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Tumor progression and pregnancy share many common features, such as immune tolerance and invasion. The invasion of trophoblasts in the placenta into the uterine wall is essential for fetal development, and is thus precisely regulated. Its deregulation has been implicated in preeclampsia, a leading cause for maternal and perinatal mortality and morbidity. Pathogenesis of preeclampsia remains to be defined. Microarray-based gene profiling has been widely used for identifying genes responsible for preeclampsia. In this review, we have summarized the recent data from the microarray studies with preeclamptic placentas. Despite the complex of gene signatures, suggestive of the heterogeneity of preeclampsia, these studies identified a number of differentially expressed genes associated with preeclampsia. Interestingly, most of them have been reported to be tightly involved in tumor progression. We have discussed these interesting genes and analyzed their potential molecular functions in preeclampsia, compared with their roles in malignancy development. Further investigations are warranted to explore the involvement in molecular network of each identified gene, which may provide not only novel strategies for prevention and therapy for preeclampsia but also a better understanding of cancer cells. The trophoblastic cells, with their capacity for proliferation and differentiation, apoptosis and survival, migration, angiogenesis and immune modulation by exploiting similar molecular pathways, make them a compelling model for cancer research.
The impact of shift work induced chronic circadian disruption on IL-6 and TNF-α immune responses
(2010)
Aim: Sleep disturbances induce proinflammatory immune responses, which might increase cardiovascular disease risk. So far the effects of acute sleep deprivation and chronic sleep illnesses on the immune system have been investigated. The particular impact of shift work induced chronic circadian disruption on specific immune responses has not been addressed so far.
Methods: Pittsburgh-Sleep-Quality-Index (PSQI) questionnaire and blood sampling was performed by 225 shift workers and 137 daytime workers. As possible markers the proinflammatory cytokines IL-6 and TNF-alpha and lymphocyte cell count were investigated. A medical examination was performed and biometrical data including age, gender, height, weight, waist and hip circumference and smoking habits were collected by a structured interview.
Results: Shift workers had a significantly higher mean PSQI score than day workers (6.73 vs. 4.66; p < 0.001). Day workers and shift workers had similar serum levels of IL-6 (2.30 vs. 2.67 resp.; p = 0.276), TNF-alpha (5.58 vs. 5.68, resp.; p = 0.841) or lymphocytes count (33.68 vs. 32.99, resp.; p = 0.404). Furthermore there were no differences in cytokine levels (IL-6 p = 0.761; TNF-alpha p = 0.759) or lymphocyte count (p = 0.593) comparing the sleep quality within the cohorts. When this calculation of sleep quality was stratified by shift and day workers irrespective of their sleep quality day workers and shift workers had similar serum levels of IL-6, TNF-alpha or lymphocytes count. Multiple linear regression analysis showed a significant correlation of lymphocytes count and smoking habits.
Conclusion: Shift work induces chronic sleep debt. Our data reveals that chronic sleep debt might not always lead to an activation of the immune system, as we did not observe differences in lymphocyte count or level of IL-6 or TNF-alpha serum concentration between shift workers and day workers. Therefore chronic sleep restriction might be eased by a long-term compensating immune regulation which (in healthy) protects against an overstimulation of proinflammatory immune mechanisms and moderates metabolic changes, as they are known from short-term sleep deprivation or sleep related breathing disorders.
Background: During the last two decades the German hospital sector has been engaged in a constant process of transformation. One obvious sign of this is the growing amount of hospital privatization. To date, most research studies have focused on the effects of privatization regarding financial outcomes and quality of care, leaving important organizational issues unexplored. Yet little attention has been devoted to the effects of privatization on physicians' working routines. The aim of this observational real-time study is to deliver exact data about physicians' work at hospitals of different ownership. By analysing working hours, further impacts of hospital privatization can be assessed and areas of improvement identified.
Methods: Observations were made by shadowing 100 physicians working in private, for-profit or non-profit as well as public hospital departments individually during whole weekday shifts in urban German settings. A total of 300 days of observations were conducted. All working activities were recorded, accurate to the second, by using a mobile personal computer.
Results: Results have shown significant differences in physicians' working activities, depending on hospital ownership, concerning working hours and time spent on direct and indirect patient care.
Conclusion: This is the first real-time analysis on differences in work activities depending on hospital ownership. The study provides an objective insight into physicians' daily work routines at hospitals of different ownership, with additional information on effects of hospital privatization.
Background: Publications related to scoliosis have increased enormously. A differentiation between publications of major and minor importance has become difficult even for experts. Scientometric data on developments and tendencies in scoliosis research has not been available to date. The aim of the current study was to evaluate the scientific efforts of scoliosis research both quantitatively and qualitatively.
Methods: Large-scale data analysis, density-equalizing algorithms and scientometric methods were used to evaluate both the quantity and quality of research achievements of scientists studying scoliosis. Density-equalizing algorithms were applied to data retrieved from ISI-Web.
Results: From 1904 to 2007, 8,186 items pertaining to scoliosis were published and included in the database. The studies were published in 76 countries: the USA, the U.K. and Canada being the most productive centers. The Washington University (St. Louis, Missouri) was identified as the most prolific institution during that period, and orthopedics represented by far the most productive medical discipline. "BRADFORD, DS" is the most productive author (146 items), and "DANSEREAU, J" is the author with the highest scientific impact (h-index of 27).
Conclusion: Our results suggest that currently established measures of research output (i.e. impact factor, h-index) should be evaluated critically because phenomena, such as self-citation and co-authorship, distort the results and limit the value of the conclusions that may be drawn from these measures. Qualitative statements are just tractable by the comparison of the parameters with respect to multiple linkages. In order to obtain more objective evaluation tools, new measurements need to be developed.
Background: Severe allergic reactions during rush-specific immunotherapy (Rush-SIT) may occur in the treatment of hymenoptera sting allergy. The objective of the present study was to examine the characteristics of allergic reactions during Rush-SIT in a cohort of patients with allergy towards hymenoptera venom in the mediterranean population of Albania.
Methods: A retrospective study was performed using the clinical reports of 37 patients with venom of bee (apinae), wasp (vespidae, subfamily vespinae) or paperwasp (vespidae, subfamily polistinae) allergy treated with Rush-SIT between 1987 and 1996. After hymenoptera sting allergy diagnosis according to anamnesis and intracutaneous tests the patient were treated with Rush-SIT. The protocol lasted 3 - 4 d with an increase in the concentration from 0.01 microg/ml to 100 microg/ml. Anaphylactic reactions were classified according to the Mueller-classification.
Results: The frequency of reactions during Rush-SIT for bee-venom was 4.7% and for wasp-venom was 1.5% (p < 0.01). The mean frequency of reactions of Mueller grade II for the bee-venom Rush-SIT patients during the first 4 d (= 26 injections) was 0.73 and for the wasp-venom Rush-SIT patients 0.15. No patient experienced a third-degree reaction. 94.6% of the patient supported an end dose of 100 microg.
Conclusions: Rush-SIT is a reliable method for the treatment of anaphylactic reactions to hymenoptera venom even in less developed countries. Bee-venom Rush-SIT was found to cause higher numbers allergic reactions than wasp or paperwasp Rush-SIT.
Background: The increasing economic pressure characterizes the current situation in health care and the need to justify medical decisions and organizational processes due to limited financial resources is omnipresent. Physicians tend to interpret this development as a decimation of their own medical influence. This becomes even more obvious after a change in hospital ownership i.e. from a public to a private profit oriented organization. In this case each work procedure is revised.
To date, most research studies have focused mainly on differences between hospitals of different ownership regarding financial outcomes and quality of care, leaving important organizational issues unexplored. Little attention has been devoted to the effects of hospital ownership on physicians' working routines.
The aim of this observational real time study is to deliver exact data about physicians' work at hospitals of different ownership.
Methods: The consequences of different management types on the organizational structures of the physicians' work situation and on job satisfaction in the ward situation are monitored by objective real time studies and multi-level psycho diagnostic measurements.
Discussion: This study is unique in its focus. To date no results have been found for computer-based real time studies on work activity in the clinical field in order to objectively evaluate a physician's work-related stress. After a complete documentation of the physicians' work processes the daily work flow can be estimated and systematically optimized. This can stimulate an overall improvement of health care services in Germany.
Background: There are several ways to conduct a job task analysis in medical work environments including pencil-paper observations, interviews and questionnaires. However these methods implicate bias problems such as high inter-individual deviations and risks of misjudgement. Computer-based observation helps to reduce these problems. The aim of this paper is to give an overview of the development process of a computer-based job task analysis instrument for real-time observations to quantify the job tasks performed by physicians working in different medical settings. In addition reliability and validity data of this instrument will be demonstrated.
Methods: This instrument was developed in consequential steps. First, lists comprising tasks performed by physicians in different care settings were classified. Afterwards content validity of task lists was proved. After establishing the final task categories, computer software was programmed and implemented in a mobile personal computer. At least inter-observer reliability was evaluated. Two trained observers recorded simultaneously tasks of the same physician.
Results: Content validity of the task lists was confirmed by observations and experienced specialists of each medical area. Development process of the job task analysis instrument was completed successfully. Simultaneous records showed adequate interrater reliability.
Conclusion: Initial results of this analysis supported the validity and reliability of this developed method for assessing physicians' working routines as well as organizational context factors. Based on results using this method, possible improvements for health professionals' work organisation can be identified.
Since 2002, a workshop entitled “Asthma in animal models” has been held once a year in Hannover, Germany. It is organized by the Fraunhofer Institute of Toxicology and Experimental Medicine in collaboration with the collaborative research centre “Sonderforschungsbereich” 587, “Immune reactions of the lung in infection and allergy” (Hannover Medical School). The aim of these meetings is an intense scientific exchange between researchers and clinicians coming from academic or industrial background. Over the years the topics within the extensive field of asthma and COPD have ranged from methodological aspects to the influence of infections and environmental factors up to perspectives in the development of new therapeutic strategies.
Within the large variety of subtypes of chronic cough, either defined by their clinical or pathogenetic causes, occupational chronic cough may be regarded as one of the most preventable forms of the disease. Next to obstructive airway diseases such as asthma or chronic obstructive pulmonary disease, which are sometimes concomitant with chronic cough, this chronic airway disease gains importance in the field of occupational medicine since classic fiber-related occupational airway diseases will decrease in the future.
Apart from acute accidents and incidental exposures which may lead to an acute form of cough, there are numerous sources for the development of chronic cough within the workplace. Over the last years, a large number of studies has focused on occupational causes of respiratory diseases and it has emerged that chronic cough is one of the most prevalent work-related airway diseases. Best-known examples of occupations related to the development of cough are coal miners, hard-rock miners, tunnel workers, or concrete manufacturing workers.
As chronic cough is often based on a variety of non-occupational factors such as tobacco smoke, a distinct separation into either occupational or personally -evoked can be difficult. However, revealing the occupational contribution to chronic cough and to the symptom cough in general, which is the commonest cause for the consultation of a physician, can significantly lead to a reduction of the socioeconomic burden of the disease.
Activation of TRPC6 channels is essential for lung ischaemia–reperfusion induced oedema in mice
(2012)
Lung ischaemia–reperfusion-induced oedema (LIRE) is a life-threatening condition that causes pulmonary oedema induced by endothelial dysfunction. Here we show that lungs from mice lacking nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox2y/−) or the classical transient receptor potential channel 6 (TRPC6−/−) are protected from LIR-induced oedema (LIRE). Generation of chimeric mice by bone marrow cell transplantation and endothelial-specific Nox2 deletion showed that endothelial Nox2, but not leukocytic Nox2 or TRPC6, are responsible for LIRE. Lung endothelial cells from Nox2- or TRPC6-deficient mice showed attenuated ischaemia-induced Ca2+ influx, cellular shape changes and impaired barrier function. Production of reactive oxygen species was completely abolished in Nox2y/− cells. A novel mechanistic model comprising endothelial Nox2-derived production of superoxide, activation of phospholipase C-γ, inhibition of diacylglycerol (DAG) kinase, DAG-mediated activation of TRPC6 and ensuing LIRE is supported by pharmacological and molecular evidence. This mechanism highlights novel pharmacological targets for the treatment of LIRE.
Previous PET and MRI studies have indicated that the degree to which pathology translates into clinical symptoms is strongly dependent on sex with women more likely to express pathology as a diagnosis of AD, whereas men are more resistant to clinical symptoms in the face of the same degree of pathology. Here we use DTI to investigate the difference between male and female white matter tracts in healthy older participants (24 women, 16 men) and participants with mild cognitive impairment (21 women, 12 men). Differences between control and MCI participants were found in fractional anisotropy (FA), radial diffusion (DR), axial diffusion (DA) and mean diffusion (MD). A significant main effect of sex was also reported for FA, MD and DR indices, with male control and male MCI participants having significantly more microstructural damage than their female counterparts. There was no sex by diagnosis interaction. Male MCIs also had significantly less normalised grey matter (GM) volume than female MCIs. However, in terms of absolute brain volume, male controls had significantly more brain volume than female controls. Normalised GM and WM volumes were found to decrease significantly with age with no age by sex interaction. Overall, these data suggest that the same degree of cognitive impairment is associated with greater structural damage in men compared with women.
The role of endocarditis, myocarditis and pericarditis in qualitative and quantitative data analysis
(2009)
The current study is the first scientometric analysis of research activity and output in the field of inflammatory disorders of the heart (endo-, myo- and pericarditis). Scientometric methods are used to compare scientific performance on national and on international scale to identify single areas of research interest. Interest and research productivity in inflammatory diseases of the heart have increased since 1990. The majority of publications about inflammatory heart disorders were published in Western Europe and North America. The United States of America had a leading position in terms of research productivity and quality; half of the most productive authors in this study came from American institutions. The analysis of international cooperation revealed research activity in countries that are less established in the field of inflammatory heart disorder research, such as Brazil, Saudi Arabia and Tunisia. These results indicate that future research of heart inflammation may no longer be influenced predominantly by a small number of countries. Furthermore, this study revealed weaknesses in currently established scientometric parameters (i.e., h-index, impact factor) that limit their suitability as measures of research quality. In this respect, self-citations should be generally excluded from calculations of h-index and impact factor.
Background: In patients with genotype 1 chronic hepatitis C infection, telaprevir (TVR) in combination with peginterferon and ribavirin (PR) significantly increased sustained virologic response (SVR) rates compared with PR alone. However, genotypic changes could be observed in TVR-treated patients who did not achieve an SVR.
Methods: Population sequence analysis of the NS3•4A region was performed in patients who did not achieve SVR with TVR-based treatment.
Results: Resistant variants were observed after treatment with a telaprevir-based regimen in 12% of treatment-naïve patients (ADVANCE; T12PR arm), 6% of prior relapsers, 24% of prior partial responders, and 51% of prior null responder patients (REALIZE, T12PR48 arms). NS3 protease variants V36M, R155K, and V36M+R155K emerged frequently in patients with genotype 1a and V36A, T54A, and A156S/T in patients with genotype 1b. Lower-level resistance to telaprevir was conferred by V36A/M, T54A/S, R155K/T, and A156S variants; and higher-level resistance to telaprevir was conferred by A156T and V36M+R155K variants. Virologic failure during telaprevir treatment was more common in patients with genotype 1a and in prior PR nonresponder patients and was associated with higher-level telaprevir-resistant variants. Relapse was usually associated with wild-type or lower-level resistant variants. After treatment, viral populations were wild-type with a median time of 10 months for genotype 1a and 3 weeks for genotype 1b patients.
Conclusions: A consistent, subtype-dependent resistance profile was observed in patients who did not achieve an SVR with telaprevir-based treatment. The primary role of TVR is to inhibit wild-type virus and variants with lower-levels of resistance to telaprevir. The complementary role of PR is to clear any remaining telaprevir-resistant variants, especially higher-level telaprevir-resistant variants. Resistant variants are detectable in most patients who fail to achieve SVR, but their levels decline over time after treatment.
Background: Diseases associated with smoking are a foremost cause of premature death in the world, both in developed and developing countries. Eliminating smoking can do more to improve health and prolong life than any other measure in the field of preventive medicine. Today's medical students will play a prominent role in future efforts to prevent and control tobacco use.
Methods: A cross-sectional, self-administered, anonymous survey of fifth-year medical students in Berlin, Germany was conducted in November 2007. The study explored the prevalence of smoking among medical students. We assessed their current knowledge regarding tobacco dependence and the effectiveness of smoking cessation methods. Students' perceived competence to counsel smokers and promote smoking cessation treatments was also explored. Analyses were based on responses from 258 students (86.6% response rate).
Results: One quarter of the medical students surveyed were current smokers. The smoking rate was 22.1% among women, 32.4% among men. Students underestimated smoking-related mortality and the negative effect of smoking on longevity. A considerable number of subjects erroneously assumed that nicotine causes coronary artery disease. Students' overall knowledge of the effectiveness of smoking cessation methods was inadequate. Only one third of the students indicated that they felt qualified to counsel patients about tobacco dependence.
Conclusions: This study reveals serious deficiencies in knowledge and counseling skills among medical students in our sample. The curriculum of every medical school should include a tobacco module. Thus, by providing comprehensive training in nicotine dependence interventions to medical students, smokers will have access to the professional expertise they need to quit smoking.
Background: Platelet activating factor and tachykinins (substance P, neurokinin A, neurokinin B) are important mediators contributing to increased airway secretion in the context of different types of respiratory diseases including acute and chronic asthma. Leukotriene receptor antagonists are recommended as add-on therapy for this disease. The cys-leukotriene-1 receptor antagonist montelukast has been used in clinical asthma therapy during the last years. Besides its inhibitory action on bronchoconstriction, only little is known about its effects on airway secretions. Therefore, the aim of this study was to evaluate the effects of montelukast on platelet activating factor- and tachykinin induced tracheal secretory activity.
Methods: The effects of montelukast on platelet activating factor- and tachykinin induced tracheal secretory activity in the rat were assessed by quantification of secreted 35SO4 labelled mucus macromolecules using the modified Ussing chamber technique.
Results: Platelet activating factor potently stimulated airway secretion, which was completely inhibited by the platelet activating factor receptor antagonist WEB 2086 and montelukast. In contrast, montelukast had no effect on tachykinin induced tracheal secretory activity.
Conclusion: Cys-leukotriene-1 receptor antagonism by montelukast reverses the secretagogue properties of platelet activating factor to the same degree as the specific platelet activating factor antagonist WEB 2086 but has no influence on treacheal secretion elicited by tachykinins. These results suggest a role of montelukast in the signal transduction pathway of platelet activating factor induced secretory activity of the airways and may further explain the beneficial properties of cys-leukotriene-1 receptor antagonists.
Introduction: Acute kidney injury (AKI) after cardiac surgery increases length of hospital stay and in-hospital mortality. A significant number of patients undergoing cardiac surgical procedures require perioperative intra-aortic balloon pump (IABP) support. Use of an IABP has been linked to an increased incidence of perioperative renal dysfunction and death. This might be due to dislodgement of atherosclerotic material in the descending thoracic aorta (DTA). Therefore, we retrospectively studied the correlation between DTA atheroma, AKI and in-hospital mortality.
Methods: A total of 454 patients were retrospectively matched to one of four groups: -IABP/-DTA atheroma, +IABP/-DTA atheroma, -IABP/+DTA atheroma, +IABP/+DTA atheroma. Patients were then matched according to presence/absence of DTA atheroma, presence/absence of IABP, performed surgical procedure, age, gender and left ventricular ejection fraction (LVEF). DTA atheroma was assessed through standard transesophageal echocardiography (TEE) imaging studies of the descending thoracic aorta.
Results: Basic patient characteristics, except for age and gender, did not differ between groups. Perioperative AKI in patients with -DTA atheroma/+IABP was 5.1% versus 1.7% in patients with -DTA atheroma/-IABP. In patients with +DTA atheroma/+IABP the incidence of AKI was 12.6% versus 5.1% in patients with +DTA atheroma/-IABP. In-hospital mortality in patients with +DTA atheroma/-IABP was 3.4% versus 8.4% with +DTA atheroma/+IABP. In patients with +DTA atheroma/+IABP in hospital mortality was 20.2% versus 6.4% with +DTA atheroma/-IABP. Multivariate logistic regression identified DTA atheroma > 1 mm (P = *0.002, odds ratio (OR) = 4.13, confidence interval (CI) = 1.66 to 10.30), as well as IABP support (P = *0.015, OR = 3.04, CI = 1.24 to 7.45) as independent predictors of perioperative AKI and increased in-hospital mortality. DTA atheroma in conjunction with IABP significantly increased the risk of developing acute kidney injury (P = 0.0016) and in-hospital mortality (P = 0.0001) when compared to control subjects without IABP and without DTA atheroma.
Conclusions: Perioperative IABP and DTA atheroma are independent predictors of perioperative AKI and in-hospital mortality. Whether adding an IABP in patients with severe DTA calcification increases their risk of developing AKI and mortality postoperatively cannot be clearly answered in this study. Nevertheless, when IABP and DTA are combined, patients are more likely to develop AKI and to die postoperatively in comparison to patients without IABP and DTA atheroma.
Background: Models of isolated and perfused kidneys are used to study the effects of drugs, hazardous or toxic substances on renal functions. Since physiological and morphological parameters of small laboratory animal kidneys are difficult to compare to human renal parameters, porcine kidney perfusion models have been developed to simulate closer conditions to the human situation, but exact values of renal parameters for different collection and perfusion conditions have not been reported so far. If the organs could be used out of regular slaughtering processes animal experiments may be avoided.
Methods: To assess renal perfusion quality, we analyzed different perfusion settings in a standardized model of porcine kidney hemoperfusion with organs collected in the operating theatre (OP: groups A-D) or in a public abattoir (SLA: group E) and compared the data to in vivo measurements in living animals (CON). Experimental groups had defined preservation periods (0, 2 and 24 hrs), one with additional albumin in the perfusate (C) for edema reduction.
Results: Varying perfusion settings resulted in different functional values (mean +/- SD): blood flow (RBF [ml/min*100 g]: (A) 339.9 +/- 61.1; (C) 244.5 +/- 53.5; (D) 92.8 +/- 25.8; (E) 153.8 +/- 41.5); glomerular filtration (GFR [ml/min*100 g]: (CON) 76.1 +/- 6.2; (A) 59.2 +/- 13.9; (C) 25.0 +/- 10.6; (D) 1.6 +/- 1.3; (E) 16.3 +/- 8.2); fractional sodium reabsorption (RFNa [%] (CON) 99.8 +/- 0.1; (A) 82.3 +/- 8.1; (C) 86.8 +/- 10.3; (D) 38.4 +/- 24.5; (E) 88.7 +/- 5.8). Additionally the tubular coupling-ratio of Na-reabsorption/O2-consumption was determined (TNa/O2-cons [mmol-Na/mmol- O2] (CON) 30.1; (A) 42.0, (C) 80.6; (D) 17.4; (E) 23.8), exhibiting OP and SLA organs with comparable results.
Conclusion: In the present study functional values for isolated kidneys with different perfusion settings were determined to assess organ perfusion quality. It can be summarized that the hemoperfused porcine kidney can serve as a biological model with acceptable approximation to in vivo renal physiology, also if the organs originate from usual slaughtering processes.
Chronic obstructive pulmonary disease (COPD) is a major global health problem and is predicted to become the third most common cause of death by 2020. Apart from the important preventive steps of smoking cessation, there are no other specific treatments for COPD that are as effective in reversing the condition, and therefore there is a need to understand the pathophysiological mechanisms that could lead to new therapeutic strategies. The development of experimental models will help to dissect these mechanisms at the cellular and molecular level. COPD is a disease characterized by progressive airflow obstruction of the peripheral airways, associated with lung inflammation, emphysema and mucus hypersecretion. Different approaches to mimic COPD have been developed but are limited in comparison to models of allergic asthma. COPD models usually do not mimic the major features of human COPD and are commonly based on the induction of COPD-like lesions in the lungs and airways using noxious inhalants such as tobacco smoke, nitrogen dioxide, or sulfur dioxide. Depending on the duration and intensity of exposure, these noxious stimuli induce signs of chronic inflammation and airway remodelling. Emphysema can be achieved by combining such exposure with instillation of tissue-degrading enzymes. Other approaches are based on genetically-targeted mice which develop COPD-like lesions with emphysema, and such mice provide deep insights into pathophysiological mechanisms. Future approaches should aim to mimic irreversible airflow obstruction, associated with cough and sputum production, with the possibility of inducing exacerbations.
Cadmium (Cd) has been in industrial use for a long period of time. Its serious toxicity moved into scientific focus during the middle of the last century. In this review, we discuss historic and recent developments of toxicological and epidemiological questions, including exposition sources, resorption pathways and organ damage processes.
Hypersecretion and chronic phlegm are major symptoms of chronic obstructive pulmonary disease (COPD) but animal models of COPD with a defined functional hypersecretion have not been established so far. To identify an animal model of combined morphological signs of airway inflammation and functional hypersecretion, rats were continuously exposed to different levels of sulfur dioxide (SO2, 5 ppm, 10 ppm, 20 ppm, 40 ppm, 80 ppm) for 3 (short-term) or 20–25 (long-term) days. Histology revealed a dose-dependent increase in edema formation and inflammatory cell infiltration in short-term-exposed animals. The submucosal edema was replaced by fibrosis after long-term-exposure. The basal secretory activity was only significantly increased in the 20 ppm group. Also, stimulated secretion was significantly increased only after exposure to 20 ppm. BrdU-assays and AgNOR-analysis demonstrated cellular metaplasia and glandular hypertrophy rather than hyperplasia as the underlying morphological correlate of the hypersecretion.
In summary, SO2-exposure can lead to characteristic airway remodeling and changes in mucus secretion in rats. As only long-term exposure to 20 ppm leads to a combination of hypersecretion and airway inflammation, only this mode of exposure should be used to mimic human COPD. Concentrations less or higher than 20 ppm or short term exposure do not induce the respiratory symptom of hypersecretion. The present model may be used to characterize the effects of new compounds on mucus secretion in the background of experimental COPD.