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Regulation and Function of Autophagy in Cigarette Smoke-Induced Cellular Stress: Implications for Chronic Obstructive Pulmonary Disease

Lam, Hilaire (2011) Regulation and Function of Autophagy in Cigarette Smoke-Induced Cellular Stress: Implications for Chronic Obstructive Pulmonary Disease. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Chronic obstructive pulmonary disease (COPD) is characterized by an abnormal inflammatory response to inhalation of noxious agents, particularly cigarette smoke (CS), which leads to a progressive and poorly reversible decline in lung function. Autophagy, a highly conserved adaptive response to cellular stresses, which removes cytoplasmic components such as organelles and long-lived proteins via encapsulation and lysosome-dependant degradation, has also been implicated in cell death pathways. We previously observed autophagy protein induction and autophagosome accumulation in in vivo and in vitro models of experimental COPD, as well as in COPD patients. The regulation and function of autophagy in CS-induced COPD have not been fully elucidated.
To delineate the role of autophagy in the response of lung epithelial cells to CS we developed a novel in vitro model of mainstream CS exposure in primary mouse tracheal epithelial cells (MTECs) differentiated at an air-liquid interface (ALI). MTEC cultures in response to CS in vitro recapitulated many features of CS exposure in vivo, including autophagosome accumulation, cilia shortening, misfolded protein aggregation, loss of tight junction integrity and cell death. In vitro we discovered that sublethal doses of CS enhanced selective autophagic flux, while CS-induced cytotoxicity was associated with decreased autophagic activity and autophagosome accumulation. We also discovered that autophagic flux is induced in vivo upon acute exposure, but is not significantly upregulated following chronic 6 month exposure to CS. Both LC3B-/- and Beclin-1+/- mice and MTEC cultures were protected from CS induced injury, indicating that these autophagy proteins promote epithelial cell death. Moreover, we investigated the effects of CS on autophagic substrates. HDAC6 regulates autophagosome-lysosome fusion, autophagic degradation of ubiquitinated protein aggregates, and cilia resorption. Cytotoxicity and protein aggregate accumulation were observed basally in HDAC6-/Y derived MTEC cultures, while CS-exposed mice were more vulnerable to emphysematous changes. Evidence of autophagic degradation of cilia components was also observed following CS treatment. These data indicate that autophagy plays a complex role in COPD pathogenesis, in which CS-induced autophagy both removes deleterious protein aggregates and contributes to apoptosis.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Lam, Hilaire
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorChoi,
Committee ChairOury, Tim tdoury@pitt.eduTDOURY
Committee MemberBeer Stolz, Donnadstolz@pitt.eduDSTOLZ
Committee MemberLotze, Michaellotzemt@upmc.eduMTL5
Committee MemberWeisz, Oraweisz@pitt.eduWEISZ
Date: 28 November 2011
Date Type: Publication
Defense Date: 8 September 2011
Approval Date: 28 November 2011
Submission Date: 17 November 2011
Access Restriction: 1 year -- Restrict access to University of Pittsburgh for a period of 1 year.
Number of Pages: 121
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: chronic obstructive pulmonary disease, COPD, cigarette smoke, autophagy, cilia, protein aggregates, LC3B, Beclin 1, histone deacetylase 6
Date Deposited: 28 Nov 2011 16:58
Last Modified: 19 Dec 2016 14:38


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