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The coronavirus disease 2019 (COVID-19) pandemic is a challenge for our healthcare system but at the same time is one of the excellent catalyzers and promoters of successful translational research. The COVID-19 is not only a simple viral infection of the bronchial system but is also a pandemic hyperinflammatory multiorgan disease. The cardiovascular system plays a causal role in this context, as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) invades host cells via the angiotensin-converting enzyme 2 (ACE-2), an enzyme in the renin-angiotensin system. Furthermore, cardiovascular comorbidities and risk factors, such as hypertension, diabetes and obesity play an important role in the severity of the course of the disease. Additional risk factors, such as gender, age, genetics and air pollution modulate both the severity of the SARS-CoV‑2 infection as well as cardiovascular diseases. As sequelae of COVID-19, increased thrombosis, myocardial infarction, myocardial inflammation and vasculitis occur, which directly damage the cardiovascular system and substantially contribute to the high morbidity and mortality. Knowledge gained from many studies on the course of the disease in patients infected with SARS-CoV‑2 has led to improved treatment possibilities, which now in the second wave are partly standardized and were, and are, in particular adapted to complications of the cardiovascular system. In this review we provide a short overview on the pathophysiology of the SARS-CoV‑2 in general and also specifically on the cardiovascular system. Furthermore, we summarize the current treatment approaches and their pathophysiological principles (status November 2020).COVID-19 („coronavirus disease 2019“) ist eine Herausforderung für unser Gesundheitssystem und gleichzeitig eine der herausragenden Katalysatoren erfolgreicher translationaler Forschung. COVID-19 ist nicht nur eine simple Viruserkrankung des Bronchialsystems, sondern eine pandemisch auftretende, hyperinflammatorische Multiorganerkrankung. Das Herz-Kreislauf-System spielt dabei eine kausale Rolle, da SARS-CoV‑2 („severe acute respiratory syndrome coronavirus 2“) Wirtszellen über ACE(„angiotensin-converting enzyme“)-2, ein Enzym des Renin-Angiotensin-Systems, befällt. Darüber hinaus spielen kardiovaskuläre Komorbiditäten und Risikofaktoren wie Bluthochdruck, Diabetes und Adipositas eine wichtige Rolle für die Schwere der Krankheitsverläufe. Zusätzliche Risikofaktoren wie Geschlecht, Alter, Genetik und Luftverschmutzung modulieren sowohl die Schwere der SARS-CoV-2-Infektion als auch kardiovaskuläre Erkrankungen. Als Folge von COVID-19 kommt es zu vermehrten Thrombosen, Herzinfarkten, Herzmuskelentzündungen und Vaskulitiden, die das kardiovaskuläre System direkt schädigen und wesentlich zur Morbidität und Mortalität beitragen. Erkenntnisse aus zahlreichen Studien zu Krankheitsverläufen von SARS-CoV-2-infizierten Patienten haben zu besseren Therapiemöglichkeiten geführt, die nun in der zweiten Welle zum Teil standardisiert und insbesondere auch an Komplikationen des kardiovaskulären Systems angepasst wurden und werden. In diesem Review geben wir einen kurzen Überblick über die Pathophysiologie des SARS-CoV-2-Virus allgemein sowie auch spezifisch auf das kardiovaskuläre System. Daraus folgend, fassen wir die aktuellen Therapieansätze und deren pathophysiologische Grundlagen (Stand November 2020) zusammen.

Das neue Coronavirus SARS(„severe acute respiratory syndrome“)-CoV(„coronavirus“)-2 hat tiefgreifende Auswirkungen auf Gesellschaft, Wirtschaft und medizinische Versorgung. Umso wichtiger ist es, die Eigenschaften des Virus zu verstehen und diagnostisch, therapeutisch wie auch epidemiologisch zu nutzen. Im vorliegenden Beitrag wird zunächst die medizinische Bedeutung der Coronaviren im Allgemeinen erläutert. Danach wird auf ACE2 („angiotensin-converting enzyme 2“) als Bindungsstelle von SARS-CoV‑2 sowie dessen möglichen Einfluss auf die Erkrankungssuszeptibilität eingegangen. Als diagnostischer Goldstandard für den Nachweis einer aktiven SARS-CoV-2-Infektion gilt der Erregerdirektnachweis mit Nukleinsäureamplifikationstechniken. Zu Beginn der Symptome ist ein Abstrich der oberen Luftwege aufgrund der dann hohen Viruslast besonders geeignet. Im späteren Verlauf kann der Direktnachweis über Proben aus den unteren Atemwegen oder über einen Stuhl- bzw. Analabstrich gelingen. Antikörper(AK)-Tests können den Erregerdirektnachweis nicht ersetzen. Insbesondere für epidemiologische Fragestellungen ist aber der Nachweis von Immunglobulin-G-AK von Interesse (Serokonversionszeit von teils mehreren Wochen). Der „plaque reduction neutralization test“ weist ausschließlich AK nach, die Viren neutralisieren. Das Verfahren ist aber aufwendig und nur in Sicherheitslaboren (L3) möglich. Zudem ist die Bedeutung dieser AK bezüglich der Immunität gegen eine Zweitinfektion unsicher. Dank moderner Technik sind bereits Tausende SARS-CoV-2-Sequenzen verfügbar, die eine Genomvariabilität zeigen. Die Mutation D614G in den „S spikes“ scheint eine höhere Infektiosität zu bedingen. Mutationen können die Diagnostik und Therapie beeinträchtigen, was ein Monitoring erforderlich macht.

Twenty years ago, an enzyme homologous to the previously known angiotensin-converting enzyme (ACE) was identified, and subsequently named ACE2. In the renin-angiotensin system (RAS), ACE2 has counter-regulatory functions against the classical effector peptide angiotensin II, for example in blood pressure regulation and cardiovascular remodeling. However, ACE2 provides an initially unexpected interesting link between virology and cardiovascular medicine. That is, ACE2 represents the binding receptor for the cellular uptake of SARS-CoV and SARS-CoV-2 viruses. Thus, ACE2 is relevant for COVID-19. In this context, it was suspected that therapy with RAS blockers might promote transmission and complications of COVID-19 by upregulation of ACE2 expression. The aim of this short review is, to describe the link between the RAS, particularly ACE2, and COVID-19. Based on our analysis and evaluation of the available findings, we justify our conclusion: important drugs such as ACE inhibitors and angiotensin receptor blockers should continue to be prescribed according to guidelines to stable patients in the context of the COVID-19 pandemic.

The genetics of contact allergy (CA) is still only partly understood, despite decades of research. This might be due to inadequately defined phenotypes used in the past. Therefore we suggested studying an extreme phenotype, namely, polysensitization (sensitization to 3 or more unrelated allergens). Another approach to unravel the genetics of CA has been the study of candidate genes. In this review, we summarize studies on the associations between genetic variation (e.g. SNPs) in certain candidate genes and CA. The following polymorphisms and mutations were studied: (1) filaggrin, (2) N-acetyltransferase (NAT1 and 2), (3) glutathione-S-transferase (GST M and T), (4) manganese superoxide dismutase, (5) angiotensin-converting enzyme (ACE), (6) tumor necrosis factor (TNF), and (7) interleukin-16 (IL16). The polymorphisms of NAT1/2, GST M/T, ACE, TNF, and IL16 were shown to be associated with an increased risk of CA. In one of our studies, the increased risk conferred by the TNF and IL16 polymorphisms was confined to polysensitized individuals. Other relevant candidate genes may be identified by studying diseases related to CA in terms of clinical symptoms, a more general pathology (inflammation) and possibly an overlapping genetic background, such as irritant contact dermatitis.

The risk for erectile dysfunction is closely linked to cardiovascular morbidities such as coronary heart disease, arterial hypertension, hypercholesterolemia, and diabetes. Molecular analysis revealed an association between the genotypes in single base polymorphisms and the risk for these cardiovascular morbidities. In this review the current knowledge of association studies of single nucleotide polymorphisms and erectile dysfunction and the response to the PDE-5 inhibitor sildenafil is described.

We studied angiotensin I converting enzyme (ACE) expression in lung tissue from patients with different forms of pulmonary hypertension (PH) in comparison with that from morphologically normal lung specimens. ACE antigen expression was analysed by immunohistochemistry in morphologically normal lung tissue from 33 patients (19 males, 32-77 years; 14 females, 34-93 years) and compared to that in specimens from 94 patients (67 males, 30-97 years; 27 females: 27-90 years) with different clinically proven forms of PH (according to Venedig classification). Type specific vessel expression pattern as described for normal lung tissue was generally intensified in arteries, arterioles and capillaries of the lung specimens with PH. Specimens with PH due to left heart disease and chronic obstructive pulmonary disease (COPD) showed only very weak or no augmented arterial ACE expression, while PH due to collagenoses or interstitial lung disease showed significantly higher ACE expression. In human PH there is--comparable to animal models--a raised ACE expression in pulmonary lung vessels, with differences between the various forms of PH. These differences in ACE expression may be relevant for subtly differentiated therapeutic anti-ACE therapy regimes.

Angiotensin I converting enzyme (ACE, CD143) is an endothelial transmembrane Zn2+-dipeptidylpeptidase. By formation of angiotensin II and degrading bradykinin it acts as a vasoconstrictor. We examined endothelial ACE expression in human pulmonary vessels in specimens from 20 female and 19 male patients (age: 34-76 years) by immunohistochemistry. In all specimens, capillary endothelial cells showed the strongest expression, followed by those in arterioles and arteries. Venules and veins showed next to no staining. The differences in staining intensities were significant ( P0.001). Sex affected neither the expression intensity nor the expression pattern. Summarizing, we demonstrate the existence of a vessel-type specific ACE expression pattern for pulmonary vessels. The nearly exclusive endothelial ACE expression in capillaries and arterial vessels points to ACE as an immunohistochemical marker for these vessels in normal lung tissue.

CD143 (angiotensin I-converting enzyme) occurs in two isoforms: a testicular form (tCD143) expressed during spermatogenesis, and a somatic form (sCD143) generally found in certain other cell types. To study these isoforms in normal and neoplastic germ cells of humans, we analyzed a broad collective of different testicular germ cell tumors (GCTs) of adults, adjacent intratubular germ cell neoplasms (IGCNs), and testicular tissues representing the regular germ cell development. Different techniques were employed on fresh frozen and formalin-fixed, paraffin-embedded tissues: CD143-mRNAs were analyzed by RT-PCR on selected cells after UV-laser-assisted cell picking and by in-situ hybridization using cRNA probes; the proteins were analyzed by semi-quantitative immunohistochemistry using monoclonal antibodies to CD143, and to PLAP/GCAP as controls. In contrast to normal germ cells bearing only tCD143 during spermiogenesis, both mRNA and protein of sCD143 were detected in neoplastic cells of all IGCNs and in the majority of seminomas. sCD143 expression also was found during testicular development, but was differently regulated in fetal germ cells and in GCTs compared with PLAP/GCAP. Thus, our findings (i) demonstrate profound changes in the expression of both CD143 isoforms during regular germ cell development and maturation, (ii) suspect sCD143 being involved in the regulation of germinal stem cell proliferation, (iii) are in agreement with the concept of an 'embryonic state' of neoplastic germ cells, (iv) indicate a close molecular relationship between IGCN and seminoma and, finally, (v) suggest sCD143 as an appropriate marker in the diagnosis of seminomas in addition to PIAP/GCAP.

Sarcoidosis, a systemic granulomatous disease of unknown cause, may involve any body organ. The most common manifestation in the head-neck area is lymph node sarcoidosis or, alternatively, Heerfordt's syndrome (with involvement of lacrimal and parotid gland and possible facial palsy). Far less common is a isolated laryngeal sarcoidosis. The typical histopathological appearance proves the diagnosis. However, obtaining representative and sufficient biopsy material in some cases may carry risks for the patients or might technically be difficult. In these cases, the clinician can fall back on two other, noninvasive diagnostic procedures: ACE level activity determination in blood serum and 67gallium citrate scintigraphy. Elevated ACE levels in combination with a positive 67gallium scintigraphy have a specificity (combined) of 99%. As a valuable side effect, this procedure sensitively may discover additional disease in the body and also serves well as a therapy-control examination. The presented case report shows clearly that these clinical methods, if combined, are sufficient for diagnosis of Heerfordt's syndrome/sarcoidosis; no additional histopathological examination is required.

Since the discovery of renin by Tigerstedt and Bergmann, the renin angiotensin system (RAS) has been recognized as an important modulator of blood pressure and volume homeostasis. Based on these functions a pathophysiological role of the RAS in the pathogenesis of hypertension and other cardiovascular disorders has been postulated. The therapeutic benefit of RAS inhibition by angiotensin converting enzyme (ACE) inhibitors and angiotensin II (ANG II) antagonists in these conditions has been shown. It remains unclear, however, whether the changes in RAS activity associated with cardiovascular disease are primary or secondary factors. It is well known that hypertension and hypertensive end-organ disease is influenced by genetic factors. Gene polymorphisms for virtually all components of the RAS have been described and investigated in clinical studies. It remains to be determined, however, how relevant these findings are for disease etiology. This review, therefore, will attempt to discuss the causal implications of these genetic studies for cardiovascular disease. The role of angiotensinogen and ACE for hypertension, coronary artery disease and other cardiovascular disorders is discussed in this context in an exemplary fashion.

The angiotensin converting enzyme (ACE) is an integral part of enzymatic cascades leading to generation of angiotensin II as well as degradation of bradykinin. For this reason, it represents an important part for the metabolism of 2 vasoactive peptides. Early in this decade, convincing experimental evidence demonstrated the induction of this enzyme in several pathophysiological conditions including myocardial infarction and left ventricular hypertrophy. In parallel, a deletion/insertion (D/I) polymorphism of the human ACE gene was discovered that was related to 14 to 50% of the interindividual variance of serum ACE activity. More recently, this polymorphism was implicated in the pathogenesis of a variety of cardiovascular disorders including myocardial infarction, left ventricular hypertrophy, hypertension as well as nephropathy.

The somatic form of CD 143 (angiotensin-I-converting enzyme) has been detected in many endothelial cells of the human body. Recently, we could identify local CD 143 overexpression in various pathological conditions e.g. in capillary endothelial proliferations at the border of myocardial infarctions and in coronary atherosclerotic plaques. Using monoclonal antibodies against CD 143, CD 31 and CD 34 we evaluated, whether CD 143 can serve as a marker of endothelial differentiation in vascular/perivascular tumors. 39 benign and malignant tumors, formalin-fixed, paraffin-embedded were investigated by APAAP immunohistochemistry using epitope retrieval techniques. Expression patterns were separately qualitatively and semiquantitatively analysed. Positive detection of epitopes was registered if more than 10% of the tumor cells were stained. CD 143 was detected in the majority of benign and malignant vascular tumors. All benign and malignant haemangioperizytomas were CD 143 negative. None of the markers detected all haemangioendotheliomas or all angiosarcomas, but the combination of CD 143 and CD 31 turned out to be positive in all haemangioendotheliomas and angiosarcomas. We conclude that most of the benign and malignant endothelial tumors express CD 143. The best discrimination of intermediate grade and malignant endothelial tumors can be achieved by analysis of the CD 143 and CD 31 co-expression.

The hemodynamic and neurohumoral effects of single and multiple doses of intravenous quinaprilat were assessed and compared with placebo in a double-blind design. The study group included 50 patients aged between 33 and 76 years with NYHA Class III and IV heart failure. The patients were randomized into three treatment groups to receive low (0.5 and 1.0 mg), medium (1.0 and 2.5 mg), or high (5.0 and 10.0 mg) intravenous doses of quinaprilat or placebo on day 1, and, based on the responses, q6h on two further days. The hemodynamic parameters were determined by right-heart catheterization. Quinaprilat is the active metabolite of quinapril, an ACE inhibitor with high affinity for the angiotensin converting enzyme, which is formulated for oral application. Compared with placebo, single and multiple doses of quinaprilat increased cardiac index by 25% (p0.05) and simultaneously decreased both peripheral vascular resistance by 25% (p0.05) and left ventricular filling pressures by 33% (p0.05). There was a dose-related decrease in mean right atrial pressure by 47% (p0.05) without significant heart rate changes (-3-5 bpm). The mean artery pressure showed a dose-related maximum decrease of 4-9 mm Hg 45-60 min after single-dose quinaprilat and of 7-10 mm Hg (p0.05) after repetitive dosing. Maximum changes were observed 15-90 min after drug application. The hemodynamic changes after multiple-dose quinaprilat were similar to those observed following single doses and generally persisted during the total observation period of 6 h. Compared with placebo, quinaprilat reduced ACE activity and angiotensin II and aldosterone concentrations, and increased plasma renin activity. There were no significant changes with regard to plasma catecholamines and the atrial natriuretic factor, although a slight decrease could be observed. The study results obtained in patients with advanced heart failure support both the safety and favorable hemodynamic and neurohumoral effects of intravenous quinaprilat over an observation period of 3 days.

BACKGROUND Many peptides now identified in the brain were previously thought of as exclusively peripheral hormones. Among those, the renin-angiotensin system (RAS) is not only found to be of great importance in peripheral vasomotor and electrolyte homeostasis but also acts as neurotransmitter or modulator in the central nervous system. Here we review a number of experiments performed by us pointing to a modulation effect of the RAS unrelated to its vasoactive mechanisms. The biochemical basis as well as the different methods employed will be described in detail. METHODS RAS enzyme activity within the different ocular structures were determined by means of fluorimetric measurements. Possible neurophysiological effects of the RAS on retinal function were established through electroretinographic in-vitro and in-vivo recordings. Immunocytochemical staining was employed to morphologically identify possible sites involved. RESULTS The performed fluorimetric measurements revealed highest Angiotensin-Converting Enzyme (ACE) activity within the neuroretina. Electroretinographic experiments have shown that variation in angiotensin-II activity is followed by reversible, dose-dependent effects on inner retinal signals. Clear evidence was found by immunohistochemistry that there is a discrete subpopulation of angiotensin-positive cells in the inner retina. CONCLUSIONS These findings demonstrate that the Renin-Angiotensin-System has neuronal sources and is physiologically active in the mammalian retina not purely related to vasoactive mechanisms. The RAS effector hormone angiotensin-II might therefore be a putative neurotransmitter in a subpopulation of retinal neurons. Reported side-effects of vasoactive substances, such as ACE-inhibitors on the visual function might be explained hereby.

A previously healthy 2 year old female child developed fever of unknown origin recurring in monthly cycles. The periodic fever attacks, family history and ethnologic criteria were in agreement with familial mediterranean fever, although further more major symptoms were missing. It was highly unusual to find repeatedly raised levels of angiotensin I converting enzyme, a finding previously not described in literature. Excluding any other differential diagnosis by intensive investigations, together with a positive metaraminol provocation test, the diagnosis of a rare, monosymptomatic variant of familial mediterranean fever was proposed. Amyloidosis was excluded by rectal biopsy. Monosymptomatic familial mediterranean fever is very seldom. We suggest to measure routinely angiotensin I converting enzyme for further evaluation of our findings.

Enhanced formation of radicals during post-ischemic reperfusion, foremost of superoxide (O2-) and hydroxyl (OH) radicals, has been directly and indirectly demonstrated in a number of tissues. However, the close chemical interrelationship of O2- and OH with other non-radical oxidants, such as hydrogen peroxide (H2O2) and hypochlorous acid (HOCl), makes it prudent to speak of reactive oxygen metabolites in conjunction with cell and organ dysfunction incurred by reperfusion. In the case of the heart, evidence for the causal involvement of such reactive molecular species includes (1) the increased formation of lipid peroxides, (2) the ability to mimic all facets of reperfusion injury (arrhythmias, contractile and vascular dysfunction, infarct extension) by exogenously applying reactive oxygen species, and (3) the propensity of a great variety of antioxidative and radical scavenging measures to afford cardioprotection during reperfusion. Potential sources of reactive oxygen metabolites in the reperfused heart are the mitochondrial redox-chain, endothelial enzymes such as cyclooxygenase, monoaminooxidase, NO-synthase and xanthine oxidase, and formed blood constituents (platelets, monocytes, granulocytes). According to our own results, adenosine, endogenously formed in the heart during ischemia, rapidly enhances adhesion of granulocytes introduced into the coronary system at reperfusion. Furthermore, small numbers of these cells suffice to induce contractile dysfunction in an isolated guinea pig heart model of ischemia-reperfusion injury, the major mediator of damage being HOCl. The striking disparity between the enormous volume of experimental data supporting involvement of reactive oxygen metabolites in reperfusion damage and the virtual lack of clinical-therapeutic regimens employing anti-oxidative measures is largely due to a still rudimentary knowledge of the homeostatic control of formation and removal of radicals and oxidants. In particular, the inability to correctly assess the individual time-course and extent of oxidative stress seems to be a major problem. Also, confounding issues such as compartmentation of radical formation as opposed to radical scavenging and the unwitting down-regulation of endogenous protective systems (e.g., of uric acid in the course of inhibiting xanthine oxidase) need to be resolved. On the other hand, we have been able to demonstrate protection by ACE inhibitors elicited via endothelially produced nitric oxide (a scavenger of O2- and OH) in the isolated heart. Thus, enhancement of endogenous protection may offer a perspective for mitigating against reperfusion damage.

Several well controlled multicenter trials demonstrated the great value of ACE-inhibitors in the treatment of heart failure. Interestingly, the mechanisms by which ACE-inhibitors improve survival of patients with heart failure are ony poorly understood. Interesting new aspects regarding the role of the renin angiotensin system in the pathophysiology of heart failure emerged from modern methods of molecular biology. For example, several alleles of the angiotensin converting enzyme or angiotensinogen genes were related to hypertension and myocardial infarction in both clinical and experimental studies. Furthermore, local renin angiotensin systems have been demonstrated in various cardiovascular tissues. These tissue renin angiotensin systems are independently regulated and may be activated in heart failure or cardiac hypertrophy. Finally, it has been shown that inhibition of angiotensin converting enzyme affects also the metabolism of bradykinin and aldosterone which may contribute to the overall pharmacodynamic profile of ACE-inhibitors in heart failure.

Recently the intravenous enzyme replacement therapy with modified beta-glucocerebrosidase has become available for patients with M. Gaucher. We report here the considerable improvement of activity and vigor in a 5 year old girl with type 1 M. Gaucher administering 60 IU/kg every two weeks for 6 months. The platelet count increased from 82-96/nl to more than 150/nl and hemoglobin from 10.8 to more than 12 g/dl. Serum acid phosphatase decreased from 14.6 U/l to 5.9. U/l and angiotensin-converting enzyme from 327 to 102 U/l. The estimation of splenic volume by MRT showed a decrease by 40%, while liver size was not reduced within 6 months of therapy. MRT proved to be useful to demonstrate the bone marrow infiltration by Gaucher cells. The enzyme replacement therapy resulted in an objective response. No side effects have been observed so far. The extreme high treatment costs enforce a considerable dose reduction for maintenance therapy.

In 39 cases with active and 36 cases with inactive sarcoidosis the angiotensin converting enzyme (ACE) and in 56 of them (21 active/35 inactive sarcoidosis) procollagen-III-peptide (P III P) content as well as the total protein content of the broncho-alveolar lavage (BAL) and of the serum were determined. These results were compared with those of a control group of 53 patients (ACE group) resp. 25 patients (P III P-group). Both the relative ACE content (ACE related to 1 g of protein) and the relative P III P content (P III P related to 1 mg of protein) showed significant increase in cases of acute sarcoidosis compared to the other two groups of patients. However, none of the three groups showed statistically significant differences in the other parameters. ACE in the BAL can therefore be regarded as a good indication of the activity of sarcoidosis. This is also true of P III P in the BAL as an indication of fibrogenesis.

In 30 patients with sarcoidosis we estimated immunohistochemically the activity of lysozyme in correlation to the activity of ACE in serum and found a positive correlation between these two parameters. We conclude, that the lysozyme content of sarcoidotic granulomas, estimated immunohistochemically, may be a useful morphological parameter of the activity of the disease, applicable on formol fixed and paraffin embedded bioptical material.

Fibrogenic effects of amorphous quartz dusts are discussed more and more during recent years. In order to study alterations due to amorphous silica (quartz glass VP 203-006) in comparison with crystalline quartz (DQ-12), an inhalation experiment in rats was carried out. Male Wistar rats were separated in two dust exposed groups (n = 35) and one control group (n = 30). The experiment was carried out in inhalation chambers with a slowly rotating animal cage for 12 months, 7 h per day, and 5 days per week. The dust concentration was 10 mg/m3. After 4 and after 8 months of inhalation, 5 animals of each group were sacrificed. After 12 months 15 rats of the dust exposed groups and 10 controls were euthanized. The remaining animals were kept for another 12 months post-inhalation period. Regarding the macroscopical appearance of the lungs, the relative organ weights and the histomorphological reaction pattern, marked dust depending differences are obvious. In the lungs of DQ-12-exposed animals diffuse structural changes occur, including fibrosis and severe reaction of macrophages. Histology of lungs from quartz glass exposed animals reveals only a slight and focally arranged cellular reaction with a few collagenous fibers. However, in both dust exposed groups the mediastinal lymph nodes are extremely enlarged with severe fibroses. Additionally, the following blood parameters were determined: lysozyme, ACE, GOT, GPT, and AP. The most pronounced changes are detectable in lysozyme and GOT after DQ-12 exposure. After quartz glass exposure, the levels of these parameters are similar to the controls. These results show that the amorphous quartz tested in this experiment (quartz-glass VP 203-006) has to be considered as a compound with certain biological effects. The establishing of occupational standards seems to be justified. But, assessing the effects, the different physical and/or chemical properties of various amorphous quartz dusts have to be considered.

Currently there are no animal models available for interstitial lung diseases with unknown origin, such as sarcoidosis. Inflammatory cells obtained from patients have several disadvantages for the in-vitro verification of pathogenetical concepts. Thus, in-vitro models are desirable. Employing cell lines we present models that are suited to study the angiotensin-converting enzyme release and the production of oxygen radicals by activated macrophages and their fusion to giant cells.

Over a period of three years, we investigated the behaviour of renin and kininase II in 26 patients with active, histologically confirmed sarcoidosis in comparison with healthy test subjects, during ergometer exercise. Renin activity was determined radioimmunologically, and kininase II by means of spectral photometry (Cushman-Lieberman method). In both groups, a significant increase in renin and kininase II during the course of exercise on the ergometer was observed, which, however, was more marked in the sarcoidosis group of patients. Furthermore, the activities of both enzymes were highly significantly elevated as compared with the group of healthy subjects in each individual phase of exercise. In addition--if we consider the average values of the two enzymes in each of the individual subjects--it would seem possible in most cases to correctly ascribe the person involved to the group healthy subjects or patients, in particular when the average values of renin and kininase II obtained as described above, are multiplied together.

Serum ACE activity measured fluorimetrically was found to be 2.95 +/- (SD) 1.76 mu mol/ml x h in 31 untreated patients with sarcoidosis. It was significantly elevated (p less than 0.001) in comparison to 38 healthy controls 0.97 +/- (SD) 0.30 mu mol/ml x h), 81 subjects with miscellaneous lung diseases, 20 corticosteroid treated patients with sarcoidosis and 15 subjects with resolved sarcoidosis. Resolution of sarcoidosis spontaneously or induced by corticosteroids was accompanied in all 17 cases by a decrease of serum ACE activity, in most cases, to normal values. On the other hand 7 out of 9 untreated patients with a chronic course of sarcoidosis did not show a comparable change of ACE. Our results reveal a close relationship between the activity of the disease and the level of ACE in the serum. The determination of the serum activity of ACE and its variations with time is quite useful in the diagnosis and follow-up of sarcoidosis and contributes to a further restriction of necessary operative procedures in the diagnosis of sarcoidosis.

In the membrane fraction of rat uterus, kinin-destroying activity was found and characterized as kininase II by means of several kininase inhibitors. It could be shown that sudies of bradykinin-receptor interactions requires the use of kininase inhibitors like phenanthroline or the use of a stable bradykinin analogue like [8-erythro-alpha-amino-beta-phenylbutyric acid]-bradykinin.

Sarcoidosis of the kidneys and liver without radiologically demonstrable lung involvement in a 44-year-old woman was shown to be the cause of a hypercalcaemia syndrome. The hypercalcaemia was presumably due to an increased production of 1,25-(OH)2-vitamin D3 which--like the increased angiotensin converting enzyme--is produced in the epithelioid and giant cells. Corticoid treatment normalized serum calcium and ACE levels and improved renal function. These observations demonstrate that measurement of ACE and 1,25-(OH)2-vitamin D3 levels is helpful in the differential diagnosis of hypercalcaemia, in view of the possibility of sarcoidosis, and should be among the diagnostic tests.

The endothelial lining contributes in many respects to the patency of the vasculature. The production of heparan sulphate, release of prostacyclin and expression of the membrane cofactor thrombomodulin that is essentially required for the activation of protein C represent important mechanisms that warrant thromboresistance. If the integrity of the vessel wall is lost, the exposed subendothelium that has been built up by the endothelial cells serves as a highly reactive surface for platelets whose adherence is facilitated by another endothelial cell product, the von Willebrand Factor. Induction of tissue factor production after exposure to endotoxin also emphasizes an important role für the endothelium in the pathogenesis of disseminated intravascular coagulation. Once thrombosis has occurred the release of plasminogen activator of tissue-type from the endothelium leads to dissolution of the clot and a functional restoration of the blood vessel.

The renin-angiotensin system (RAS) has long been known as a hormonal system, which is important for the maintenance of volume homeostasis, and which contributes under certain circumstances to the pathogenesis of hypertension and cardiac failure. More recent findings have demonstrated that the individual components of this system can also be synthesized locally in tissue, e.g. in the brain, the vascular wall, the kidney, the adrenals, and the heart. Although the role of locally generated angiotensin within cardiovascular- and body volume regulation needs to be further investigated, it has already become clear that the mechanism of action of drugs interfering with the RAS is not confined to the circulating RAS, but also includes an interaction with local renin-angiotensin systems. These agents, particularly the converting enzyme inhibitors, have proved to be indispensible tools for elucidating the function of local renin-angiotensin systems, in addition to being therapeutically useful in the treatment of cardiovascular diseases.

Serum ACE activity was examined in cases of diseases of the thyroid gland. The enzyme activity was compared with the concentration of total serum thyroxine (TT4) and total serum triiodothyronine (TT3). For this purpose the medical data of a group of healthy test persons (85 male and 85 female) were contrasted with those of a group of 162 patients attending the out-patient department for thyroid gland diseases in our hospital (28 male and 134 female, of whom 112 were aged between 21 and 60, and 50 above the age of 60). Among the patients there were 36 cases of euthyroid goiter, 59 of untreated and 36 of treated hyperthyroidism, 25 of hypothyroidism of varied genesis, and 6 patients suffering from as yet untreated thyroid cancer. We observed significant differences in ACE activity in the different groups. In cases of disorder of the thyroid gland there was a positive correlation between enzyme activity and hormone data. Where other causes which may influence its activity can be excluded, ACE reflects the effect of the hormones of the thyroid gland on the tissue. We kept under observation 15 patients suffering from thyroid cancer altogether, of whom 6 had no previous treatment, whereas in 9 thyroidectomy had been carried out, followed by radioactive iodine therapy. Irrespective of the timing of the examination, there was a significant increase in serum ACE activity (on average 365 U/l, as against 282 U/l, p less than 0.01), if metastasis had occurred.

In 67 patients thought to have renovascular hypertension, plasma renin activity was measured in both renal veins and peripherally (common femoral v.) before and after administration of 25 mg captopril. Other antihypertensive medication, except diuretics and ACE inhibitors, had been discontinued. The renin ratio, renin secretion indices before and after ACE inhibition, as well as the percentage rise in peripheral plasma renin activity, after captopril were calculated from the measured data. The diagnostic and prognostic value of the various calculation models were compared on the basis of blood pressure changes in 29 patients after intervention (28 operations, one percutaneous transluminal angioplasty). Of the various calculations the renin ratio after ACE stimulation--measuring plasma renin activity separately for each side--was of the greatest value in discriminating for renovascular hypertension (sensitivity 89%, specificity 100%). Comparable results in the discrimination for renovascular hypertension were achieved by determining the rise in peripheral plasma renin activity after captopril. This method is, therefore, a simple, noninvasive test for diagnosing renovascular hypertension with great accuracy even while existing medication is being continued.

In 43 patients with inoperable bronchogenic carcinoma--32 small cell and 11 squamous or large cell--Angiotensin-Converting-Enzyme (ACE) activity in serum was determined before and every 3-5 weeks during cytotoxic chemotherapy. ACE-activity prior to therapy was 10.7 U +/- 1.17 SE as compared to the normal values 20.4 U +/- 1.8 SE which was statistically significant (p less than 0.01). There was no significant difference between the basal values of patients with small cell and not small cell-carcinoma of the lung. Only for patients with small cell-carcinoma of the lung a significant rise in ACE-activity could be obtained. Mean values of these patients reached normal levels in case they had complete remission, which was achieved in the limited disease group in 82% of patients. The present data suggest, that ACE-activities in serum correspond well to the clinical course in patients with small cell carcinoma of the lung. The decision on the individual mode of therapy may thus become more substantiated by serial determinations of ACE in the course of treatment.

Serum angiotensin converting enzyme (ACE) activity was studied in 50 patients with sarcoidosis (39 active, 11 inactive sarcoidosis), as well as in 50 control patients (34 chronic lung diseases, 9 Hodgkin-disease, 7 rheumatoid arthritis). There is a significant difference (p less than 0.001) of ACE-activity between sarcoidosis patients and controls, and between active (without steroid treatment) and inactive sarcoidosis. Steroid treatment apparently lowers ACE-activity in sarcoidosis, however, without evidence for clinical improvement. Increased ACE-activity was also found in a patient with primary biliary cirrhosis.

The antihypertensive effect of captopril was tested on 19 patients with essential hypertension, WHO grade I or II. In 11 patients blood pressure levels returned to normal over an observation period of 12 weeks at a dose of 3 C 50-150 mg daily (group A). In eight patients with grade II hypertension the absolute blood-pressure reduction was the same, but did not reach normal levels (group B). Although additional intake of propranolol, at a dose of 3 X 40 mg daily, achieved further reduction, normal pressures were still not attained. Initial blood pressure levels were higher and plasma-renin activity lower in patients of group B than of group A. There was a definite rise in plasma-renin activity with captopril, but corresponding to the suppression of plasma-renin in severe hypertension it was less. There was a fall in plasma-aldosterone levels, corresponding to a reduced angiotensin II level as a result of inhibition of the converting enzyme. The fall in plasma-aldosterone activity was less in severe hypertension, although there was the same inhibition of converting enzyme activity in both groups. Normochromic anaemia was noted in three patients, requiring further observation and explanation. No patient developed orthostatic hypotension or reflex tachycardia.

The diagnostic evidence of the ACE and CP activity alone is limited with regard to the specifity of sarcoidosis. In connection with the X-ray diagnostics and the histological ascertainment the determination of the two enzyme activities, however, is an enrichment of the programme of diagnostics. High ACE- and CP-values speak for the presence of numerous sarcoidosis granulomas and for the affection of many organs, respectively, when the sarcoidosis is ascertained. This fact is valuable in the diagnostics of sarcoidosis of the myocardium. For therapy controls or investigations of the course of the disease the two enzymes are to be used, since they give references to the activity of the disease. In this case the sensitivity of the ACE-determination seems to be larger than that one of the collagen peptidase.

Serum sIL-2-R levels were measured in 28 sarcoidosis patients at multiple time points before, during, and after therapy, with a mean follow-up time of 10.2 +/- 5.2 months, and the results compared with the clinical activity of the disease. Before therapy, 20 out of 24 episodes with active disease exhibited elevated levels of sIL-2-R (918 +/- 362 U/ml). In inactive disease after tapering off corticoid therapy the sIL-2-R levels were 453 +/- 274 U/ml. Disease activity under therapy also correlated with sIL-2-R serum levels. 23 out of 29 episodes with signs of activity under therapy had elevated sIL-2-R levels (808 +/- 409 U/ml). Only three of 28 patients in whom disease activity ceased after therapy had been initiated had raised sIL-2-R levels (mean: 401 +/- 140 U/ml). These results demonstrate that the activity of pulmonary sarcoidosis is reflected accurately by the serum levels of sIL-2-R, suggesting that the course of the disease can be monitored by this approach.

The relationship between the clinical course and SACE activity was analyzed by observing 133 patients with histologically confirmed sarcoidosis (74 stage I, 59 stage II) at intervals of 6.2 +/- 2.6 months during a period of 32.9 +/- 11.9 months. At the end of the follow-up period the patients were grouped into 4 categories concerning their chest x-ray changes: (a) improved (53); (b) unchanged (38); (c) progressive (9); (d) relapses (33). In group (a) initially elevated SACE always decreased, in (b) it often remained above the normal range; (c) and (d) always coincided with rising SACE. Out of 56 relapses observed 53 (95%) were associated with pathologically elevated SACE. There were significantly more relapses (35) in stage II compared to 21 in stage I sarcoidosis. SACE activities were measured in 109 patients placed on steroids. As a rule initially elevated SACE concentrations fell rapidly after initiation of steroid therapy. However SACE was found to be above the normal range after four weeks of therapy in 21 patients (19,3%), 5 in stage I and 16 in stage II, indicating an unfavourable course of the disease. Serial measurements of SACE are a very useful indicator of the activity of sarcoidosis and are helpful for monitoring the effects of corticosteroid therapy, having also some prognostic significance.