Biasing the lipoxin A
            <sub>4</sub>
            /formyl peptide receptor 2 pushes inflammatory resolution

Filep, János G.

doi:10.1073/pnas.1317798110

Cited by 49 publications

(58 citation statements)

References 20 publications

(23 reference statements)

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“…In response to lung inflammation, airway epithelial cells 15-LOX-derived 15S-hydroxyeicosatetraenoic acid can be transformed by neutrophil 5-LOX to an unstable epoxytetraene intermediate that is converted by enzymatic hydrolysis to LXA 4 and LXB 4 (15). LXA 4 binds specifically and reversibly to ALX/FPR2, a G protein-coupled receptor, with a K d of ∼0.5 nM (15,28,29). In the present study, we found that both human MSCs and human AT II cells express biosynthetic enzymes and receptors for LXA 4 We have previously reported that clinical-grade human MSCs restored alveolar fluid clearance to a normal level and decreased inflammation in ex vivo human lungs injured with live E. coli bacteria (5).…”

Section: Discussionmentioning

confidence: 99%

Human Mesenchymal Stem (Stromal) Cells Promote the Resolution of Acute Lung Injury in Part through Lipoxin A4

Fang

Abbott

Cheng

et al. 2015

The Journal of Immunology

137

123

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Previous studies demonstrated that bone marrow–derived mesenchymal stem (stromal) cells (MSCs) reduce the severity of acute lung injury in animal models and in an ex vivo perfused human lung model. However, the mechanisms by which MSCs reduce lung injury are not well understood. In the present study, we tested the hypothesis that human MSCs promote the resolution of acute lung injury in part through the effects of a specialized proresolving mediator lipoxin A4 (LXA4). Human alveolar epithelial type II cells and MSCs expressed biosynthetic enzymes and receptors for LXA4. Coculture of human MSCs with alveolar epithelial type II cells in the presence of cytomix significantly increased the production of LXA4 by 117%. The adoptive transfer of MSCs after the onset of LPS-induced acute lung injury (ALI) in mice led to improved survival (48 h), and blocking the LXA4 receptor with WRW4, a LXA4 receptor antagonist, significantly reversed the protective effect of MSCs on both survival and the accumulation of pulmonary edema. LXA4 alone improved survival in mice, and it also significantly decreased the production of TNF-α and MIP-2 in bronchoalveolar lavage fluid. In summary, these experiments demonstrated two novel findings: human MSCs promote the resolution of lung injury in mice in part through the proresolving lipid mediator LXA4, and LXA4 itself should be considered as a therapeutic for acute respiratory distress syndrome.

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Section: Discussionmentioning

confidence: 99%

Human Mesenchymal Stem (Stromal) Cells Promote the Resolution of Acute Lung Injury in Part through Lipoxin A4

Fang

Abbott

Cheng

et al. 2015

The Journal of Immunology

137

123

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“…Analyses of cell behavior indicated, besides defective recruitment, a direct impairment of phagocyte functions in Fpr2/3 −/− neutrophils. Although not in these settings, studies have demonstrated the importance of AnxA1, LXA 4 , and more recently resolvin D 1 in promoting particle phagocytosis and efferocytosis by immune cells (17,33,34) together with ineffectiveness in cells lacking Fpr2/3 (35).…”

Section: Discussionmentioning

confidence: 99%

Nonredundant protective properties of FPR2/ALX in polymicrobial murine sepsis

Gobbetti

Coldewey

Chen

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

106

104

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Significance Sepsis defines a syndrome with poor clinical management characterized by overlapping phases of excessive inflammation temporally aligned with an immunosuppressed state. We define an endogenous pathway centered on formyl-peptide receptor 2/3 (Fpr2/3)—ortholog to human FPR2/ALX (receptor for lipoxin A4)—that protects the host against polymicrobial sepsis. Using null mice and proof-of-concept experiments with a peptide–agonist, we demonstrate how engagement of Fpr2/3 is crucial to enact nonredundant functions that span from control of cell recruitment and phagocytosis, modulation of soluble mediator generation, to containment of bacteremia, thus preventing spreading to vital organs and opening new opportunities to manipulate the host response in sepsis.

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“…Moreover, constitutive dimerization of the FPR system was shown to be ligand-dependent, indicating that agonist binding and its dimerization state contribute to the signaling signature of this system. 80 These unique findings bring a better understanding on the complexity of the FPR2/ALXR signaling and provide a better basis for the development of novel therapeutic approaches, 81 (Figure 4) from human leukocytes as a product originating from AA via the lipoxygenase pathway ( Figure 2). 82 The term lipoxin was proposed since these trihydroxytetraenes arise from the interactions of multiple distinct lipoxygenase pathways 83 shown to occur via trans-cellular and cell−cell interactions (reviewed in ref 24).…”

Section: Fpr2/alxr As a Target For The Roimentioning

confidence: 99%

FPR2/ALXR Agonists and the Resolution of Inflammation

2014

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The resolution of inflammation (RoI), once believed to be a passive process, has lately been shown to be an active and delicately orchestrated process. During the resolution phase of acute inflammation, novel mediators, including lipoxins and resolvins, which are members of the specialized pro-resolving mediators of inflammation, are produced. FPR2/ALXR, a receptor modulated by some of these lipids as well as by peptides (e.g., annexin A1), has been shown to be one of the receptors involved in the RoI. The aim of this perspective is to present the concept of the RoI from a medicinal chemistry point of view and to highlight the effort of the research community to discover and develop antiinflammatory/pro-resolution small molecules to orchestrate inflammation by activation of FPR2/ALXR.

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Biasing the lipoxin A ₄ /formyl peptide receptor 2 pushes inflammatory resolution

Cited by 49 publications

References 20 publications

Human Mesenchymal Stem (Stromal) Cells Promote the Resolution of Acute Lung Injury in Part through Lipoxin A4

Human Mesenchymal Stem (Stromal) Cells Promote the Resolution of Acute Lung Injury in Part through Lipoxin A4

Nonredundant protective properties of FPR2/ALX in polymicrobial murine sepsis

FPR2/ALXR Agonists and the Resolution of Inflammation

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Biasing the lipoxin A 4 /formyl peptide receptor 2 pushes inflammatory resolution

Cited by 49 publications

References 20 publications

Human Mesenchymal Stem (Stromal) Cells Promote the Resolution of Acute Lung Injury in Part through Lipoxin A4

Human Mesenchymal Stem (Stromal) Cells Promote the Resolution of Acute Lung Injury in Part through Lipoxin A4

Nonredundant protective properties of FPR2/ALX in polymicrobial murine sepsis

FPR2/ALXR Agonists and the Resolution of Inflammation

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Product

Resources

About

Biasing the lipoxin A ₄ /formyl peptide receptor 2 pushes inflammatory resolution