Meng Fanyong, Mambetsariev Isa, Tian Yufeng, Beckham Yvonne, Meliton Angelo, Leff Alan, Gardel Margaret L, Allen Michael J, Birukov Konstantin G, Birukova Anna A
1 Lung Injury Center, Section of Pulmonary and Critical Care Medicine, Department of Medicine, and.
Am J Respir Cell Mol Biol. 2015 Feb;52(2):152-61. doi: 10.1165/rcmb.2013-0468OC.
Reversible changes in lung microstructure accompany lung inflammation, although alterations in tissue micromechanics and their impact on inflammation remain unknown. This study investigated changes in extracellular matrix (ECM) remodeling and tissue stiffness in a model of LPS-induced inflammation and examined the role of lipoxin analog 15-epi-lipoxin A4 (eLXA4) in the reduction of stiffness-dependent exacerbation of the inflammatory process. Atomic force microscopy measurements of live lung slices were used to directly measure local tissue stiffness changes induced by intratracheal injection of LPS. Effects of LPS on ECM properties and inflammatory response were evaluated in an animal model of LPS-induced lung injury, live lung tissue slices, and pulmonary endothelial cell (EC) culture. In vivo, LPS increased perivascular stiffness in lung slices monitored by atomic force microscopy and stimulated expression of ECM proteins fibronectin, collagen I, and ECM crosslinker enzyme, lysyl oxidase. Increased stiffness and ECM remodeling escalated LPS-induced VCAM1 and ICAM1 expression and IL-8 production by lung ECs. Stiffness-dependent exacerbation of inflammatory signaling was confirmed in pulmonary ECs grown on substrates with high and low stiffness. eLXA4 inhibited LPS-increased stiffness in lung cross sections, attenuated stiffness-dependent enhancement of EC inflammatory activation, and restored lung compliance in vivo. This study shows that increased local vascular stiffness exacerbates lung inflammation. Attenuation of local stiffening of lung vasculature represents a novel mechanism of lipoxin antiinflammatory action.
肺微结构的可逆性变化伴随着肺部炎症，尽管组织微力学的改变及其对炎症的影响尚不清楚。本研究调查了脂多糖（LPS）诱导的炎症模型中细胞外基质（ECM）重塑和组织硬度的变化，并研究了脂氧素类似物15-表-脂氧素A4（eLXA4）在减轻炎症过程中硬度依赖性加重方面的作用。通过原子力显微镜对活肺切片进行测量，以直接测量气管内注射LPS引起的局部组织硬度变化。在LPS诱导的肺损伤动物模型、活肺组织切片和肺内皮细胞（EC）培养中评估了LPS对ECM特性和炎症反应的影响。在体内，通过原子力显微镜监测发现，LPS增加了肺切片中血管周围的硬度，并刺激了ECM蛋白纤连蛋白、I型胶原蛋白和ECM交联酶赖氨酰氧化酶的表达。硬度增加和ECM重塑加剧了LPS诱导的肺ECs中血管细胞黏附分子1（VCAM1）和细胞间黏附分子1（ICAM1）的表达以及白细胞介素8（IL-8）的产生。在高硬度和低硬度基质上生长的肺ECs中证实了炎症信号的硬度依赖性加重。eLXA4抑制了肺横截面中LPS增加的硬度，减弱了硬度依赖性增强的EC炎症激活，并在体内恢复了肺顺应性。本研究表明，局部血管硬度增加会加剧肺部炎症。减轻肺血管局部硬化代表了脂氧素抗炎作用的一种新机制。
