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Войти в исследования Journal of inflammation research · 2026
Lipoxin A4 Attenuates E. coli-Induced ARDS-Like Lung Injury in Mice via ALX/FPR2-Dependent Macrophage Reprogramming.
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Zhang Bingxue, Xu Meng, Deng Yanling, Li Donghui, Shen Jun, Pan Chun, He Hongli
Аннотация
BACKGROUND: Acute respiratory distress syndrome (ARDS) remains a severe inflammatory lung disorder with limited disease-modifying therapies. Lipoxin A4 (LXA4) is an endogenous specialized pro-resolving mediator that can modulate macrophage responses; however, its role in bacterial ARDS-like injury and the underlying ALX/FPR2-associated mechanism remain incompletely defined. To determine whether post-injury LXA4 attenuates Escherichia coli (E. coli)-induced ARDS-like lung injury in mice and whether these effects are associated with ALX/FPR2-dependent macrophage reprogramming.
METHODS: Male C57BL/6J mice were randomized to PBS, ARDS, LXA4, or LXA4 + WRW4 groups (n=6 per group per time point). Mice were challenged intratracheally with E. coli (2 × 10^6 CFU in 50 μL) and treated 4 h later with intravenous LXA4 (7 μg /kg), with or without intraperitoneal WRW4 (1.8 mg/kg) administered at the time of LXA4 dosing. Bronchoalveolar lavage fluid (BALF), plasma, and lung tissue samples were collected at 24 h and 72 h for histology, injury scoring, BALF protein, bacterial burden, cytokine and lipid mediator ELISA, ROS, and HO-1 analyses. In vitro, MH-S alveolar macrophages were stimulated with LPS (1 μg/mL) and treated with LXA4 (200 nM), with or without WRW4 (10 μM), to assess cytokine secretion, STAT1/STAT3 expression, iNOS/CD206 markers, and cell-associated GFP-E. coli uptake.
RESULTS: LXA4 reduced macroscopic and histological lung injury, the lung wet weight-to-body weight ratio, BALF IL-6, IL-1β and TNF-α levels, BALF protein leakage, and BALF bacterial burden after E. coli challenge. LXA4 also increased circulating LXA4 while decreasing LTB4, LTC4, and PGE2, reduced lung ROS, and enhanced HO-1 expression. In MH-S cells, LXA4 decreased pro-inflammatory cytokine release, increased IL-10, promoted an M2-like marker profile, and enhanced cell-associated GFP-E. coli uptake. WRW4 attenuated these effects, supporting pharmacological involvement of ALX/FPR2 signaling.
CONCLUSION: LXA4 alleviates bacterial ARDS-like lung injury in mice and promotes pro-resolving macrophage features, with effects attenuated by ALX/FPR2 antagonism. These findings support LXA4/ALX-FPR2 signaling as a preclinical pro-resolving strategy that warrants validation in cell-specific and clinically representative ARDS models.
METHODS: Male C57BL/6J mice were randomized to PBS, ARDS, LXA4, or LXA4 + WRW4 groups (n=6 per group per time point). Mice were challenged intratracheally with E. coli (2 × 10^6 CFU in 50 μL) and treated 4 h later with intravenous LXA4 (7 μg /kg), with or without intraperitoneal WRW4 (1.8 mg/kg) administered at the time of LXA4 dosing. Bronchoalveolar lavage fluid (BALF), plasma, and lung tissue samples were collected at 24 h and 72 h for histology, injury scoring, BALF protein, bacterial burden, cytokine and lipid mediator ELISA, ROS, and HO-1 analyses. In vitro, MH-S alveolar macrophages were stimulated with LPS (1 μg/mL) and treated with LXA4 (200 nM), with or without WRW4 (10 μM), to assess cytokine secretion, STAT1/STAT3 expression, iNOS/CD206 markers, and cell-associated GFP-E. coli uptake.
RESULTS: LXA4 reduced macroscopic and histological lung injury, the lung wet weight-to-body weight ratio, BALF IL-6, IL-1β and TNF-α levels, BALF protein leakage, and BALF bacterial burden after E. coli challenge. LXA4 also increased circulating LXA4 while decreasing LTB4, LTC4, and PGE2, reduced lung ROS, and enhanced HO-1 expression. In MH-S cells, LXA4 decreased pro-inflammatory cytokine release, increased IL-10, promoted an M2-like marker profile, and enhanced cell-associated GFP-E. coli uptake. WRW4 attenuated these effects, supporting pharmacological involvement of ALX/FPR2 signaling.
CONCLUSION: LXA4 alleviates bacterial ARDS-like lung injury in mice and promotes pro-resolving macrophage features, with effects attenuated by ALX/FPR2 antagonism. These findings support LXA4/ALX-FPR2 signaling as a preclinical pro-resolving strategy that warrants validation in cell-specific and clinically representative ARDS models.