Copper as the most likely pathogenic divergence factor between lung fibrosis and emphysema.

Although fibrosis and emphysema are in many ways on opposite ends of the pulmonary parenchymal disease spectrum, they seem to share common pathomechanistic steps. This is illustrated by the coexistence of both entities in lungs of individuals with combined pulmonary fibrosis and emphysema. Macroproteins elastin and collagen are major constituents of the pulmonary extracellular matrix. The prevailing paradigm states that emphysema is caused by an imbalance between destructive proteolytic and protective antiproteolytic enzymes leading to accelerated degradation of elastin fibers in the lungs. Rates of elastin breakdown, however, are equally enhanced in patients with idiopathic pulmonary fibrosis (IPF) and emphysema. Excessive accumulation of collagen is a hallmark of IPF. Surprisingly, collagen levels in the lung parenchyma of patients with emphysema are also higher than in controls. The concentration of elastin fibers is elevated in fibrotic lungs, despite accelerated elastinolysis, suggesting that elastin repair is also enhanced in IPF. Since elastin concentrations are reduced in emphysematous lungs, the factor of divergence between emphysema and fibrosis seems to be the degree of elastin repair. Multiple elastin repair steps can be deduced of which tropoelastin synthesis and crosslinking of tropoelastin polymers by the copper dependent enzyme lysyl oxidase seem to be the most important ones. We suspect that the distinction in the pathogeneses of lung fibrosis and emphysema depends on the local availability of copper to activate sufficient lysyl oxidase for elastin crosslinking, and suggest assessing the effects of inhalation therapy with copper plus heparin in emphysema and heparin monotherapy in IPF.

Increased circulating desmosine and age-dependent elastinolysis in idiopathic pulmonary fibrosis.

Although chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) seem to be opposite entities from a clinical perspective, common initial pathogenic steps have been suggested in both lung diseases. Emphysema is caused by an elastase/anti-elastase imbalance leading to accelerated elastin degradation. Elastinolysis is however, also accelerated in the IPF patients' lungs. The amino acids desmosine and isodesmosine (DES) are unique to elastin. During the degradation process, elastases liberate DES from elastin fibers. Blood DES levels consequently reflect the rate of systemic elastinolysis and are increased in COPD. This is the first report describing elevated DES levels in IPF patients. We also demonstrated that the age-related increment of DES concentrations is enhanced in IPF. Our current study suggests that elastinolysis is a shared pathogenic step in both COPD and IPF. Further investigation is required to establish the relevance of accelerated elastin degradation in IPF and to determine whether decelerating this process leads to slower progression of lung fibrosis and better survival for patients with IPF.

Should vitamin K be supplemented instead of antagonised in patients with idiopathic pulmonary fibrosis?

INTRODUCTION: There is an ongoing need for additional interventions in idiopathic pulmonary fibrosis (IPF) as antifibrotic drugs currently available only inhibit and do not stall disease progression. Vitamin K is a co-factor for the activation of coagulation factors. However, it is also required to activate proteins with functions outside of the coagulation cascade, such as matrix Gla protein (MGP), a defender against soft tissue calcification. Vitamin K antagonists are anticoagulants that are, for unknown reasons, associated with increased mortality in IPF. Areas covered: We advance the hypothesis that modulation of vitamin K-dependent MGP activation in IPF patients by either vitamin K antagonism or administration may result in acceleration and deceleration of fibrosis progression, respectively. Furthermore, shortfall in vitamin K could be suspected in IPF based on the high prevalence of certain co-morbidities, such as vascular calcification and lung cancer. Expert commentary: We hypothesize that vitamin K status is reduced in IPF patients. This, in combination with studies suggesting that vitamin K may play a role in lung fibrosis pathogenesis, would provide a rationale for conducting a clinical trial assessing the potential mitigating effects of vitamin K administration on progression of lung fibrosis, prevention of co-morbidities and mortality in IPF.

Systematic review with meta-analysis: Dietary adherence influences normalization of health-related quality of life in coeliac disease.

BACKGROUND & AIMS: Gluten-free diet is the keystone of coeliac disease treatment. Despite adherence, some patients continue to suffer from symptoms that negatively influence health-related quality of life (HRQoL). Therefore we performed a systematic review and meta-analysis to assess the effect of gluten-free diet on HRQoL in coeliac disease. We specifically sought for determinants that negatively influenced HRQoL. METHODS: We systematically searched PubMed, EMBASE, CINAHL, PsycINFO and Cochrane Library for studies assessing HRQoL in untreated or treated adults using validated HRQoL-questionnaires from 1960 to September 2015, comparing HRQoL: (1) before and after gluten-free diet initiation or (2) in patients and non-coeliac controls. RESULTS: We included eighteen studies and sixteen were suitable for meta-analysis. Gluten-free diet significantly improves HRQoL, for psychological general well-being (PGWB)-Total (mean difference (MD) 7.34, 95% confidence interval (CI) [1.96; 12.72]; p = 0.008), SF-36 Mental Component Score (MCS) (MD 7.37, 95% CI [1.84; 12.90]; p = 0.009) and SF-36 Physical Component Score (PCS) (MD 5.72, 95% CI [1.50; 9.95]; p = 0.008). Treated patients had similar HRQoL compared with controls for PGWB-Total (MD -0.72, 95% CI [-2.71; 1.27]; p = 0.48), but significantly lower levels for SF-36 MCS (MD -4.09, 95% CI [-6.17; -2.01]; p = 0.0001) and PCS (MD -4.57, 95% CI [-6.97; -2.17]; p = 0.0002). Symptom-detected gluten-free diet adhering patients have lower HRQoL compared with screening-detected patients (MD -3.73, 95% CI [-6.77;-0.69]; p = 0.02) Strict adhering patients have better HRQoL compared with non-strict adhering patients for SF-36 MCS (MD 7.70, 95% CI [4.61; 10.79]; p < 0.00001) and for SF-36 PCS (MD 3.23, 95% CI [1.33; 5.14]; p = 0.0009). CONCLUSIONS: Gluten-free diet significantly improves but does not normalize HRQoL in adults with coeliac disease. Dietary adherence improves HRQoL. Better (self-reported) dietary adherence results in higher HRQoL.

Propionibacterium acnes isolated from lymph nodes of patients with sarcoidosis.

Propionibacterium acnes has been repeatedly suggested as a candidate causative agent of sarcoidosis. It is the only microorganism that has been isolated from sarcoid lesions by bacterial culture so far and this has been described in Japanese patients only. We report two non-Japanese patients in whom mediastinoscopy was performed in order to obtain lymph node tissue for histopathology, which was suggestive for sarcoidosis. Bacterial culture of these uncontaminated mediastinal lymph nodes revealed P. acnes in both patients. As shown in these two cases, P. acnes can be isolated from sterile biopsied sarcoid lymph nodes of non-Japanese patients and supports the belief that there is an etiologic link between P. acnes sarcoidosis. Further elucidation could provide an opening to novel strategies using antibiotics for treating sarcoidosis.