Lipoxin A₄ Attenuates Microvascular Fluid Leak During Inflammation

Background: The release of proinflammatory cytokines during inflammation disturbs the endothelial barrier and can initiate significant intravascular volume loss. Proinflammatory cytokines also induce the expression of anti-inflammatory mediators, such as lipoxin, which promote the resolution of inflammation. Our hypothesis is that lipoxin A₄ (LXA₄) reverses the increased microvascular fluid leak observed during inflammatory conditions. Materials and Methods: Microvascular fluid leak (L_p) was measured in rat mesenteric venules using a micro-cannulation technique. L_p was measured under the following conditions: (1) LXA₄ (100 nM) alone (n = 5), (2) LXA₄ (100 nM) administered after endothelial hyperpermeability induced by a continuous perfusion of 10 nM platelet activating factor (PAF) (n = 5), (3) LXA₄ (100 nM) perfused after inflammation induced by a systemic bolus of 10 mg/kg lipopolysaccharide (LPS) (n = 5), and (4) LXA₄ (100 nM) perfused after LPS-induced inflammation during inhibition of c-Jun N-terminal kinase (n = 4). Results: LXA₄ alone slightly increased L_p from baseline (L_p-baseline = 1.05 ± 0.03, L_p-LXA₄ = 1.55 ± 0.04; P < 0.0001). PAF increased L_p 4-fold (L_p-baseline = 1.20 ± 0.10, L_p-PAF = 4.49 ± 0.95; P < 0.0001). LXA₄ administration after PAF decreased L_p 66% versus PAF alone (from 4.49 ± 0.95 to 1.54 ± 0.13; P = 0.0004). LPS-induced inflammation increased L_p over 2-fold (L_p-baseline = 1.05 ± 0.03, L_p-LPS = 2.27 ± 0.13; P < 0.0001). LXA₄ administration after LPS decreased L_p 42% versus LPS alone (from 2.27 ± 0.13 to 1.31 ± 0.05; P < 0.0001). The effect of c-Jun N-terminal kinase inhibition during LPS-induced inflammation attenuated the decrease in leak cause by LXA₄ by 51% (P = 0.0002). Conclusion: After either LPS or PAF, LXA₄ attenuated the intravascular volume loss caused by these inflammatory mediators. The activity of LXA₄ may be partly mediated by the c-Jun N-terminal kinase signaling pathway. These data support an anti-inflammatory role for LXA₄ and suggests a potential pharmacologic role for LXA₄ during inflammation.