Immune crosstalk in lung injury and fibrosis

University Of Michigan At Ann Arbor, Ann Arbor MI

Investigators

Abstract

Abstract: The lung is generally effective in maintaining homeostasis despite constant exposure to injury and pathogens that can lead to acute and chronic infections, dysregulated repair, and fibrosis. Our broad-ranging past work has helped to identify that fibrosis is associated with pathologic accumulation of myeloid cells and the acquisition of transitional type 2 epithelial cells (AEC2s). Furthermore, we have shown that heparin-binding epidermal like growth factor (HB-EGF) produced by AEC2s is necessary for accumulation of pathologic myeloid cells and development of fibrosis, likely through juxtacrine signaling that requires cell-cell contact. Additional work from our laboratory has highlighted that fibrotic lungs are more susceptible to infection and that both bacterial and viral infections can exacerbate fibrosis with poor outcomes. Interestingly, fibrotic lungs are impaired in their ability to recruit neutrophils to clear gram-positive bacteria, while this is not true for gram-negative ones. The mechanistic basis for this differential susceptibility to bacteria in fibrotic lungs is unexplored. Thus, two goals of the current proposal will be first to study epithelial HB-EGF regulation of fibrosis and crosstalk with myeloid cells and second to uncover mechanisms for impaired innate immunity against gram-positive infections in fibrosis. Our past work has also identified that the impaired ability of patients post-hematopoietic stem cell transplant to be able to clear bacterial lung infections is related to overproduction of prostaglandin E2 which signals via the EP2 receptor on myeloid cells to impair function. Unfortunately, using systemic delivery of cyclooxygenase (COX) inhibitors to try and block this pathologic PGE2 secretion has significant toxicities, necessitating the need to develop cell-specific therapies. The third goal of this project will be to test delivery of COX inhibitors or EP2 antagonists conjugated to dextran nanoparticles which can uniquely target phagocytes in the lung. We believe that these nanoparticles will be a significant advance in delivering myeloid-specific therapeutics in many lung diseases. Finally, the fourth goal of this project will be to again study the impact of crosstalk between lung structural cells (epithelial cells and fibroblasts) with innate immune cells to understand how expression of TLR9 in structural cells ultimately regulates the functional activity of myeloid cells to clear bacterial infection post-influenza. Thus, this outstanding investigator award is broadly focused on how cross-talk between structural cells and immune cells can regulate pathogenesis and host defense in multiple models. The insights gained from these novel and ambitious goals will provide new insights into the pathogenesis of lung diseases and will identify and test new therapeutics. It will also allow the PI to continue to mentor trainees and faculty, to perform important scientific service and to serve in important leadership roles.