Cell-type-specific crosstalk between p38 MAPK and Rho signaling in lung micro- and macrovascular barrier dysfunction induced by Staphylococcus aureus-derived pathogens.
Cell-type-specific crosstalk between p38 MAPK and Rho signaling in lung micro- and macrovascular barrier dysfunction induced by Staphylococcus aureus-derived pathogens.
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金黄色葡萄球菌衍生病原体引起的肺微血管和大血管屏障功能障碍中 p38 MAPK 和 Rho 信号之间的细胞类型特异性串扰。
DOI：
10.1016/j.trsl.2013.03.005
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发表时间：
2013
期刊：
影响因子：
--
通讯作者：
Birukova,AnnaA
中科院分区：
文献类型：
--
作者：
Wu,Tinghuai;Xing,Junjie;Birukova,AnnaA
Lung inflammation and alterations in endothelial cell (EC) micro- and macrovascular permeability are key events to development of acute lung injury. Using ECs derived from human pulmonary artery and lung microvasculature, we investigated the interplay between p38 stress mitogen-activated protein kinase (MAPK) and Rho guanosine triphosphatase signaling in inflammatory and hyperpermeability responses. Both cell types were treated with Staphylococcus aureus-derived peptidoglycan (PepG) and lipoteichoic acid (LTA) with or without pretreatment with p38 MAPK or Rho kinase inhibitors. LTA and PepG increased permeability markedly in both pulmonary macrovascular and microvascular ECs. Agonist-induced hyperpermeability was accompanied by cytoskeletal remodeling, disruption of cell-cell contacts, formation of paracellular gaps, and activation of p38 MAPK, nuclear factor kappa-B (NFκB), and Rho/Rho kinase signaling. In macrovascular ECs, pharmacologic inhibition of Rho kinase with Y27632 suppressed p38 MAP kinase cascade activation significantly, whereas inhibition of p38 MAPK with SB203580 had no effect on Rho activation. In contrast, inhibition of p38 MAPK in microvascular ECs suppressed LTA/PepG-induced activation of Rho, whereas the Rho inhibitor suppressed activation of p38 MAPK. Inhibition of either p38 MAPK or Rho kinase attenuated activation of NFκB signaling substantially. These results demonstrate cell-type-specific differences in signaling induced by Staphylococcus aureus-derived pathogens in pulmonary endothelium. Thus, although Gram-positive bacterial compounds caused barrier dysfunction in both EC types, it was induced by a different pattern of crosstalk between Rho, p38 MAPK, and NFκB signaling. These observations may have important implications in defining microvasculature-specific therapeutic strategies aimed at the treatment of sepsis and acute lung injury induced by Gram-positive bacterial pathogens.
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