Expressions of MMP-12, TIMP-4, and Neutrophil Elastase in PBMCs and Exhaled Breath Condensate in Patients with COPD and Their Relationships with Disease Severity and Acute Exacerbations

Hao, Wendong; Li, Manxiang; Zhang, Yunqing; Zhang, Cailian; Xue, Yani

doi:10.1155/2019/7142438

Cited by 23 publications

(21 citation statements)

References 28 publications

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“…Moreover, serum NE protein level was significantly higher in COPD ‘exacerbator with emphysema phenotype’ patients compared with healthy subjects. This is consistent with previous studies,23 24 which indicated that NE levels in serum and peripheral blood mononuclear cells of COPD patients are much higher than in healthy subjects. In addition, the serum NE level of severe–very severe patients (GOLD 3&4) was significantly higher than that of mild–moderate patients (GOLD 1&2).…”

Section: Discussionsupporting

confidence: 93%

Severity of chronic obstructive pulmonary disease with ‘exacerbator with emphysema phenotype’ is associated with potential biomarkers

Hao

Zhang

et al. 2019

Postgraduate Medical Journal

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ObjectiveThe present study was designed to investigate the biomarkers levels of fractalkine (FKN), neutrophil elastase (NE) and matrix metalloproteinase-12 (MMP-12) in chronic obstructive pulmonary disease (COPD) with ‘exacerbator with emphysema phenotype’ and to evaluate the associations between the biomarkers levels and the severity of disease by spirometric measurements.MethodsA total of 84 COPD patients and 49 healthy controls were enrolled in our study. ELISA were utilised to detect the FKN, MMP-12 and NE in serum from all subjects.ResultsFKN (p<0.001), NE (p=0.039) and MMP-12 (p<0.001) in serum of COPD patients showed higher levels than that of healthy control subjects. Serum FKN (p<0.001), MMP-12 (p<0.001) and NE (p=0.043) levels were significantly higher in severe and very severe COPD patients than that in mild and moderate COPD patients. Circulating FKN, MMP-12 and NE expression levels were significantly elevated (p<0.001) in COPD smokers compared with COPD non-smokers. The smoke pack years were negatively correlated with FEV1%pred (r=−0.5036), FEV1/FVC ratio (r=−0.2847) (FEV, forced expiratory volume; FVC, forced vital capacity). Similarly, we observed a strong positive correlation between the smoke pack years and serum levels of FKN (r=0.4971), MMP-12 (r=0.4315) and NE (r=0.2754). FEV1%pred was strongly negatively correlated with cytokine levels of FKN (r=−0.4367), MMP-12 (r=−0.3295) and NE (r=−0.2684). Likewise, FEV1/FVC ratio was negatively correlated with mediators of inflammation levels of FKN (r=−0.3867), MMP-12 (r=−0.2941) and NE (r=−0.2153).ConclusionSerum FKN, MMP-12 and NE concentrations in COPD patients are directly associated with the severity of COPD with ‘exacerbator with emphysema phenotype’. This finding suggests that FKN, MMP-12 and NE might play an important role in the pathophysiology of COPD.

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Section: Discussionsupporting

confidence: 93%

Severity of chronic obstructive pulmonary disease with ‘exacerbator with emphysema phenotype’ is associated with potential biomarkers

Hao

Zhang

et al. 2019

Postgraduate Medical Journal

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“…levels promotes the migration and differentiation of monocytes in lung tissue, amplifying the inflammatory process [44][45][46]. The chronic inflammation of the lungs results in alterations in the parenchyma architecture, a process known as tissue remodeling, due an unbalance between active MMPs and its inhibitors, TIMP [47,48]. In concordance with this notion, CS group presented, in association with pulmonary neutrophilia, alveolar enlargement as well as loss of alveolar parenchyma, collagen deposition, and destruction of elastic fibers.…”

Section: Plos Onementioning

confidence: 77%

Oral feeding with probiotic Lactobacillus rhamnosus attenuates cigarette smoke-induced COPD in C57Bl/6 mice: Relevance to inflammatory markers in human bronchial epithelial cells

et al. 2020

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COPD is a prevalent lung disease with significant impacts on public health. Affected airways exhibit pulmonary neutrophilia and consequent secretion of pro-inflammatory cytokines and proteases, which result in lung emphysema. Probiotics act as nonspecific modulators of the innate immune system that improve several inflammatory responses. To investigate the effect of Lactobacillus rhamnosus (Lr) on cigarette smoke (CS)-induced COPD C57Bl/6 mice were treated with Lr during the week before COPD induction and three times/week until euthanasia. For in vitro assays, murine bronchial epithelial cells as well as human bronchial epithelial cells exposed to cigarette smoke extract during 24 hours were treated with Lr 1 hour before CSE addition. Lr treatment attenuated the inflammatory response both in the airways and lung parenchyma, reducing inflammatory cells infiltration and the production of proinflammatory cytokines and chemokines. Also, Lr-treated mice presented with lower metalloproteases in lung tissue and lung remodeling. In parallel to the reduction in the expression of TLR2, TLR4, TLR9, STAT3, and NF-κB in lung tissue, Lr increased the levels of IL-10 as well as SOCS3 and TIMP1/2, indicating the induction of an anti-inflammatory environment. Similarly, murine bronchial epithelial cells as well as human bronchial epithelial cells (BEAS) exposed to CSE produced pro-inflammatory cytokines and chemokines, which were inhibited by Lr treatment in association with the production of anti-inflammatory molecules. Moreover, the presence of Lr also modulated the expression of COPD-associated transcription found into BALF of COPD mice group, i.e., Lr downregulated expression of NF-κB and STAT3, and inversely upregulated increased expression of SOCS3. Thus, our findings indicate that Lr modulates the balance between pro-and anti-inflammatory cytokines in human bronchial epithelial cells upon CS exposure and it can be a useful tool to improve the lung inflammatory response associated with COPD.

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“…Neutrophils also activate MMPs through production of elastase (47,48), so we reasoned that elevated neutrophil-mediated inflammation observed in the Il17ra −/− mice could be due to dysregulated MMPs and could impact the process of wound healing (49,50). The increased levels of Mmp10 and Mmp3 in the WT tissue during OM were diminished in the Il17ra −/− tissue (Figure 5A).…”

Section: Enhanced Neutrophil Response In Il-17ra-deficient Micementioning

confidence: 99%

Tissue Damage in Radiation-Induced Oral Mucositis Is Mitigated by IL-17 Receptor Signaling

et al. 2021

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Oral mucositis (OM) is a treatment-limiting adverse side effect of radiation and chemotherapy. Approximately 80% of patients undergoing radiotherapy (RT) for head and neck cancers (HNC) develop OM, representing a major unmet medical condition. Our understanding of the immunopathogenesis of OM is limited, due in part to the surprising paucity of information regarding healing mechanisms in the oral mucosa. RNAseq of oral tissue in a murine model that closely mimics human OM, showed elevated expression of IL-17 and related immune pathways in response to head and neck irradiation (HNI). Strikingly, mice lacking the IL-17 receptor (IL-17RA) exhibited markedly more severe OM. Restoration of the oral mucosa was compromised in Il17ra−/− mice and components associated with healing, including matrix metalloproteinase 3, 10 and IL-24 were diminished. IL-17 is typically associated with recruitment of neutrophils to mucosal sites following oral infections. Unexpectedly, in OM the absence of IL-17RA resulted in excessive neutrophil recruitment and immunopathology. Instead, neutrophil activation was IL-1R-driven in Il17ra−/− mice. Blockade of IL-1R and depletion of neutrophils lessened the severity of damage in these mice. Overall, we show IL-17 is protective in OM through multiple mechanisms including restoration of the damaged epithelia and control of the neutrophil response. We also present a clinically relevant murine model of human OM to improve mechanistic understanding and develop rational translational therapeutics.

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Expressions of MMP-12, TIMP-4, and Neutrophil Elastase in PBMCs and Exhaled Breath Condensate in Patients with COPD and Their Relationships with Disease Severity and Acute Exacerbations

Cited by 23 publications

References 28 publications

Severity of chronic obstructive pulmonary disease with ‘exacerbator with emphysema phenotype’ is associated with potential biomarkers

Severity of chronic obstructive pulmonary disease with ‘exacerbator with emphysema phenotype’ is associated with potential biomarkers

Oral feeding with probiotic Lactobacillus rhamnosus attenuates cigarette smoke-induced COPD in C57Bl/6 mice: Relevance to inflammatory markers in human bronchial epithelial cells

Tissue Damage in Radiation-Induced Oral Mucositis Is Mitigated by IL-17 Receptor Signaling

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