Date of Award

2021

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Bioengineering

First Advisor

Rahim R. Rizi

Second Advisor

Maurizio Cereda

Abstract

Acute respiratory distress syndrome (ARDS) is a condition of rapid onset hypoxemia, pulmonary edema and collapse resulting from inflammatory lung injury, often requiring mechanical ventilation to avoid immediate death. Yet ventilator-induced lung injury (VILI) can also worsen ARDS progression. Developing and refining strategies to reduce VILI requires a thorough understanding of its mechanisms of onset and propagation. The main objective of this project is to develop computed tomography (CT)-based markers capable of predicting injury progression in ARDS, and to use these markers to test the efficacy of prone position ventilation in combination with therapeutic treatment (Imatinib) in ameliorating this progression.Early ventilation in the prone position improves blood gases and decreases mortality in ARDS, but the efficacy of prone positioning may change between early and later stages of injury. Furthermore, baseline characteristics of the primary injury may influence therapeutic response. Understanding the interaction between injury progression and prone positioning’s efficacy may help to target the patients who will benefit most from this therapy and could also help to refine both its timing and indications. Through a series of experiments porcine models of lung injury and patients with acute respiratory distress syndrome (ARDS), we found that the effects of prone positioning on lung aeration may depend on both the stage of lung injury and duration of prior ventilation—potentially limiting the clinical efficacy of this treatment if applied late. Restoring or protecting the endothelial barrier could minimize vascular damage in highly perfused tissue. Imatinib, a tyrosine kinase inhibitor used to treat chronic myelogenous leukemia, reduces injury severity in pre-clinical ARDS models as well as pulmonary leak index in clinical ARDS patients by inhibiting the Abl-related gene as well as related kinases and platelet-derived growth factor receptor (PDGFR), which are important in maintaining endothelial integrity. Our results using sequential CT scans showed that Imatinib mitigated lung injury in mechanically ventilated rats and reduced mortality while delaying functional and radiological injury progression. Imatinib also attenuated edema (lung tissue mass on CT) and capillary leak (BAL protein concentration), and treated animals displayed fewer histological and biological markers of inflammatory lung injury.

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