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Tissue specific Cish expression supports alveolar macrophage homeostatic function

Shoger, Karsen E. (2020) Tissue specific Cish expression supports alveolar macrophage homeostatic function. Master's Thesis, University of Pittsburgh. (Unpublished)

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Abstract

Macrophages play critical roles in defense against microbes and clearance of dead cells, but also perform tissue specific functions in homeostasis. Distinct gene expression signatures in macrophages isolated from varying tissues are largely determined by environmental signals. Specifically, the lung is highly susceptible to environmental changes, such as O2 pressure and inhalation of particulate and microbes. Alveolar macrophages are shaped by the lung environment and have critical tissue-specific functions in initiating and resolving lung inflammation, and in maintaining lung structure via surfactant and lipid catabolism. While research speculates lung specific factors form alveolar macrophage phenotype and homeostatic function, the specific signals and regulators remain largely unknown. Therefore, we sought to explore lung specific cytokine signals and downstream signaling regulators that shape homeostatic functions of alveolar macrophages.
We found Cytokine Inducible SH2 Containing Protein (Cish), a SOCS family member known to regulate the JAK-STAT5 pathway, is basally expressed in a tissue-specific manner in alveolar macrophages. Further, we found that the STAT5 activating cytokine GM-CSF regulates Cish expression in alveolar macrophages and observed reduced alveolar macrophage Cish expression with GM-CSF blockade in the lung. Cish knockout mice exhibit enlarged “foamy” alveolar macrophages, impaired surfactant metabolism, and dysregulated response to GM-CSF, all hallmarks of pulmonary alveolar proteinosis. Thus, we show alveolar macrophage Cish expression is directly linked to lung specific factors, namely GM-CSF, and influences surfactant homeostasis in the lung, a critical homeostatic function of alveolar macrophages.
The lung is an especially critical site of protection as it is a barrier site that is constantly exposed to inhaled particulate and microbes and possesses a fragile structure. Alveolar macrophages act as sentinels in the lung, protecting this sensitive tissue from challenge while maintaining proper homeostasis and structure. From a public health perspective, continuing to elucidate the specific mechanisms by which alveolar macrophages mediate lung homeostasis is essential to providing cutting edge health care and to continuing to develop therapeutic treatments that can provide cures instead of simply mitigating symptoms of pulmonary disease. Here, we highlight one of many yet to be uncovered regulators of lung homeostasis.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Shoger, Karsen E.kas434@pitt.edukas434
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorGottschalk, Rachelrachel.gottschalk@pitt.edurachel.gottschalk
Committee MemberMailliard, Robbierbm19@pitt.edurbm19
Committee MemberMattila, Joshuajmattila@pitt.edujmattila
Date: 29 January 2020
Date Type: Publication
Defense Date: 3 December 2019
Approval Date: 29 January 2020
Submission Date: 20 November 2019
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 55
Institution: University of Pittsburgh
Schools and Programs: Graduate School of Public Health > Infectious Diseases and Microbiology
Degree: MS - Master of Science
Thesis Type: Master's Thesis
Refereed: Yes
Uncontrolled Keywords: Alveolar macrophage GM-CSF STAT5 Signaling Tissue homeostasis Lung Pulmonary alveolar proteinosis surfactant
Date Deposited: 29 Jan 2020 20:09
Last Modified: 29 Jan 2020 20:09
URI: http://d-scholarship.pitt.edu/id/eprint/37796

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