Date of Award

January 2022

Document Type

Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Huanxing Sun

Second Advisor

Erica L. Herzog

Abstract

A subset of sarcoidosis patients develops fibrotic interstitial lung disease (sarcoidosis-associated FILD, or S-FILD), a poorly understood condition characterized by the intrapulmonary accumulation of extracellular matrix (ECM) and recruited immune cells. We proposed that the interaction between these entities induces immunologic abnormalities that may contribute to fibrosis. To test this hypothesis, we created an ECM-based lung mimetic of scaffolds generated from decellularized human lungs. We compared the anatomic appearance, biochemical composition, mechanical characteristics, and immunomodulatory properties of Control or S-FILD scaffolds (CLS vs SLS). Anatomic evaluation achieved via histology revealed altered tissue architecture while biochemical evaluation achieved via LC/MS based proteomics and imaging mass cytometry revealed differential content of core matrisome proteins. Assessment of tissue mechanics by rheology showed an increase in shear modulus reflecting enhanced stiffness of the S-FILD ECM. Relative to CLS, SLS induced sarcoidosis peripheral blood mononuclear cells to adopt an altered ECM remodeling profile characterized by enhanced procollagen 1α1 expression and reduced MMP-9 activity. These findings suggest that the S-FILD microenvironment may promote the immunopathogenesis and progression of disease.

Comments

This thesis is restricted to Yale network users only. This thesis is permanently embargoed from public release.

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