Chronic Innate Immune Adaptation to Organic Dust

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DESCRIPTION (provided by applicant) Organic dust exposure is an important occupational hazard for persons who work in swine confinement barns. Organic dust exposure to naive individuals results in an intense systemic and pulmonary inflammatory response that attenuates over time, suggestive of immunologic adaptation. However, despite evidence for adaptation to the exposure, one-third of all workers develop chronic lung disease. This important observation suggests that repeat organic dust exposure modulates the immune system response. Numerous studies have characterized the inflammatory response to a single organic dust exposure, but there have been few studies characterizing the response to repeat exposures. Utilizing a newly developed murine model, the investigators have demonstrated that mice adapt to repeat swine facility organic dust exposure, yet manifest evidence of lung tissue inflammation. This led them to explore the innate immune inflammatory response to repeat versus single organic dust exposure. In human monocytes, the investigators found that a unique inflammatory response occurs to repeat swine facility organic dust exposure as compared to a single exposure, which is independent of endotoxin. Repeat exposure to swine facility dust results in diminished tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-6, and IL-1-beta, but persistently elevated IL-8 and IL-10 compared to a single dust challenge in human monocytes. Elevated IL-10 suppresses pro-inflammatory cytokines, but has also been associated with mucus metaplasia and lung tissue inflammation in mice. Preliminary data also suggest that the inflammatory response to organic dust may be mediated through protein kinase C (PKC) activity. Based on these novel observations, the investigators hypothesize that chronic innate immune inflammatory adaptation responses occur with repeat organic dust exposure. To test this hypothesis, they will perform experiments outlined in three specific aims. In aim 1, the investigators will characterize and establish the inflammatory mediators involved with repeat versus single organic dust exposure in human monocytes. In aim 2, they will determine the mechanisms of repeat versus single organic dust-induced inflammation focusing on the key role of PKC activation. In aim 3, the investigators will determine the role of specific inflammatory mediators and PKC activation using an in vivo model of repeat versus single organic dust exposure in mice. Finally, the candidate is an adult allergist and immunologist with an interest in organic dust-induced diseases. She is a well-supported candidate with a long-standing interest in becoming a physician scientist who will benefit highly from a Clinical Scientist Development Award.