Defense Date

2016

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Biomedical Engineering

First Advisor

Dr. Rebecca Heise

Second Advisor

Dr. Alpha Fowler

Abstract

Abstract

Background

The majority of patients requiring mechanical ventilation are over the age of 65 and advanced age is known to increase the severity of ventilator-induced lung injury (VILI) and mortality. However, the mechanisms which predispose aging ventilator patients to increased mortality rates are not fully understood.

Pulmonary edema is a hallmark of VILI and the severity of edema increases with age. Ventilation with conservative fluid management decreases mortality rates in acute respiratory distress (ARDS) patients, but has not been investigated in VILI. We hypothesized that age-associated increases in pulmonary edema promote age-related increases in ventilator-associated mortality. Endoplasmic reticulum (ER) stress can disrupt cellular functions and plays a key role in many disease states. The severity of ER stress also increases with age. We hypothesized that age-associated increases in ER stress also increase in the severity of VILI.

Finally, serum Vitamin C (VitC) levels also decrease with age. VitC treatments have been shown to decrease mortality rates in murine models of ARDS by and attenuate pulmonary edema. We hypothesize that VitC treatments will attenuate ventilator induced pulmonary edema in our aged murine subjects.

Methods

Mechanical Ventilation: Young and old mice were mechanically ventilated with either high tidal volume (HVT) or low tidal volume (LVT) for with either liberal or conservative fluid support. One group received VitC treatment prior to ventilation.

Cell Stretch: Alveolar epithelial cells (ATIIs) from young and old mice were harvested, cultured, and mechanically stretched. Treatment groups received ER stress inhibitor 4-PBA.

Results

Both advanced age and HVT ventilation significantly increased inflammation, injury, and decreased survival rates. Conservative fluid support significantly diminished pulmonary edema decreased mortality rates. VitC treatments significantly decreased pulmonary edema and improved pulmonary mechanics. Mechanical stretch promoted ER Stress and upregulated proinflammatory gene expression and secretion in aged ATIIs. ER stress inhibition attenuated all of these effects.

Conclusion

Conservative fluid management alone attenuated age-associated increases in ventilator-associated mortality. VitC treatments decreased pulmonary edema and partially restore pulmonary mechanics in old mice ventilated with HVT. ER stress inhibition decreased stretch induced proinflammatory gene expression and protein secretion in aged mechanically stretched ATII cells.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

8-12-2016

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