Resolving Occupational Exposure-Induced Lung Disease

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Occupational lung diseases are the primary cause of occupation-associated illness in the U.S. based on frequency, severity, and preventability of the illnesses. Most occupational lung diseases are caused by repeated, long-term exposure to hazardous agents, but even a severe single exposure can damage the lungs. There are currently no medical therapies available to ameliorate lung injury/inflammation without exerting untoward side effects. The inability to adequately treat workers following occupational inflammatory exposure leads to chronic disease, and workers with respiratory disease have a higher incidence of filing for disability compared to those without respiratory disease. Importantly, there is a re-emergence in traditional respiratory occupational hazards caused by bacteria biological agents such as endotoxin. Exposures to endotoxin are high in agricultural production and emerging sectors such as waste treatment, recycling, biotech food production and processing industries. The COVID19 pandemic rapidly transpired as a devastating occupational respiratory viral-induced health illness significantly impacting workers of food processing plants with limited efficacious therapies. Without guidelines or therapies for the management of occupational exposure-induced lung injury/inflammation, there is an urgent and unmet need to identify alternative approaches to reduce disease burden. Our long-term goal is to find new strategies to promote the resolution of occupational exposure-associated lung inflammatory disease before it progresses to irreversible lung disease. Our recent discoveries using single cell RNA sequencing coupled with flow cytometry strongly implicate the recruited monocyte/macrophage, and we uncovered that delivering amphiregulin and interleukin (IL)-10 as lung-directed therapies appear to beneficially effect lung recovery processes post-occupational exposures. Our central hypothesis is that targeted cellular and mediator interventional approaches following various occupational inflammatory inhalant exposures can be developed to hasten lung recovery to reduce disease development. To model occupational bacterial and viral component- induced lung inflammation, Toll-like receptor (TLR) agonists and agriculture organic dust extract will be utilized. We seek to test our hypothesis by addressing three independent and synergistic aims. In Aim 1, we will determine the time-dependent cellular and specific monocyte/macrophage lung cell events following occupational exposures and whether targeting these cells hastens lung recovery. In Aim 2, we will determine the role of amphiregulin as a potential lung-directed therapeutic approach in the resolution inhalant occupational exposures. In Aim 3, we will determine how inhalant IL-10 treatment works to promote repair in the recovery process after lung inflammation induced by occupational exposures. The results of these studies will have an important positive impact because they lay the pre-clinical groundwork for understanding key cellular and mediator responses, and the ultimate development of new strategies to treat occupational exposure-induced lung inflammation prior to the development of irreversible lung disease.