David Bennett

Oxidative stress in the pathogenesis of diffuse lung diseases: A review

Oxidative stress is an imbalance between oxidants (reactive oxygen and nitrogen species) and antioxidants that may affect lipids, DNA, carbohydrates and proteins. The lung is continuously exposed to endogenous and exogenous oxidants (cigarette smoke, mineral dust, ozone, radiation). Reactive oxygen and nitrogen species are mainly produced by phagocytes as well as by polymorphonuclear, alveolar, bronchial and endothelial cells. A potential role of oxidative stress in the pathogenesis of diffuse lung diseases (particularly idiopathic pulmonary fibrosis) has been demonstrated. Increased oxidant levels and decreased antioxidant defences can contribute to the progression of idiopathic pulmonary fibrosis and other diffuse lung diseases. The growing number of papers on the different aspects of oxidant/antioxidant imbalance in diffuse lung diseases in the last decade reflects increasing interest in this topic and suggests that specific DLDs may be characterized by specific patterns of oxidation and antioxidant responses. The study of oxidative stress can provide insights into etiopathogenesis and favour the discovery of new treatments. In this review of the literature on oxidants and antioxidants in diffuse lung diseases, the focus is on idiopathic pulmonary fibrosis, sarcoidosis, pneumoconiosis and pulmonary fibrosis associated with systemic sclerosis.

Serum Chitotriosidase Levels in Patients with Allergic and Non-Allergic Asthma

Since the data did not have a normal distribution (Shapiro-Wilk’s test), statistical differences were detected by the Kruskal-Wallis test (p !0.05. ) Serum concentrations of chitotriosidase were 48.72 8 31 nmol/h/ml in allergic asthmatics, 51.5 8 29 nmol/h/ml in non-allergic asmathics and 21.42 8 11 nmol/h/ml in controls ( fig. 1 ). Significant differences were found between the concentrations of chitotriosidase in asthmatics and controls (p ! 0.05 ). Concentra-tions of chitotriosidase greater than normal values were observed in 60% of allergic and 63% of non-allergic asthmatics. No signifi-cant differences were found between chitotriosidase concentra-tions in allergic and non-allergic patients, although the highest concentrations of chitotriosidase were found in 4 patients with documented allergy to dust and moulds. . a l tj e l ec Tre [8] s tudied serum chitotriosidase activity in vari-ous lung diseases, finding concentrations of chitotriosidase in a small population of asthmatics similar to ours. Unfortunately this study did not divide patients according to their history of allergy or specify whether any groups of patients had higher chitotriosi-dase concentrations. Asthma is a complex inflammatory disorder of the airways characterized by bronchial hyper-reactivity to different stimuli, and its pathogenesis is not always completely clear. Chitinases and chitinase-like proteins have recently been proposed as molecules involved in the pathogenesis of asthma with a possible role as prognostic biomarkers [1–6] . Higher serum concentrations of YKL-40 (chitinase-3-like-1), a ‘mammalian chitinase-like protein’, have been reported [2, 4, 5] in asthma patients and hyper-responsive subjects than in con-trols. The YKL-40 gene has been associated with genetic suscep-tibility to the disease. Acid mammalian chitinase (AMCase) has been studied in animal models of airway inflammation [3] and AMCase gene expression has been investigated in detail in BAL fluid macrophages and epithelial brushing from asthma patients [1, 5] . Another member of the chitinase 1 family not yet studied in detail in asthma is chitotriosidase, an enzyme produced by acti-vated macrophages, structurally similar to YKL-40 but having chitinolytic activity [7, 8] . In the last 5 years our research group has investigated the role of chitotriosidase in the pathogenesis of different inflammatory lung diseases, such as sarcoidosis [9] . Here we analyzed serum concentrations of chitotriosidase in al-lergic and non-allergic asthma patients and in a group of controls to evaluate its potential involvement in the different pathways of inflammation occurring in this disease.Ch itotriosidase concentrations were measured in serum sam-ples from 23 patients with allergic asthma, 19 non-allergic asth-matics and 35 healthy controls by a fluorimetric method (Sigma, St. Louis, Mo., USA). Selected patients with PC20 methacholine less than 8 mg/ml were followed at our centre for almost 5 years. They were divided into allergic and non-allergic groups according to medical history, prick test and RAST test results. All patients performed lung function tests, chest X-ray and total IgE analysis at the time of serum sampling. Statistical analysis was performed using Windows software (2005) Graph Pad Prism version 4.0.

Helicobacter pylori seroprevalence in patients with idiopathic pulmonary fibrosis

To the Editor: In 2007, the European Respiratory Journal published a letter by Ibrahim [1] in which it was suggested that micro-aspiration of Helicobacter pylori from gastric juice secondary to gastro-oesophageal reflux disease (GORD) may cause or contribute to the development of idiopathic pulmonary fibrosis (IPF) through recurrent lung insult. This hypothesis was derived from the observation that GORD is common in IPF patients [2, 3], while in the general population the prevalence of GORD exceeds that of IPF. Ibrahim [1] postulated that only a small proportion of subjects with GORD develop IPF, probably those with H. pylori in their gastric juice. This theory has not yet been investigated and no data is available in the literature on the relationship between H. pylori infection and IPF. H. pylori is a Gram-negative, spiral bacterium. There are two major groups of H. pylori microorganisms: type I, which expresses the vacuolating cytotoxin VacA and the cytotoxin-associated gene CagA and is responsible for mucosal damage, inducing local inflammatory response; and type II, which expresses neither of these proteins and does not determine any injury [4]. Type I strains, which have the chromosomal insertion called Cag, are endowed with increased inflammatory function that may determine further augmentation of local and systemic cytokines [5]. H. pylori infection is very common all over the world and does not seem to have sex or racial prevalence. CagA H. pylori strains play a role in gastroduodenal ulcers and the development of gastric cancer. H. pylori infection was recently demonstrated to protect against gastro-oesophageal reflux disease and reflux esophagitis [6], to be associated with several extragastric disorders [7] and to play a role …

Biomarkers in sarcoidosis: the contribution of system biology.

Purpose of review System biology is an interdisciplinary approach with the purpose to evaluate the experimental results of ‘-omics’ sciences as a whole. The ‘-omics’ sciences do not start generally from a-priori assumptions and are aimed to study the constituents of a specific biological domain (genome, transcriptome, proteome and metabolome) in a given state, using different high-throughput technologies (as polymerase chain reaction, arrays, liquid chromatography, mass spectrometry, etc.) and allowing a hermeneutical integration and recomposition of the experimental information. The aim of the present review is to explore the main new findings of system biology studies applied to sarcoidosis in the last year. Recent findings The main new findings of sarcoidosis that were highlighted by different studies in the last year (including miRNAs, TGF-&bgr; pathway, TNF-&agr; and related proteins, vesicle trafficking, vitamin D and lipid metabolism, analyzed by system biology) are presented in this article. Summary System biology is a useful approach to combine different experimental results to study the pathogenesis of sarcoidosis and to identify groups of new molecules and mediators with potential clinical application as biomarkers.

Diffuse panbronchiolitis in a patient with common variable immunodeficiency: a casual association or a pathogenetic correlation?

Diffuse panbronchiolitis (DPB) is an idiopathic inflammatory disease that seems to have an immunological pathogenesis and that causes a severe progressive suppurative and obstructive respiratory disorder. Common variable immunodeficiency (CVID) is the most common serious primary immunodeficiency and it is often associated with respiratory diseases. Herein, we describe a case of DPB in a 41-year-old man affected by CVID. We examined the patient’s lungs, focusing on the characteristics of the inflammatory cells and of the foamy macrophagic nodules typical of DPB. Immunohistochemical typing of the lymphocytic infiltrate showed that B-cells were almost absent, matching the immunological profile of CVID. The case described is the first case reported in the literature of DPB in a patient affected by CVID. Moreover it seems to confirm the correlation between an immunodeficiency status and the development of DPB and provides more information on the accumulation of nodules of foamy macrophages in DPB.Virtual slidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/5310709471138338.

Airway-Centered Pleuroparenchymal Fibroelastosis Associated with Non-Necrotizing Granulomas: A Rare New Entity

Pleuroparenchymal fibroelastosis is a rare form of upper-lobe-dominant progressive pulmonary fibrosis characterized histologically by visceral pleural thickening with collagenous fibrosis, subpleural elastosis, and intra-alveolar collagenous fibrosis. It was first described 25 years ago by Amitani et al. This report firstly describes a new variant or rare phenotype of PPFE with airway involvement, minimal pleuroparenchymal connections, and non-necrotizing granulomas.

Bronchial stenosis following lung transplant: an innovative approach with a modified endobronchial emphysema valve

To the Editor, Airway complications (AC) after lung transplant (LT) are relative common and include bronchial stenosis (BS), suture dehiscence, granulation tissue, bronchomalacia, and fistula. BS is the commonest complication; management is wideranging and different endobronchial approaches have been proposed. We report a 61-years old man who underwent a bilateral LT for chronic obstructive pulmonary disease (COPD) at our Institution and 16 weeks after developed a BS. At time of diagnosis pulmonary function tests showed a FEV1 drop (212%) and bronchoscopy revealed the presence of a stenosis of the right lower lobe bronchus after apical segmental subdivision (3 mm of diameter and 4 mm of length)— peripheral bronchial structures appeared patent. Any previous bronchoscopies did not show any alterations of bronchial canalization or early sign of stenosis. Before BS occurrence, 5 weeks after LT, the patient experienced an acute rejection episode (A3 grade) promptly treated with pulsed steroid therapy and with complete remission. Several balloon dilations (Cordis Powerflex® Pro 6 mm diameter) were performed but stenosis always recurred. Six months after BS diagnosis a stent placement was proposed and, due to the particular localization and extension, we implanted a modified endobronchial valve designed for emphysema treatment (Pulmonx Zephyr® 4.0 endobronchial valve). In particular, we removed central silicon flaps maintaining the device structure intact (Figure 1). By flexible bronchoscope, the modified valve was placed at stenosis level using a flexible delivery catheter with no complications (Figure 2). No more bronchial dilations were necessary and 12-month follow-up showed a complete BS stabilization with unmodified valve patency, adequate fluids clearance, and pulmonary ventilation. Unfortunately, the patient developed bronchiolitis obliterans syndrome (BOS) and he died 28 months after LT. The last CT scan, 15 days before the exitus, still showed valve patency and adequate placement. Several risk factors have been identified to AC development, in particular donor/recipient factors, surgical technique, infections, and immunosuppressant therapy seem to be the most determinant. Early acute rejection episodes, as our patient experienced, have also been associated to BS development. BS is the commonest AC (prevalence range from 1.6% to 32%); more frequently the stenosis involves bronchial anastomosis, although distal localizations to segmental and subsegmental bronchi, as in the present case, have been reported. Therapeutic approaches depend on the severity and the localization of the stenosis; dilation and ablation are commonly repeatedly performed to gain stabilization. Nevertheless, recurrent BS may benefit of stenting procedures. Different stents (SEMS, silicon, hybrid, and biodegradable stents) have been proposed, but no single method has demonstrated clear superiority and procedure decision mainly depends to single institutions and operators experience. Some complex BS even need open surgical approaches.

Exhaled nitric oxide in idiopathic and non-idiopathic interstitial lung disease

Background: Recently, fractional exhaled nitric oxide (FENO) has been studied as a potential marker of many interstitial lung diseases (ILD), such as idiopathic pulmonary fibrosis (IPF) or systemic sclerosis associated ILD, and their severity. Aim and Objectives: to investigate the role of FeNO in the differential diagnosis between ILDs. Methods: We measured FeNO at multiple flow-rates (50-100-150 and 350 ml/s) and alveolar concentration of NO (CalvNO) in 50 healthy controls and 135 patients affected by ILD: 50 with IPF, 20 with idiopathic non-specific interstitial pneumonia (NSIP), 20 with chronic hypersensitivitis pneumonia (cHP) and 45 with connective tissue disease related ILD (CTD-ILD). Receiver operating characteristic curves were conducted to evaluate diagnostic accuracy of eNO parameters for CTD-ILD. Results: ILD patients reported higher values of FeNO 150-350 and CalvNO than controls (CalvNO: p Conclusions: FeNO 150-350 and CalvNO levels are elevated in patients with ILD. Interestingly, patients with CTD-ILD showed the highest values, suggesting a possible role of NO in lung inflammation and fibrosis associated with rheumatological disease. Further studies are needed to confirm the potential role of CalvNO in discriminating between CTD and non-CTD-ILD.

Posttransplant solid organ malignancies in lung transplant recipients: a single-center experience and review of the literature

Purpose Solid-organ tumor incidences are higher in solid organ transplant patients than in the general population. The aim of this study was to analyze solid-organ tumor frequency and characteristics in a population of lung transplant patients and provide a brief review of the literature. Methods A retrospective analysis was conducted of all patients who underwent a lung transplant in the Lung Transplant Program at the University Hospital of Siena, Italy, from 2001 to 2014 (n = 119). Patients’ demographics, pretransplant characteristics, immunosuppressive therapy, and infectious factors were recorded. Results Nine patients with a median age of 59.0 years (range 50–63) of our cohort developed a solid-organ tumor (7.5%). Most of the patients experienced nonmelanoma skin cancer (44.4%); the others were diagnosed with lung cancer (22.2%), breast cancer (22.2%), and colon-rectal cancer (11.2%). The median time from transplantation to tumor diagnosis was 895.0 days (range 321–2046). No differences in pretransplant characteristics, immunosuppressive therapy, or infectious factors were found between patients who developed solid organ tumors and those who did not. Conclusions The present study confirmed that de novo malignancies are a major issue in lung transplant patients; in particular, skin and lung cancers demonstrated a higher incidence rate. Oncologic treatment of these patients is complex, requiring close collaboration between the transplant team and oncologist. Strict screening programs are key factors for an early diagnosis and to allow for prompt treatment resulting in a better outcome.