The role of Beta-arrestins in respiratory pathophysiology and tumorigenesis: going a step beyond the cell surface.

Beta-arrestins are small cytosolic proteins that have been known so far as negative feedback regulators of G-protein coupled receptors (GPCRs). This receptor superfamily, characterized by a heptahelical transmembrane motif, mediates the signals of a multitude of extracellular ligands including chemokines, cytokines, hormones and growth factors. Beta-arrestins "arrest" the GPCR signaling capability through its desensitization and internalization. However, novel roles for these molecules have emerged and research demonstrates that beta-arrestins can mediate intracellular signaling independently of their effects on G-protein stimulation. Acting as scaffolding proteins, they can lead to the assembly of intracellular signalsomes that can activate or inhibit the function of various signaling cascades, such as the MAP kinase, JNK and NF-kappaB cascades, ultimately affecting gene expression. Finally, they can even regulate gene transcription by modulating histone acetylation and chromatin assembly. This pleiotropic activity of beta-arrestins can regulate both physiologic and pathophysiologic responses and will be reviewed in the context of lung inflammatory diseases and lung cancer.

Sex hormone alterations and systemic inflammation in a group of male COPD smokers and their correlation with the +138 insA/delA endothelin-1 gene polymorphism. A case-control study.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterized by the presence of a low-grade systemic inflammation that is implicated in the pathogenesis of numerous extrapulmonary manifestations, such as hypogonadism. Endothelin-1 (ET-1) is a molecule that demonstrates pro-inflammatory properties and can augment the airway and systemic inflammation. Single nucleotide polymorphisms (SNPs) of the ET-1 gene that increase ET-1 serum levels are an important area of investigation. We examined the alterations in inflammatory markers [C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR)] and in the levels of testosterone, free testosterone, follicle stimulating hormone (FSH) and luteinizing hormone (LH) in a group of male COPD smokers when compared to their age-matched controls and how these alterations relate to the presence of a functional ET-1 SNP, the adenine insertion SNP +138 insA/delA. MATERIALS AND METHODS: In this case control study, 80 male control smokers and 82 male COPD smokers were recruited for comparison. Among the male COPD smokers, 37 were carriers of the +138 insA/delA SNP. Two COPD subgroups according to genotype were formed: (1) A group of 45 males homozygous for the wild type allele (3A/3A) and (2) a group of 37 males heterozygous for the mutant allele (3A/4A). RESULTS: Levels of testosterone and free testosterone were lower in the COPD group and even lower in the 3A/4A COPD group. CRP and ESR levels were higher in both COPD groups, but their elevation was statistically significant only for the 3A/4A COPD group. Testosterone and free testosterone levels correlated positively with PaO2 for both COPD groups. An inverse correlation between testosterone and CRP was demonstrated for the 3A/4A COPD subgroup. CONCLUSIONS: Levels of testosterone correlated to FEV1, hypoxemia and weakly to CRP. The synchronous presence of the +138 insA/delA SNP resulted in even greater sex hormone level decline probably due to the presence of a more intense systemic inflammation.

Association of ET-1 gene polymorphisms with COPD phenotypes in a Caucasian population.

BACKGROUND AND AIM: The phenotypic expression of COPD consists of pulmonary emphysema and chronic bronchitis. An imprecise phenotypic definition may result in inconsistencies among genetic studies regarding COPD pathogenesis. Endothelin-1 gene polymorphisms have been linked to increased susceptibility of COPD development. The present study examined the involvement of +138 insA/delA and G198T ET-1 polymorphisms with emphysematous and bronchitic COPD phenotypes. METHODS: In order to narrow down the phenotypic choices to either COPD-associated pulmonary emphysema or chronic bronchitis, a DLCO < 60% predicted threshold was chosen as an indicator of severe emphysema. 116 COPD smokers and 74 non-related, non-COPD smokers were evaluated. RESULTS: Statistical analysis showed that the 4A allele of the +138insA/delA SNP and the 4A:T haplotype were associated predominantly with a chronic bronchitis phenotype, whereas the TT genotype of the G198T SNP was found to be protective from emphysema development. CONCLUSIONS: The presence of both the 4A and T allele seems to modify the final expression of COPD towards a chronic bronchitis phenotype, since the G:3A haplotype was associated with a predominantly emphysematous phenotype in our study.

Local renin-angiotensin II systems, angiotensin-converting enzyme and its homologue ACE2: their potential role in the pathogenesis of chronic obstructive pulmonary diseases, pulmonary hypertension and acute respiratory distress syndrome.

Renin-angiotensin II-aldosterone axis has long been known as a regulator of blood pressure and fluid homeostasis. Yet, local renin-angiotensin II systems have been discovered and novel actions of angiotensin II (AngII) have emerged among which its ability to act as a immunomodulator and profibrotic molecule. The enzyme responsible for its synthesis, Angiotensin-converting-enzyme (ACE), is present in high concentrations in lung tissue. In the present paper, we review data from studies of the past decade that implicate AngII and functional polymorphisms of the ACE gene that increase ACE activity with increased susceptibility for asthma and chronic obstructive pulmonary disease (COPD) and for pulmonary hypertension. Moreover, drugs that inhibit the synthesis of AngII (ACE inhibitors) or that antagonize its actions on its receptors (Angiotensin II receptor blockers -ARBs) have been shown to provide beneficial effects. Another recent discovery reviewed is the presence of a homologue of ACE, ACE2, which cleaves a single amino acid from AngII and forms a heptapeptide with vasodilatory actions, Ang 1-7. The balance between ACE and ACE2 is crucial for controlling AngII levels. ACE and ACE2 also appear to modify the severity of Acute Respiratory Distress Syndrome (ARDS), with ACE2 playing a protective role. Finally, mention is made to the recent discovery of ACE2 as a receptor for the SARS Corona Virus.

Decline in FEV1 related to genetic polymorphisms (+138insA/delA and Lys198Asn) of the endothelin-1 gene in COPD. A pilot study.

BACKGROUND: Endothelin-1 (ET-1) is a potent vasoconstrictor and bronchoconstrictor but it has been shown to have also proinflammatory properties. Its ability to attract inflammatory cells in its site of production, upregulates the synthesis of adhesion molecules and stimulates the release of cytokines. The fact that cytokines have the ability to induce its synthesis and release, creates a dynamic loop for self-preservation and augmentation of the airway inflammation in Chronic Obstructive Pulmonary Disease (COPD), even after the ceasing of the noxious stimulus, i.e., cigarette smoke. Therefore, functional polymorphisms that may lead to increased levels of ET-1 may also cause an increased susceptibility to COPD development. MATERIALS AND METHODS: We analyzed the longitudinal effect on lung function of two ET-1 gene polymorphisms in a population of 190 smokers (95 non-COPD and 95 COPD smokers). The two polymorphisms involved an insertion polymorphism (+138 adenine insertion 3A/4A, 138bp downstream from the transcription start site, exon 1) and a single nucleotide transversion polymorphism on exon 5 (G/T, Lys198Asn). A total of 190 subjects were enrolled in the study for each polymorphism and were followed for 3 years by annual spirometry sessions. RESULTS: The adjusted annual decline of forced expiratory volume in 1 second (dFEV1) was greater for those having at least one copy of the mutated gene ins/delA compared to those with the wild type allele both in the non-COPD smokers group (mean difference in dFEV, of 19.4 ml/year, p = 0.004) and COPD smokers (mean difference in dFEV1 of 11.15 ml/year, p = 0.003). On the contrary, those heterozygous for the Lys198Asn polymorphism were found to have a slower decline in FEV1 compared to those homozygous for the wild type allele. The non-COPD smokers group had a gain-in-loss of 11,24 ml/year (p < 0.001) while the COPD-smokers group had a slower decline of 11.42 ml/year (p = 0.002). Those homozygous for the polymorphisms examined show an even greater deviation from those with the wild type allele but due to the small number comprising their group, the results don't have enough statistical power. Though, they still show the trend of the effect the polymorphisms have on annual FEV1 decline. CONCLUSIONS: The present data shows that ET-1 and its functional polymorphisms may be implicated in COPD phenotype and severity.

Miliary pattern due to occupational lung disease in a patient with laryngeal cancer.

Inhalation of metal dusts and fumes can induce a wide range of respiratory disorders, including granulomatosis, chemical pneumonitis and pulmonary interstitial disease. Laryngeal cancer is the most common cancer of the upper aerodigestive tract. We present a patient with occupational lung disease whose chest CT showed miliary nodular pattern, with concurrent laryngeal cancer who had been engaged in type printing for 22 years. Histology of the laryngeal lession showed squamous cell laryngeal cancer. Histology of the nodules showed a foreign body granulomatous response with several foreign body cells, most probably due to exposure to numerous inorganic (lanthanides, elements such us La, Ce, Nd, Sm, EU, Tb, Lu) and organic particles (such us acrylates, epoxy- and urethane-acrylates).

Pulmonary complications in diabetes mellitus.

Clear decrements in lung function have been reported in patients with diabetes over the past two decades, and many reports have suggested plausible pathophysiological mechanisms. However, there are no reports of functional limitations of activities of daily living ascribable to pulmonary disease in patients with diabetes. This review attempts to summarize the available information from the present literature, to describe the nature of the lung dysfunction in diabetes and the emerging clinical implications of such dysfunction.

Human genes in TB infection: their role in immune response.

Tuberculosis (TB) caused by the human pathogen Mycobacterium tuberculosis, is the leading cause of morbidity and mortality caused by infectious agents worldwide. Recently, there has been an ongoing concern about the clarification of the role of specific human genes and their polymorphisms involved in TB infection. In the vast majority of individuals, innate immune pathways and T-helper 1 (Th1) cell mediated immunity are activated resulting in the lysis of the bacterium. Firstly, PTPN22 R620W polymorphism is involved in the response to cases of infection. The Arg753Gln polymorphism in TLR-2 leads to a weaker response against the M. tuberculosis. The gene of the vitamin D receptor (VDR) has a few polymorphisms (BsmI, ApaI, Taq1, FokI) whose mixed genotypes alter the immune response. Solute carrier family 11 member (SLC11A1) is a proton/divalent cation antiporter that is more familiar by its former name NRAMP1 (natural resistance associated macrophage protein 1) and can affect M. tuberculosis growth. Polymorphisms of cytokines such as IL-10, IL-6, IFN-g, TNF-a, TGF-b1 can affect the immune response in various ways. Finally, a major role is played by M. tuberculosis antigens and the Ras-associated small GTP-ase 33A. As far as we know this is the first review that collates all these polymorphisms in order to give a comprehensive image of the field, which is currently evolving.

Indications, results and complications of flexible fiberoptic bronchoscopy: a 5-year experience in a referral population in Greece.

The aim of this study was to retrospectively review the indications, results and complications of flexible fiberoptic bronchoscopy (FFB) in an University teaching Hospital. Also, we present the radiological findings for the major causes according to computed tomography of the chest performed within 48 h of fiberoptic bronchoscopy. A total of 4,098 FFBs were performed from January 1, 2003 to December 30, 2007. For diagnostic purposes, 3769 FFBs performed (92%) and for therapeutic purposes 329 FFBs (8%) performed. Haemoptysis was the most common indication for FFB (21%), followed by fever/suspected infection (19%) and chronic cough (18%). The most common results of the diagnostic workup was nonspecific inflammation of the tracheobronchial tree (31% for haemoptysis, 38.7% for fever and 48.5% for chronic cough), with malignancy ranking second (17%, 26.1% and 26% respectively). The cytological results showed adenocarcinoma to be the most common lung cancer in both sexes (37.3% for men and 39.7% for women). The mortality rate was 0.04% and the frequency for major and minor complications was 0.56% and 0.33%, respectively. In conclusion, flexible fiberoptic bronchoscopy is a safe procedure and can play a major role in both diagnosis and treatment, as long as the requisites of preparation and supervision are followed.

Does CPAP therapy improve erectile dysfunction in patients with obstructive sleep apnea syndrome?

OBJECTIVE: The aim of the study was to examine the quality of the characteristics of Erectile Dysfunction (ED) in men with Obstructive Sleep Apnea Syndrome (OSAS) and to investigate whether there is an improvement with the use of continuous positive airway pressure (CPAP) therapy. MATERIALS AND METHODS: Fifteen men with OSAS and sexual dysfunction have been investigated in this follow-up study. The treatment period was for 12 weeks and the therapeutic CPAP levels were determined during the full night of the therapeutic titration. RESULTS: In our 15 treated patients, the International Index Erectile Function (IIEF) total and all domain scores had increased after the CPAP treatment compared to the baseline, except for that of sexual desire domain. CONCLUSIONS: CPAP therapy can improve the sexual function in ED patients with OSAS.

Urinothorax: an unexpected cause of pleural effusion in a patient with non-Hodgkin lymphoma.

Urinothorax is a rather rare cause of pleural effusion and its potential mechanism is urinary tract obstruction or trauma that results in urine leakage and accumulation inside the pleural space. Patients with non-Hodgkin lymphoma could present with pleural effusion due to mediastinal lymphadenopathy or extrathoracic manifestation such as urinary tract obstruction, the latter described in our case report. Physicians must be aware even of the more occult mechanisms of pleural fluid accumulations which could point to extrathoracic manifestations of involvement.

Obstructive sleep apnoea syndrome and genes.

Obstructive sleep apnoea (OSA) is a complex disease entity strongly influenced by genetic factors, especially those that affect obesity and fat distribution, upper airway muscle tone, craniofacial morphology, ventilatory control and sleep, giving rise to the OSA phenotype. OSA can also be considered a metabolic syndrome which adversely affects multiple organ systems, especially the cardiovascular system and the brain. The most widely used clinical marker for the diagnosis of OSA is the apnoea-hypopnoea index, calculated by polysomnography. A percentage of 35 to 40% of its variance can be attributed to genetic factors. Therefore, the identification and elucidation of the genes implicated in the pathogenesis of OSA becomes a matter of extensive research and could lead to the development of therapeutic agents that can have a beneficial effect on the natural course of OSA.

The metabolic aspects and hormonal derangements in obstructive sleep apnoea syndrome and the role of CPAP therapy.

Obstructive sleep apnea syndrome (OSAS) is part of a metabolic syndrome, whose main aspects are obesity, hypertension and diabetes, already incriminated for cardiovascular events. The evaluation of the effect of OSAS on the hormonal profile of patients shows a number of complex interactions that preclude the exact role of this syndrome among the numerous derangements on hormone levels as well as the effect of continuous positive airway pressure treatment, since many of the changes are known to occur with obesity as well. The clarification of the exact role and the mechanisms underlying these changes will help to stratify the cardiovascular and other health risks of this syndrome as well as the better application of CPAP therapy.