated NF-κB signalling pathway. Triptolide may therefore be a promising potential therapeutic agent for ALI treatment, which may ultimately aid the clinical therapy for patients with ALI.

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“…A natural diterpenoid from Tripterygium wilfordii Hook F, triptolide (19), inhibited NF-κB activation of PAR2 (IC 50 14 nM) by 2f-LIGRLO-NH 2 (10 μM) in A549/NF-κB-luc cells, 195 but it was not selective and also inhibited substance P induced, neurokinin receptor 1 (NK1) mediated production of IL-8 (IC 50 23 nM, A549/Tacr1 cells). 195 This compound 19 was reported to be toxic after oral administration to rats.…”

Section: ■ Par2 Antagonistsmentioning

confidence: 99%

“…195 This compound 19 was reported to be toxic after oral administration to rats. 196 The morpholine 20 (IC 50 57 μM,iCa 2+ , HT29 cells), spiroindane 21 (GB83, IC 50 2 μM) and spiroindene 22 (GB88, IC 50 1 μM) compounds were derived from the nonpeptidic PAR2 agonist 16 ( Figure 4).…”

Section: ■ Par2 Antagonistsmentioning

confidence: 99%

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Novel agonists & antagonists for protease-activated receptor 2 and C3a receptor

Yau¹

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About 30-40% of all drugs currently in the market place target G-protein coupled receptors, however of the 900 plus GPCRs predicted to exist only about 30 are targeted by approved drugs. Two novel human GPCRs were investigated in this thesis, namely protease-activated receptor 2 (PAR2) and C3a receptor (C3aR). These membranebound receptors are implicated in a variety of diseases in which inflammation is a common component, making them attractive targets for drugs that can treat such disorders. This thesis describes the rational design, synthesis and in vitro assay of ligands targeting these two GPCRs and they will become useful probes for investigating the pathology of inflammatory disorders and may lead to possible future treatments.Chapter 1 of this thesis summarises peptidic and non-peptidic ligands for proteaseactivated receptor and C3a receptor reported in the literature to date, together with their known physiological effects.Chapter 2 examines structure-activity relationships for analogues of the only known potent PAR2 antagonist (GB88) discovered at IMB. The chemical features of GB88 were investigated separately by dividing the molecule into fragments, which were independently varied to study the effect of structure on agonist/antagonist function of the ligands. A potent and selective PAR2 agonist (132) was developed with EC 50 of 0.4 µM in calcium release assays on HT29 cells. Agonist 132 has comparable agonist potency and better ligand efficiency to 2f-LIGRLO-NH 2 , which was previously the most potent PAR2 agonist prior to these studies. In addition, a new PAR2 antagonist was developed (167), which was 2-fold more potent than GB88 in the calcium mobilisation assay.Chapter 3 describes the non-peptidic PAR2 agonist (GB110) and SAR studies for the truncation of this compound that led to the development of new PAR2 antagonists (192, 209, 211, 212). These ligands inhibited the activation of PAR2 induced by 1 µM 2f-LIGRLO-NH 2 with IC 50 0.4-0.6 µM in the calcium release assay.Chapter 4 evaluates the anti-inflammatory properties of newly developed PAR2antagonists (133, 159, 167, 192 -from Chapters 2 & 3) in both in vivo and in vitro experiments. The most potent PAR2 antagonists (167 and 192) were stable in rat plasma and rat liver homogenates and were able to inhibit PAR2 activation induced by peptide agonist 2f-LIGRLO-NH 2 as well as the endogenous activator, trypsin. These iv antagonists have been demonstrated to be anti-inflammatory agents, inhibiting proinflammatory cytokine release (IL6 and TNF-α) and were effective in relieving joint inflammation in rat models of arthritis.Chapter 5 explores various aromatic heterocycles that confer a turn conformation to ligands and this mimics the turn conformation observed for the C-terminus of C3a in its crystal structure. The study investigates how the hydrogen bonding capabilities of heteroatoms in each heterocycle affect the binding and functions of the ligands.Increasing the hydrogen bond acceptor properties of the heterocycle improves binding affinity...

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Identification Of Triptolide, A Natural Diterpenoid Compound, As An Inhibitor Of Lung Inflammation

Cited by 11 publications

References 0 publications

Post-Exposure Antioxidant Treatment in Rats Decreases Airway Hyperplasia and Hyperreactivity Due to Chlorine Inhalation

Post-Exposure Antioxidant Treatment in Rats Decreases Airway Hyperplasia and Hyperreactivity Due to Chlorine Inhalation

Anti-inflammatory effects of triptolide by inhibiting the NF-κB signalling pathway in LPS-induced acute lung injury in a murine model

Novel agonists & antagonists for protease-activated receptor 2 and C3a receptor

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