miR‐146a regulates mechanotransduction and pressure‐induced inflammation in small airway epithelium

Abstract

Mechanical ventilation generates biophysical forces, including high transmural pressures, which exacerbate lung inflammation. This study sought to determine whether microRNAs (miRNAs) respond to this mechanical force and play a role in regulating mechanically induced inflammation. Primary human small airway epithelial cells (HSAEpCs) were exposed to 12 h of oscillatory pressure and/or the proinflammatory cytokine TNF-α. Experiments were also conducted after manipulating miRNA expression and silencing the transcription factor NF-κB or toll-like receptor proteins IRAK1 and TRAF6. NF-κB activation, IL-6/IL-8/IL-1β cytokine secretion, miRNA expression, and IRAK1/TRAF6 protein levels were monitored. A total of 12 h of oscillatory pressure and TNF-α resulted in a 5- to 7-fold increase in IL-6/IL-8 cytokine secretion, and oscillatory pressure also resulted in a time-dependent increase in IL-6/IL-8/IL-1β cytokine secretion. Pressure and TNF-α also resulted in distinct patterns of miRNA expression, with miR-146a being the most deregulated miRNA. Manipulating miR-146a expression altered pressure-induced cytokine secretion. Silencing of IRAK1 or TRAF6, confirmed targets of miR-146a, resulted in a 3-fold decrease in pressure-induced cytokine secretion. Cotransfection experiments demonstrate that miR-146a's regulation of pressure-induced cytokine secretion depends on its targeting of both IRAK1 and TRAF6. MiR-146a is a mechanosensitive miRNA that is rapidly up-regulated by oscillatory pressure and plays an important role in regulating mechanically induced inflammation in lung epithelia.

Influence of Inspiration to Expiration Ratio on Cyclic Recruitment and Derecruitment of Atelectasis in a Saline Lavage Model of Acute Respiratory Distress Syndrome*

“…The general principle that shortening exhalation times can prevent end-expiratory collapse without an increase in intrinsic PEEP, however, was also demonstrated in the study by Syringe et al (34), in that study by increasing RR. Other potential mechanisms of VILI that could accompany IRV, such as higher static stretch and higher mean airway pressures, possibly resulting in increased inflammation (35)(36)(37)(38), were not addressed in our study. IRV also carries some risk of increasing intrinsic PEEP, if not carefully monitored.…”

Evidence that miR‐146a attenuates aging‐ and trauma‐induced osteoarthritis by inhibiting Notch1, IL‐6, and IL‐1 mediated catabolism

“…We were the first to identify miR‐146a as a mechanoresponsive microRNA along with miR‐365 through cytomechanical screening of microRNA microarray (Guan, Yang, Wei & Chen, 2011). Since then, multiple studies have supported the role of miR‐146a as a mechano‐miR (Huang, Crawford, Higuita‐Castro, Nana‐Sinkam & Ghadiali, 2012; Li et al., 2012). In this study, we further show that, while cyclic load of human articular chondrocytes in 3D culture in physiological range stimulated miR‐146a expression, mechanical overload inhibited miR‐146a expression.…”

In vivo biological response to extracorporeal shockwave therapy in human tendinopathy

“…There is a surprising lack of literature to support the induction of IL-8 by mechanical loading in connective tissue, given that the biological mechanisms of IL-8 are well documented (Baggiolini and Clark-Lewis, 1992). However, mechanically induced up-regulation of IL-8 is not new; shear stresses and mechanical stretch increase IL-8 gene expression (Cheng et al, 2007) and secretion (Iwaki et al, 2009;Okada et al, 1998) in vascular endothelial cells, while vibration and oscillatory pressure changes increase IL-8 secretion in bronchial epithelium (Huang et al, 2012;Puig et al, 2005).…”