Resolution of Acute Inflammation in the Lung

Levy, Bruce D.; Serhan, Charles N.

doi:10.1146/annurev-physiol-021113-170408

Cited by 253 publications

(240 citation statements)

References 148 publications

Supporting

Mentioning

236

Contrasting

Unclassified

Order By: Relevance

“…These results have important clinical implications for patients with ARDS including transfused, critically ill patients. Platelet depletion is impractical, as is aspirin therapy in many critically ill patients, but treatment with ATL, or perhaps other anti-inflammatory and proresolving mediators, 44 is an attractive approach. Further, the measurement of LPA in patients with ARDS and other critical illnesses could be a useful biomarker of inflammation and could be measured serially to assess therapeutic responses to treatment with pro-resolving lipid mediators.…”

Section: Discussionmentioning

confidence: 99%

Aspirin-triggered 15-epi-lipoxin A4 regulates neutrophil-platelet aggregation and attenuates acute lung injury in mice

Ortiz-Muñoz

Mallavia

Bins

et al. 2014

Blood

168

176

View full text Add to dashboard Cite

• Neutrophil-platelet aggregates are dynamically formed in the lung in response to injury and are regulated by aspirin-triggered lipoxin.• The therapeutic effect of aspirin in acute lung injury is in large part mediated by the production of pro-resolving lipid mediators.Evidence is emerging that platelets are major contributors to innate immune responses in conditions such as acute lung injury (ALI). Platelets form heterotypic aggregates with neutrophils, and we hypothesized that lipoxin mediators regulate formation of neutrophilplatelet aggregates (NPA) and that NPA significantly contribute to ALI. Lipopolysaccharide (LPS)-induced lung injury was accompanied by platelet sequestration, activation, intra-alveolar accumulation, and NPA formation within both blood and alveolar compartments. Using lung intravital microscopy, we observed the dynamic formation of NPA during physiologic conditions, which sharply increased with ALI. Aspirin (ASA) treatment significantly reduced lung platelet sequestration and activation, NPA formation, and lung injury. ASA treatment increased levels of ASA-triggered lipoxin (ATL; 15-epi-lipoxin A 4 ), and blocking the lipoxin A 4 receptor (ALX) with a peptide antagonist (Boc2) or using ALX knockouts (Fpr2/3 2/2 ) reversed this protection. LPS increased NPA formation in vitro, which was reduced by ATL, and engagement of ALX by ATL on both neutrophils and platelets was necessary to prevent aggregation. In a model of transfusion-related acute lung injury (TRALI), Boc2 also reversed ASA protection, and treatment with ATL in both LPS and TRALI models protected from ALI. We conclude that ATL regulates neutrophil-platelet aggregation and that platelet-neutrophil interactions are a therapeutic target in lung injury. (Blood. 2014;124(17):2625-2634

show abstract

Section: Discussionmentioning

confidence: 99%

Aspirin-triggered 15-epi-lipoxin A4 regulates neutrophil-platelet aggregation and attenuates acute lung injury in mice

Ortiz-Muñoz

Mallavia

Bins

et al. 2014

Blood

168

176

View full text Add to dashboard Cite

show abstract

“…Biosynthesis of LXA 4 has been established at sites of lung inflammation in the upper and lower airways and the vasculature (26,27). 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).…”

Section: Discussionmentioning

confidence: 99%

“…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%

“…Recent findings indicate that resolution is not merely a passive termination of inflammation, but rather an active biochemical and metabolic process (14). Several mediators, pathways, and molecular systems contribute to altered alveolar endothelial and epithelial permeability (15). Among these, lipoxins were the first lipid mediators recognized to have dual anti-inflammatory and proresolution activities (14,16).…”

mentioning

confidence: 99%

“…Lipoxins are biosynthesized by the sequential actions of lipoxygenases and other enzymes to produce bioactive trihydroxytetraenes, structures that are found in all eicosanoids of this class. In humans, initial oxidation of arachidonic acid via 15-lipoxygenase and then by 5-lipoxygenase is one route of lipoxin biosynthesis that has been observed in mucosal tissues such as the respiratory tract, gastrointestinal tract, and oral cavity that results from the interactions between epithelial cells and leukocytes (15). A role for lipoxin A 4 (LXA 4 ) in alveolar epithelial cells and ALI is still not fully understood, although previous studies suggested that aspirin-triggered 15-epi-LXA 4 induces apoptosis in neutrophils in situ and facilitates resolution of myeloperoxidase-sustained neutrophil-dependent pulmonary inflammation (17).…”

mentioning

confidence: 99%

See 2 more Smart Citations

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

Self Cite

137

123

View full text Add to dashboard Cite

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.

show abstract

A Dual‐Action Molecule Suppresses S. aureus Infection as an Inhibitor Targeting Hla Pore Formation and TLR2 Signaling

Wang

Jiang

et al. 2022

Advanced Biology

View full text Add to dashboard Cite

including pneumonia, sepsis and meningitis, and other chronic infections. [1] Novel antibiotics are the most favorable choice, however, the lack of innovative antibiotic development coupled with the frequent emergence of resistant strains may send us back to a preantibiotic era. Increasing evidence suggests that the excessive use of broad-spectrum antibiotics is associated with the risk of many metabolic and inflammatory diseases and some potential diseases related to the disruption of microbiota. [2][3] The rising prevalence of multidrug-resistant and highly virulent strains increases the urgent need for new therapies independent of antibacterial activity.S. aureus produces diverse exotoxins to facilitate its colonization and spreading during infection, and one of the most well-characterized exotoxins is Hla, a typical β-barrel pore-forming cytotoxin expressed by almost all clinical isolates. [4] Hla plays indispensable role in the pathogenesis of invasive infections, phagosome escape, and partially the triggering of the immune response. [5] Hla-induced activation of a disintegrin and metalloproteinase 10 is a critical mechanism of barrier disruption that greatly contributes to the pathogenesis of lethal S. aureus infections by enabling effective spreading. [6] Hla pore-dependent activation of NOD-like receptor protein 3 inflammasome is a successful example of pathogens exploiting host inflammatory signaling by enhancing the pathogenesis of severe S. aureus infection via inducing necrosis. [7] Moreover, Hla is exploited to manipulate adaptive immunity against S. aureus, suppressing the antigen-specific memory T cell response by disturbing DC-T cell crosstalk. [8] Notably, the pore formation activity of Hla is required for these cellular events as the inactive mutant H35L retains the ability to bind the membrane while impaired pore formation fails to act in these cases. The critical role of Hla in S. aureus pathogenesis renders it a developing therapeutic target for virulence-specific strategies aiming to attenuate the pathogenicity of S. aureus rather than directly kill bacteria.Host innate immune response is the first line of defense against S. aureus infection, promoting bacterial clearance and limiting the inciting injury of infection and systemic spreading through neutrophil chemotaxis, phagocytosis and inflammation. [9] However, inflammation is a double-edged sword. In most Antibiotic resistance is the greatest challenge for the treatment of Staphylococcus aureus (S. aureus) infection under the global antibiotic resistance crisis. With the bottleneck period of the development of new antibiotics, novel alternative agents are urgently in need. In this study, the small molecule amentoflavone is identified as a dual-action inhibitor of Hla, a pore-forming virulence determinant particularly important for S. aureus pathogenicity and Toll-like receptor 2 (TLR2) signaling, which triggers inflammation response upon recognizing pathogen-associated molecular patterns. Amentoflavone treatment conferred effective protec...

show abstract

Resolution of Acute Inflammation in the Lung

Cited by 253 publications

References 148 publications

Aspirin-triggered 15-epi-lipoxin A4 regulates neutrophil-platelet aggregation and attenuates acute lung injury in mice

Aspirin-triggered 15-epi-lipoxin A4 regulates neutrophil-platelet aggregation and attenuates acute lung injury in mice

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

A Dual‐Action Molecule Suppresses S. aureus Infection as an Inhibitor Targeting Hla Pore Formation and TLR2 Signaling

Contact Info

Product

Resources

About