Project Details
Description
Project Summary
The Acute Respiratory Distress Syndrome affects as many as 190,000 people each year and has a mortality
rate as high as 46% despite improvement in beside management of mechanical ventilation strategies. There is
no specific therapy for ARDS, and novel therapeutic concepts are urgently needed. We have discovered that
the zinc-dependent metallothionein pathway exerts anti-inflammatory and cytoprotective effects during cell
stretch in vitro and during ventilator-induced lung injury in vivo, and in human subjects with ARDS. Our central
hypothesis/premise is that lung stretch initiates zinc-dependent lung protective molecular responses. A key
corollary of this hypothesis is that zinc repletion represents a low-risk, high reward therapeutic approach to
prevent and/or treat ARDS. However, regulation of zinc stores/metabolism is complex. In particular, low
plasma zinc levels do not necessarily reflect low tissue stores of zinc, and there is substantial heterogeneity in
zinc metabolism amongst critically ill patients. Thus, tailoring a safe and effective zinc supplementation
strategy for ARDS requires mechanistic and clinical data. We propose to examine the biologic and clinical
endpoints of zinc deficiency and response to zinc repletion in studies spanning cells to humans. In Aim 1, we
will determine the impact of zinc repletion on the response to cell stretch in vitro, examining the
pharmacokinetics, time course, and zinc import/export mechanisms underlying zinc repletion using models
mirroring human ARDS. In Aim 2, we will determine the effect of chemical rescue of zinc deficiency in
response to cell stretch using murine models of human ARDS to examine the pharmacokinetics, time course,
dosing strategy/interval, tissue/cellular zinc stores, and underlying mechanism of restoration of zinc deficiency
in both male and female mice. In Aim 3, we will determine the incidence and impact of zinc deficiency in
human ARDS through a comprehensive analysis of zinc levels in ARDS subjects throughout the course of
illness that will enable us to correlate zinc levels with clinical outcomes, as well as biomarkers of inflammation,
oxidant stress, epithelial injury, zinc transporter status, and host defense. These studies will reveal, for the first
time, the impact of zinc deficiency on the pathogenesis and therapy of ARDS and enable us to determine
which patients might benefit from zinc repletion during ARDS. Our long-term goal is to develop the first
targeted therapeutic and preventive strategy for ARDS. Importantly a Phase 1 trial recently completed
enrollment testing zinc supplementation to augment the immune response in sepsis, providing a foundation for
rapid clinical translation of this project.
Status | Finished |
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Effective start/end date | 4/1/19 → 3/31/24 |
Funding
- National Heart, Lung, and Blood Institute: $691,901.00
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