Sergio Scrimini

Differential effects of smoking and COPD upon circulating myeloid derived suppressor cells

BACKGROUND Chronic obstructive pulmonary disease (COPD) is characterized by an enhanced and persistent innate and acquired immune response to tobacco smoking. Myeloid-derived suppressor cells (MDSCs) modulate T-cell responses by down-modulating the T cell receptor ζ chain (TCR ζ) through the catabolism of l-arginine. The effects of smoking on MDSCs and their potential participation in COPD immunopathogenesis have not been explored so far. METHODS To investigate it, we compared the level of circulating Lineage-/HLA-DR-/CD33+/CD11b+ MDSCs, the serum concentration of arginase I (ARG I) and the expression of peripheral T-cell receptor ζ chain (TCR ζ) in never smokers, smokers with normal spirometry and COPD patients. Flow cytometry was used to quantify circulating MDSCs and TCR ζ expression. Serum ARG I levels were determined by ELISA. RESULTS The main findings of this study were that: (1) current smoking upregulates and activates circulating MDSCs both in smoker controls and COPD patients; and, (2) at variance with the smokers with normal spirometry, in patients with COPD this effect persists after quitting smoking and is accompanied by a significant and specific down-regulation of the TCR ζ chain expression in circulating T lymphocytes. CONCLUSION Smoking modulates circulating MDSCs. Their regulation appears altered in patients with COPD.

Expansion of myeloid-derived suppressor cells in chronic obstructive pulmonary disease and lung cancer: potential link between inflammation and cancer

AbstractBackground Chronic obstructive pulmonary disease (COPD) is a risk factor for lung cancer (LC). Myeloid-derived suppressor cells (MDSCs) down-regulate the T cell receptor ζ chain (TCR ζ) through l-arginine deprivation and lead to T cell dysfunction and deficient antitumor immunity. We hypothesized that abnormally high levels of MDSCs in COPD patients may alter tumor immunosurveillance.MethodsWe compared the proportion of circulating MDSCs (Lin-HLA-DR-/CD33+/CD11b+) (by flow cytometry), arginase I (ARG I) serum levels (by ELISA), and expression levels of TCR ζ on circulating lymphocytes (by flow cytometry) in 28 patients with LC, 62 subjects with COPD, 41 patients with both LC and COPD, 40 smokers with normal spirometry and 33 non-smoking controls. T cell proliferation assays were performed in a subgroup of participants (CFSE dilution protocol).ResultsWe found that: (1) circulating MDSCs were up-regulated in COPD and LC patients (with and without COPD); (2) MDSCs expansion was associated with TCR ζ down-regulation in the three groups; (3) in LC patients, these findings were independent of COPD and tobacco smoking exposure; (4) TCR ζ down-regulation correlates with T cell hyporesponsiveness in COPD and LC patients.ConclusionsThese results suggest that tumor immunosurveillance might be impaired in COPD and may contribute to the increased risk of LC reported in these patients.

Células mieloides supresoras: potencial vínculo entre la enfermedad pulmonar obstructiva crónica y el cáncer de pulmón

Chronic obstructive pulmonary disease (COPD) and lung cancer (LC) are prevalent diseases and are a leading cause of morbidity and mortality worldwide. There is strong evidence to show that COPD is an independent risk factor for LC. Chronic inflammation plays a significant pathogenic role in COPD comorbidities, particularly in LC. On the one hand, cellular and molecular inflammatory mediators promote carcinogenesis and, on the other, chronic inflammation impairs the capacity of the immune system to identify and destroy pre-malignant and malignant cells, a process known as tumor immune surveillance. This altered antitumor immunity is due in part to the expansion of myeloid-derived suppressor cells (MDSC), which are characterized by an ability to suppress the antitumor activity of T-cells by down-regulation of the T-cell receptor ζ chain (TCRζ) through the catabolism of L-arginine. COPD and LC patients share a common pattern of expansion and activation of circulating MDSC associated with TCRζ downregulation and impaired peripheral T-cell function. The objectives of this study were to review the evidence on the association between COPD and LC and to analyze how MDSC accumulation may alter tumor immune surveillance in COPD, and therefore, promote LC development.

EPOC y asma

Chronic obstructive pulmonary disease and asthma are both highly prevalent inflammatory diseases characterized by airway obstruction with distinct pathogenic mechanisms and different degrees of response to antiinflammatory therapy. However, forms of presentation that show overlap between both diseases and which are not clearly represented in clinical trials are frequently encountered in clinical practice. These patients may show accelerated loss of pulmonary function and have a worse prognosis. Therefore their early identification is essential. Biomarkers such as bronchial hyperreactivity or nitric oxide in exhaled air have yielded discrepant results. Phenotypic characterization will allow treatment with inhaled corticosteroids to be individually tailored and optimized.

Bone marrow characterization in COPD: a multi-level network analysis

BackgroundBone marrow (BM) produces hematopoietic and progenitor cells that contribute to distant organ inflammation and repair. Chronic obstructive pulmonary disease (COPD) is characterized by defective lung repair. Yet, BM composition has not been previously characterized in COPD patients.MethodsIn this prospective and controlled study, BM was obtained by sternum fine-needle aspiration in 35 COPD patients and 25 healthy controls (10 smokers and 15 never-smokers). BM cell count and immunophenotype were determined by microscopy and flow cytometry, respectively. Circulating inflammatory (C-reactive protein, IL-6, IL-8) and repair markers (HGF, IGF, TGF-β, VEGF) were quantified by ELISA. Results were integrated by multi-level network correlation analysis.ResultsWe found that: (1) there were no major significant pair wise differences between COPD patients and controls in the BM structural characteristics; (2) multi-level network analysis including patients and controls identifies a relation between immunity, repair and lung function not previously described, that remains in the COPD network but is absent in controls; and (3) this novel network identifies eosinophils as a potential mediator relating immunity and repair, particularly in patients with emphysema.ConclusionsOverall, these results suggest that BM is activated in COPD with impaired repair capacity in patients with more emphysema and/or higher circulating eosinophils.

The role of myeloid-derived suppressor cells in the relationship between chronic obstructive pulmonary disease and lung cancer

Chronic obstructive pulmonary disease (COPD) is characterized by chronic pulmonary and systemic inflammation. There is strong evidence showing that COPD is an independent risk factor for lung cancer (LC). Chronic inflammatory response can affect all stages of tumour development, from tumour initiation to metastasis. Inflammation also alters tumour immune surveillance. Myeloid-derived suppressor cells (MDSC) are a heterogeneous mixture of immature granulocytic and monocytic cells characterized by an ability to suppress the antitumour activity of T-cells by down-regulation of the T-cell receptor chain (TCR ζ) through the catabolism of l-arginine. COPD and lung cancer share a common pattern of expansion of MDSC associated with TCR ζ downregulation and T-cell dysfunction. MDSC may impair tumour immunosurveillance in COPD and can potentially facilitate tumour initiation and growth, contributing to explain the increased incidence of lung cancer reported in these patients. Introduction Chronic obstructive pulmonary disease (COPD) is an inflammatory lung disease characterized by airflow obstruction associated with destruction of lung parenchyma caused by chronic inhalation of gases and noxious particles, primarily tobacco smoke. Comorbidities and exacerbations contribute to the severity of the disease [1]. COPD is highly prevalent and affects approximately 10% of adults worldwide [2]. It is the third most common cause of death in the United States, and it is estimated that it will be the third leading cause of death and disability worldwide by 2020 [3]. Comorbidities associated with COPD crucially influence the clinical symptoms, progress and prognosis of the disease [1]. Lung cancer is one of the most significant and common causes of death in COPD patients. Although the underlying mechanisms are not fully understood, lung cancer and COPD are clearly associated, possibly due to chronic inflammation [4-6]. Rudolf Virchow first suggested the potential link between inflammation and cancer in the 19th century. During the last decades there has been clear evidence that chronic inflammation plays a key role at every stage of tumourigenesis, from tumour initiation to tumour progression and metastatic dissemination [7]. Inflammatory cells produce a variety of molecules that can cause DNA mutations, genomic instability, malignant cell proliferation, neovascularization, invasion and metastasis. Chronic inflammation may also favour cancer development by disarming the capacity of the immune system to detect Correspondence to: Dr. Jaume Sauleda, M.D., PhD, Hospital Universitari Son Espases, C/Valldemossa 79, Planta 0, Mod. C, 07010, Palma de Mallorca, España, Spain, Tel: 871206718, Fax: 871-90.97.24, E-mail: jaume.sauleda@ssib.es