title: Stimulation of Rho signaling by pathologic mechanical stretch is a "second hit" to Rho-independent lung injury induced by IL-6.
abstract: Most patients with acute lung injury (ALI) and acute respiratory distress syndrome of septic and nonseptic nature require assisted ventilation with positive pressure, which at suboptimal range may further exacerbate lung dysfunction. Previous studies described enhancement of agonist-induced Rho GTPase signaling and endothelial cell (EC) permeability in EC cultures exposed to pathologically relevant cyclic stretch (CS) magnitudes. This study examined a role of pathologic CS in modulation of pulmonary EC permeability caused by IL-6, a cytokine increased in sepsis and acting in a Rho-independent manner. IL-6 increased EC permeability, which was associated with activation of Jak/signal transducers and activators of transcription, p38 MAP kinase, and NF-κB signaling and was augmented by EC exposure to 18% CS. Rho kinase inhibitor Y-27632 suppressed the synergistic effect of 18% CS on IL-6-induced EC monolayer disruption but did not alter the IL-6 effects on static EC culture. 18% CS also increased IL-6-induced ICAM-1 expression by pulmonary EC and neutrophil adhesion, which was attenuated by Y-27632. Intratracheal IL-6 administration in C57BL/6J mice increased protein content and cell count in bronchoalveolar lavage fluid. These changes were augmented by high tidal volume mechanical ventilation (HTV; 30 ml/kg, 4 h). Intravenous injection of Y-27632 suppressed IL6/HTV-induced lung injury. In conclusion, this study proposes a novel mechanism contributing to two-hit model of ALI: in addition to synergistic effects on Rho-dependent endothelial hyper-permeability triggered by thrombin, TNFα, LPS, or other agonists, ventilator-induced lung injury-relevant CS may also exacerbate Rho-independent mechanisms of EC permeability induced by other inflammatory mediators such as IL-6 via mechanisms involving Rho activity.
authors.affiliation: Lung Injury Center, Section of Pulmonary and Critical Medicine, Dept. of Medicine, Univ. of Chicago, Chicago, IL 60637, USA.
authors.forename: Anna A
authors.initials: AA
authors.lastname: Birukova
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Tian
authors.forename: Angelo
authors.initials: A
authors.lastname: Meliton
authors.forename: Alan
authors.initials: A
authors.lastname: Leff
authors.forename: Tinghuai
authors.initials: T
authors.lastname: Wu
authors.forename: Konstantin G
authors.initials: KG
authors.lastname: Birukov
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism; D055371:Acute Lung Injury / Q000209:etiology / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D000577:Amides / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000378:metabolism; D017097:Electric Impedance; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D015850:Interleukin-6 / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008168:Lung / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010539:Permeability; D059748:Proteolysis; D011651:Pulmonary Artery / Q000166:cytology; D011725:Pyridines / Q000494:pharmacology; D011897:Random Allocation; D012121:Respiration, Artificial / Q000009:adverse effects; D015398:Signal Transduction; D013314:Stress, Mechanical; D013312:Stress, Physiological; D020741:rho GTP-Binding Proteins / Q000378:metabolism*; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000577:Amides; D003598:Cytoskeletal Proteins; D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins; D011725:Pyridines; C108830:Y 27632; D054460:rho-Associated Kinases; D020741:rho GTP-Binding Proteins