The Influence of Aging and Mechanical Stretch in Alveolar Epithelium ER Stress and Inflammation

Abstract

Ventilator-Induced lung injury (VILI) is a form of acute lung injury that is initiated or exacerbated by mechanical ventilation. The aging lung is more susceptible to lung injury. Harmful mechanical stretch of the alveolar epithelium is a recognized mechanism of VILI, yet little is known about how mechanical stretch affects aged epithelial cells. An activated response known as Endoplasmic Reticulum (ER) Stress occurs at the cellular level, which is increased with aging. The disrupted ER function results in disruption in cellular homeostasis, apoptosis, and inflammation. We hypothesized that age and mechanical stretch increase proinflammatory gene expression that is mediated by ER stress. Type II alveolar epithelial cells (ATII) were harvested from C57Bl6/J mice 8 weeks (young) and 20 months (old) of age. The cells were cyclically mechanically stretched at 15% change in surface area for up to 24 hours. Prior to stretch, groups were administered 4-PBA or vehicle as a control. Mechanical stretch upregulated both ER stress and proinflammatory gene expression in ATIIs. Age-matched and mis-matched monocyte recruitment by ATII conditioned media was quantified. Administration of 4-PBA attenuated both the ER stress and proinflammatory increases from stretch and/or age and significantly reduced monocyte migration to ATII conditioned media. Age increases susceptibility to stretch-induced ER stress and downstream inflammation in a primary ATII epithelial cell model.

miR-214 is Stretch-Sensitive in Aortic Valve and Inhibits Aortic Valve Calcification

“…It has been well established that ATF4 is a pro-osteogenic transcription factor 8,36 . Valentine et al 60 showed that exposure of mouse type II alveolar epithelial cells (ATII) to 15% stretch resulted in significant increase of ATF4 expression compared to static control. Yang et al 71 reported that 10% stretch significantly upregulated ATF4 expression in human periodontal ligament cells (hPDLCs) compared to static control.…”