Identification of Neutrophil Activation Markers as Novel Surrogate Markers of CF Lung Disease

Räth, Timo; Zwaschka, Lisa; Hage, Lisa; Kügler, Marion; Menendez, Katrin Menendez; Naehrlich, Lutz; Schulz, Richard; Roderfeld, M; Roeb, Elke

doi:10.1371/journal.pone.0115847

Cited by 14 publications

(3 citation statements)

References 50 publications

(71 reference statements)

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“…Our studies extend the limited available observations that have already been published on examining HA pathobiology in the progression of CF airway disease or as a marker of clinical exacerbation (17). In fact, HA serum levels have not been found to be impacted by advanced lung disease in pediatric and adult patients with CF (28). Locally in the lung, HA at one time was reported to be the only detectable GAG in CF (29), although other sugars have been subsequently identified, which may also play an important role in CF pathophysiology (30).…”

Section: Discussionsupporting

confidence: 71%

Pathological Hyaluronan Matrices in Cystic Fibrosis Airways and Secretions

Matuska¹,

Comhair

Farver³

et al. 2016

Am J Respir Cell Mol Biol

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Hyaluronan (HA) has been used in treatment of cystic fibrosis (CF) via a nebulizer and has demonstrated success in clinical outcomes. HA is an important glycosaminoglycan that is cross-linked by heavy chains (HCs) from inter-α-inhibitor during inflammation. HC cross-linked HA (HC-HA) becomes significantly more adhesive for leukocytes than non-cross-linked HA, which can enhance inflammation. Our studies tested the hypothesis that HC-HA is present in CF airways and that altered ratios of HC-HA to its degradation into relatively lower molecular weight HA contribute to the pathophysiology of chronic inflammation in CF. We evaluated the distribution, levels, and size of HC-HA within CF, healthy, and diseased control lung, bronchus, and sputum tissues by histological and biochemical approaches. HC-HA was significantly elevated in CF, with deposits around the pulmonary vasculature, airway submucosa, and in the stroma of the submucosal glands. The increased infiltration of leukocyte populations correlated with the distribution of HC-HA matrices in the airways. Elevated lung tissue HC-HA correlated with decreased HA levels in CF mucus and sputum compared with controls, suggesting that aberrant degradation and cross-linking of HA in lung tissue is a unique feature of CF. The accumulation and degradation of proinflammatory HC-HA in CF lung tissue suggests that aberrant HA catabolism and cross-linking may contribute to chronic inflammation in airway tissues and affect mucus viscosity in CF airways.

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Section: Discussionsupporting

confidence: 71%

Pathological Hyaluronan Matrices in Cystic Fibrosis Airways and Secretions

Matuska¹,

Comhair

Farver³

et al. 2016

Am J Respir Cell Mol Biol

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“…In addition, each patient received regular haematological and biochemical investigation as well as a pulmonary function test (FEV1, VC) [ 9 , 10 ].…”

Section: Methodsmentioning

confidence: 99%

Assessment of pathologic increase in liver stiffness enables earlier diagnosis of CFLD: Results from a prospective longitudinal cohort study

et al. 2017

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About 30% of patients with Cystic Fibrosis (CF) develop CF-associated liver disease (CFLD). Recent studies have shown that transient elastography (TE), as a method to quantify liver stiffness, allows non-invasive diagnosis of CFLD in adults and children with CF. Within this study we aimed to prospectively identify patients at risk for development of CFLD by longitudinal analysis of liver stiffness and fibrosis scores in a 5-year follow-up. 36 pediatric and 16 adult patients with initial liver stiffness below the cut-off value indicative of CFLD (6.3 kPa) were examined by transient elastography for 4-5 years. TE, APRI-, and FIB-4-scores were assessed and compared by Kruskal-Wallis test and receiver operating characteristic (ROC)-analysis. Frequencies were compared by Chi 2 -test. Among the 36 patients participating in this study, a subgroup of 9 patients developed liver stiffness >6.3 kPa after 4-5 years with an increase of ΔTE >0.38 kPa/a (the group with increasing liver stiffness was labelled TE inc ). APRI-and FIB-4 scores confirmed the rationale for grouping. The frequency of CFLD assessed by conventional diagnosis was significantly higher in TE inc -group compared to the control group (TE norm ). None of the adult CF patients matched criteria for TE incgroup. For the first time it was shown that the non-invasive longitudinal assessment of TE allows identification of patients with progression of CFLD in a subgroup of juvenile but not in adult CF patients. Comparing TE to conventional fibrosis-scores underlined the strength of the continuous assessment of liver stiffness for the exact diagnosis of progressive CFLD. The newly described cut-off for pathologic increase of liver stiffness, ΔTE cutoff = 0.38kPa/a, might enable to detect developing CFLD using consequent follow up TE measurements before reaching the level of stiffness indicating established CFLD. Nevertheless, the limited size of the analyzed cohort should encourage a prospective, multi-center, long term follow up study to confirm the suggested cut-off for the rise in liver stiffness.PLOS ONE | https://doi.org/10.1371/journal.pone

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“…Another study of adults and children with moderate-to-severe CF lung disease reported elevated serum MMP-8, MMP-9, and TIMP-1 levels in clinically stable CF patients, and higher serum MMP-8 and MMP-9 levels in adult CF patients having acute pulmonary exacerbations. 53 However, serum MMP-8, MMP-9, and TIMP-1 levels were not correlated with CF liver disease or pancreatic insufficiency in this cohort.…”

Section: Mmp Levels In Cf Blood Samplesmentioning

confidence: 55%

Matrix metalloproteinases in cystic fibrosis: pathophysiologic and therapeutic perspectives

Owen

Jojas-Quintero²

2016

MNM

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Cystic fibrosis (CF) is the most common inherited disease in the Caucasian population. CF is caused by loss-of-function mutations in the CFTR gene leading to an altered electrolyte and water movement into the airway surface liquid, dehydration of the mucus layer, defective mucociliary clearance, and increased susceptibility to airway bacterial infections. CF is characterized by airway neutrophilic inflammation and activation of airway epithelial cells leading to increased airway levels of various matrix metalloproteinases (MMPs). Herein, we review MMP structure, regulation, and activity, along with the literature on MMPs expression in CF and the contributions of MMPs to CF pathogenesis. Numerous studies report elevated levels of MMPs (especially MMP-8, MMP-7, and MMP-9) in blood and/or lung samples from CF patients and have correlated MMP levels with measures of lung inflammation and injury and/or clinical parameters. No study has yet investigated the contributions of MMPs to the pathogenesis of CF using MMP gene-targeted murine of CF. Based upon the known activities of MMPs in animal models of other lung diseases, we hypothesize that some MMPs (such as MMP-8 and MMP-9) may amplify airway inflammation, and promote airway injury and airway-remodeling processes, or inhibit chloride epithelial transport by inhibiting activation of the CFTR (MMP-2). Other MMPs (such as MMP-7 and MMP-12) may limit the severity of CF by activating host defense proteins to enhance pathogen clearance from the airways, directly killing pathogens that colonize the airways of CF patients and/or promoting epithelial repair. We discuss potential approaches to selectively target MMPs to develop novel therapies that limit the high morbidity and mortality associated with CF.

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Identification of Neutrophil Activation Markers as Novel Surrogate Markers of CF Lung Disease

Cited by 14 publications

References 50 publications

Pathological Hyaluronan Matrices in Cystic Fibrosis Airways and Secretions

Pathological Hyaluronan Matrices in Cystic Fibrosis Airways and Secretions

Assessment of pathologic increase in liver stiffness enables earlier diagnosis of CFLD: Results from a prospective longitudinal cohort study

Matrix metalloproteinases in cystic fibrosis: pathophysiologic and therapeutic perspectives

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