Airway Lipoxin A₄Generation and Lipoxin A₄Receptor Expression Are Decreased in Severe Asthma

Abstract

Rationale: Airway inflammation is common in severe asthma despite antiinflammatory therapy with corticosteroids. Lipoxin A 4 (LXA 4 ) is an arachidonic acid-derived mediator that serves as an agonist for resolution of inflammation. Objectives: Airway levels of LXA 4 , as well as the expression of lipoxin biosynthetic genes and receptors, in severe asthma. Methods: Samples of bronchoalveolar lavage fluid were obtained from subjects with asthma and levels of LXA 4 and related eicosanoids were measured. Expression of lipoxin biosynthetic genes was determined in whole blood, bronchoalveolar lavage cells, and endobronchial biopsies by quantitative polymerase chain reaction, and leukocyte LXA 4 receptors were monitored by flow cytometry. Measurements and Main Results: Individuals with severe asthma had significantly less LXA 4 in bronchoalveolar lavage fluids (11.2 6 2.1 pg/ml) than did subjects with nonsevere asthma (150.1 6 38.5 pg/ml; P , 0.05). In contrast, levels of cysteinyl leukotrienes were increased in both asthma cohorts compared with healthy individuals. In severe asthma, 15-lipoxygenase-1 mean expression was decreased fivefold in bronchoalveolar lavage cells. In contrast, 15-lipoxgenase-1 was increased threefold in endobronchial biopsies, but expression of both 5-lipoxygenase and 15-lipoxygenase-2 in these samples was decreased. Cyclooxygenase-2 expression was decreased in all anatomic compartments sampled in severe asthma. Moreover, LXA 4 receptor gene and protein expression were significantly decreased in severe asthma peripheral blood granulocytes. Conclusions: Mechanisms underlying pathological airway responses in severe asthma include lipoxin underproduction with decreased expression of lipoxin biosynthetic enzymes and receptors. Together, these results indicate that severe asthma is characterized, in part, by defective lipoxin counterregulatory signaling circuits.

Aspirin-Triggered Lipoxin and Resolvin E1 Modulate Vascular Smooth Muscle Phenotype and Correlate with Peripheral Atherosclerosis

“…This is consistent with results from human patients with severe asthma, who also show deficiencies in lipoxin production. 27 While the independent association be- tween ATL and PAD was maintained in a multivariable model, there was significant interaction between plasma ATL values and patient age. Given that we did not have an age-matched control population, the conclusions drawn must be tempered.…”

Pilot application of lipoxin A4 analog and lipoxin A4 receptor agonist in asthmatic children with acute episodes

“…LXA 4 analogs blocked both airway hyper-responsiveness and pulmonary inflammation in a murine model of asthma (21). Furthermore, the powerful anti-inflammatory properties of LX provide a rationale for its application in the treatment of asthma, along with the observations of defective LX generation in uncontrolled asthma (23)(24)(25). A previous study also demonstrated that insufficient generation of LXA 4 and overproduction of LTs may be responsible for a worsening of asthma in children (26).…”

Lipoxin A4 exerts protective effects against experimental acute liver failure by inhibiting the NF-κB pathway

“…Previous studies have shown that LXA4 can attenuate airway inflammation following lipopolysaccharide (LPS)-induced lung injury in mice (6), reduce systemic inflammation and improve Lipoxin A4 exerts protective effects against experimental acute liver failure by inhibiting the NF-κB pathway survival rates in a rat model of sepsis (7), suppress inflammation-induced mechanical hypersensitivity in rats (8), and inhibit pulmonary and renal fibrosis in animal models (9,10). In addition, the levels of LXA4 are decreased in patients with asthma (11). The activation of nuclear factor-κB (NF-κB) is necessary for many inflammatory reactions, and LXA4 has been proven to reduce the expression of tumor necrosis factor-α (TNF-α) and the activation of NF-κB in a rabbit model of paracetamol-induced acute hepatic injury (12).…”