Reutershan Jörg, Vollmer Irene, Stark Stefanie, Wagner Rosalyn, Ngamsri Kristian-Christos, Eltzschig Holger K
Department of Anesthesiology and Intensive Care Medicine, University of Tübingen, Tübingen, Germany.
FASEB J. 2009 Feb;23(2):473-82. doi: 10.1096/fj.08-119701. Epub 2008 Oct 6.
Extracellular adenosine has been implicated as anti-inflammatory signaling molecule during acute lung injury (ALI). The main source of extracellular adenosine stems from a coordinated two-step enzymatic conversion of precursor nucleotides via the ecto-apyrase (CD39) and the ecto-5'-nucleotidase (CD73). In the present study, we hypothesized a critical role of CD39 and CD73 in mediating pulmonary neutrophil (PMN) transmigration during lipopolysaccharide (LPS) -induced lung injury. Initial studies revealed that pulmonary CD39 and CD73 transcript levels were elevated following LPS exposure in vivo. Moreover, LPS-induced accumulation of PMN into the lungs was enhanced in cd39(-/-) or cd73(-/-) mice, particularly into the interstitial and intra-alveolar compartment. Such increases in PMN trafficking were accompanied by corresponding changes in alveolar-capillary leakage. Similarly, inhibition of extracellular nucleotide phosphohydrolysis with the nonspecific ecto-nucleoside-triphosphate-diphosphohydrolases inhibitor POM-1 confirmed increased pulmonary PMN accumulation in wild-type, but not in gene-targeted mice for cd39 or cd73. Finally, treatment with apyrase or nucleotidase was associated with attenuated pulmonary neutrophil accumulation and pulmonary edema during LPS-induced lung injury. Taken together, these data reveal a previously unrecognized role for CD39 and CD73 in attenuating PMN trafficking into the lungs during LPS-induced lung injury and suggest treatment with their soluble compounds as a therapeutic strategy.
细胞外腺苷在急性肺损伤（ALI）期间被认为是一种抗炎信号分子。细胞外腺苷的主要来源是通过胞外ATP双磷酸酶（CD39）和胞外5'-核苷酸酶（CD73）对前体核苷酸进行两步协同酶促转化。在本研究中，我们假设CD39和CD73在脂多糖（LPS）诱导的肺损伤中介导肺中性粒细胞（PMN）迁移中起关键作用。初步研究表明，体内暴露于LPS后，肺组织中CD39和CD73的转录水平升高。此外，在cd39（-/-）或cd73（-/-）小鼠中，LPS诱导的PMN在肺内的积聚增加，特别是在间质和肺泡内区域。PMN迁移的这种增加伴随着肺泡-毛细血管渗漏的相应变化。同样，用非特异性胞外核苷三磷酸二磷酸水解酶抑制剂POM-1抑制细胞外核苷酸磷酸水解，证实野生型小鼠肺内PMN积聚增加，但cd39或cd73基因靶向小鼠则不然。最后，在LPS诱导的肺损伤期间，用ATP双磷酸酶或核苷酸酶治疗与肺中性粒细胞积聚和肺水肿减轻有关。综上所述，这些数据揭示了CD39和CD73在LPS诱导的肺损伤期间减轻PMN向肺内迁移方面以前未被认识的作用，并表明用它们的可溶性化合物进行治疗是一种治疗策略。
