Alveolar macrophage proteinase/antiproteinase expression in lung function and emphysema

Ishii, Takeo; Abboud, Raja T.; Wallace, Alison; English, John; Finley, Richard J.; Shumansky, Karey; Paré, Peter D.; Sandford, Andrew J.

doi:10.1183/09031936.00174612

Cited by 43 publications

(29 citation statements)

References 59 publications

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“…Increased inflammation correlates with poorer lung function in patients with COPD (Turato et al, 2002;Donaldson et al, 2005;Aronson et al, 2006;Hancox et al, 2007), and small airway fibrosis contributes to airflow restriction through exaggerated tissue contraction, perhaps through the altered balance between fibrotic MMPs and their inhibitors (Hogg et al, 2004;Rennard, 2006;Salazar and Herrera, 2011;Churg et al, 2012;Jankowich and Rounds, 2012). Increases in the levels of alveolar macrophage-associated MMPs negatively correlate with forced expiratory volume in 1 s/forced vital capacity in COPD patients (Ishii et al, 2013). We have shown that depletion of macrophages by clodronate improves transpulmonary and airway resistance as well as dynamic compliance in experimental COPD (Beckett et al, 2013), which possibly occurs through the reduction in MMPs.…”

Section: Bjpmentioning

confidence: 99%

The inhibitor of semicarbazide‐sensitive amine oxidase, PXS‐4728A, ameliorates key features of chronic obstructive pulmonary disease in a mouse model

Schilter

Liu

et al. 2016

British J Pharmacology

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BACKGROUND AND PURPOSEChronic obstructive pulmonary disease (COPD) is a major cause of illness and death, often induced by cigarette smoking (CS). It is characterized by pulmonary inflammation and fibrosis that impairs lung function. Existing treatments aim to control symptoms but have low efficacy, and there are no broadly effective treatments. A new potential target is the ectoenzyme, semicarbazidesensitive mono-amine oxidase (SSAO; also known as vascular adhesion protein-1). SSAO is elevated in smokers' serum and is a pro-inflammatory enzyme facilitating adhesion and transmigration of leukocytes from the vasculature to sites of inflammation. EXPERIMENTAL APPROACHPXS-4728A was developed as a low MW inhibitor of SSAO. A model of COPD induced by CS in mice reproduces key aspects of human COPD, including chronic airway inflammation, fibrosis and impaired lung function. This model was used to assess suppression of SSAO activity and amelioration of inflammation and other characteristic features of COPD. KEY RESULTSTreatment with PXS-4728A completely inhibited lung and systemic SSAO activity induced by acute and chronic CS-exposure. Daily oral treatment inhibited airway inflammation (immune cell influx and inflammatory factors) induced by acute CS-exposure. Therapeutic treatment during chronic CS-exposure, when the key features of experimental COPD develop and progress, substantially suppressed inflammatory cell influx and fibrosis in the airways and improved lung function. CONCLUSIONS AND IMPLICATIONSTreatment with a low MW inhibitor of SSAO, PXS-4728A, suppressed airway inflammation and fibrosis and improved lung function in experimental COPD, demonstrating the therapeutic potential of PXS-4728A for this debilitating disease.Abbreviations BALF, bronchoalveolar lavage fluid; COPD, chronic obstructive pulmonary disease; CS, cigarette smoke; EM, extracellular matrix; G-CSF, granulocyte-colony stimulating factor; MLI, mean linear intercept; SSAO, semicarbazide-sensitive amine oxidase IntroductionChronic obstructive pulmonary disease (COPD) is the third leading cause of chronic morbidity and death worldwide, and its prevalence is increasing (Lozano et al., 2012). It is a heterogeneous disease variously comprising debilitating and complex pathological features including chronic pulmonary inflammation (bronchitis), fibrosis and emphysema (Keely et al., 2011;Fricker et al., 2014). These features combine to impair lung function and result in reduced oxygen transfer leading to breathlessness. Cigarette smoke (CS) exposure is the primary etiological agent in Western countries, accounting for more than 90% of cases. Once induced, the patients' condition often continues to deteriorate, even after cessation of smoking. Wood and cooking smoke and pollution are also important risk factors particularly in developing nations (Fabbri et al., 2004;Eisner et al., 2010;Ko and Hui, 2012).There are no cures for COPD, and current treatments have substantial limitations. High doses of corticosteroids, long-acting β-adrenoceptor agonists, ...

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Section: Bjpmentioning

confidence: 99%

The inhibitor of semicarbazide‐sensitive amine oxidase, PXS‐4728A, ameliorates key features of chronic obstructive pulmonary disease in a mouse model

Schilter

Liu

et al. 2016

British J Pharmacology

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“…Ishii et al illustrated the inverse relationship of MMP12 mRNA expression levels in alveolar macrophages with a measure of airflow obstruction, the FEV 1 /FVC ratio. [35]…”

Section: Chromosome 11q22: Mmp12mentioning

confidence: 99%

Integrative genomics of chronic obstructive pulmonary disease

Hobbs

Hersh

2014

Biochemical and Biophysical Research Communications

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Chronic obstructive pulmonary disease (COPD) is a complex disease with both environmental and genetic determinants, the most important of which is cigarette smoking. There is marked heterogeneity in the development of COPD among persons with similar cigarette smoking histories, which is likely partially explained by genetic variation. Genomic approaches such as genomewide association studies and gene expression studies have been used to discover genes and molecular pathways involved in COPD pathogenesis; however, these “first generation” omics studies have limitations. Integrative genomic studies are emerging which can combine genomic datasets to further examine the molecular underpinnings of COPD. Future research in COPD genetics will likely use network-based approaches to integrate multiple genomic data types in order to model the complex molecular interactions involved in COPD pathogenesis. This article reviews the genomic research to date and offers a vision for the future of integrative genomic research in COPD.

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“…Further molecular studies of the involved proteins might shed more light on this. We previously reported SNPs associated with CST3 mRNA and protein levels in alveolar macrophages 19. However, in the latter study, higher CST3 mRNA in alveolar macrophages was associated with higher FEV 1 .…”

Section: Discussionmentioning

confidence: 61%

Genetic regulation of gene expression in the lung identifiesCST3andCD22as potential causal genes for airflow obstruction

Lamontagne

Timens

Hao

et al. 2014

Thorax

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Background COPD is a complex chronic disease with poorly understood pathogenesis. Integrative genomic approaches have the potential to elucidate the biological networks underlying COPD and lung function. We recently combined genome-wide genotyping and gene expression in 1111 human lung specimens to map expression quantitative trait loci (eQTL). Objective To determine causal associations between COPD and lung function-associated single nucleotide polymorphisms (SNPs) and lung tissue gene expression changes in our lung eQTL dataset. Methods We evaluated causality between SNPs and gene expression for three COPD phenotypes: FEV 1 % predicted, FEV 1 /FVC and COPD as a categorical variable. Different models were assessed in the three cohorts independently and in a meta-analysis. SNPs associated with a COPD phenotype and gene expression were subjected to causal pathway modelling and manual curation. In silico analyses evaluated functional enrichment of biological pathways among newly identified causal genes. Biologically relevant causal genes were validated in two separate gene expression datasets of lung tissues and bronchial airway brushings. Results High reliability causal relations were found in SNP-mRNA-phenotype triplets for FEV 1 % predicted (n=169) and FEV 1 /FVC (n=80). Several genes of potential biological relevance for COPD were revealed. eQTL-SNPs upregulating cystatin C (CST3) and CD22 were associated with worse lung function. Signalling pathways enriched with causal genes included xenobiotic metabolism, apoptosis, protease-antiprotease and oxidant-antioxidant balance. Conclusions By using integrative genomics and analysing the relationships of COPD phenotypes with SNPs and gene expression in lung tissue, we identified CST3 and CD22 as potential causal genes for airflow obstruction. This study also augmented the understanding of previously described COPD pathways.

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Alveolar macrophage proteinase/antiproteinase expression in lung function and emphysema

Cited by 43 publications

References 59 publications

The inhibitor of semicarbazide‐sensitive amine oxidase, PXS‐4728A, ameliorates key features of chronic obstructive pulmonary disease in a mouse model

The inhibitor of semicarbazide‐sensitive amine oxidase, PXS‐4728A, ameliorates key features of chronic obstructive pulmonary disease in a mouse model

Integrative genomics of chronic obstructive pulmonary disease

Genetic regulation of gene expression in the lung identifiesCST3andCD22as potential causal genes for airflow obstruction

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