Journal
AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY
Volume 302, Issue 9, Pages L965-L975Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajplung.00292.2011
Keywords
cyclic stretch; actin; interleukin-6; vascular permeability; endothelium
Categories
Funding
- National Heart, Lung, and Blood Institute [HL-87823, HL-076259, HL-058064, HL-089257, HL-107920]
- American Heart Association
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Birukova AA, Tian Y, Meliton A, Leff A, Wu T, Birukov KG. Stimulation of Rho signaling by pathologic mechanical stretch is a second hit to Rho-independent lung injury induced by IL-6. Am J Physiol Lung Cell Mol Physiol 302: L965-L975, 2012. First published February 17, 2012; doi: 10.1152/ajplung.00292.2011.-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-kappa B 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, TNF alpha, 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.
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