Osthol attenuates neutrophilic oxidative stress and hemorrhagic shock-induced lung injury via inhibition of phosphodiesterase 4

Tsai, Yung-Fong; Yu, Huang-Ping; Chung, Pei-Jen; Leu, Yann‐Lii; Kuo, Liang-Mou; Chen, Chun-Yu; Hwang, Tsong‐Long

doi:10.1016/j.freeradbiomed.2015.08.008

Cited by 49 publications

(36 citation statements)

References 55 publications

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“…The PKA inhibitor H89 is unable to abolish the inhibitory effects of GMC on fMLF-induced superoxide anion production and elastase release. FPR1-mediated neutrophil activation increases intracellular cAMP concentrations, thereby reducing respiratory burst and elastase degranulation [20,21]. Agents mediated by PKA signaling, such as PDE4 inhibitors, synergistically increase cAMP levels in fMLFstimulated neutrophils [20,21].…”

Section: Discussionmentioning

confidence: 99%

“…LDH levels are presented as the relative percentage of the total LDH. Total LDH levels were measured by lysing the cells using Triton X-100 (0.1%) [21].…”

Section: Analysis Of the Lactate Dehydrogenase Levelmentioning

confidence: 99%

“…The assay was blocked by the administration of dodecyltrimethylammonium bromide (0.5%). Following centrifugation at 3, 000 × g, the supernatant of the samples was obtained to measure cAMP levels using a commercial enzyme immunoassay kit (Amersham Biosciences, Buckinghamshire, UK) [21].…”

Section: Determination Of Camp Concentrationsmentioning

confidence: 99%

“…Following treatment with DMSO or GMC, fMLF, WKYMVm, or LTB4 were administered to induce calcium mobilization. The peak intracellular calcium concentration ([Ca 2+ ] i ) was calculated by determination of the fluorescence intensity based on the protocol described in our previous study [21].…”

Section: Determination Of Calcium Concentrations In Neutrophilsmentioning

confidence: 99%

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Garcinia Multiflora Inhibits FPR1-Mediated Neutrophil Activation and Protects Against Acute Lung Injury

Tsai

Yang

Chang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Formyl peptide receptors (FPRs) recognize different endogenous and exogenous molecular stimuli and mediate neutrophil activation. Dysregulation of excessive neutrophil activation and the resulting immune responses can induce acute lung injury (ALI) in the host. Accordingly, one promising approach to the treatment of neutrophil-dominated inflammatory diseases involves therapeutic FPR1 inhibition. Methods: We extracted a potent FPR1 antagonist from Garcinia multiflora Champ. (GMC). The inhibitory effects of GMC on superoxide anion release and elastase degranulation from activated human neutrophils were determined with spectrophotometric analysis. Reactive oxygen species (ROS) production and the FPR1 binding ability of neutrophils were assayed by flow cytometry. Signaling transduction mediated by GMC in response to chemoattractants was assessed with a calcium influx assay and western blotting. A lipopolysaccharide (LPS)-induced ALI mouse model was used to determine the therapeutic effects of GMC in vivo. Results: GMC significantly reduced superoxide anion release, the reactive oxidants derived therefrom, and elastase degranulation mediated through selective, competitive FPR1 blocking in N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLF)-stimulated human neutrophils. In cell-free systems, GMC was unable to scavenge superoxide anions or suppress elastase activity. GMC produced a right shift in fMLF-activated concentration-response curves and was confirmed to be a competitive FPR1 antagonist. GMC binds to FPR1 not only in neutrophils, but also FPR1 in neutrophil-like THP-1 and hFPR1-transfected HEK293 cells. Furthermore, the mobilization of calcium and phosphorylation of mitogen-activated protein kinases and Akt, which are involved in FPR1-mediated downstream signaling, was competitively blocked by GMC. In an in vivo study, GMC significantly reduced pulmonary edema, neutrophil infiltration, and alveolar damage in LPS-induced ALI mice. Conclusion: Our findings demonstrate that GMC is a natural competitive FPR1 inhibitor, which makes it a possible anti-inflammatory treatment option for patients critically inflicted with FPR1-mediated neutrophilic lung damage.

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Section: Discussionmentioning

confidence: 99%

“…LDH levels are presented as the relative percentage of the total LDH. Total LDH levels were measured by lysing the cells using Triton X-100 (0.1%) [21].…”

Section: Analysis Of the Lactate Dehydrogenase Levelmentioning

confidence: 99%

Section: Determination Of Camp Concentrationsmentioning

confidence: 99%

Section: Determination Of Calcium Concentrations In Neutrophilsmentioning

confidence: 99%

See 2 more Smart Citations

Garcinia Multiflora Inhibits FPR1-Mediated Neutrophil Activation and Protects Against Acute Lung Injury

Tsai

Yang

Chang

et al. 2018

Cell Physiol Biochem

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“…Dodecyltrimethylammonium bromide (0.5%) was used to hydrolyze cell membranes and release intra-cellular cAMP. Samples were centrifuged at 3000× g for 5 min at 4 °C to acquire cleared supernatants, which were then used to determine cAMP levels according to the manufacturer's instructions [42], [43].…”

Section: Methodsmentioning

confidence: 99%

Ugonin U stimulates NLRP3 inflammasome activation and enhances inflammasome-mediated pathogen clearance

et al. 2017

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The NOD-like receptor pyrin domain 3 (NLRP3) inflammasome contains Nod-like receptors, a subclass of pattern recognition receptors, suggesting that this complex has a prominent role in host defenses. Various structurally diverse stimulators activate the NLRP3 inflammasome through different signaling pathways. We previously reported that ugonin U (UgU), a natural flavonoid isolated from Helminthostachys zeylanica (L) Hook, directly stimulates phospholipase C (PLC) and triggers superoxide release in human neutrophils. In the present study, we showed that UgU induced NLRP3 inflammasome assembly and subsequent caspase-1 and interleukin (IL)-1β processing in lipopolysaccharide-primed human monocytes. Moreover, UgU elicited mitochondrial superoxide generation in a dose-dependent manner, and a specific scavenger of mitochondrial reactive oxygen species (ROS) diminished UgU-induced IL-1β and caspase-1 activation. UgU induced Ca2+ mobilization, which was inhibited by treatment with inhibitors of PLC or inositol triphosphate receptor (IP3R). Blocking Ca2+ mobilization, PLC, or IP3R diminished UgU-induced IL-1β release, caspase-1 activation, and mitochondrial ROS generation. These data demonstrated that UgU activated the NLPR3 inflammasome activation through Ca2+ mobilization and the production of mitochondrial ROS. We also demonstrated that UgU-dependent NLRP3 inflammasome activation enhanced the bactericidal function of human monocytes. The ability of UgU to stimulate human neutrophils and monocytes, both of which are professional phagocytes, and its capacity to activate the NLRP3 inflammasome, which is a promising molecular target for developing anti-infective medicine, indicate that UgU treatment should be considered as a possible novel therapy for treating infectious diseases.

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Pathophysiological effects of intravenous phosphodiesterase type 4 inhibitor in addition to surfactant lavage in meconium‐injured newborn piglet lungs

Chen

Lin

Lee

et al. 2020

Pediatric Pulmonology

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Background Nonsteroidal anti‐inflammatory drugs, such as selective phosphodiesterase type 4 (PDE4) inhibitors have potential anti‐inflammatory and respiratory smooth muscle relaxation effects. This study aimed to investigate the pathophysiological effects of an intravenous PDE4 inhibitor (rolipram) and surfactant lavage (SL) in a newborn piglet model of meconium aspiration syndrome (MAS). Methods MAS was induced in 25 newborn piglets, which were randomly divided into control and four SL treatment groups administered with different doses of intravenous rolipram (0, 0.1, 0.5, and 1 mg/kg). Cardiopulmonary variables were monitored and recorded. The experimental time was 4 hours. Serial blood was drawn for blood gas and biomarker analyses. Lung tissue was examined for histological analysis. Results All SL‐treated groups revealed improved oxygenation during the 4‐hour experiments and had significantly lower peak inspiratory pressure levels than the control group at the end of experiments. All SL plus rolipram‐treated groups exhibited significantly higher lung compliance than the control group. However, the animals receiving high‐dose (0.5 and 1.0 mg/kg) rolipram demonstrated significantly elevated heart rates. Lung histology of the nondependent sites revealed significantly lower lung injury scores in all SL‐treated groups compared with that in the control group, but there were no differences among the rolipram‐treated groups. Conclusions In addition to SL, intravenous PDE4 inhibitors may further improve lung compliance in treating MAS; however, it is necessary to consider cardiovascular adverse effects, primarily tachycardia. Further investigations are required before the clinical application of intravenous PDE4 inhibitor as an anti‐inflammatory agent to treat severe MAS.

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Osthol attenuates neutrophilic oxidative stress and hemorrhagic shock-induced lung injury via inhibition of phosphodiesterase 4

Cited by 49 publications

References 55 publications

Garcinia Multiflora Inhibits FPR1-Mediated Neutrophil Activation and Protects Against Acute Lung Injury

Garcinia Multiflora Inhibits FPR1-Mediated Neutrophil Activation and Protects Against Acute Lung Injury

Ugonin U stimulates NLRP3 inflammasome activation and enhances inflammasome-mediated pathogen clearance

Pathophysiological effects of intravenous phosphodiesterase type 4 inhibitor in addition to surfactant lavage in meconium‐injured newborn piglet lungs

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