Mapping Immune Cell Responses to High Pressures in Decompression Illness
Abstract
Approved for Public ReleaseBACKGROUND: As divers descend, their lungs experience significant increases in pressure tomatch that of t,he surrounding environment. This increased pressure drives gas to dissolve intopulmonary vessels that can nucleate upon decompressio,n. Circulation of these nucleated bubblescause a host of issues described by decompression illness (DCI). While the presence of bubb,les invessels is related to DCI, their abundance does not correlate with clinical symptoms, obfuscatingdiagnostic efforts and the et,iology of DCI. Our central hypothesis is that immune cells in the lungsand blood are influenced by the dissolution of gases generate,d from diving, which contribute toimmune activation states that underly DCI.RATIONALE: Immune cells respond to a myriad of signals i,n a tightly coordinated manner.While much is known about their responses to molecular cues, their responses to physical cues areless, understood. Growing evidence suggests that dissolved gases play an important role in immuneresponses (e.g., cell activation, microp,article formation, cytokine secretion). However, few studiesif any have examined the underlying epigenetic factors that govern cellu,lar responses to conditionsfrom diving in a physiologically accurate manner. This project will address this gap by developinga press,urized lung-on-a-chip device that recapitulates diving scenarios by permitting ,e blood.APPROACH: We will test our hypothesis in three objectives. First, we will study how peripheralblood mononuclear cells (e.g.,, monocytes, neutrophils, and immature dendritic cells) respond toconditions from diving using the pressurized lung-on-a-chip device., Second, we will perform opengenome-wide screens on peripheral blood monocytes to identify genes responsible for phenotypicchanges.,Third, we will examine the response of primary alveolar macrophages. These studies willreveal how different types of immune cells re,spond to diving in a physiologically relevant manner,and they will provide insight into the variability of immune responses across i,ndividuals.OUTCOMES: The outcome of this work will be an improved understanding of how immune cellsin the lungs and blood respond to, conditions from diving. This will be performed using a lung-ona-chip device that permits efficient gas exchange from the compressed, air phase into blood, whichis consistent with lung physiology during diving. Using this device, we will (i) identify key genesrespo,nsible for cellular responses to dissolved gases and (ii) determine if immune responsespotentially leading to DCIare due to oxygen, toxicity or to an elevated partial pressure of nitrogenby adjusting the composition of compressed air.IMPACT ON THE DOD: The signif,icance of this project lies in its ability to show how differenttypes of immune cells respond to diving in a physiologically accurat,e manner. This device providesthe unique ability to perform physiologically relevant experiments with controls that are difficultto,replicate in human subjects. We will show if immune cell reactions to increased dissolved gasesare deterministic. If so, this device, could be used as a tool to predictand identifyindividualswho are more suspectable to severe DCI. Such predictive power could have, long-term implicationsin identifying at-risk individuals to ensure safer diving practices and guiding the development ofnew therapi,es. The scope of this work directly aligns with the mission of the Undersea Medicine& Performance Program at the ONR, as it serves t,o better understand the pathology of DCI, and itmay eventually lead to new opportunities to mitigate it.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 13, 2022
- Source ID
- N000142212541
Entities
People
- Charles Shields
Organizations
- Office of Naval Research
- Regents of the University of Colorado
- United States Navy