The usefulness of MMP-9, TIMP-1 and MMP-9/TIMP-1 ratio for diagnosis and assessment of COPD severity

Dimić-Janjić, Sanja; Hoda, Mir Alireza; Milenković, Branislava; Kotur-Stevuljevic, Jelena; Stjepanović, Mihailo; Gompelmann, Daniela; Janković, Jelena; Miljković, Milica; Milin-Lazović, Jelena; Djurdjevic, Natasa; Marić, Dragana; Milivojevic, Ivan; Popević, Spasoje

doi:10.1186/s40001-023-01094-7

Cited by 11 publications

(2 citation statements)

References 44 publications

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“…The changes in the functions of activated macrophages require further investigation. Matrix metalloproteinase 9 (MMP9) and transforming growth factor beta (TGF-β) were considered important hazardous cytokines in the pathogenesis of COPD, as they respectively participated in the processes of alveolar structure destruction and airway remodeling [ 42 – 44 ]. The RT-qPCR analysis found the elevated mRNA levels of TGFB1 and MMP9 in CM-treated THP-1 cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

Targeting CCL2-CCR2 signaling pathway alleviates macrophage dysfunction in COPD via PI3K-AKT axis

Dong,

Zhu

et al. 2024

Cell Commun Signal

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Background Chronic obstructive pulmonary disease (COPD) remains a leading cause of morbidity and mortality worldwide, characterized by persistent respiratory symptoms and airflow limitation. The involvement of C–C motif chemokine ligand 2 (CCL2) in COPD pathogenesis, particularly in macrophage regulation and activation, is poorly understood despite its recognized role in chronic inflammation. Our study aims to elucidate the regulatory role and molecular mechanisms of CCL2 in the pathogenesis of COPD, providing new insights for therapeutic strategies. Methods This study focused on the CCL2-CCR2 signaling pathway, exploring its role in COPD pathogenesis using both Ccl2 knockout (KO) mice and pharmacological inhibitors. To dissect the underlying mechanisms, we employed various in vitro and in vivo methods to analyze the secretion patterns and pathogenic effects of CCL2 and its downstream molecular signaling through the CCL2-CCR2 axis. Results Elevated Ccl2 expression was confirmed in the lungs of COPD mice and was associated with enhanced recruitment and activation of macrophages. Deletion of Ccl2 in knockout mice, as well as treatment with a Ccr2 inhibitor, resulted in protection against CS- and LPS-induced alveolar injury and airway remodeling. Mechanistically, CCL2 was predominantly secreted by bronchial epithelial cells in a process dependent on STAT1 phosphorylation and acted through the CCR2 receptor on macrophages. This interaction activated the PI3K-AKT signaling pathway, which was pivotal for macrophage activation and the secretion of inflammatory cytokines, further influencing the progression of COPD. Conclusions The study highlighted the crucial role of CCL2 in mediating inflammatory responses and remodeling in COPD. It enhanced our understanding of COPD's molecular mechanisms, particularly how CCL2's interaction with the CCR2 activates critical signaling pathways. Targeting the CCL2-CCR2 axis emerged as a promising strategy to alleviate COPD pathology. Graphical Abstract

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Section: Resultsmentioning

confidence: 99%

Targeting CCL2-CCR2 signaling pathway alleviates macrophage dysfunction in COPD via PI3K-AKT axis

Dong,

Zhu

et al. 2024

Cell Commun Signal

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“…Our findings revealed that extracellular PCSK9 induces inflammatory cytokines and activates inflammatory pathways, suggesting that elevated levels of PCSK9 in BALF trigger inflammation in the airways and potentially contribute to inflammatory exacerbations in disease conditions. Role of MMP9 is implicated in fibrosis 29 and severity of COPD 30 . In our investigation, PCSK9-stimulated PBEC induced MMP9, suggesting a potential cause of tissue injury and exacerbation in COPD.…”

Section: Discussionmentioning

confidence: 99%

Contrasting Effects of Endogenous and extracellular PCSK9 on Inflammation, Lipid alteration and Cell death.

Ghalali,

Alhamdan,

Upadhyay

et al. 2024

Preprint

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Proprotein convertase subtilisin/kexin type 9 (PCSK9) is one of the major regulators of low-density lipoprotein receptor (LDLR). While information on role and regulation of PCSK9 in lung is very limited, recent discovery of PCSK9 in A549 highlights a potential function of PCSK9 in lung. Our study focuses on understanding the role and regulation of PCSK9 in the lung. Experiments involved measurement of PCSK9 in bronchioalveolar lavage fluid (BALF), single cell sequencing analysis, and exposure of lung epithelial cells to PCSK9, cigarette smoke extract (CSE), and staurosporine. Inhibition of endogenous PCSK9 expression was followed by bulk RNA sequencing. PCSK9 levels were higher in BALF of smokers with or without chronic obstructive pulmonary diseases (COPD) compared to BALF of nonsmokers. PCSK9-stimulated cells induced proinflammatory cytokines and activation of MAPKp38. PCSK9 transcripts were highly expressed in healthy individuals compared to COPD, pulmonary fibrosis or pulmonary systemic sclerosis. CSE reduced PCSK9 levels in undifferentiated PBEC but induced in differentiated PBEC. PCSK9 inhibition affected biological pathways, inducing lipid peroxidation, and higher level of apoptosis in response to staurosporine. Our results suggest that higher levels of PCSK9 in BALF acts as an inflammatory marker. Furthermore, extracellular and endogenous PCSK9 play different roles.

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Identification of candidate genes and molecular mechanisms related to asthma progression using bioinformatics

Zou,

Meng,

et al. 2024

Sleep Breath

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Background Asthma is a heterogeneous disorder. This study aimed to identify changes in gene expression and molecular mechanisms associated with moderate to severe asthma. Methods Differentially expressed genes (DEGs) were analyzed in GSE69683 dataset among moderate asthma and its controls as well as between severe asthma and moderate asthma. Key module genes were identified via co-expression analysis, and the molecular mechanism of the module genes was explored through enrichment analysis and gene set enrichment analysis (GSEA). GSE89809 was used to verify the characteristic genes related to moderate and severe asthma. Results Accordingly, 2540 DEGs were present between moderate asthma and the control group, while 6781 DEGs existed between severe asthma and moderate asthma. These genes were identified into 14 co-expression modules. Module 7 had the highest positive correlation with severe asthma and was recognized to be a key module by STEM. Enrichment analysis demonstrated that the module genes were mainly involved in oxidative stress-related signaling pathways. The expression of HSPA1A, PIK3CG and PIK3R6 was associated with moderate asthma, while MAPK13 and MMP9 were associated with severe asthma. The AUC values were verified by GSE89809. Additionally, 322 drugs were predicted to target five genes. Conclusion These results identified characteristic genes related to moderate and severe asthma and their corresponding molecular mechanisms, providing a basis for future research.

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The usefulness of MMP-9, TIMP-1 and MMP-9/TIMP-1 ratio for diagnosis and assessment of COPD severity

Cited by 11 publications

References 44 publications

Targeting CCL2-CCR2 signaling pathway alleviates macrophage dysfunction in COPD via PI3K-AKT axis

Targeting CCL2-CCR2 signaling pathway alleviates macrophage dysfunction in COPD via PI3K-AKT axis

Contrasting Effects of Endogenous and extracellular PCSK9 on Inflammation, Lipid alteration and Cell death.

Identification of candidate genes and molecular mechanisms related to asthma progression using bioinformatics

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