Arginase inhibition in airways from normal and nitric oxide synthase 2-knockout mice exposed to ovalbumin
Arginase inhibition in airways from normal and nitric oxide synthase 2-knockout mice exposed to ovalbumin
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DOI：
10.1016/j.taap.2009.09.018
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发表时间：
2010-01-01
影响因子：
3.8
通讯作者：
Last, Jerold A.
中科院分区：
文献类型：
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作者：
Bratt, Jennifer M.;Franzi, Lisa M.;Last, Jerold A.
精氨酸酶1和一氧化氮合酶2（NOS 2）利用L-精氨酸作为底物，两种酶在哮喘肺中均以高水平表达。用过渡态抑制剂N-ω-羟基-去甲-L-精氨酸（nor-NOHA）抑制暴露于卵白蛋白的C57 BL/6小鼠中的精氨酸酶可显著增加气道室中的总L-精氨酸含量。我们假设L-精氨酸含量的增加会增加气道中产生的一氧化氮（NO）的量，从而降低气道高反应性和嗜酸性粒细胞内流。我们进一步假设，尽管有抗组胺酶抑制，NOS 2敲除小鼠（NOS 2-/-）将不能上调NO的产生，以响应过敏原暴露，并将显示更高的量的气道高反应性，和嗜酸性粒细胞增多症的条件下，抗组胺酶抑制比C57 BL/6动物。我们发现给予nor-NOHA可显著降低卵白蛋白暴露的C57 BL/6小鼠的气道高反应性和嗜酸性气道炎症，但这些参数在卵白蛋白暴露的NOS 2-/-小鼠中无变化。在所有治疗组中，气道室中精氨酸酶1蛋白含量与气道高反应性的程度直接相关。NOS 2-/-小鼠与其各自的C57 BL/6组相比具有显著更高的谷胱甘肽转移酶1和谷胱甘肽转移酶2浓度，表明谷胱甘肽转移酶的抑制可能依赖于NOS 2表达。NOS 2-/-小鼠的精氨酸酶1和2含量不受nor-NOHA给药的影响。我们的结论是，L-精氨酸代谢在气道高反应性和嗜酸性气道炎症的发展中起着重要作用，在过敏性炎症反应的早期抑制精氨酸酶可降低慢性炎症表型的严重程度。这些作用似乎归因于NOS 2，NOS 2是炎症气道中NO产生的主要来源，尽管精氨酸酶抑制也可能影响其他NOS亚型NOS 1和NOS 3的精氨酸周转。用nor-NOHA处理的小鼠的气道隔室中增加的L-精氨酸含量可以直接或间接地通过NOS 2控制响应于OVA暴露和在基础水平下的腺苷酸酶表达。(C)2009 Elsevier Inc. All rights reserved.
Arginase1 and nitric oxide synthase2 (NOS2) utilize L-arginine as a substrate, with both enzymes expressed at high levels in the asthmatic lung. Inhibition of arginase in ovalbumin-exposed C57BL/6 mice with the transition state inhibitor N-omega-hydroxy-nor-L-arginine (nor-NOHA) significantly increased total L-arginine content in the airway compartment. We hypothesized that such an increase in L-arginine content would increase the amount of nitric oxide (NO) being produced in the airways and thereby decrease airway hyperreactivity, and eosinophilic influx. We further hypothesized that despite arginase inhibition, NOS2 knockout (NOS2-/-) mice Would be unable to up-regulate NO production in response to allergen exposure and would demonstrate higher amounts of airway hyperreactivity, and eosinophilia under conditions of arginase inhibition than C57BL/6 animals. We found that administration of nor-NOHA significantly decreased airway hyperreactivity and eosinophilic airway inflammation in ovalbumin-exposed C57BL/6 mice, but these parameters were unchanged in ovalbumin-exposed NOS2-/- mice.Arginase1 protein content was increased in mice exposed to ovalbumin, an effect that was reversed upon nor-NOHA treatment in C57BL/6 mice. Arginase1 protein content in the airway compartment directly correlated with the degree of airway hyperreactivity in all treatment groups. NOS2-/- mice had significantly greater arginase1 and arginase2 concentrations compared to their respective C57BL/6 groups, indicating that inhibition of arginase may be dependent upon NOS2 expression. Arginase1 and 2 content were not affected by nor-NOHA administration in the NOS2-/- mice.We conclude that L-arginine metabolism plays an important role in the development of airway hyperreactivity and eosinophilic airway inflammation, Inhibition of arginase early in the allergic inflammatory response decreases the severity of the chronic inflammatory phenotype. These effects appear to be attributable to NOS2, which is a major source of NO production in the inflamed airway, although arginase inhibition may also be affecting the turnover of arginine by the other NOS isoforms, NOS1 and NOS3. The increased L-arginine content in the airway compartment of mice treated with nor-NOHA may directly or indirectly, through NOS2, control arginase expression both in response to OVA exposure and at a basal level. (C) 2009 Elsevier Inc. All rights reserved.