Role of microtubule-associated signaling in Staphylococcus aureus-induced lung injury.

This study tested the role of microtubules (MT) in the mechanisms of SA-induced ALI. EC dysfunction was accompanied by decrease in acetylated tubulin, MT destabilization, and increased activity of histone deacetylase-6 (HDAC6) as a result of oxidative stress. HDAC6 inhibition using gene-specific siRNA or tubastatin A rescued SA-induced EC barrier disruption monitored by measurements of electrical resistance and macromolecular permeability. SA-induced EC dysfunction was associated with impaired MT-mediated delivery of cytoplasmic linker-associated protein 2 to the cell periphery limiting its interaction with adherens junction proteins and accompanied by increased Rho activity via activation of MT-bound Rho-specific GEF-H1, which was abolished by HDAC6 inhibition. SA also induced activation of NF-kB signaling and expression of adhesion molecules ICAM1 and VCAM1, which was HDAC6-dependent and mediated, at least in part, by GEF-H1/Rho mechanism. In vivo, HDAC6 knockout mice and wild type mice treated with HDAC6 inhibitor were partially protected from ALI caused by heat-killed or live SA, as determined by Evans blue extravasation into lung tissue, increased cell and protein content and inflammatory cytokines levels in lavage fluid. Altogether, these results demonstrate a novel signaling axis of SA-induced ROS-dependent upregulation of HDAC6 activity resulting in MT destabilization and subsequent activation of GEF-H1/Rho pathway of EC permeability and inflammation.
Source: European Respiratory Journal - Category: Respiratory Medicine Authors: Tags: Mechanisms of Lung Injury and Repair Source Type: research