Inhibition of calcineurin/NFATc4 signaling attenuates ventilator­induced lung injury.

Ventilator­induced lung injury (VILI) is a life­threatening condition caused by the inappropriate use of mechanical ventilation (MV). However, the precise molecular mechanism inducing the development of VILI remains to be elucidated. In the present study, it was revealed that the calcineurin/NFATc4 signaling pathway mediates the expression of adhesion molecules and proinflammatory cytokines essential for the development of VILI. The present results revealed that a high tidal volume ventilation (HV) caused lung inflammation and edema in the alveolar walls and the infiltration of inflammatory cells. The calcineurin activity and protein expression in the lungs were increased in animals with VILI, and NFATc4 translocated into the nucleus following calcineurin activation. Furthermore, the translocation of NFATc4 and lung injury were prevented by a calcineurin inhibitor (CsA). Thus, the present results highlighted the critical role of the calcineurin/NFATc4 signaling pathway in VILI and suggest that this pathway coincides with the release of ICAM­1, VCAM­1, TNF­α and IL­1ß.

Transient receptor potential vanilloid 4 is a critical mediator in LPS mediated inflammation by mediating calcineurin/NFATc3 signaling.

Transient Receptor Potential Vanilloid 4 (TRPV4) ion channel is thought to be an essential component of inflammatory response. However, its role and mechanism in regulating acute lung injury (ALI) and macrophages activation are not well characterized. In our study, we observe that blockade of TRPV4 using GSK2193874 or HC-067047 greatly improve the pneumonedema, the lung pathologic changes, the up-regulation of proinflammatory cytokines and the neutrophil infiltration in LPS-induced lung injury. In vitro, knockdown of TRPV4 in macrophages reduces the levels of pro-inflammatory cytokines, ROS production, Ca2+ concentration in cytoplasma and the activation of calcineurin/NFATc3 signaling. Importantly, change of extracellular Ca2+ in culture medium prevents LPS-induced NFATc3 nuclear translocation, up-regulation of proinflammatory cytokines and ROS production in macrophages. Inhibition of calcineurin with cyclosporine A, FK506 down-regulates the levels of NFATc3 nuclear translocation and proinflammatory cytokines expression. Our results demonstrate that TRPV4-dependent Ca2+ influx contributes to LPS-induced macrophage activation by calcineurin-NFATc3 pathway.

Facile synthesis and intrinsic conductivity of novel pyrrole copolymer nanoparticles with inherent self-stability.

Intrinsically self-stabilized nanoparticles of a copolymer from 4-sulfonic diphenylamine (SD) and pyrrole (PY) were facilely synthesized in HCl solution at 10 degrees C by a chemically oxidative polymerization. The critical reaction parameters such as SD/PY ratio, polymerization time, and oxidant species were studied to significantly optimize the polymerization yield, size, conductivity, and solubility of the final copolymer particles. The molecular structure, size, size distribution, and morphology of the particles were analyzed by IR spectroscopy, laser particle-size analysis (LPA), atomic force microscopy, and transmission electron microscopy (TEM). It was found that the polymerization yield of the SD/PY (50/50) copolymers increased dramatically in the initial 2 h of polymerization and then slowly enlarged in the subsequent 22 h. However, the copolymerization yield for the polymerization time of 24 h exhibited a nonlinear dependence on the SD/PY molar ratio, i.e., a maximum at 10/90 and a minimum at 80/20. The number-average diameter, Dn, of the copolymer particles strongly depended on the SD/PY ratio, decreasing rapidly from 6402 to 291 nm as the SD/PY molar ratio changed from 30/70 to 50/50, whereas the polydispersity index, PDI = Dw/Dn (where Dw is the weight-average diameter), surprisingly maintained very small values, decreasing slightly from 1.21 to 1.08. The SD/PY (80/20) copolymer particles prepared with (NH4)2S2O8 as the oxidant had the smallest size of ca. 10 nm by TEM and the lowest Dw/Dn value of 1.03 by LPA, whereas the copolymer particles prepared with FeCl3 as the oxidant exhibited the second smallest size of ca. 20 nm by TEM and the highest conductivity. The conductivity of the SD/PY (50/50) copolymers rose first and then decreased with increasing polymerization time from 10 min to 24 h, exhibiting a maximum (0.217 S/cm) at 12 h. It is of interest that the copolymer particles with SD/PY molar ratios in the range between 50/50 and 80/20 surprisingly exhibited the smallest size, the narrowest size distribution, and the highest conductivity at the same time. In particular, the copolymer nanoparticles exhibited high purity, clean surfaces, good self-stability, high conductivity, and strong chemoresistance that were very important to nanomaterial processibility and application. The obtained copolymers were partially soluble in concentrated H2SO4, demonstrating a new direction for synthesizing a soluble pyrrole copolymer.