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Title: Mechanisms of pulmonary cell activation during ventilator-induced lung injury
Author: Woods, Samantha
ISNI:       0000 0004 6059 2765
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2016
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Mechanical ventilation is a life-saving intervention, but through exacerbating inflammation, it can contribute to mortality, known as ventilator-induced lung injury (VILI). Patients with acute respiratory distress syndrome (ARDS) are particularly susceptible to VILI, however, it is recognised that over-distension of the lung should also be avoided in patients with healthy lungs, whom are also at risk of VILI. It is important to minimise the adverse effects of mechanical ventilation, yet our understanding of how over-distension promotes the devastating inflammatory response in VILI remains poor. In this project, the kinetics of cellular activation were investigated within the lungs of mice following short periods of high tidal volume ventilation using phospho-flow cytometry. The results revealed that the alveolar epithelium is activated prior to alveolar macrophages, suggesting that the epithelium could be responsible for stimulating their activation. The activation observed was very rapid, leading me to hypothesise that communication between these two cell types could either occur via the release of soluble mediators, or through a direct-contact dependent mechanism. Subsequent experiments led to the theory that alveolar macrophages may become activated in response to stretch through the detection of the damage-associated molecular pattern ATP, which is rapidly released by the alveolar epithelium in response to cyclic stretching. These experiments also revealed that pulmonary endothelial cells may be the most sensitive pulmonary cell type to mechanical ventilation in vivo, indicating that stretch-induced inflammation could be immediately disseminated to the systemic circulation. This concept is in contrast to the current ‘decompartmentalisation’ model in which inflammatory mediators released within the alveolar space leak into the vasculature only following the breakdown of the alveolar-capillary barrier. This discovery has important implications for our understanding of the pathogenesis of multiple organ failure which is the most common cause of death in ARDS patients and therefore warrants further research.
Supervisor: Takata, Masao ; Wilson, Michael Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral