ADENOSINE DEAMINASE THAT ACTS ON RNA 1 P150 IN ALVEOLAR MACROPHAGE IS INVOLVED IN LPS-INDUCED LUNG INJURY

Previous studies showed adenosine deaminase that acts on RNA (ADAR1) up-regulated in alveolar macrophages (AMs) by LPS treatment, whereas its roles in acute lung injury (ALI) are still unclear. Here, we report that up-regulation of inducible ADAR1 p150 isoform in macrophages stimulated with LPS and in AMs harvested from an ALI rat model. Knockdown of ADAR1 p150 by small interfering RNA in AMs suppressed macrophage inflammatory protein 1 (MIP-1) secretion while enhancing that of IL-10 compared with those control cells upon LPS stimulation. To further confirm the role of p150 in AMs, adoptive transfer of LPS-activated NR8383 cells was performed in healthy rats, and severity of inflammatory response was assessed by investigating cellular pattern in bronchoalveolar lavage fluid and calculating alveolar-arterial oxygen difference [D(A-a)O2]. Acute lung injury was induced by LPS-activated NR8383 cells with either normal or lower ADAR1 expression levels, and ALI in rats and the lung inflammation was attenuated significantly by knockdown ADAR1 p150 in transferred cells both in polymorphonuclear leukocyte infiltration and D(A-a)O2. The roles of MIP-1 and IL-10 in the development of ALI were also tested in animals receiving neutralizing antibodies. Administration of anti-MIP-1 inhibited lung polymorphonuclear leukocytes infiltration and lung damage, as well as D(A-a)O2, whereas anti-IL-10 reversed the protection effects. In conclusion, ADAR1 p150 is functionally significant in the development of ALI. It likely exerts its effects in part by mediating the expression of proinflammatory and anti-inflammatory cytokines and influencing tissue neutrophil recruitment and D(A-a)O2. It also implied that ADAR1 inhibitors may help attenuate local inflammatory lung damage.