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Alterations of CCSP expression and macrophages metabolism in the development of silica-induced pulmonary inflammation and fibrosis

Marrocco, Antonella (2020) Alterations of CCSP expression and macrophages metabolism in the development of silica-induced pulmonary inflammation and fibrosis. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Silicosis is a lethal pneumoconiosis, for which no therapy is available. Silicosis is a public health threat: more than 2.2 million people/year in the US and 230 million/year worldwide, are exposed to silica, and consequently are at increased risk of active mycobacterial tuberculosis (TB), and lung cancer. The initial response to silica is mediated by the innate immunity in a two-stage process: 1)injury of conducting epithelium at distal lung, loss of Club cells secretory protein (CCSP), and impairment of regenerative capacity; 2)phagocytosis of silica by macrophages, metabolic alterations, oxidative stress, and release of reactive-oxygen-species (ROS) and inflammatory cytokines, such as Interleukin-(IL-)1β, Tumor necrosis factor-(TNF-)α, Interferon-(IFN-)β. However, the specific role of airway epithelium and macrophage in the pathogenesis of silicosis in humans is poorly understood.
This study focuses on whether silica-induced inflammation compromises the Club cells ability to regenerate bronchiolar and/or alveolar epithelium and on the macrophages metabolic alterations that occurs upon phagocytosis of silica, leading to chronic inflammation.
Using wild-type and CCSP-deficient (CCSP-/-) mice we exhibit that the development of the silicotic nodules in the lung is characterized by peri-bronchiolar inflammatory cell recruitment and tissue fibrosis, that compromises the expression and proliferation of CCSP-expressing progenitor cells and limits the reparative properties of the distal airway epithelium, resulting in exacerbation of silicosis. We reveal an immunomodulatory role for CCSP in response to silica both in mice and in human lungs.
Subsequently, using murine RAW 264.7 macrophage cell lines, and state- of- art techniques, such as high-resolution respirometer and liquid chromatography-high resolution mass spectrometry (LC-HRMS), to determine the effects of silica on mitochondrial respiration, and the changes in central carbon metabolism of silica-exposed macrophages, we demonstrate that in contrast to the prevalent view, crystalline silica alone induces an innate immune response without previous macrophage activation with LPS, and yet different from the one LPS-induced, since they affect differently the CII of ETC, which plays a crucial role in macrophages survival and silica-induced inflammation.
Our data highlight the urgency to validate these concepts and elucidate the mechanisms underlying the silica-induced impairment of macrophages, development of inflammation and fibrosis, and consequent increased TB risk.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Marrocco, Antonellaantonella_marrocco@yahoo.itanm240
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorOrtiz, Luis A.lao1@pitt.edulao1
Committee ChairPitt, Brucebrucep@pitt.edubrucep
Committee MemberPearce, Linda Llip10@pitt.edulip10
Committee MemberPeterson, Jamesjimmyp@pitt.edujimmyp
Committee MemberWendell, Stacy Lgstacy@pitt.edugstacy
Date: 30 July 2020
Date Type: Publication
Defense Date: 5 June 2020
Approval Date: 30 July 2020
Submission Date: 25 May 2020
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 122
Institution: University of Pittsburgh
Schools and Programs: Graduate School of Public Health > Environmental and Occupational Health
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: silica, macrophages, RAW 264.7, IC-21, CCSP, metabolism, metabolic reprogramming, Club cells
Date Deposited: 31 Jul 2020 03:12
Last Modified: 15 Sep 2020 18:46
URI: http://d-scholarship.pitt.edu/id/eprint/39095

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