Epithelium-dependent effect of L-glutamate on airways: involvement of prostaglandins.

We investigated the effect of the excitatory amino acid (EAA) receptor agonists L-glutamate, N-methyl-D-aspartate (NMDA), (RS)-a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and kainic acid on KCl-induced contractions of rabbit tracheal smooth muscle, as well as the role of epithelium and endogenously produced nitric oxide and prostaglandins on these responses. L-Glutamate decreased KCI-induced contractions up to 30%. This effect was attenuated by epithelium removal, tetrodotoxin, methylene blue and indomethacin but not by NG-nitro-L-arginine methyl ester. While NMDA, AMPA and kainic acid had no effect, the combination of NMDA + kainic acid decreased KCI-induced contractions. These results suggest that, in rabbit trachea, L-glutamate has, at least in part, an epithelium-dependent effect mediated via prostaglandin formation and that the EAA receptors involved are non-classical

Resting Tension Affects eNOS Activity in a Calcium-Dependent Way in Airways

The alteration of resting tension (RT) from 0.5 g to 2.5 g increased significantly airway smooth muscle contractions induced by acetylcholine (ACh) in rabbit trachea. The decrease in extracellular calcium concentration [Ca2+]o from 2 mM to 0.2 mM reduced ACh-induced contractions only at 2.5 g RT with no effect at 0.5 g RT. The nonselective inhibitor of nitric oxide synthase (NOS), NG-nitro-L-arginine methyl ester (L-NAME) increased ACh-induced contractions at 2.5 g RT. The inhibitor of inducible NOS, S-methylsothiourea or neuronal NOS, 7-nitroindazole had no effect. At 2.5 g RT, the reduction of [Ca2+]o from 2 mM to 0.2 mM abolished the effect of L-NAME on ACh-induced contractions. The NO precursor L-arginine or the tyrosine kinase inhibitors erbstatin A and genistein had no effect on ACh-induced contractions obtained at 2.5 g RT. Our results suggest that in airways, RT affects ACh-induced contractions by modulating the activity of epithelial NOS in a calcium-dependent, tyrosine-phosphorylation-independent way

Calprotectin in lung diseases

Calprotectin (CLP) is a heterodimer formed by two S-100 calcium-binding cytosolic proteins, S100A8 and S100A9. It is a multifunctional protein expressed mainly by neutrophils and released extracellularly by activated or damaged cells mediating a broad range of physiological and pathological responses. It has been more than 20 years since the implication of S100A8/A9 in the inflammatory process was shown; however, the evaluation of its role in the pathogenesis of respiratory diseases or its usefulness as a biomarker for the appropriate diagnosis and prognosis of lung diseases have only gained attention in recent years. This review aimed to provide current knowledge regarding the potential role of CLP in the pathophysiology of lung diseases and describe how this knowledge is, up until now, translated into daily clinical practice. CLP is involved in numerous cellular processes in lung health and disease. In addition to its anti-microbial functions, CLP also serves as a molecule with pro- and anti-tumor properties related to cell survival and growth, angiogenesis, DNA damage response, and the remodeling of the extracellular matrix. The findings of this review potentially introduce CLP in daily clinical practice within the spectrum of respiratory diseases

Causes and Pathogenesis of Malignant Mesothelioma

Malignant mesothelioma (MM) is a malignancy that arises from the mesothelium, a thin layer of tissue that covers the body’s serous cavities, such as the pleural, peritoneal, pericardial, and tunica vaginalis of the testis. More than 80% of all mesothelioma cases originate from the pleura and approximately 75–80% of patients are males. It is almost always fatal with most of those affected dying within a year of diagnosis. Asbestos exposure is the most common cause of MM, which mostly affects the pleura. Various factors, including other mineral fibers, carbon nanotubes, or genetic mutations, are also suggested to have a role in the development of MM. The involvement of asbestos, other mineral fibers, nanotechnological products, the simian virus SV40, ionizing radiation, genetic factors, and inflammation in the development of MM has been discussed in this chapter. This study focuses on the role of other mineral fibers, such as erionite, fluoroedenite, balangeroite, and carbon nanotubes, as well as genetic mutations in BAP1 and other genes, in the pathogenesis of MM. The etiology of MM is considered to be complex, and greater knowledge of the pathogenetic pathways may lead to the identification of effective and personalized treatment targets

IL-33/ST2 Axis in Organ Fibrosis

Interleukin 33 (IL-33) is highly expressed in barrier sites, acting via the suppression of tumorigenicity 2 receptor (ST2). IL-33/ST2 axis has long been known to play a pivotal role in immunity and cell homeostasis by promoting wound healing and tissue repair. However, it is also involved in the loss of balance between extensive inflammation and tissue regeneration lead to remodeling, the hallmark of fibrosis. The aim of the current review is to critically evaluate the available evidence regarding the role of the IL-33/ST2 axis in organ fibrosis. The role of the axis in tissue remodeling is better understood considering its crucial role reported in organ development and regeneration. Generally, the IL-33/ST2 signaling pathway has mainly anti-inflammatory/anti-proliferative effects; however, chronic tissue injury is responsible for pro-fibrogenetic responses. Regarding pulmonary fibrosis mature IL-33 enhances pro-fibrogenic type 2 cytokine production in an ST2- and macrophage-dependent manner, while full-length IL-33 is also implicated in the pulmonary fibrotic process in an ST2-independent, Th2-independent fashion. In liver fibrosis, evidence indicate that when acute and massive liver damage occurs, the release of IL-33 might act as an activator of tissue-protective mechanisms, while in cases of chronic injury IL-33 plays the role of a hepatic fibrotic factor. IL-33 signaling has also been involved in the pathogenesis of acute and chronic pancreatitis. Moreover, IL-33 could be used as an early marker for ulcer-associated activated fibroblasts and myofibroblast trans-differentiation; thus one cannot rule out its potential role in inflammatory bowel disease-associated fibrosis. Similarly, the upregulation of the IL-33/ST2 axismay contribute to tubular cell injury and fibrosis via epithelial to mesenchymal transition (EMT) of various cell types in the kidneys. Of note, IL-33 exerts a cardioprotective role via ST2 signaling, while soluble ST2 has been demonstrated as a marker of myocardial fibrosis. Finally, IL-33 is a crucial cytokine in skin pathology responsible for abnormal fibroblast proliferation, leukocyte infiltration and morphologic differentiation of human endothelial cells. Overall, emerging data support a novel contribution of the IL-33/ST2 pathway in tissue fibrosis and highlight the significant role of the Th2 pattern of immune response in the pathophysiology of organ fibrosis

Heterozygous Alterations of TNFRSF13B/TACI in Tonsillar Hypertrophy and Sarcoidosis

TNFRSF13B/TACI defects have been associated with CVID pathogenesis and/or phenotype, especially the development of benign lymphoproliferation and autoimmunity. Our purpose was to investigate the role of TNFRSF13B/TACI defects in the pathogenesis of two common lymphoproliferative disorders, namely, sarcoidosis and tonsillar hypertrophy (TH). 105 patients (71 with sarcoidosis and 34 with TH, including 19 without infectious causative and 15 due to Haemophilus influenzae) were analyzed for TNFRSF13B/TACI defects. Two out of 19 TH patients without infectious cause (10.5%) and 2 patients with sarcoidosis (2.8%) displayed rare TNFRSF13B/TACI defects (I87N, L69TfsX12, E36L, and R202H, resp.). Both mutations identified in TH patients have been assessed as deleterious for protein function, while the patient with the R202H mutation and sarcoidosis exhibited also sIgG4D. Our study further supports the notion that TNFRSF13B/TACI defects alone do not result in CVID but may be also found frequently in distinct clinical phenotypes, including benign lymphoproliferation and IgG subclass deficiencies

Ashtrays and Signage as Determinants of a Smoke-Free Legislation’s Success

Introduction: Successful smoke-free legislation is dependent on political will, enforcement and societal support. We report the success and pitfalls of a non-enforced nationwide smoke-free legislation in Greece, as well as ways in which compliance and enforcement-related factors, including ashtrays and signage, may impact indoor secondhand smoke (SHS) concentrations. Methods: A follow-up study of venues (n = 150, at baseline, n = 75 at 2-year follow-up) in Greece assessed indoor particulate matter with a diameter less than 2.5 micrometers (PM2.5) concentrations attributable to SHS smoke every six months for two years (n = 455 venue/measurements). Results: Following the implementation of the 2010 smoke-free legislation, mean PM2.5 concentrations attributable to SHS fell from 175.3 µg/m3 pre-ban to 84.52 µg/m3 immediately post-ban, increasing over subsequent waves (103.8 µg/m3 and 158.2 µg/m3 respectively). Controlling for potential influential factors such as ventilation, time of day, day of week, city and venue type, all post-ban measurements were still lower than during the pre-ban period (Wave 2 beta: −118.7, Wave 3 beta: −87.6, and Wave 4 beta: −69.9). Outdoor or indoor signage banning smoking was not found to affect SHS concentrations (beta: −10.9, p = 0.667 and beta: −18.1, p = 0.464 respectively). However, ashtray or ashtray equivalents were strong determinants of the existence of indoor SHS (beta: +67 µg/m3, p = 0.017). Conclusions: While the public may be supportive of smoke-free legislation, adherence may decline rapidly if enforcement is limited or nonexistent. Moreover, enforcement agencies should also focus on the comprehensive removal of ashtray equivalents that could act as cues for smoking within a venue

Sleep disordered breathing from preschool to early adult age and its neurocognitive complications: A preliminary report

Objective: The onset and development of sleep disordered breathing (SDB) remains unclear in an age - dependent manner. Despite treatment, persistent symptoms such as snoring and excessive daytime sleepiness, as well as cognitive impairment may be present. The aim of the research was to determine the prevalence of residual symptoms of SDB in adolescence and early adulthood, the predisposing factors and its neurocognitive complications. Methods: In the present pilot study-cohort, a questionnaire was utilized to 154 people (average age: 17.9 ± 3), who as children (mean age: 5.3 ± 1.4) had AHI ≥2.5 episodes/h. They were divided into two groups based on AHI = 5 episodes/h. Depending on the results, they were invited to undergo a repeated polysomnography (PSG) and complete the Montreal Cognitive Assessment (MoCA) test. Statistical analysis was made with IBM SPSS software. Results: Out of the total, 35.7% claimed to still snore. AHI was negatively correlated to the severity of residual symptoms (Mann-Witney U test, p <0.005). According to repeated PSGs, 9/17 met the criteria for OSAS, while high BMI was associated with the severity of new AHI (chi squared test, p<0.005). Additionally, 7/16 scored below the MoCA baseline (<26/30). The characteristics of cognitive declines were mapped, with most prominent having been visuospatial, short - term memory and naming/language deficits. Discussion: A significant percentage of children with sleep breathing disorder present with residual symptoms during their transition to early adulthood, as well as undiagnosed neurocognitive complications. Clinicians suspicion for the underlying neurocognitive complications is required, even in young adults, while guidelines on monitoring pediatric OSAS patients after treatment should be addressed

Vibration Response Imaging: evaluation of rater agreement in healthy subjects and subjects with pneumonia

<p>Abstract</p> <p>Background</p> <p>We evaluated pulmonologists variability in the interpretation of Vibration response imaging (VRI) obtained from healthy subjects and patients hospitalized for community acquired pneumonia.</p> <p>Methods</p> <p>The present is a prospective study conducted in a tertiary university hospital. Twenty healthy subjects and twenty three pneumonia cases were included in this study. Six pulmonologists blindly analyzed images of normal subjects and pneumonia cases and evaluated different aspects of VRI images related to the quality of data aquisition, synchronization of the progression of breath sound distribution and agreement between the maximal energy frame (MEF) of VRI (which is the maximal geographical area of lung vibrations produced at maximal inspiration) and chest radiography. For qualitative assessment of VRI images, the raters' evaluations were analyzed by degree of consistency and agreement.</p> <p>Results</p> <p>The average value for overall identical evaluations of twelve features of the VRI image evaluation, ranged from 87% to 95% per rater (94% to 97% in control cases and from 79% to 93% per rater in pneumonia cases). Inter-rater median (IQR) agreement was 91% (82-96). The level of agreement according to VRI feature evaluated was in most cases over 80%; intra-class correlation (ICC) obtained by using a model of subject/rater for the averaged features was overall 0.86 (0.92 in normal and 0.73 in pneumonia cases).</p> <p>Conclusions</p> <p>Our findings suggest good agreement in the interpretation of VRI data between different raters. In this respect, VRI might be helpful as a radiation free diagnostic tool for the management of pneumonia.</p