Roles of airway smooth muscle dysfunction in chronic obstructive pulmonary disease

Yan, Furong; Gao, Hongzhi; Zhao, Hong; Bhatia, Madhav; Zeng, Yiming

doi:10.1186/s12967-018-1635-z

Cited by 43 publications

(32 citation statements)

References 67 publications

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“…However, aberrant smooth muscle activity can cause chronic obstructive pulmonary disease (COPD). In particular, smooth muscle remodelling can impede airway contractility and relaxation, causing thick masses that obstruct airflow (reviewed in Yan et al [108]). Smooth muscle cells in individuals with COPD show remarkably high p-ASK1 protein levels [73].…”

Section: Cardiopulmonary Disease: Ask1 Mediates Heart and Lung Phenotmentioning

confidence: 99%

ASK1 inhibition: a therapeutic strategy with multi-system benefits

2020

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p38 mitogen-activated protein kinases (P38α and β) and c-Jun N-terminal kinases (JNK1, 2, and 3) are key mediators of the cellular stress response. However, prolonged P38 and JNK signalling is associated with damaging inflammatory responses, reactive oxygen species-induced cell death, and fibrosis in multiple tissues, such as the kidney, liver, central nervous system, and cardiopulmonary systems. These responses are associated with many human diseases, including arthritis, dementia, and multiple organ dysfunctions. Attempts to prevent P38-and JNK-mediated disease using small molecule inhibitors of P38 or JNK have generally been unsuccessful. However, apoptosis signal-regulating kinase 1 (ASK1), an upstream regulator of P38 and JNK, has emerged as an alternative drug target for limiting P38-and JNK-mediated disease. Within this review, we compile the evidence that ASK1 mediates damaging cellular responses via prolonged P38 or JNK activation. We discuss the potential benefits of ASK1 inhibition as a therapeutic and summarise the studies that have tested the effects of ASK1 inhibition in cell and animal disease models, in addition to human clinical trials for a variety of disorders. Keywords Apoptosis signal-regulating kinase 1. MAP3K5. Clinical trial. ROS. MAPK. p38. JNK Mitogen-activated protein kinase kinase kinase 5 (MAP3K5), commonly known as apoptosis signal-regulating kinase 1 (ASK1), has emerged as a target for preventing p38 mitogen-activated protein kinase (MAPK14, 11, and 12/ P38α, β, and γ) and c-Jun N-terminal kinase (MAPK8, 9, and 10/JNK1, 2, and 3)-mediated cell death and disease. Both P38 and JNK are associated with reactive oxygen species (ROS)-induced disease 1 , and numerous studies have demonstrated that P38 and JNK inhibition ameliorates cell death [3-7]. However, complete inhibition of P38 or JNK in vivo is problematic, given that these ubiquitously expressed proteins are also critical for cell survival and homeostatic and/ or metabolic functions [8-11]. This is highlighted by the embryonic lethality of homozygous P38α and Jnk1/2 knockout mice [12, 13]. In addition, homozygous P38β knockout mice exhibit defective skeletal development [14] and homozygous Jnk1 knockout mice spontaneously develop intestinal tumours [15]. Negative outcomes have also been reported due to partial P38 or Jnk expression, with heterozygous P38α knockout mice developing progressive renal dysfunction [16] and heterozygous Jnk1 knockout mice exhibiting altered weight gain, hyperinsulinaemia, insulin resistance, inflammatory cytokine disruption, and reduced viability [17]. Serious side effects have also been observed when pharmacological inhibition of P38 or JNK is pursued in vivo [14, 18, 19]. For example, pamapimod, a P38 (α and β) inhibitor, did not significantly reduce joint swelling or improve mobility in individuals with rheumatoid arthritis in a phase II clinical trial. However, 35% of the participants receiving daily pamapimod (300 mg) experienced infection, 20% developed a skin rash, 15% became dizzy, and 13% had e...

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Section: Cardiopulmonary Disease: Ask1 Mediates Heart and Lung Phenotmentioning

confidence: 99%

ASK1 inhibition: a therapeutic strategy with multi-system benefits

2020

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“…[ 25 ] Increased levels of phospholipids and choline‐containing lipids have also been linked to the metastasis of cancer cells in past lipidomic studies. [ 26,27 ] Researchers examining the plasma metabolome of mice implanted with LLC using UPLC‐QTOF/MS noted glycerophospholipid metabolism to be the most significantly disturbed metabolic pathway in their study. [ 28 ] Our serum samples expressed similar dyslipidemias in tumor‐bearing mice evidenced by increased levels of triglycerides, PUFA, and PC compared with that in healthy mice.…”

Section: Resultsmentioning

confidence: 99%

CRAFT for NMR lipidomics: Targeting lipid metabolism in leucine‐supplemented tumor‐bearing mice

Johnson

Puppa

Merwe

et al. 2020

Magnetic Reson in Chemistry

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Lipid profiling by 1H‐NMR has gained increasing utility in many fields because of its intrinsically quantitative, nondestructive nature and the ability to differentiate small molecules based on their spectral location. Most nuclear magnetic resonance (NMR) techniques for metabolite quantification use frequency domain analysis that involves many user‐dependent steps such as phase and baseline correction and quantification by either manual integration or peak fitting. Recently, Bayesian analysis of time‐domain NMR data has been shown to reduce operator bias and increase automation in NMR spectroscopy. In this study, we demonstrate the use of CRAFT (complete reduction to amplitude–frequency table), a Bayesian‐based approach to automate processing in NMR‐based lipidomics using lipid standards and tissue samples of healthy and tumor‐bearing mice supplemented with leucine. Complex mixtures of lipid standards were prepared and examined using CRAFT to validate it against conventional Fourier transform (FT)‐NMR and derive a fingerprint to be used for analyzing lipid profiles of serum and liver samples. CRAFT and FT‐NMR were comparable in accuracy, with CRAFT achieving higher correlation in quantifying several lipid species. Analysis of the serum lipidome of tumor‐bearing mice revealed hyperlipidemia and no signs of hepatic triglyceride accumulation compared with that of the healthy group demonstrating that the tumor‐bearing mice were in a state of precachexia. Leucine‐supplementation was associated with minimal changes in the lipid profile in both tissues. In conclusion, our study demonstrates that the CRAFT method can accurately identify and quantify lipids in complex lipid mixtures and murine tissue samples and, hence, will increase automation and reproducibility in NMR‐based lipidomics.

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“…There is also evidence that progesterone may affect airway smooth muscle constriction, although these reports are limited to animal studies 35. In addition to regulating bronchodilation and bronchoconstriction, in vitro studies report that oestrogen can also modulate the proliferation of airway smooth muscle cells,36 37 which is a key feature of COPD 38. Oestrogen’s proinflammatory and anti-inflammatory effects have been documented in other female-predominant diseases39 and may also play a role in COPD, as chronic inflammation is another hallmark of the disease.…”

Section: Discussionmentioning

confidence: 99%

Female reproductive history in relation to chronic obstructive pulmonary disease and lung function in UK biobank: a prospective population-based cohort study

2019

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ObjectivesSex differences in respiratory physiology and predilection for developing chronic obstructive pulmonary disease (COPD) have been documented, suggesting that female sex hormones may influence pathogenesis. We investigated whether aspects of female reproductive health might play a role in risk of COPD among women.DesignPopulation-based prospective cohort study.SettingUK Biobank recruited across 22 centres in the UK between 2006 to 2010.Primary and secondary outcomes measuresWe examined a range of female reproductive health indicators in relation to risk of COPD-related hospitalisation/death (n=271 271) using Cox proportional hazards regression; and lung function (n=273 441) using linear regression.ResultsParity >3 was associated with greater risk of COPD-related hospitalisation/death (adjusted HR 1.45; 95% CI: 1.16 to 1.82) and lower forced expiratory volume at 1 second/forced vital capacity ratio (FEV1/FVC) (adjusted mean difference −0.06; 95% CI: -0.07 to 0.04). Any oral contraception use was associated with lower risk of COPD-related hospitalisation/death (adjusted HR 0.85; 95% CI: 0.74 to 0.97) and greater FEV1/FVC (adjusted mean difference 0.01; 95% CI: 0.003 to 0.03). Late menarche (age >15) and early menopause (age <47) were also associated with greater risk of COPD-related hospitalisation/death (but not lung function), while endometriosis was associated with greater FEV1/FVC (not COPD-related hospitalisation/death). Early menarche (age <12 years) was associated with lower FEV1/FVC (but not COPD hospitalisation/death). Associations with polycystic ovary syndrome (PCOS) or ovarian cysts, any hormone replacement therapy (HRT) use, hysterectomy-alone and both hysterectomy and bilateral oophorectomy were in opposing directions for COPD-related hospitalisation/death (greater risk) and FEV1/FVC (positive association).ConclusionsMultiple female reproductive health indicators across the life course are associated with COPD-related hospitalisation/death and lung function. Further studies are necessary to understand the opposing associations of PCOS/ovarian cysts, HRT and hysterectomy with COPD and objective measures of airway obstruction.

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Roles of airway smooth muscle dysfunction in chronic obstructive pulmonary disease

Cited by 43 publications

References 67 publications

ASK1 inhibition: a therapeutic strategy with multi-system benefits

ASK1 inhibition: a therapeutic strategy with multi-system benefits

CRAFT for NMR lipidomics: Targeting lipid metabolism in leucine‐supplemented tumor‐bearing mice

Female reproductive history in relation to chronic obstructive pulmonary disease and lung function in UK biobank: a prospective population-based cohort study

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