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Role and Regulation of Autophagy Mechanism During Cigarette Smoke Exposure.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Role and Regulation of Autophagy Mechanism During Cigarette Smoke Exposure./
作者:	Bagam, Prathyusha.
出版者:	Ann Arbor : ProQuest Dissertations & Theses, : 2020,
面頁冊數:	187 p.
附註:	Source: Dissertations Abstracts International, Volume: 81-11, Section: B.
Contained By:	Dissertations Abstracts International81-11B.
標題:	Environmental studies. -
電子資源:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=27960275
ISBN:	9798643175353

Role and Regulation of Autophagy Mechanism During Cigarette Smoke Exposure.
Bagam, Prathyusha.

Role and Regulation of Autophagy Mechanism During Cigarette Smoke Exposure. - Ann Arbor : ProQuest Dissertations & Theses, 2020 - 187 p.

Source: Dissertations Abstracts International, Volume: 81-11, Section: B.

Thesis (Ph.D.)--Southern University and Agricultural and Mechanical College, 2020.

This item is not available from ProQuest Dissertations & Theses.

Cigarette smoke (CS) is the chief etiological factor for Chronic Obstructive Pulmonary Disease (COPD). Oxidative stress induced by CS results in dysregulated production of reactive oxygen species (ROS), leading to DNA/protein damage and/or cell death. Earlier studies have demonstrated a functional role of autophagy in COPD, however, there is paucity of information regarding the associated molecular mechanisms. In this regard, autophagy mechanism has been shown to play critical role in regulating inflammatory responses; maintaining protein and organelle homeostasis; and cellular viability in smoke-related pathologies. In this context, we intended to study the impact of cigarette smoke extract (CSE) and secondhand smoke (SHS) in regulating autophagy process in our study models. The expression and activation of autophagy proteins is regulated by Fork head box class O (FOXO) transcription factors. Our preliminary findings revealed, CSE-mediated induction of inflammatory responses and regulation of transcription factors FOXO3 and FOXO1 in human lung adenocarcinoma cells with type II characteristics (A549). We thus hypothesized important role of FOXO transcription factors in CSE-induced inflammation and autophagy. To test our hypothesis, we challenged A549 cells with CSE for 24 hr. We observed: (i) reducedexpression of FOXO3, while increase in the expression of FOXO1 in CSE-challenged A549 cells; (ii) FOXO3 knockdown in A549 cells augmented CSE-induced IL-6, CCL-2 and IL-8 production, expression of several autophagy proteins (mTOR, Beclin-1, ATG12, ATG16 ATG5 and LC3), antioxidant enzymes (MnSOD and catalase); and FOXO1 expression; (iii) FOXO1 knockdown, on the contrary, abrogated the expression of autophagy proteins in CSE challenged A549 cells; (iv) ChIP assay results showed increase in the binding of FOXO1 transcription factor at the promoter regions of autophagy genes-Beclin-1, ATG5, ATG12, ATG16, and LC3/ATG8 in CSE-challenged A549 cells. Overall, our results provide evidence for FOXO3-dependent FOXO1-mediated regulation of autophagy in CSE challenged cells. Acetylation and deacetylation of histones/non-histone proteins by histone acetyltransferases (HATs) and HDACs respectively, regulate gene transcription depending on the trigger and study model. We used histone deacetylase inhibitor benzyl isothiocyanate (BITC), a naturally occurring constituent of cruciferous vegetables, to determine the possibility of nutrivention approach in mitigating CSE-mediated regulation of autophagic flux and inflammatory responses. Interestingly, pre-treatment with BITC rescued CSE-induced expression of autophagy proteins (ATG5, ATG16 and LC3) and inflammatory mediators (IL-6, CCL-2 & IL-8) in A549 cells. Since pattern recognition receptors (PRRs) play critical role in inducing immune responses following exposure to wide variety of stimulus, we first determined the key PRRs regulated during CSE-challenge. Since membrane bound Toll-like receptors have been well studied, we focused on cytosolic Nod-like receptor (NLR) family members. Our observations revealed that NLRP10 and NLRP12 were significantly induced in CSE-challenged A549 cells and also in the lungs of SHS-exposed C57Bl/6 mice. The NLR family member, NLRP10 (aka NOD8, PAN5, PYNOD), is the only member of this family which lacks leucine rich repeat (LRR) domain, responsible for the detection of pathogens and danger associated molecular patterns (PAMPs/DAMPs). Therefore, we hypothesized that NLRP10 may have a major regulatory role in CSE- or SHS-induced inflammation/autophagy. We, therefore, used wild-type (Nlrp10+/+) and NLRP10-deficient (Nlrp10-/-) mice on the C57Bl/6 background and exposed them to SHS or filtered air- for 6 weeks (acute exposure). Our findings revealed important role of NLRP10 in secondhand smoke or CSE- induced inflammation and autophagy. Collectively, our results demonstrate important role of NLRP10 in regulating cigarette smoke-induced: 1) NF-κB and MAPKs induction; 2) production of pro-inflammatory cytokines and chemokines; and 3) autophagy proteins. Interestingly, pre-treatment with rIL-17 significantly rescued NLRP10 induced responses during CS-exposure. In brief, our findings suggest that NLRP10 may contribute significantly towards the onset and progression of CS-induced pathologies. Our findings also provide the basis for future interventional studies which may target the key autophagy proteins and/or cytosolic PRRs for the better management of CS-induced inflammation/pathologies.

ISBN: 9798643175353Subjects--Topical Terms:

2122803
Environmental studies.
Subjects--Index Terms:

A549

Role and Regulation of Autophagy Mechanism During Cigarette Smoke Exposure.
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506 $a This item is not available from ProQuest Dissertations & Theses.
506 $a This item must not be sold to any third party vendors.
520 $a Cigarette smoke (CS) is the chief etiological factor for Chronic Obstructive Pulmonary Disease (COPD). Oxidative stress induced by CS results in dysregulated production of reactive oxygen species (ROS), leading to DNA/protein damage and/or cell death. Earlier studies have demonstrated a functional role of autophagy in COPD, however, there is paucity of information regarding the associated molecular mechanisms. In this regard, autophagy mechanism has been shown to play critical role in regulating inflammatory responses; maintaining protein and organelle homeostasis; and cellular viability in smoke-related pathologies. In this context, we intended to study the impact of cigarette smoke extract (CSE) and secondhand smoke (SHS) in regulating autophagy process in our study models. The expression and activation of autophagy proteins is regulated by Fork head box class O (FOXO) transcription factors. Our preliminary findings revealed, CSE-mediated induction of inflammatory responses and regulation of transcription factors FOXO3 and FOXO1 in human lung adenocarcinoma cells with type II characteristics (A549). We thus hypothesized important role of FOXO transcription factors in CSE-induced inflammation and autophagy. To test our hypothesis, we challenged A549 cells with CSE for 24 hr. We observed: (i) reducedexpression of FOXO3, while increase in the expression of FOXO1 in CSE-challenged A549 cells; (ii) FOXO3 knockdown in A549 cells augmented CSE-induced IL-6, CCL-2 and IL-8 production, expression of several autophagy proteins (mTOR, Beclin-1, ATG12, ATG16 ATG5 and LC3), antioxidant enzymes (MnSOD and catalase); and FOXO1 expression; (iii) FOXO1 knockdown, on the contrary, abrogated the expression of autophagy proteins in CSE challenged A549 cells; (iv) ChIP assay results showed increase in the binding of FOXO1 transcription factor at the promoter regions of autophagy genes-Beclin-1, ATG5, ATG12, ATG16, and LC3/ATG8 in CSE-challenged A549 cells. Overall, our results provide evidence for FOXO3-dependent FOXO1-mediated regulation of autophagy in CSE challenged cells. Acetylation and deacetylation of histones/non-histone proteins by histone acetyltransferases (HATs) and HDACs respectively, regulate gene transcription depending on the trigger and study model. We used histone deacetylase inhibitor benzyl isothiocyanate (BITC), a naturally occurring constituent of cruciferous vegetables, to determine the possibility of nutrivention approach in mitigating CSE-mediated regulation of autophagic flux and inflammatory responses. Interestingly, pre-treatment with BITC rescued CSE-induced expression of autophagy proteins (ATG5, ATG16 and LC3) and inflammatory mediators (IL-6, CCL-2 & IL-8) in A549 cells. Since pattern recognition receptors (PRRs) play critical role in inducing immune responses following exposure to wide variety of stimulus, we first determined the key PRRs regulated during CSE-challenge. Since membrane bound Toll-like receptors have been well studied, we focused on cytosolic Nod-like receptor (NLR) family members. Our observations revealed that NLRP10 and NLRP12 were significantly induced in CSE-challenged A549 cells and also in the lungs of SHS-exposed C57Bl/6 mice. The NLR family member, NLRP10 (aka NOD8, PAN5, PYNOD), is the only member of this family which lacks leucine rich repeat (LRR) domain, responsible for the detection of pathogens and danger associated molecular patterns (PAMPs/DAMPs). Therefore, we hypothesized that NLRP10 may have a major regulatory role in CSE- or SHS-induced inflammation/autophagy. We, therefore, used wild-type (Nlrp10+/+) and NLRP10-deficient (Nlrp10-/-) mice on the C57Bl/6 background and exposed them to SHS or filtered air- for 6 weeks (acute exposure). Our findings revealed important role of NLRP10 in secondhand smoke or CSE- induced inflammation and autophagy. Collectively, our results demonstrate important role of NLRP10 in regulating cigarette smoke-induced: 1) NF-κB and MAPKs induction; 2) production of pro-inflammatory cytokines and chemokines; and 3) autophagy proteins. Interestingly, pre-treatment with rIL-17 significantly rescued NLRP10 induced responses during CS-exposure. In brief, our findings suggest that NLRP10 may contribute significantly towards the onset and progression of CS-induced pathologies. Our findings also provide the basis for future interventional studies which may target the key autophagy proteins and/or cytosolic PRRs for the better management of CS-induced inflammation/pathologies.
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