Identification and Preclinical Assessment of Novel Therapeutic Modalities in Environmental Exposure-induced Lung Disease

Author

Aaron D. Schwab, University of Nebraska Medical CenterFollow

ORCID ID

0000-0003-1142-7790

Graduation Date

Spring 5-10-2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Medical Sciences Interdepartmental Area

First Advisor

Jill A. Poole

Abstract

Environmental lung diseases are preventable respiratory conditions either caused or made worse by inhaled environmental exposures. Contemporarily, environmental lung diseases are most associated with workplace exposures given specific occupational processes aerosolize inflammatory agents that can be inhaled at high concentrations. Although a considerable amount is known regarding immunoglobulin (Ig)E-mediated responses to environmental exposures, little is known about non-IgE mediated respiratory conditions resulting from lipopolysaccharide (LPS)-enriched organic dust exposure(s). Chronic respiratory diseases such as asthma, hypersensitivity pneumonitis, chronic obstructive pulmonary disease (COPD), and pulmonary fibrosis have all been identified as environmental lung diseases caused or exacerbated by such environmental dusts. Therapeutic approaches for the management of environmental exposure induced lung inflammation are limited and without evidence of chronic disease risk mitigation. The work herein aims to address this knowledge gap by furthering mechanistic understanding of environmental exposure-induced lung inflammation while also identifying and assessing targeted therapeutic approaches to mitigate inflammatory consequences resulting from inhaled environmental exposure(s) and decrease chronic lung disease risk.

First, we delineated the magnitude and distribution of C-C motif chemokine receptor 2 (CCR2)⁺ inflammatory monocytes and monocyte-derived macrophages trafficked to the lung following environmental exposures. These cell populations have been implicated in facilitating the transition from acute inflammation to chronic disease development, so we subsequently determined whether targeting these lung populations would attenuate inflammatory consequences induced by these environmentally derived exposures. Secondly, we assessed the therapeutic potential of the anti-inflammatory and anti-fibrotic interleukin (IL)-10 in an acute organic dust extract (ODE) and repeated LPS exposure contexts to determine its ability to mitigate local and systemic inflammatory consequences resulting from these exposures. Finally, we characterized the role of aconitate decarboxylase 1 (ACOD1) in mediating lung inflammatory processes resulting from inhaled exposures and then assessed the therapeutic potential of a cell-permeable itaconate formulation, 4-octyl itaconate (4OI), post-environmental exposure. Notably, we corroborated a role for recruited, transitioning monocyte-macrophages in environmental exposure induced lung disease, established preclinical groundwork demonstrating the ability of IL-10 to mitigate environmental exposure induced lung disease and associated pathologic consequences, and demonstrated that ACOD1 plays a central role in mediating the lung pro-inflammatory response to inhaled environmental exposures.

Comments

2025 Copyright, the authors

Recommended Citation

Schwab, Aaron D., "Identification and Preclinical Assessment of Novel Therapeutic Modalities in Environmental Exposure-induced Lung Disease" (2025). Theses & Dissertations. 902.
https://digitalcommons.unmc.edu/etd/902