Inhibition of calcineurin/NFATc4 signaling attenuates ventilator‑induced lung injury

Abstract

Ventilator-induced lung injury (Vili) is a life-threatening 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 icaM-1, VcaM-1, TnF-α and il-1β.

Single cell transcriptomic analysis of murine lung development on hyperoxia-induced damage

“…6b ; Supplementary Data 7 ). Increased expression of Vcam1 was previously reported in the lungs of mechanically ventilated rats 39 and increased Cd44 levels were associated with protective effects in hyperoxia-exposed mice 40 . Signals received by Myofib.…”

AGEs exacerbates coronary microvascular dysfunction in NoCAD by activating endoplasmic reticulum stress-mediated PERK signaling pathway

“…Our previous investigation showed that PERK phosphorylation increased the enzymatic activity of its down-stream effecter CaN by direct contact [12]. Activated CaN facilitates the nuclear translocation of NFATc4, which further modulates the transcription of targeted genes including Fas/FasL, COX2 and pro-inflammatory cytokines [15,16,30]. Our in vivo and in vitro studies data showed that PERK silencing inhibited PERK phosphorylation, leading to down-regulation of CaN activity and attenuation of NFATc4 nuclear translocation in CEMCs.…”

“…Moreover, we also proved that calcineurin (CaN) was a direct downstream effecter of PERK signaling, which facilitated activation of nuclear factor of activated T-cells (NFAT) [12,13]. The activation of PERK/CaN/NFAT pathway was reported to induce cell apoptosis through Fas/FasL pathway and to initiate transcriptions of targeted genes such as interleukins (IL), tumor necrosis factors (TNF) and thromboxanes (TXA) [14][15][16].…”

“…Up-regulation and formation of Fas/FasL complex recruits Fas-associated death domain proteins (FADD), triggers caspase cascade activation and eventually induces cell apoptosis [31]. CaN/NFATc4 pathway activation leads to synthesis and release of inflammatory cytokines including ILs and TNFs [15]. In the current study, we found PERK depletion effectively inhibited CaN/NFATc4 pathway activation and thus attenuated cell apoptosis and production of pro-inflammatory cytokines in CMECs isolated from AGEs-exposed NoCAD mice and AGEs-treated primary CMECs respectively.…”

Mitochondrial Disruption Is Involved in the Effect of Nuclear Factor of Activated T cells, Cytoplasmic 4 on Aggravating Cardiomyocyte Hypertrophy

“…NFATc4-induced inflammation response in different cell types, leading to increases in inflammatory factors and cytokines, which also leads to activations of PDK and Akt sequentially. 18,[23][24][25] In H9C2 cells, overexpression of NFATc4 promoted phosphorylation of PDK1 (Fig. 8A), whereas reduction was observed with the knockdown of NFATc4 (Fig.…”