Deficiency of Integrin β4 Results in Increased Lung Tissue Stiffness and Responds to Substrate Stiffness via Modulating RhoA Activity.
Deficiency of Integrin β4 Results in Increased Lung Tissue Stiffness and Responds to Substrate Stiffness via Modulating RhoA Activity.
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DOI：
10.3389/fcell.2022.845440
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发表时间：
2022
影响因子：
5.5
通讯作者：
Xiang Y
中科院分区：
文献类型：
--
作者：
Chi Y;Chen Y;Jiang W;Huang W;Ouyang M;Liu L;Pan Y;Li J;Qu X;Liu H;Liu C;Deng L;Qin X;Xiang Y
细胞外基质（ECM）和上皮细胞之间的相互作用在肺发育中起着关键作用。我们的研究发现，条件性整合素β4（ITGB 4）基因敲除小鼠出现肺发育不良和肺组织僵硬度增加。根据我们先前关于ITGB 4在支气管上皮细胞（BEC）中的功能的研究，我们假设在胚胎阶段ITGB 4表达的降低导致异常ECM重塑和增加的组织硬度，从而损害BEC运动性和损害肺发育。在这项研究中，我们使用原子力显微镜（AFM）检查了正常和ITGB 4缺陷小鼠的肺组织硬度，并证明ITGB 4缺陷导致肺组织硬度增加。ECM成分胶原、弹性蛋白和赖氨酰氧化酶（LOX）家族的检测显示，与正常组相比，ITGB 4缺陷小鼠中VI型胶原、弹性蛋白和LOXL 4的表达显著升高。通过视频显微镜和流式细胞术评价气道上皮细胞在正常和刚性基质上的迁移和增殖能力。用激光共聚焦显微镜观察细胞骨架的形态，用荧光共振能量转移（FRET）显微镜观察RhoA的活性。结果表明，ITGB 4缺陷细胞的迁移和增殖明显受到抑制，细胞骨架稳定性沿着下降，RhoA活性降低，尤其是在刚性基质上培养的细胞。这些结果表明，ITGB 4表达减少导致肺组织硬度增加，并损害支气管上皮细胞对基质硬度的适应，这可能与支气管肺发育不良的发生有关。
The interaction between extracellular matrix (ECM) and epithelial cells plays a key role in lung development. Our studies found that mice with conditional integrin β4 (ITGB4) knockout presented lung dysplasia and increased stiffness of lung tissues. In accordance with our previous studies regarding the functions of ITGB4 in bronchial epithelial cells (BECs), we hypothesize that the decreased ITGB4 expression during embryonic stage leads to abnormal ECM remodeling and increased tissue stiffness, thus impairing BECs motility and compromising lung development. In this study, we examined lung tissue stiffness in normal and ITGB4 deficiency mice using Atomic Force Microscopy (AFM), and demonstrated that ITGB4 deficiency resulted in increased lung tissue stiffness. The examination of ECM components collagen, elastin, and lysyl oxidase (LOX) family showed that the expression of type VI collagen, elastin and LOXL4 were significantly elevated in the ITGB4-deficiency mice, compared with those in normal groups. Airway epithelial cell migration and proliferation capacities on normal and stiff substrates were evaluated through video-microscopy and flow cytometry. The morphology of the cytoskeleton was detected by laser confocal microscopy, and RhoA activities were determined by fluorescence resonance energy transfer (FRET) microscopy. The results showed that migration and proliferation of ITGB4 deficiency cells were noticeably inhibited, along decreased cytoskeleton stabilization, and hampered RhoA activity, especially for cells cultured on the stiff substrate. These results suggest that decreased ITGB4 expression results in increased lung tissue stiffness and impairs the adaptation of bronchial epithelial cells to substrate stiffness, which may be related to the occurrence of broncho pulmonary dysplasia.
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影响因子：
6.5
作者：
Brinckmann, J;Neess, CM;Scharffetter-Kochanek, K
通讯作者：
Scharffetter-Kochanek, K
影响因子：
5.3
作者：
Bober, Marta;Enochsson, Charlotte;Morgelin, Matthias
通讯作者：
Morgelin, Matthias
DOI：
10.1016/j.jtcvs.2013.10.039
发表时间：
2014-07-01
影响因子：
6
作者：
Hsu, Han-Shui;Liu, Chen-Chi;Hung, Shih-Chieh
通讯作者：
Hung, Shih-Chieh
DOI：
10.1164/arrd.1985.131.4.568
发表时间：
1985-01-01
期刊：
AMERICAN REVIEW OF RESPIRATORY DISEASE
影响因子：
--
作者：
BRUCE, MC;WEDIG, KE;FANAROFF, AA
通讯作者：
FANAROFF, AA
影响因子：
3.5
作者：
Bonaldo, P;Braghetta, P;Bressan, GM
通讯作者：
Bressan, GM