Lung repair mechanisms mediated by the immune-fibroblast interface

PROJECT SUMMARY The pulmonary mesenchyme, which includes fibroblasts and smooth muscle, provides critical support for resident epithelial progenitors, but how it contributes to lung injury resolution is unclear. As a barrier organ the lung is constantly exposed to inhaled particulates, allergens, and respiratory pathogens. This barrage of exposures is countered by mucous secretions, antimicrobial agents, and sentinel immune cells. In the case of a more severe insult that causes lung damage, the inflammatory response and activation of wound-healing fibroblasts ensues. The research program described here seeks to elucidate how signaling between resident fibroblasts and immune cells controls the length and successful outcome of the lung injury repair response. Further, this research will test a new model proposed for the origins of human lung disease by testing how dysfunctional epithelial cells perpetuate the inflammation-driven fibroblast response. The overarching goal of this program is to determine the molecular pathways utilized by distinct fibroblast subsets and how they converge to shape the immune status of the lung. These questions will be explored by using our unique genetic mouse models for fibroblast lineages and in vivo models of respiratory dysfunction including chemical-induced injury or influenza infection. Moreover, we propose to employ a combination of sequencing analysis and establish novel organoid models to explore the interactions of fibroblast subsets and tissue resident immune cells. Together, our efforts will provide new insights in the mechanisms of lung repair resolution and build a foundation for novel future contributions.