Autophagy plays an essential role in cigarette smoke-induced expression of MUC5AC in airway epithelium

Zhou, Jia; Zhao, Yun; Zhou, Hongbin; Wang, Yong; Wu, Yangjie; Li, Zhou-Yang; Xuan, Nanxia; Zhang, Chao; Huang, Wen; Ying, Songmin; Li, Wen; Shen, Huahao; Chen, Zhihua

doi:10.1152/ajplung.00418.2015

Cited by 65 publications

(59 citation statements)

References 45 publications

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“…Although CSE has previously been shown to correlate with MUC5AC expression in vivo and in vitro, CSE does not alter MUC5B expression in our lung tissue cohort in either our control or IPF populations. Although previous work has shown a correlation between mucin expression and cigarette smoke exposure in lung tissue, the primary mucin affected is MUC5AC [221][222][223], not MUC5B. Decidedly, our cohort is limited in finding association between MUC5B expression and cigarette smoke exposure.…”

Section: Discussionmentioning

confidence: 75%

Regulation of MUC5B Expression in Idiopathic Pulmonary Fibrosis

Helling

Gerber

Kadiyala

et al. 2017

Am J Respir Cell Mol Biol

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Idiopathic pulmonary fibrosis (IPF) is the most common and the most aggressive fibrosing interstitial lung disease (ILD). Despite recent promising clinical trials, IPF remains incurable and largely untreatable. Genetic studies have identified several risk loci for both sporadic and familial forms of IPF. A single variant upstream of MUC5B is predicted to account for more than 30% of all IPF risk. This variant, rs35705950, is associated with expression of MUC5B in healthy lung tissue. However, the mechanism underlying the relationship between rs35705950 and MUC5B expression remains unclear.The first goal of my thesis research was to determine whether rs35705950 is also a risk factor for other forms of ILD. Genomic DNA from individuals with IPF, HP, COPD, iNSIP, and RB-ILD was obtained and genotyped for the common MUC5B promoter variant. In these populations the risk allele was associated with IPF and iNSIP which suggested a potential shared disease mechanism. Additionally, I showed that in the IPF and control populations rs35705950 is associated with lung MUC5B expression.The second goal of my thesis research was to investigate MUC5B promoter DNA methylation which has previously been shown to play a role in MUC5B expression.Methylation analysis of the 4KB region upstream of MUC5B identified two differentially methylated regions (DMRs) associated with IPF, one DMR associated with MUC5B iv expression, and one DMR associated with rs35705950. The IPF, MUC5B expression, and rs35705950 associated DMRs are all differentially methylated at a cluster of 11 CpG motifs. overlapping DMR, including the motif disrupted by rs35705950. These findings suggest that DNA methylation may play a role in MUC5B gene regulation and IPF risk.Next, I used cross species analysis to identify highly conserved domains within the overlapping DMR. Evolutionary conservation indicated selective pressures to maintain sequences overtime and suggests biological importance. The overlapping DMR contains a highly conserved binding motif for FOXA2, a transcription factor. Further analysis using ChIP-qPCR, reporter constructs, and siRNA, established a role for FOXA2 in regulation of MUC5B expression in lung tissue. Additionally, siRNA knock down identified 3 other transcription factors which are associated with MUC5B expression; STAT3, HOXA9 and ZBTB7A. These transcriptional regulators provide insight into possible therapeutic intervention for MUC5B dysregulation and IPF.The form and content of this abstract are approved. I recommend its publication.

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Section: Discussionmentioning

confidence: 75%

Regulation of MUC5B Expression in Idiopathic Pulmonary Fibrosis

Helling

Gerber

Kadiyala

et al. 2017

Am J Respir Cell Mol Biol

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“…24 Several studies [25][26][27] have also reported that H5N1 infection induces autophagic cell death or inflammatory response in lung epithelial cells, and blocking autophagy not only reduces the epithelial cell death, but also ameliorates H5N1-induced ALI and mortality. In the models of lung injury induced by cigarette smoke 28,29 or environmental particulate matter, 30 autophagy also appears to mediate the epithelial cell death, inflammatory response, and mucus hyperproduction. In contrast, 2 recent studies have demonstrated that the autophagic protein LC3B exerts a protective role against hyperoxiainduced lung epithelial injury and cell death.…”

Section: Discussionmentioning

confidence: 99%

Activation of MTOR in pulmonary epithelium promotes LPS-induced acute lung injury

et al. 2016

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MTOR (mechanistic target of rapamycin [serine/threonine kinase]) plays a crucial role in many major cellular processes including metabolism, proliferation and macroautophagy/autophagy induction, and is also implicated in a growing number of proliferative and metabolic diseases. Both MTOR and autophagy have been suggested to be involved in lung disorders, however, little is known about the role of MTOR and autophagy in pulmonary epithelium in the context of acute lung injury (ALI). In the present study, we observed that lipopolysaccharide (LPS) stimulation induced MTOR phosphorylation and decreased the expression of MAP1LC3B/LC3B (microtubule-associated protein 1 light chain 3 β)-II, a hallmark of autophagy, in mouse lung epithelium and in human bronchial epithelial (HBE) cells. The activation of MTOR in HBE cells was mediated by TLR4 (toll-like receptor 4) signaling. Genetic knockdown of MTOR or overexpression of autophagy-related proteins significantly attenuated, whereas inhibition of autophagy further augmented, LPS-induced expression of IL6 (interleukin 6) and IL8, through NFKB signaling in HBE cells. Mice with specific knockdown of Mtor in bronchial or alveolar epithelial cells exhibited significantly attenuated airway inflammation, barrier disruption, and lung edema, and displayed prolonged survival in response to LPS exposure. Taken together, our results demonstrate that activation of MTOR in the epithelium promotes LPS-induced ALI, likely through downregulation of autophagy and the subsequent activation of NFKB. Thus, inhibition of MTOR in pulmonary epithelial cells may represent a novel therapeutic strategy for preventing ALI induced by certain bacteria.

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“…Hoshino et al showed p53 binds to Parkin and restricts its translocation to mitochondria which compromises autophagy and promotes mitochondrial dysfunction (Hoshino et al, 2013). A recent study shows mtROS-dependent autophagy by CS extract regulates mucin expression (MUC5AC) through the c-Jun N-terminal kinase (JNK) and activator protein-1 (AP-1) signaling pathway in human bronchial epithelial cells thereby re-emphasizing how autophagy inhibition can be targeted for treating chronic lung diseases (Zhou et al, 2016). Another report demonstrates role of mitochondrial E3 ubiquitin protein ligase 1 (MUL1) in CS-induced pulmonary endothelial cell death and dysfunction via Akt ubiquitination/degradation (Kim et al, 2016).…”

Section: Mitophagy and Senescence: Implications For Copd Pathogenesismentioning

confidence: 99%

Mitochondrial redox system, dynamics, and dysfunction in lung inflammaging and COPD

Lerner

Sundar

Rahman

2016

The International Journal of Biochemistry & Cell Biology

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Myriad forms of endogenous and environmental stress will disrupt mitochondrial function by impacting critical processes in mitochondrial homeostasis such as mitochondrial redox system, oxidative phosphorylation, biogenesis, and mitophagy. External stressors that interfere with the steady state activity of mitochondrial functions are generally associated with an increase in reactive oxygen species, inflammatory response, and induction of cellular senescence (inflammaging) via mitochondrial damage associated molecular patterns (DAMPS) which are the key events in the pathogenesis of chronic obstructive pulmonary disease (COPD) and its exacerbations. In this review, we highlight the primary mitochondrial quality control mechanisms that are influenced by oxidative stress/redox system, including role of mitochondria during inflammation and cellular senescence, and how mitochondrial dysfunction contributes to the pathogenesis of COPD and its exacerbations via pathogenic stimuli.

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Autophagy plays an essential role in cigarette smoke-induced expression of MUC5AC in airway epithelium

Cited by 65 publications

References 45 publications

Regulation of MUC5B Expression in Idiopathic Pulmonary Fibrosis

Regulation of MUC5B Expression in Idiopathic Pulmonary Fibrosis

Activation of MTOR in pulmonary epithelium promotes LPS-induced acute lung injury

Mitochondrial redox system, dynamics, and dysfunction in lung inflammaging and COPD

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