Presented By: Biomedical Engineering
Biomedical Engineering Seminar Series
Hannah Viola, Postdoctoral Research Fellow, Shea Lab, Biomedical Engineering, University of Michigan
Nanoparticles target monocytes to promote resolution of pulmonary fibrosis
Abstract:
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressively fatal lung disease of unknown etiology that affects over 80,000 Americans and leads to death or lung transplantation within 5 years for more than half of patients. IPF is characterized by progressive, intractable fibrotic remodeling of the distal lungs mediated by key pathogenic cell types, especially activated fibroblasts (i.e., myofibroblasts), distal lung epithelial cells, and recruited myeloid cells. In IPF, these key cell types cooperate in a self-perpetuating, dysregulated, and pathogenic wound healing response that emerges from a “perfect storm” of suceptibility factors including chronic lung injury (e.g. smoking); certain genetic and epigenetic modifications; and cellular senescence due to natural aging. Only two therapies are FDA-approved for IPF, and while they have slowed progression in some patients, they do not halt or reverse disease and can have severe side effects. Therefore, therapies are urgently needed that not only disrupt the disease process to halt progression, but actually promote reversal of fibrotic remodeling to restore homeostatic lung structure and function. Fibrosis reversal occurs spontaneously in the lung under certain conditions, allowing a comparison to the failure of resolution in IPF. Fibrosis resolution is a complex process that requires specific activation states, functional behaviors, and communication circuits between multiple cell types that culminate in fibrinolysis and restoration of normal tissue.
In particular, monocytes and their derivatives (macrophages, dendritic cells) are central to successful resolution. They coordinate myofibroblast and epithelial phenotypes via prolific secretion of myriad cytokines, enzymes, lipids, and other signaling molecules; secrete collagen degrading enzymes (i.e., matrix metalloproteases) to clear the injury-induced extracellular matrix (ECM); promote apoptosis of myofibroblasts; remove and process debris (dead cells, degraded proteins/ECM); and regulate the adaptive response to avoid autoimmunity. Critically, monocytes in the IPF lung do not facilitate resolution, and instead acquire a profibrotic monocyte-derived macrophage (Mo-AM) phenotype that drives disease through pathologic communication with structural cells. Here, we show that degradable poly(lactic-co-glycolic acid) nanoparticles (NPs) promote fibrosis resolution by priming circulating monocytes to become pro-resolving, rather than profibrotic, upon arrival in the lung. NPs reduce and possibly reverse lung collagen deposition in the single-dose bleomycin mouse model of pulmonary fibrosis. NPs also dramatically increase the presence of Ly6C lo non-classical monocytes (NCMOs) in the lung and spleen. NCMOs are known as anti-inflammatory promoters of tissue repair and vascular maintenance, but their functions in IPF are poorly studied. However, bulk RNA-sequencing
of NP- vs Vehicle-treated lungs identified upregulation of genes associated with fibrosis resolution that are enhanced in nonclassical monocytes (e.g., the key collagenase Mmp13). Overall, our data suggests that NPs are capable of reprogramming monocytes’ functional behaviors in the fibrotic lung to promote fibrinolysis and brestoration of function.
Abstract:
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressively fatal lung disease of unknown etiology that affects over 80,000 Americans and leads to death or lung transplantation within 5 years for more than half of patients. IPF is characterized by progressive, intractable fibrotic remodeling of the distal lungs mediated by key pathogenic cell types, especially activated fibroblasts (i.e., myofibroblasts), distal lung epithelial cells, and recruited myeloid cells. In IPF, these key cell types cooperate in a self-perpetuating, dysregulated, and pathogenic wound healing response that emerges from a “perfect storm” of suceptibility factors including chronic lung injury (e.g. smoking); certain genetic and epigenetic modifications; and cellular senescence due to natural aging. Only two therapies are FDA-approved for IPF, and while they have slowed progression in some patients, they do not halt or reverse disease and can have severe side effects. Therefore, therapies are urgently needed that not only disrupt the disease process to halt progression, but actually promote reversal of fibrotic remodeling to restore homeostatic lung structure and function. Fibrosis reversal occurs spontaneously in the lung under certain conditions, allowing a comparison to the failure of resolution in IPF. Fibrosis resolution is a complex process that requires specific activation states, functional behaviors, and communication circuits between multiple cell types that culminate in fibrinolysis and restoration of normal tissue.
In particular, monocytes and their derivatives (macrophages, dendritic cells) are central to successful resolution. They coordinate myofibroblast and epithelial phenotypes via prolific secretion of myriad cytokines, enzymes, lipids, and other signaling molecules; secrete collagen degrading enzymes (i.e., matrix metalloproteases) to clear the injury-induced extracellular matrix (ECM); promote apoptosis of myofibroblasts; remove and process debris (dead cells, degraded proteins/ECM); and regulate the adaptive response to avoid autoimmunity. Critically, monocytes in the IPF lung do not facilitate resolution, and instead acquire a profibrotic monocyte-derived macrophage (Mo-AM) phenotype that drives disease through pathologic communication with structural cells. Here, we show that degradable poly(lactic-co-glycolic acid) nanoparticles (NPs) promote fibrosis resolution by priming circulating monocytes to become pro-resolving, rather than profibrotic, upon arrival in the lung. NPs reduce and possibly reverse lung collagen deposition in the single-dose bleomycin mouse model of pulmonary fibrosis. NPs also dramatically increase the presence of Ly6C lo non-classical monocytes (NCMOs) in the lung and spleen. NCMOs are known as anti-inflammatory promoters of tissue repair and vascular maintenance, but their functions in IPF are poorly studied. However, bulk RNA-sequencing
of NP- vs Vehicle-treated lungs identified upregulation of genes associated with fibrosis resolution that are enhanced in nonclassical monocytes (e.g., the key collagenase Mmp13). Overall, our data suggests that NPs are capable of reprogramming monocytes’ functional behaviors in the fibrotic lung to promote fibrinolysis and brestoration of function.
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