Caveolin-1 regulates NF-κB activation and lung inflammatory response to sepsis induced by lipopolysaccharide
Caveolin-1 regulates NF-κB activation and lung inflammatory response to sepsis induced by lipopolysaccharide
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DOI：
10.4049/jimmunol.177.7.4853
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发表时间：
2006-10-01
影响因子：
4.4
通讯作者：
Malik, Asrar B.
中科院分区：
文献类型：
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作者：
Garrean, Sean;Gao, Xiao-Pei;Malik, Asrar B.
小窝蛋白-1是小窝的主要结构和信号蛋白，参与NO介导的细胞信号传导事件，但其在炎症中的确切作用尚不清楚。使用caveolin-1-knockout（Cav-1（-/-））小鼠，我们探讨了caveolin-1在腹腔注射LPS诱导的脓毒症的肺部炎症反应中的作用。LPS攻击的野生型（WT）肺表现出中性粒细胞隔离（-16倍）、肺微血管渗透性K-f、K-c（类似于5.7倍）和水肿形成（类似于1.6倍）显着增加。与WT相比，Cav-1（-/-）肺显示LPS诱导的中性粒细胞隔离的显著减弱（类似于11倍增加）和微血管屏障破坏和水肿形成的抑制。预防Cav-1（-/-）小鼠的肺损伤与响应于LPS攻击的死亡率降低相关。为了解决Cav-1（-/-）肺中炎症和损伤减少的基础，我们检查了NO的作用，因为已知其血浆浓度在Cav-1（-/-）小鼠中增加。Cav-1（-/-）小鼠肺表现出相对于WT内皮NO合酶（eNOS）衍生的NO产生的显著增加，这与小窝蛋白-1作为eNOS活性的负调节剂的作用一致。Cav-1（-/-）肺同时显示NF-κ B B活性抑制和诱导型NO合酶和ICAM-1转录降低。在Cav-1（-/-）小鼠中，LPS与NO合酶抑制剂硝基-L-精氨酸的共同给药阻止了NF-κ B B活性的抑制，并恢复了肺多形核白细胞对LPS攻击的反应。因此，小窝蛋白-1通过其调节eNOS衍生的NO产生的能力，是NF-κ B活化和对LPS的肺部炎症反应的关键决定因素。
Caveolin-1, the principal structural and signaling protein of caveolae, is implicated in NO-mediated cell signaling events, but its precise role in inflammation is not well understood. Using caveolin-1-knockout (Cav-1(-/-)) mice, we addressed the role of caveolin-1 in the lung inflammatory response to sepsis induced by i.p. injection of LPS. LPS-challenged wild-type (WT) lungs exhibited significant increases in neutrophil sequestration (-16-fold), lung microvascular permeability K-f,K-c (similar to 5.7-fold), and edema formation (similar to 1.6-fold). Compared with WT, Cav-1(-/-) lungs showed marked attenuation of LPS-induced neutrophil sequestration (similar to 11-fold increase) and inhibition of microvascular barrier breakdown and edema formation. Prevention of lung injury in Cav-1(-/-) mice was associated with decreased mortality in response to LPS challenge. To address the basis of the reduced inflammation and injury in Cav-1(-/-) lungs, we examined the role of NO because its plasma concentration is known to be increased in Cav-1(-/-) mice. Cav-1(-/-) mouse lungs demonstrated a significant increase in endotheliall NO synthase (eNOS)-derived NO production relative to WT, which is consistent with the role of caveolin-1 as a negative regulator of eNOS activity. Cav-1(-/-) lungs concurrently showed suppression of NF-kappa B activity and decreased transcription of inducible NO synthase and ICAM-1. Co-administration of LPS with the NO synthase inhibitor nitro-L-arginine in Cav-1(-/-) mice prevented the suppression of NF-kappa B activity and restored lung polymorphonuclear leukocyte sequestration in response to LPS challenge. Thus, caveolin-1, through its ability to regulate eNOS-derived NO production, is a crucial determinant of NF-kappa B activation and the lung inflammatory response to LPS.