Chitinase activation in patients with fungus-associated cystic fibrosis lung disease.

BACKGROUND: Chitinases have recently gained attention in the field of pulmonary diseases, particularly in asthma and chronic obstructive pulmonary disease, but their potential role in patients with cystic fibrosis (CF)-associated lung disease remains unclear. OBJECTIVE: The aim of this study was to assess chitinase activity systemically and in the airways of patients with CF and asthma compared with healthy subjects. Additionally, we assessed factors that regulate chitinase activity within the lungs of patients with CF. METHODS: Chitinase activities were quantified in serum and bronchoalveolar lavage fluid from patients with CF, asthmatic patients, and healthy control subjects. Mechanistically, the role of CF airway proteases and genetic chitinase deficiency was assessed. RESULTS: Chitinase activity was systemically increased in patients with CF compared with that in healthy control subjects and asthmatic patients. Further stratification showed that chitinase activity was enhanced in patients with CF colonized with Candida albicans compared with that in noncolonized patients. CF proteases degraded chitinases in the airway microenvironment of patients with CF. Genetic chitinase deficiency was associated with C albicans colonization in patients with CF. CONCLUSION: Patients with CF have enhanced chitinase activation associated with C albicans colonization. Therefore chitinases might represent a novel biomarker and therapeutic target for CF-associated fungal disease.

Cystic fibrosis disease severity correlates with plasma levels of desmosine and isodesmosine, biomarkers of elastin degradation.

Novel methodological approaches now demonstrate that the unique elastin degradation products desmosine and isodesmosine are detectable in plasma of cystic fibrosis patients and correlate to lung function, exacerbation frequency and disease progression http://bit.ly/2VwZOcx.

Neutrophil elastase increases airway epithelial nonheme iron levels.

Alpha-1-antitrypsin (A1AT) deficiency is characterized by increased neutrophil elastase (NE) activity and oxidative stress in the lung. We hypothesized that NE exposure generates reactive oxygen species by increasing lung non-heme iron. To test this hypothesis, we measured bronchoalveolar lavage (BAL) iron and ferritin levels, using inductively coupled plasma (ICP) optical emission spectroscopy and an ELISA respectively, in A1AT-deficient patients and healthy subjects. To confirm the role of NE in regulating lung iron homeostasis, we administered intratracheally NE or control buffer to rats and measured BAL and lung iron and ferritin. Our results demonstrated that A1AT-deficient patients and rats post-elastase exposure have elevated levels of iron and ferritin in the BAL. To investigate the mechanism of NE-induced increased iron levels, we exposed normal human airway epithelial cells to either NE or control vehicle in the presence or absence of ferritin, and quantified intracellular iron uptake using calcein fluorescence and ICP mass spectroscopy. We also tested whether NE degraded ferritin in vitro using ELISA and western analysis. We demonstrated in vitro that NE increased intracellular non-heme iron levels and degraded ferritin. Our results suggest that NE digests ferritin increasing the extracellular iron pool available for cellular uptake.

Alpha-1-antitrypsin deficiency: current concepts.

Since the condition was first described four decades ago, alpha-1-antitrypsin (A1AT) deficiency has served as a model for other disease processes. A1AT is the archetypal serpin designed to ensnare proteases, a process that involves significant conformational change within the molecule. Mutations in the A1AT gene lead to misfolding of the protein and accumulation within the endoplasmic reticulum of hepatocytes resulting in two different pathologic processes. First, the accumulation of mutant A1AT protein has a directly toxic effect on the liver, resulting in hepatitis and cirrhosis. Second, the resultant decrease in circulating A1AT results in protease-antiprotease imbalance at the lung surface and emphysema ensues. A1AT deficiency therefore can be seen as two distinct disease processes: a conformational disease of the liver and a protease-antiprotease imbalance of the lung. This two-stage model of disease in A1AT deficiency is elegant in its simplicity and goes a long way to explaining the clinical manifestations that occur in patients with the condition. However, some aspects of the disease are not readily explained. Recent findings suggest that there is more to the lung damage in A1AT deficiency than simple proteolytic insult and that the presence of the mutant protein itself is proinflammatory and may indeed cause chronic injury to the cells that produce it. This review discusses some of the emerging concepts in alpha-1-antitrypsin research and outlines the implications these new ideas may have for treatment of this condition.