Therapeutic effect of Lipoxin A4 in malaria-induced acute lung injury

Abstract

Acute lung injury (ALI) models are characterized by neutrophil accumulation, tissue damage, alteration of the alveolar capillary membrane, and physiological dysfunction. Lipoxin A₄ (LXA₄ ) is an anti-inflammatory eicosanoid that was demonstrated to attenuate lipopolysaccharide-induced ALI. Experimental models of severe malaria can be associated with lung injury. However, to date, a putative effect of LXA₄ on malaria (M)-induced ALI has not been addressed. In this study, we evaluated whether LXA₄ exerts an effect on M-ALI. Male C57BL/6 mice were randomly assigned to the following five groups: noninfected; saline-treated Plasmodium berghei-infected; LXA₄ -pretreated P. berghei-infected (LXA₄ administered 1 h before infection and daily, from days 0 to 5 postinfection), LXA₄ - and LXA₄ receptor antagonist BOC-2-pretreated P. berghei-infected; and LXA₄ -posttreated P. berghei-infected (LXA₄ administered from days 3 to 5 postinfection). By day 6, pretreatment or posttreatment with LXA₄ ameliorate lung mechanic dysfunction reduced alveolar collapse, thickening and interstitial edema; impaired neutrophil accumulation in the pulmonary tissue and blood; and reduced the systemic production of CXCL1. Additionally, in vitro treatment with LXA₄ prevented neutrophils from migrating toward plasma collected from P. berghei-infected mice. LXA₄ also impaired neutrophil cytoskeleton remodeling by inhibiting F-actin polarization. Ex vivo analysis showed that neutrophils from pretreated and posttreated mice were unable to migrate. In conclusion, we demonstrated that LXA₄ exerted therapeutic effects in malaria-induced ALI by inhibiting lung dysfunction, tissue injury, and neutrophil accumulation in lung as well as in peripheral blood. Furthermore, LXA₄ impaired the migratory ability of P. berghei-infected mice neutrophils.

Keywords: LXA4 receptor; Plasmodium berghei; cytoskeleton remodeling; lung; specialized proresolving mediators.