Lipoxins in asthma: potential therapeutic mediators on bronchial inflammation?

Abstract

Arachidonic acid metabolism represents an important source of mediators with ambivalent actions. Among these, lipoxins (LXs) are the first agents identified and recognized as anti-inflammatory endogenous lipid mediators, which are involved in the resolution of inflammation and are present in the airways of asthmatic patients. Lipoxins result mainly from the interaction between 5 and 15-lipoxygenases (LO) and their levels are modulated by the degree of bronchial inflammation as well as by the long-term glucocorticoid treatments. In the airways, LX synthesis is higher in mild asthmatics than in severe asthmatics, whereas in vitro chemokine release inhibition by LXs is more effective in cells from severe asthmatics than from mild asthmatics. LipoxinA(4) effects on interleukin (IL)-8 released by blood mononuclear cells and on calcium influx in epithelial cells are mediated by the specific receptor ALX. Lipoxin generation by lung epithelial cells depends mainly on 15-LO activity. Mild asthmatics present higher 15-LOb expression at the epithelium level than severe patients, whereas the LX deficit in severe asthma is associated with an up-regulation of the 15-LOa expressions. Therefore, bronchial epithelial cells become a target for therapeutic intervention and LXs represent a potential therapeutic solution for bronchial inflammation resolution in asthma.

Decreased Levels of Lipoxin A4 and Annexin A1 in Wheezy Infants

“…LXA4 and ANXA1 are mediators which have anti-inflammatory effects [12,17]. In human studies, it has been shown that the level of LXA4 is low in severe asthma [9,10,18].…”

“…Asthma is one of the most important chronic inflammatory diseases, characterized by variable airflow obstruction and airway hyperresponsiveness in childhood. A large number of mediators that affect the airways play a role in the pathogenesis of asthma [3]. Lipoxins are the first agents determined to be anti-inflammatory endogenous lipid mediators involved in the resolution of inflammation [4].…”

LXA4stimulates ZO-1 expression and transepithelial electrical resistance in human airway epithelial (16HBE14o-) cells

“…The effects of the endogenous lipoxin isomer, the LXA 4 (5S,6R,15S-trihydroxy-7,9,13-trans-11-cis-eicosatetraenoic acid), have been reported on leukocyte trafficking via modulation of chemotaxis, adhesion, transmigration, and phagocytic clearance of apoptotic cells (13,20,39). In airway epithelial cells, since the first detection of LXA 4 in bronchoalveolar lavage in 1990, an anomalous low production of LXA 4 has been reported in airway of cystic fibrosis (CF) and severe asthmatic patients, which could explain the persistent inflammation in these severe airway diseases (6,8,24,29,49). In a previous study, we have shown that airway epithelial cells are a biological target for LXA 4 .…”

“…They are synthesized at inflammation sites, and their anti-inflammatory properties have been widely reported (4,31,34,44). The effects of the endogenous lipoxin isomer, the LXA 4 (5S,6R,15S-trihydroxy-7,9,13-trans-11-cis-eicosatetraenoic acid), have been reported on leukocyte trafficking via modulation of chemotaxis, adhesion, transmigration, and phagocytic clearance of apoptotic cells (13,20,39).…”

Lipoxin A4-mediated KATP potassium channel activation results in cystic fibrosis airway epithelial repair

“…Lipoxins are eicosanoids formed by lipoxygenases from arachidonic acid and play a key role in the resolution of inflammation (2,6,19,41). In addition, lipoxin A 4 (LXA 4 ) has been reported to have other functions such as regulation of airway epithelial ion transport and airway surface liquid layer dynamics in CF (4,15,46).…”