Constitutive activation of the SRC family kinase Hck results in spontaneous pulmonary inflammation and an enhanced innate immune response.
Constitutive activation of the SRC family kinase Hck results in spontaneous pulmonary inflammation and an enhanced innate immune response.
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DOI：
10.1084/jem.20020873
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发表时间：
2002-09-02
期刊：
影响因子：
--
通讯作者：
Dunn AR
中科院分区：
文献类型：
--
作者：
Ernst M;Inglese M;Scholz GM;Harder KW;Clay FJ;Bozinovski S;Waring P;Darwiche R;Kay T;Sly P;Collins R;Turner D;Hibbs ML;Anderson GP;Dunn AR
为了确定HCK的生理作用，HCK是在骨髓单核细胞中表达的酪氨酸激酶的Src家族中的一个功能冗余成员，我们建立了Hck F/F“敲入”小鼠，这些小鼠携带COOH末端的靶向酪氨酸(Y)到苯丙氨酸(F)的替代，HCK蛋白中的负调控Y499-残基。与hkK−/−“功能丧失”小鼠不同，hkF/F“功能获得”小鼠自发地获得了一种肺部病理，其特征是肺实质、肺泡腔和血管周围广泛的嗜酸性粒细胞和单核细胞浸润，以及传导气道内明显的上皮粘液化生。Hck F/F小鼠的肺显示轻度肺气肿和肺纤维化区域，与炎症一起导致老年小鼠肺功能改变和呼吸窘迫。经鼻注射脂多糖后，小鼠表现出过度的肺天然免疫反应，表现为基质金属蛋白酶和肿瘤坏死因子α的过度释放。类似地，Hck F/F小鼠在全身注射脂多糖后对内毒素血症高度敏感，来自Hck F/F小鼠的巨噬细胞和中性粒细胞在体外表现出增强的效应功能(例如，一氧化氮和肿瘤坏死因子α的产生、趋化和脱颗粒)。根据已证实的HCK与白细胞整合素的功能联系，我们认为HCK的结构性激活可能模仿了白细胞的黏附依赖启动。因此，我们的观察共同表明，在Hck F/F小鼠中，先天免疫反应增强，从而使先天免疫从可逆的生理宿主防御反应转向导致不可逆的组织损伤。
To identify the physiological role of Hck, a functionally redundant member of the Src family of tyrosine kinases expressed in myelomonocytic cells, we generated HckF/F “knock-in” mice which carry a targeted tyrosine (Y) to phenylalanine (F) substitution of the COOH-terminal, negative regulatory Y499-residue in the Hck protein. Unlike their Hck−/− “loss-of-function” counterparts, HckF/F “gain-of-function” mice spontaneously acquired a lung pathology characterized by extensive eosinophilic and mononuclear cell infiltration within the lung parenchyma, alveolar airspaces, and around blood vessels, as well as marked epithelial mucus metaplasia in conducting airways. Lungs from HckF/F mice showed areas of mild emphysema and pulmonary fibrosis, which together with inflammation resulted in altered lung function and respiratory distress in aging mice. When challenged transnasally with lipopolysaccharide (LPS), HckF/F mice displayed an exaggerated pulmonary innate immune response, characterized by excessive release of matrix metalloproteinases and tumor necrosis factor (TNF)α. Similarly, HckF/F mice were highly sensitive to endotoxemia after systemic administration of LPS, and macrophages and neutrophils derived from HckF/F mice exhibited enhanced effector functions in vitro (e.g., nitric oxide and TNFα production, chemotaxis, and degranulation). Based on the demonstrated functional association of Hck with leukocyte integrins, we propose that constitutive activation of Hck may mimic adhesion-dependent priming of leukocytes. Thus, our observations collectively suggest an enhanced innate immune response in HckF/F mice thereby skewing innate immunity from a reversible physiological host defense response to one causing irreversible tissue damage.
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白介素5缺乏消除小鼠哮喘模型中的嗜酸性粒细胞，气道高反应性和肺损伤。
影响因子：
15.3
作者：
Foster, PS;Hogan, SP;Ramsay, AJ;Matthaei, KI;Young, IG
通讯作者：
Young, IG
影响因子：
64.5
作者：
CARTWRIGHT, CA;ECKHART, W;KAPLAN, PL
通讯作者：
KAPLAN, PL
影响因子：
64.5
作者：
IMAMOTO, A;SORIANO, P
通讯作者：
SORIANO, P
影响因子：
2.2
作者：
FALK, W;GOODWIN, RH;LEONARD, EJ
通讯作者：
LEONARD, EJ
DOI：
10.1165/ajrcmb.13.1.7598937
发表时间：
1995-07-01
影响因子：
6.4
作者：
COYLE, AJ;LEGROS, G;ANDERSON, GP
通讯作者：
ANDERSON, GP