The diagnostic challenge of pulmonary tumour thrombotic microangiopathy as a presentation for metastatic gastric cancer: a case report and review of the literature.

BACKGROUND: Pulmonary tumour thrombotic microangiopathy (PTTM) is a rare complication of metastatic cancer with a distinct histological appearance which presents with dyspnoea and pulmonary arterial hypertension and leads to death in hours to days. It is a challenging diagnosis to make ante mortem, in part due to the rapid clinical decline. Herein, we report a case of a young woman initially felt to have pulmonary sarcoidosis but who then died eight days later from what was found at post mortem to be PTTM. CASE PRESENTATION: A 41 year old Caucasian woman presented with progressive dyspnoea. Computed tomography of her thorax showed diffuse tiny centrilobular nodules in a tree-in-bud appearance along with small volume mediastinal lymphadenopathy. A presumptive diagnosis of pulmonary sarcoidosis was made; bronchoscopy with transbronchial lung biopsy was arranged to confirm the diagnosis. However, she rapidly deteriorated and died eight days later. Post mortem examination revealed metastatic poorly differentiated gastric adenocarcinoma with PTTM being the final cause of death. CONCLUSION: This case demonstrates the diagnostic difficulties in such a rare and rapidly fatal oncological complication; a greater awareness amongst clinicians may help make a positive diagnosis in the short window of time available. Little is known about its pathogenesis, and even less about optimal management strategies. We review the literature to demonstrate the clinical characteristics that might provide clues towards an ante mortem diagnosis, and highlight how imatinib may provide the key to treating PTTM.

[Pathogenesis of chronic obstructive pulmonary disease. Molecular mechanisms (part II)]. / Patogeneza przewleklej obturacyjnej choroby pluc. Czesc II. Podloze molekularne.

Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality worldwide. Smoking is considered the major cause of the disease. Relatively little is known about the molecular mechanisms underlying inflammatory response in smokers' lungs and how this relates to the susceptibility to the disease, particularly why only 10-15% of smokers develop COPD. Recent development in molecular biology techniques allowed the insight into the inner space of the cell, to the levels far beyond the reach of the traditional methods. We review recent hypotheses on cellular and molecular background of COPD with emphasis on the potential role of histone acetylation, as a key modulator of enhanced gene transcription responsible for proinflammatory cytokines production in COPD. Authors propose a role for modification of nucleosomal structure in inflammatory cytokine gene transcription in response to smoking. Cigarette smoke causes oxidative stress altering the balance between histone deacetylation and acetylation in favor of acetylation. This can contribute to the airflow obstruction in smokers susceptible to the development of COPD. Furthermore, histone acetylation seems to be a potential mechanism exclusive to smokers with susceptibility to COPD based on the transcription of specific pro- and anti-inflammatory cytokine combinations.

[Pathogenesis of chronic obstructive pulmonary disease. Cellular mechanisms (part I)]. / Patogeneza przewleklej obturacyjnej choroby pluc. Czesc i. podloze komórkowe.

Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality worldwide. Smoking is considered the major cause of the disease. All smokers develop airway inflammation through oxidative stress with macrophages, neutrophiles, lymphocytes, eosinophils, NK-cells and mediators involved. Macrophages through the activation of Nuclear Factor kappa B (NF.-kappaB) release proinflammatory mediators, lymphocyte chemotactic agents and elastolytic enzymes, activate neutrophil driven serine proteases and GM-CSF. Neutrophiles release IL-8 which in turn recruits neutrophils to the airways. In response to cigarette smoke lung epithelium may release TNF-alpha, TGF-beta, IL-1beta, GM-CSF, IL-8 reactive oxygen species (ROS). Increased number of lymphocyte T CD8+ and CD4+ subpopulations may lead to lung epithelium cells apoptosis and necrosis through perphorines and granzyme-B and TNF-alpha activation. Moreover, increased expression of IL-6, IL-10, IL-12, IL-13, and INF-gamma is observed. Authors indicate the possibility of new treatment strategies such as: agents directed against adhesion molecules, chemokines, phosphodiesterase 4, p38 MAPK, NF.-kappaB phosphoinositide-3-kinase gamma, TGF-beta, NOS synthase, serine proteinases and matrix metalloproteinases.

The effect of smoking on the transcriptional regulation of lung inflammation in patients with chronic obstructive pulmonary disease.

RATIONALE: Chronic obstructive pulmonary disease (COPD) is believed to result from an abnormal inflammatory response in the lungs to noxious particles and gases usually found in cigarette smoke. OBJECTIVES: In this study, the molecular mechanisms for the enhanced proinflammatory cytokine gene transcription in COPD were investigated. METHODS: Lung tissue was examined from 56 subjects undergoing resection for peripheral lung tumors as follows: current smokers with (n = 14) and without COPD (n = 17), ex-smokers with COPD (n = 13), and nonsmokers (n = 12). The levels of inhibitor kappaB-alpha (IkappaB-alpha), histone deacetylase 2 (HDAC2), acetylated (ac-) histone H3 and H4, the transcription factor nuclear factor-kappaB (NF-kappaB), proinflammatory cytokine messenger RNA, and 8-isoprostane were measured. MEASUREMENTS AND MAIN RESULTS: IkappaB-alpha levels were significantly decreased in healthy smokers and current and ex-smoking patients with COPD when compared with nonsmokers (p < 0.001), with an associated increase in NF-kappaB DNA binding in current smokers (p < 0.05). An increase in acetylated histone 4 (ac-H4; p < 0.01) was found in current smokers. Conversely, ex-smokers with COPD showed an increase in ac-H3 (p < 0.05). Decreased levels of cytoplasmic, but not nuclear, HDAC2 protein levels were detected. From the cytokine profiles, no significant differences were detected; however, interleukin-12p40 expression correlated with ac-H4 in current smokers with COPD (p < 0.01). CONCLUSION: These data propose a role for modification of nucleosomal structure in inflammatory cytokine gene transcription in response to smoking. The imbalance between histone deacetylation and acetylation in favor of acetylation may contribute to the enhanced inflammation in smokers susceptible to the development of COPD.

Oxidative stress and cigarette smoke alter chromatin remodeling but differentially regulate NF-kappaB activation and proinflammatory cytokine release in alveolar epithelial cells.

Oxidative stress is implicated in lung inflammation due to its effect on proinflammatory gene transcription. Changes in gene transcription depend on chromatin remodeling and the relative activities of histone acetyltransferases (HATs) and histone deacetylases (HDACs). Alterations in the nuclear histone acetylation:deacetylation balance may result in uncontrolled transcription of specific proinflammatory genes. We studied the effect of hydrogen peroxide (H2O2) and cigarette smoke condensate (CSC) on histone acetylation:deacetylation in human alveolar epithelial cells (A549). H2O2 and CSC significantly increased acetylation of histone H4 proteins and were associated with decreased HDAC activity and HDAC2 levels in A549 cells. Also, the decreased HDAC2 activity was due to protein modification by aldehydes and nitric oxide products. Pretreatment of A549 cells with N-acetyl-l-cysteine attenuated the oxidant-mediated reduction in HDAC activity. Treatment of A549 cells with CSC did not cause nuclear factor-kappaB (NF-kappaB) activation or expression and release of either interleukin (IL)-8 or IL-6. However, H2O2, tumor necrosis factor-alpha (TNF-alpha), and IL-1beta significantly increased NF-kappaB activation and expression of IL-8 compared with control cells. Interestingly, CSC dose dependently inhibited TNF-alpha- and IL-1beta-mediated NF-kappaB activation and IL-8 expression. Thus, H2O2 and CSC enhance acetylation of histone proteins and decrease histone deacetylase activity but differentially regulate proinflammatory cytokine release in alveolar epithelial cells.

[Influence of orthopnoea position on spirometric and plethysmographic parameters in patients with chronic obstructive pulmonary disease ]. / Wplyw pozycji orthopnoe na wskazniki spirometryczne i pletyzmograficzne u chorych na przewlekla obturacyjna chorobe pluc (POChP).

Chronic obstructive pulmonary disease (COPD) is characterized by the lack or only slight reversibility of obstruction which can be assessed by spirometry after inhalation of short-acting beta 2-mimetic (e.g. Salbutamol). The aim of the study was to determine if subjective decrease in dyspnoea sensation notified by COPD patients in orthopnoea position is reflected in spirometry and plethysmography. The study was carried out in the group of 30 patients with COPD (FEV1 = 30-70% of predicted value) as well as in 30 sex- and age-matched non-smoking healthy subjects. We observed the increase of spirometric parameters (FEV1, FEV1%VC, FEF75, PEF) and the decrease of plethysmographic parameters (RTOT, RV, RV%TLC) after the change from the initial to orthopnoea position (p < 0.001). The obtained results show that orthopnoea position leads to the decline of obstruction degree, pulmonary hyperinflation and the decrease of dyspnoea sensation.

[Antibodies seroprevalence for mycoplasma pneumoniae antigens in patients with bronchial asthma]. / Czestosc wystepowania przeciwcial dla antygenów Mycoplasma pneumoniae u chorych na astme oskrzelowa.

Microorganisms causing respiratory system infections, mainly viruses but also bacteria, among which there are atypical such as Chlamydophila pneumoniae, play a role in etiopathogenesis of bronchial asthma. Mycoplasma pneumoniae is suggested to take part in the initiation and the bronchial asthma exacerbation. The aim of the paper was to determine the frequency of occurrence of anti-Mycoplasma pneumoniae antibodies in serum of patients suffering from bronchial asthma in comparison with the control group of healthy persons. The presence of IgG, IgM and IgA class anti-Mycoplasma pneumoniae antibodies was assessed by immunoenzymatic assay ELISA. Serologic markers of Mycoplasma pneumoniae infection were more frequently observed in patients with bronchial asthma (15%) than in the control group (5.13%). The diagnosis of Mycoplasma pneumoniae infection is especially important in patients with bronchial asthma. The pathogen causing bronchial hyperreactivity is eliminated by the appropriate antibiotic therapy, which allows reducing the dose of inhaled corticosteroids. The immunoenzymatic assay determining the level and class of specific antibodies to find mycoplasmatic infection quickly and precisely.

[Incidence of selected bacterial pathogens of the respiratory tract in patients with bronchial asthma]. / Czestosc wystepowania wybranych bakteryjnych patogenów dróg oddechowych u chorych na astme oskrzelowa.

Chronic bacterial infections intensify the reactivity of bronchi and aggravate the course and the control of asthma. They cause the disorders of both function and the structure of respiratory epithelium. Not only structural elements of bacteria but also their toxins intensify the release of mediators of the inflammatory reaction (leucotriens, histamine, IL1, IL4, IL6, IL8, TNF alpha). The aim of our research is to determine the prevalence of microorganisms, which can have an influence on the course of asthma. Moraxella catarrhalis has been the most frequent isolated pathogen (23.7%) in patients with bronchial asthma. We have received only individual isolations of Streptococcus pneumoniae and Haemophilus influenzae strains. Bacterial flora of the upper respiratory tract in patients with bronchial asthma has been more diverse in comparison with microflora of airways in healthy subjects. The significant percentage of Candida isolation in asthmatics (over 30% in bronchial tree secretion) poses the high risk of incidence of mycotic complications of inhaled steroids. In patients with asthma bronchial tree secretion is more valuable diagnostic material than pharyngeal swab.