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Microtubule stability is affected by oxidative stress and contributes to lung injury and barrier dysfunction
Author(s) -
Birukova Anna A,
Tian Yufeng,
Sarich Nicolene,
Meliton Angelo
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.914.10
Subject(s) - oxidative stress , microbiology and biotechnology , reactive oxygen species , vascular permeability , inflammation , chemistry , signal transduction , endothelial dysfunction , biology , immunology , biochemistry , endocrinology
Pathologic activation of redox signaling by inflammatory agents causes endothelial cell (EC) activation and barrier dysfunction. Microtubules (MT) play an important role in the regulation of vascular endothelial permeability, but their impact in modulation of inflammation and EC barrier is not well understood. This study examined effects of LPS‐induced oxidative stress on MT dynamics and involvement of MT in the LPS‐induced mechanisms of Rho GTPase activation, EC permeability and lung injury. LPS treatment of pulmonary vascular EC induced elevation of reactive oxygen species (ROS) and oxidative stress leading to cytoskeletal remodeling, EC hyper‐permeability, increased neutrophil adhesion and activation of inflammatory signaling. LPS also triggered ROS‐dependent disassembly of the microtubule network leading to activation of MT‐dependent signaling. Stabilization of MT or inhibition of MT‐associated Rho‐specific GEF activity suppressed LPS‐induced EC barrier dysfunction in vitro and attenuated vascular leak and lung inflammation in vivo. These studies demonstrate for the first time the mechanism of ROS‐induced Rho activation via destabilization of MT and GEF‐H1‐dependent activation of Rho signaling leading to pulmonary EC barrier dysfunction and exacerbation of LPS‐induced inflammation. Funding: NHLBI HL089257 , HL107920