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A Study of Macrophages in the Aging Liver and in the Host Response to Engineered Lung Scaffolds

Stahl, Elizabeth C. (2019) A Study of Macrophages in the Aging Liver and in the Host Response to Engineered Lung Scaffolds. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Macrophages are innate immune cells that contribute to tissue remodeling and homeostasis, respond to foreign antigens, and regulate the recruitment and activation of auxiliary immune cells. In chronic disease or a foreign body reaction, macrophages drive inflammation, leading to tissue damage and fibrosis. As such, understanding the developmental and phenotypic diversity of macrophages is of interest in both the pathobiology of disease as well as the design of novel therapeutics and materials. This dissertation examines macrophage biology in two contexts: the aging liver and the host response to engineered lung scaffolds.
The liver contains two subsets of macrophages: a stable population of embryonically-derived Kupffer cells and a transient population of monocyte-derived macrophages. The dynamics of hepatic macrophages during the process of aging is unknown and may influence the development of chronic liver disease. Studies presented here demonstrate an increase in hepatic macrophages from naturally aged (19-months-old) mice compared to young counterparts (3-months-old). Macrophages from aged livers express significantly greater amounts of CD11b surface antigen and upregulate arginase strongly after exposure to interleukin-4, suggesting monocytic origins and a predisposition towards an alternatively activated phenotype. Aged livers also exhibit increased triglycerides and pro-inflammatory signals, including monocyte chemoattractant protein (MCP-1). Inhibiting MCP-1 signaling reduced lipids and inflammation but did not significantly alter the macrophage population. Additional methods to modulate hepatic macrophages remain to be studied in the context of age-associated pathologies.
Following implantation of biomaterials, macrophages are recruited and polarize to a classical or alternatively activated phenotype, which can influence the outcome of the foreign body response. A positive outcome is associated with reduced inflammation and is crucial for the success of animal-derived organs to be used for xenotransplantation. Studies presented herein demonstrate that the removal of the foreign Gal-epitope from decellularized porcine lung scaffolds improves the host response in non-human primates, in part by reducing CD86 expression on macrophages and preventing substantial adaptive immune recognition upon reimplantation.
Taken together, these studies further the understanding of macrophage biology in the aging liver and in the host response to Gal-epitopes and demonstrate novel strategies to reduce inflammation in chronic disease and tissue engineering contexts.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Stahl, Elizabeth C.ecs40@pitt.eduecs40
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorBrown, Bryanbrownb@upmc.edubryanbrown
Committee ChairMonga, Satdarshansmonga@pitt.edusmonga
Committee MemberMars, Wendywmars@pitt.eduwmars
Committee MemberStolz, Donnadonna.stolz@pitt.edudonna.stolz
Committee MemberDuncan, Andrewduncana@pitt.eduduncana
Committee MemberWagner, Williamwagnerwr@upmc.eduwagnerwr
Date: 21 February 2019
Date Type: Publication
Defense Date: 7 December 2018
Approval Date: 21 February 2019
Submission Date: 7 January 2019
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 156
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Cellular and Molecular Pathology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: liver macrophage aging biomaterials host response
Date Deposited: 21 Feb 2019 15:31
Last Modified: 21 Feb 2019 15:31


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