Peroxisome Proliferator-Activated Receptor (PPARγ) Plays a Protective Role in Cigarette Smoking-Induced Inflammation via AMP-Activated Protein Kinase (AMPK) Signaling

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Abstract

Background

Cigarette smoking is a well-known risk factor in multiple chronic pulmonary diseases. This study aims to investigate the role of peroxisome proliferator-activated receptor (PPAR) γ in cigarette smoking-induced inflammation.

Material/Methods

Cigarette smoking extract (CSE) was employed to induce inflammation in bronchial epithelial cells (BECs). After CSE administration, several autophagy-related proteins (Beclin1, autophagy-related gene (ATG)5, ATG7, p62, and LC3) and PPARγ levels were examined by western blot. Subsequently, PPARγ agonists and antagonist were used to treat CSE-induced BECs, several inflammatory factors (interleukin (IL)-6, IL-8, inducible nitric oxide synthase (iNOS), and cyclooxygenase (COX)-2) and autophagy-related proteins were detected to measure the inflammatory and autophagy levels. Then LC3 knockdown was performed to verify the role of autophagy in CSE-induced inflammation. Finally, the AMP-activated protein kinase (AMPK) and its downstream S6 kinase (S6K) were detected in CSE-stimulated BECs.

Results

CSE administration caused insufficient autophagy and the decrease of PPARγ in BECs. The PPARγ agonists ameliorate the CSE-induced inflammation and promote the autophagy development, evidenced by the changes of inflammatory factors and autophagy-related proteins. Loss-of-function experiments demonstrated that the PPARg played an anti-inflammatory role in an autophagy-dependent manner. In addition, CSE administration inactivated the AMPK signaling, which was restored by PPARγ agonists. The effects of PPARγ agonists on inflammation and autophagy could be abolished by AMPK inhibitor.

Conclusions

We demonstrated that PPARγ played a protective role in CSE-induced inflammation and autophagy by activating AMPK signaling in BECs, which may provide investigation basis for clinical therapy of chronic pulmonary diseases.

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Most cited references 23

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The AMP-activated protein kinase cascade--a unifying system for energy control.

David Carling (2004)

AMP-activated protein kinase (AMPK) is the downstream component of a protein kinase cascade that acts as an intracellular energy sensor maintaining the energy balance within the cell. This pivotal role of AMPK places it in an ideal position for regulating whole-body energy metabolism, and AMPK might play a part in protecting the body from metabolic diseases such as type 2 diabetes and obesity. Mutations in AMPK cause cardiac hypertrophy and arrhythmia. Recent findings have identified LKB1--a protein kinase that is mutated in a hereditary form of cancer--as a candidate for the upstream kinase in the AMPK cascade. AMPK could provide a link in human diseases of which the underlying cause is due to defects in energy metabolism.

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Autophagy: regulation and role in development.

E Rücker, Dan J Ledbetter, Alison N. Hale … (2013)

Autophagy is an evolutionarily conserved cellular process through which long-lived proteins and damaged organelles are recycled to maintain energy homeostasis. These proteins and organelles are sequestered into a double-membrane structure, or autophagosome, which subsequently fuses with a lysosome in order to degrade the cargo. Although originally classified as a type of programmed cell death, autophagy is more widely viewed as a basic cell survival mechanism to combat environmental stressors. Autophagy genes were initially identified in yeast and were found to be necessary to circumvent nutrient stress and starvation. Subsequent elucidation of mammalian gene counterparts has highlighted the importance of this process to normal development. This review provides an overview of autophagy, the types of autophagy, its regulation and its known impact on development gleaned primarily from murine models.

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Is Open Access

PPARγ deficiency results in severe, accelerated osteoarthritis associated with aberrant mTOR signalling in the articular cartilage

Faezeh Vasheghani, Yue Zhang, Ying-Hua Li … (2015)

Objectives We have previously shown that peroxisome proliferator-activated receptor gamma (PPARγ), a transcription factor, is essential for the normal growth and development of cartilage. In the present study, we created inducible cartilage-specific PPARγ knockout (KO) mice and subjected these mice to the destabilisation of medial meniscus (DMM) model of osteoarthritis (OA) to elucidate the specific in vivo role of PPARγ in OA pathophysiology. We further investigated the downstream PPARγ signalling pathway responsible for maintaining cartilage homeostasis. Methods Inducible cartilage-specific PPARγ KO mice were generated and subjected to DMM model of OA. We also created inducible cartilage-specific PPARγ/mammalian target for rapamycin (mTOR) double KO mice to dissect the PPARγ signalling pathway in OA. Results Compared with control mice, PPARγ KO mice exhibit accelerated OA phenotype with increased cartilage degradation, chondrocyte apoptosis, and the overproduction of OA inflammatory/catabolic factors associated with the increased expression of mTOR and the suppression of key autophagy markers. In vitro rescue experiments using PPARγ expression vector reduced mTOR expression, increased expression of autophagy markers and reduced the expression of OA inflammatory/catabolic factors, thus reversing the phenotype of PPARγ KO mice chondrocytes. To dissect the in vivo role of mTOR pathway in PPARγ signalling, we created and subjected PPARγ-mTOR double KO mice to the OA model to see if the genetic deletion of mTOR in PPARγ KO mice (double KO) can rescue the accelerated OA phenotype observed in PPARγ KO mice. Indeed, PPARγ-mTOR double KO mice exhibit significant protection/reversal from OA phenotype. Significance PPARγ maintains articular cartilage homeostasis, in part, by regulating mTOR pathway.

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Author and article information

Journal

Journal ID (nlm-ta): Med Sci Monit

Journal ID (iso-abbrev): Med. Sci. Monit

Journal ID (publisher-id): Medical Science Monitor

Title: Medical Science Monitor : International Medical Journal of Experimental and Clinical Research

Publisher: International Scientific Literature, Inc.

ISSN (Print): 1234-1010

ISSN (Electronic): 1643-3750

Publication date Collection: 2018

Publication date (Electronic): 25 July 2018

Volume: 24

Pages: 5168-5177

Affiliations

[1 ]Department of Respiratory Medicine, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning, P.R. China

[2 ]Department of Respiratory Medicine, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, P.R. China

Author notes

Corresponding Author: Qiuyue Wang, e-mail: qywangcmu@ 123456163.com

[A]

Study Design

[B]

Data Collection

[C]

Statistical Analysis

[D]

Data Interpretation

[E]

Manuscript Preparation

[F]

Literature Search

[G]

Funds Collection

Article

Publisher ID: 909285

DOI: 10.12659/MSM.909285

PMC ID: 6071495

PubMed ID: 30044769

SO-VID: 636c32e7-00e4-4c1f-9ac3-61032e3187c4

License:

This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International ( CC BY-NC-ND 4.0)

Peroxisome Proliferator-Activated Receptor (PPARγ) Plays a Protective Role in Cigarette Smoking-Induced Inflammation via AMP-Activated Protein Kinase (AMPK) Signaling

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Abstract

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Material/Methods

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Most cited references 23

The AMP-activated protein kinase cascade--a unifying system for energy control.

Autophagy: regulation and role in development.

PPARγ deficiency results in severe, accelerated osteoarthritis associated with aberrant mTOR signalling in the articular cartilage

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