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Published on: May 2, 2018
LXA4 Inhibits Lipopolysaccharide-Induced Inflammatory Cell Accumulation by Resident Macrophages in Mice
Hong-Xia Mei1, Yang Ye1, Hao-Ran Xu1
1Department of Anesthesia and Critical Care, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325027, People's Republic of China.
Introduction:
Alveolar macrophages that regulate the inflammatory response in lungs are the main target cell for the treatment of inflammatory pulmonary pathologies, such as acute respiratory distress syndrome (ARDS). Yolk sac derived alveolar resident macrophages play an important role in the pulmonary inflammatory response. With regards to anti-inflammatory actions, lipoxin A4 (LXA4) has been identified as an inflammatory "braking signal".
Methods:
In vivo, LXA4 (0.1 µg/mouse) was injected intraperitoneally after intratracheal (1 mg/kg) lipopolysaccharide (LPS) administration; flow cytometry was used to measure peripheral blood monocyte derived recruited macrophage and neutrophil numbers; resident alveolar macrophage was depleted by liposome clodronate; CXCL2, CCL2, MMP9 level was detected by RT-PCR and ELISA. In vitro, sorted resident macrophages (1×106) were cultured with LPS (1 μg/mL) and LXA4 (100 nmol/mL) with or without BOC-2 (10 μM) for 24 h to gain a better understanding of the mechanisms of LXA4.
Results:
LXA4 inhibited tumor necrosis factor-a (TNF-a) and interleukin-1β (IL-1β) production induced by LPS. LXA4 also mediated LPS-induced macrophage recruitment and showed that this was dependent on CCL2 secretion and release by resident macrophages. LXA4 protects lung tissue by inhibiting neutrophil recruitment, partly through the CXCL2/MMP-9 signaling pathway. CXCL2 and MMP-9 are mainly expressed by resident macrophages and neutrophils, respectively. Finally, LXA4's beneficial effects were abrogated by BOC-2, an LXA4 receptor inhibitor.
Conclusion:
These results suggest that LXA4 may be a promising therapy for preventing and treating ARDS.
Insights
Lipoxin A4 (LXA4) reduces lung inflammation and protects against acute respiratory distress syndrome (ARDS) by inhibiting inflammatory cell recruitment and cytokine production. LXA4 shows promise as a novel therapy for ARDS.
Area of Science:
- Pulmonary immunology
- Inflammatory signaling pathways
- Macrophage biology
Background:
- Alveolar macrophages are key targets for treating inflammatory lung diseases like ARDS.
- Resident macrophages are crucial for pulmonary inflammation.
- Lipoxin A4 (LXA4) acts as an endogenous anti-inflammatory "braking signal".
Purpose of the Study:
- To investigate the therapeutic potential of LXA4 in acute respiratory distress syndrome (ARDS).
- To elucidate the mechanisms by which LXA4 modulates pulmonary inflammation.
Main Methods:
- In vivo studies involved LPS-induced ARDS model in mice, LXA4 administration, and analysis of immune cell populations and cytokine/chemokine levels.
- In vitro studies utilized cultured resident macrophages treated with LPS and LXA4, with or without a receptor inhibitor.
- Flow cytometry, RT-PCR, and ELISA were employed for quantitative analysis.
Main Results:
- LXA4 significantly inhibited LPS-induced TNF-α and IL-1β production.
- LXA4 reduced macrophage and neutrophil recruitment to the lungs, dependent on CCL2 and CXCL2/MMP-9 pathways.
- The anti-inflammatory effects of LXA4 were confirmed via blockade with an LXA4 receptor inhibitor (BOC-2).
Conclusions:
- LXA4 demonstrates significant anti-inflammatory effects in a preclinical model of ARDS.
- LXA4's mechanism involves modulating macrophage recruitment and neutrophil infiltration via specific signaling pathways.
- LXA4 represents a potential therapeutic agent for the prevention and treatment of ARDS.
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