PROJECT SUMMARY
Environmental lung diseases are preventable disorders caused or made worse by adverse, inhaled exposures
to inflammation-inducing aerosolized agents such as endotoxin (lipopolysaccharide/LPS) and microbial
component-enriched organic dust. Every situation along the exposure continuum from long-term, low-level
exposure to one-time, high-dose exposure can cause lung injury and subsequent disease. Anthropogenic climate
change and associated industrial and agricultural intensification synergistically elevate worker and non-worker
risk of adverse respiratory health outcomes. Environmental inhaled exposures can cause significant lung and
airway inflammatory diseases including asthma, chronic bronchitis, pulmonary fibrosis, and chronic obstructive
pulmonary disease (COPD). Despite advances in understanding the key inflammatory signaling pathways
involved in initiating the lung inflammatory response, there remains a paucity of knowledge and efficacious
therapeutic options to hasten recovery and halt progression towards a chronic disease state. Our recent studies
strikingly demonstrate environmental exposure-induced recruitment and activation of distinct lung monocyte-
macrophage subpopulations involved in disease pathogenesis. Additionally, our bulk RNA sequencing, single
cell (sc) RNA sequencing, and monocyte/macrophage subpopulation-specific transcriptomic analyses of lung
homogenate harvested from mice given inhaled environmental exposures robustly implicate the aconitate
decarboxylase 1 (ACOD1)-itaconate immunometabolic pathway as a potential central regulator. The proposed
studies herein will be the first to investigate environmental exposure-induced lung disease through an
immunometabolic lens. To this end, I hypothesize that the ACOD1-itaconate axis operates as a critical, negative
regulator of lung monocyte/macrophage inflammatory processes in environmental exposure-induced lung injury
and inflammation. In Specific Aim 1, I will determine the functional effect of ACOD1-itaconate pathway induction
and modulation on human monocyte-derived macrophage differentiation and effector responses amidst
environmental inflammatory exposures. In Specific Aim 2, the role of the ACOD1 signaling pathway in mediating
lung inflammatory, resolving, and functional processes will be assessed in ACOD1 deficient mice exposed to
inhaled, environmental inflammatory agents. Additionally, I will determine the therapeutic potential of lung-
targeted, exogenous itaconate administration in hastening recovery following inhaled environmental exposure.
The results of these studies will have an important positive impact by establishing the pre-clinical groundwork
for understanding the ACOD1-itaconate axis in the context of environmental exposure-induced lung disease.
Completion of these aims will optimally inform the development of novel therapies capable of preventing
irreversible lung disease post-environmental exposure.
