Matrikines are key regulators in modulating the amplitude of lung inflammation in acute pulmonary infection.
Matrikines are key regulators in modulating the amplitude of lung inflammation in acute pulmonary infection.
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DOI：
10.1038/ncomms9423
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发表时间：
2015-09-24
影响因子：
16.6
通讯作者：
Snelgrove RJ
中科院分区：
文献类型：
--
作者：
Akthar S;Patel DF;Beale RC;Peiró T;Xu X;Gaggar A;Jackson PL;Blalock JE;Lloyd CM;Snelgrove RJ
生物活性基质片段（matrikines）已被确定在无数的疾病，但其对气道炎症的演变的影响尚未得到证实。我们最近描述了一种途径，其中基质因子和中性粒细胞化学引诱物脯氨酸-甘氨酸-脯氨酸（PGP）可以被酶白三烯A4水解酶（LTA 4 H）降解。LTA 4 H通常在促炎性白三烯B4的产生中起作用，因此LTA 4 H表现出相反的促炎性和抗炎性活性。这种继发性抗炎活性的生理意义仍然未知。在这里，我们表明，使用容易解决的肺部炎症模型，这种次要活动的损失导致更明显和持续的炎症和疾病，由于PGP的积累。PGP可加重嗜酸性炎症和蛋白酶失衡，进一步降解细胞外基质，产生使炎症持续的片段。这突出了LTA 4 H的次级抗炎活性的关键作用，因此对目前正在开发的全球LTA 4 H抑制剂的产生具有影响。 蛋白酶在炎症过程中降解细胞外基质，释放能够募集中性粒细胞的肽。在这里，作者表明，这种生物活性肽的降解酶白三烯A4水解酶是至关重要的，以限制小鼠细菌感染期间的肺部炎症。
Bioactive matrix fragments (matrikines) have been identified in a myriad of disorders, but their impact on the evolution of airway inflammation has not been demonstrated. We recently described a pathway where the matrikine and neutrophil chemoattractant proline–glycine–proline (PGP) could be degraded by the enzyme leukotriene A4 hydrolase (LTA4H). LTA4H classically functions in the generation of pro-inflammatory leukotriene B4, thus LTA4H exhibits opposing pro- and anti-inflammatory activities. The physiological significance of this secondary anti-inflammatory activity remains unknown. Here we show, using readily resolving pulmonary inflammation models, that loss of this secondary activity leads to more pronounced and sustained inflammation and illness owing to PGP accumulation. PGP elicits an exacerbated neutrophilic inflammation and protease imbalance that further degrades the extracellular matrix, generating fragments that perpetuate inflammation. This highlights a critical role for the secondary anti-inflammatory activity of LTA4H and thus has consequences for the generation of global LTA4H inhibitors currently being developed. Proteases degrade extracellular matrix during inflammation, releasing peptides that can recruit neutrophils. Here the authors show that degradation of such bioactive peptide by the enzyme leukotriene A4 hydrolase is critical to limit pulmonary inflammation during bacterial infection in mice.