<i>Pseudomonas aeruginosa</i>
            sabotages the generation of host proresolving lipid mediators

Flitter, Becca A.; Hvorecny, Kelli L.; Ono, Emiko; Eddens, Taylor; Yang, Jun; Kwak, Daniel H.; Bahl, Christopher D.; Hampton, Thomas H.; Morisseau, Christophe; Hammock, Bruce D.; Liu, Xinyu; Lee, Janet; Kolls, Jay K.; Levy, Bruce D.; Madden, Dean R.; Bomberger, Jennifer M.

doi:10.1073/pnas.1610242114

Cited by 65 publications

(81 citation statements)

References 56 publications

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“…Furthermore, 14, 15-EET could stimulate the production of 15-epi LXA 4 [33], a dual anti-inflammatory and specialized pro-resolving mediator (SPM) that exert an essential role in inhibiting neutrophil activation and restoring homeostasis [13]. Although we did not observe the increase of lipoxins after cupping treatment for 24 hrs, 14, 15-EET significantly reduced IL-6 and TNF-α and in LPS-stimulated macrophages.…”

Section: Discussionmentioning

(Expert classified)

Anti- Versus Pro-Inflammatory Metabololipidome Upon Cupping Treatment

Zhang

Wang

Lei

et al. 2018

Cell Physiol Biochem

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Background/Aims: This study aimed to explore the metabololipidome in mice upon cupping treatment. Methods: A nude mouse model mimicking the cupping treatment in humans was established by administrating four cupping sets on the back skin for 15 minutes. UPLC-MS/ MS was performed to determine the PUFA metabolome in mice skin and blood before and after cupping treatment. The significantly changed lipids were administered in macrophages to assess the production of pro-inflammatory cytokines IL-6 and TNF-α by ELISA. Results: The anti-inflammatory lipids, e.g. PGE₁, 5,6-EET, 14,15-EET, 10S,17S-DiHDoHE, 17R-RvD1, RvD5 and 14S-HDoHE were significantly increased while pro-inflammatory lipids, e.g. 12-HETE and TXB₂ were deceased in the skin or plasma post cupping treatment. Cupping treatment reversed the LPS-stimulated IL-6 and TNF-α expression in mouse peritoneal exudates. Moreover, 5,6-EET, PGE₁ decreased the level of TNF-α, while 5,6-EET, 5,6-DHET downregulated IL-6 production in macrophages. Importantly, 14,15-EET and 14S-HDoHE inhibited both IL-6 and TNF-α induced by lipopolysaccharide (LPS). 17-RvD1, RvD5 and PGE₁ significantly reduced the LPS-initiated TNF-α, while TXB₂ and 12-HETE further upregulated the LPS-enhanced IL-6 and TNF-α expression in macrophages. Conclusion: Our results reveal the identities of anti-inflammatory versus pro-inflammatory metabolipidome and suggest the potential therapeutic mechanism of cupping treatment.

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Section: Discussionmentioning

(Expert classified)

Anti- Versus Pro-Inflammatory Metabololipidome Upon Cupping Treatment

Zhang

Wang

Lei

et al. 2018

Cell Physiol Biochem

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“…In addition to cSO, we also observed significant active-site side-chain shifts for another previously identified substrate, racemic cis -14(15)-epoxy-5Z,8Z,11Z-eicosatrienoic acid (14,15-EET, PDB ID: 5JYC) (Flitter et al, 2016). 14 R ,15 S -EET opens the active site to bulk solvent in two locations, creating a tunnel through the enzyme (Figure 6F).…”

Section: Resultsmentioning

confidence: 67%

“…Through a combination of X-ray structures and specific-activity measurements, we have outlined the substrate preferences for a bacterial epoxide hydrolase that sabotages human signaling networks (Flitter et al, 2016; MacEachran et al, 2007; Swiatecka-Urban, 2005). While the active site is constrained, it also exhibits a surprising degree of localized conformational flexibility that greatly expands the range of substrates it can accommodate.…”

Section: Resultsmentioning

confidence: 99%

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Active-Site Flexibility and Substrate Specificity in a Bacterial Virulence Factor: Crystallographic Snapshots of an Epoxide Hydrolase

et al. 2017

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Summary The CFTR inhibitory factor (Cif) is an epoxide-hydrolase virulence factor from Pseudomonas aeruginosa, with catalytic activity that perturbs essential host-defense networks. Its targets are largely unknown, but include an epoxy-fatty acid. In this class of signaling molecules, chirality can be an important determinant of physiological output and potency. Here we explore the active-site chemistry of this two-step α/β-hydrolase and its implications for an emerging class of virulence enzymes. In combination with hydrolysis data, crystal structures of 15 trapped hydroxyalkyl-enzyme intermediates reveal the stereochemical basis of Cif’s substrate specificity, as well as its regioisomeric and enantiomeric preferences. The structures also reveal distinct sets of conformational changes that enable the active site to expand dramatically in two directions, accommodating a surprising array of potential physiological epoxide targets. These new substrates may contribute to Cif’s diverse effects in vivo, and thus to the success of P. aeruginosa and other pathogens during infection.

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“…The lungs of cystic fibrosis patients with recurrent Pseudomonas aeruginosa infection often represent a chronic hyper-inflammatory environment. Detailed lipid mediator analyses indicate that this pathogen secretes cystic fibrosis transmembrane conductance regulator inhibitory factor (Cif) which hydrolyzes 14,15-epoxyeicosatrienoic acid, thereby inhibiting the production of the proresolving lipid mediator 15-epi lipoxin A4 [38*]. …”

Section: Oxidative Lipidomics In Critical Illness and Related Pathophmentioning

confidence: 99%

Oxidative lipidomics: applications in critical care

Anthonymuthu¹,

Kim‐Campbell

Bayır

2017

Current Opinion in Critical Care

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Purpose of the review Lipid peroxidation has long been established as a key player in the pathophysiology of critical care illnesses. Recent developments in oxidative lipidomics have aided in deciphering the molecular mechanisms of lipid oxidation. This review discusses the achievements and recent developments of oxidative lipidomics and its contribution to the understanding of critical illness. Recent findings Most studies involving acute injury focus on identifying the end products of lipid peroxidation. This misses the early events and targets of peroxidation mechanisms. Recent developments in LC-MS based oxidative lipidomics have enabled the identification of a wide variety of enzymatically generated lipid oxidation products both in clinical as well as animal injury models. Such lipid mediators have been found to play an important role in injury, inflammation, and recovery in disease states such as sepsis or head trauma. Summary Oxidative stress produces multiple lipid oxidation products either through enzymatic pathways or through free radical reactions. These products are often biologically active and can contribute to the regulation of cellular signaling. Oxidative lipidomics has contributed to the understanding of lipid peroxidation products, the mechanism of their production, time course of development after injury, and synergistic functioning with other regulatory processes in the body. These advances in knowledge will help guide the future development of interventions in critical illness.

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Pseudomonas aeruginosa sabotages the generation of host proresolving lipid mediators

Cited by 65 publications

References 56 publications

Anti- Versus Pro-Inflammatory Metabololipidome Upon Cupping Treatment

Anti- Versus Pro-Inflammatory Metabololipidome Upon Cupping Treatment

Active-Site Flexibility and Substrate Specificity in a Bacterial Virulence Factor: Crystallographic Snapshots of an Epoxide Hydrolase

Oxidative lipidomics: applications in critical care

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