Intra-alveolar Edema Research Articles

Quercetin as a therapeutic agent activate the Nrf2/Keap1 pathway to alleviate lung ischemia-reperfusion injury

Lung ischemia-reperfusion injury (LIRI) causes oxidative stress, inflammation, and immune system activation. The Nrf2/Keap1/HO-1 pathway is important in cellular defense against these effects. Quercetin, a flavonoid with antioxidant, anti-inflammatory, and anti-cancer properties, has been investigated. Our aim in this study was to investigate the effect of quercetin on preventing lung ischemia-reperfusion injury and the role of the Nrf2/Keap1/HO-1 pathway. Sixty-four male Wistar rats were divided into four distinct groups(n = 16). Sham, lung ischemia-reperfusion (LIR), Saline + LIR, Quercetin + LIR (30 mg/kg i.p for a week before LIR). LIR groups were subjected to 60 min of ischemia (left pulmonary artery, vein, and bronchus) and 120 min of reperfusion. Our assessment encompassed a comprehensive analysis of various factors, including the evaluation of expression Nrf2, Keap1, and Heme Oxygenase-1 (HO-1) levels and NF-κB protein. Furthermore, we examined markers related to inflammation (interleukin-1β and tumor necrosis factor alpha), oxidative stress (malondialdehyde, total oxidant status, superoxide dismutase, glutathione peroxidase, total antioxidant capacity), lung edema (Wet/dry lung weight ratio and total protein concentration), apoptosis (Bax and Bcl2 protein), and histopathological alterations (intra-alveolar edema, alveolar hemorrhage, and neutrophil infiltration). Our results show that ischemia-reperfusion results in heightened inflammation, oxidative stress, apoptosis, lung edema, and histopathological damage. Quercetin showed preventive effects by reducing these markers, acting through modulation of the Nrf2/Keap1 pathway and inhibiting the NF-κB pathway. This anti-inflammatory effect, complementary to the antioxidant effects of quercetin, provides a multifaceted approach to cell protection that is important for developing therapeutic strategies against ischemia-reperfusion injury and could be helpful in preventive strategies against ischemia-reperfusion.

A Case Series of Butane Intoxication Fatalities in the Southeastern Anatolia Region of Türkiye

Aim: Volatile solvent abuse (VSA), is the third most common form of substance abuse after alcohol and cigarettes. The aim of this study was to determine the incidence of fatalities due to butane gas. 
 Material and Methods: From 8,075 autopsies conducted in our center in Şanlıurfa, Türkiye in a 10-year period, 10 deaths were determined to be due to butane gas intoxication. 
 Results: All the fatalities were males (mean age: 17.6 years). Friends reported chronic use of lighter gas by the fatalities prior to the incident. In contrast, close relatives stated that it was the first instance of VSA. The preferred inhalation methods were bagging (i.e., inhaling gas from a plastic bag, n=4) and direct inhalation (i.e., spraying the gas directly in the mouth, n=6). The scene of incident findings revealed more than one lighter gas cartridge at the scene in nine cases and many lighters at the scene in one case. The autopsy examinations revealed minimal grazing on the body in three cases and no traumatic findings in seven cases. Butane was detected in blood samples in all 10 cases and in lung tissue samples in eight cases. In all 10 cases, there were areas of intra-alveolar swelling, edema, and bleeding in the lungs. 
 Conclusion: The actual incidence of VSA-related deaths is likely much higher than the number of reported cases, as our center is located near the Syrian border and has one of the highest populations of children and young people in Türkiye.

A Case of Solitary Pulmonary Capillary Hemangioma

Solitary pulmonary capillary hemangioma (SPCH) is a very rare disease that has been reported to be difficult to diagnose preoperatively because the unenhanced computed tomography (CT) findings resemble adenocarcinoma in appearance. On the other hand, the findings of contrast-enhanced (CE) CT have not been reported as far as we could find in PubMed. In this article, we report a case of SPCH with its chest radiograph and dynamic CECT. Dynamic CECT could depict the pathologic features of capillary proliferation, especially dense in the central component of the lesion, edema, and congestion of the alveolar interstitium, and intra-alveolar edema in the periphery of the lesion. Dynamic CECT might be helpful for differentiating SPCH from other solitary pulmonary nodules.

Intermittent Ex Vivo Lung Perfusion in a Porcine Model for Prolonged Lung Preservation.

Ex vivo lung perfusion expands the lung transplant donor pool and extends preservation time beyond cold static preservation. We hypothesized that repeated regular ex vivo lung perfusion would better maintain lung grafts. Ten pig lungs were randomized into 2 groups. The control underwent 16 h of cold ischemic time and 2 h of cellular ex vivo lung perfusion. The intermittent ex vivo lung perfusion group underwent cold ischemic time for 4 h, ex vivo lung perfusion (first) for 2 h, cold ischemic time for 10 h, and 2 h of ex vivo lung perfusion (second). Lungs were assessed, and transplant suitability was determined after 2 h of ex vivo lung perfusion. The second ex vivo lung perfusion was significantly associated with better oxygenation, limited extravascular water, higher adenosine triphosphate, reduced intraalveolar edema, and well-preserved mitochondria compared with the control, despite proinflammatory cytokine elevation. No significant difference was observed in the first and second perfusion regarding oxygenation and adenosine triphosphate, whereas the second was associated with lower dynamic compliance and higher extravascular lung water than the first. Transplant suitability was 100% for the first and 60% for the second ex vivo lung perfusion, and 0% for the control. The second ex vivo lung perfusion had a slight deterioration in graft function compared to the first. Intermittent ex vivo lung perfusion created a better condition for lung grafts than cold static preservation, despite cytokine elevation. These results suggested that intermittent ex vivo lung perfusion may help prolong lung preservation.

Development of the Waterhouse-Friderichsen syndrome after infection with SARS-CoV-2 in a patient with rheumatoid arthritis and secondary AA-adrenal amyloidosis

The COVID-19 pandemic has also affected rheumatic diseases. A clinical case of the development of the Waterhouse-Friderichsen syndrome after SARS-CoV-2 infection in a patient with secondary AA - adrenal amyloidosis is presented. Description of the case. Patient G.G., 57 years old, was hospitalized for several hours on May 20, 2023 at the Cheboksary Regional Hospital with a diagnosis of severe viral interstitial pneumonia. Secondary AA adrenal amyloidosis. Acute adrenal insufficiency. She was admitted with complaints of an increase in body temperature up to 38.20C. Computed tomography of the chest organs showed signs of bilateral viral interstitial pneumonia (the percentage of lung damage was 74%). The diagnosis of COVID-19 was based on a positive PCR test in nasopharyngeal swabs. Blood pressure - 80 / 40 mm Hg. Art. D - dimer - 786 ng / ml (not higher - 243 ng / ml). Despite treatment, the patient died. At autopsy in the lungs, dystelectasis, hyaline membranes, intraalveolar edema. In the adrenal glands - the deposition of amyloid masses, foci of necrosis of the cortical layer and hemorrhage. Signs of DIC - syndrome. Conclusion. The peculiarity of the case is the development of the Waterhouse-Frideriksen syndrome without signs of sepsis.

Comparison of ultrasound signs, computed tomography data and morphological examination of the lungs in patients with coronavirus infection: post hoc analysis

INTRODUCTION: Ultrasound examination (US) of the lungs has shown high efficiency in the diagnosis of COVID-19 pneumonia. The aim of the research was studying the correspondence of computed tomography (CT) US signs of the lungs and morphological data in patients with COVID-19 pneumonia. MATERIALS AND METHODS: The post hoc analysis included 388 patients who simultaneously underwent ultrasound and CT of the lungs. Lung ultrasound was performed according to the 16-zone “Russian Protocol”. Morphological data were obtained from the results of pathoanatomic examination of deceased patients. RESULTS: The comparison of signs detected by CT and ultrasound of the lungs was performed during a multidimensional correspondence analysis. The analysis was carried out using a three-dimensional solution that explained 64.9 % of inertia (p < 0.001). CT signs of “ground glass opacity” (100 %) corresponded to the B-line at ultrasound (100 %), CT of the consolidation sign (44.8 %) — ultrasound signs of consolidation (46.9 %), aerobronchogram of CT (34 %) — aerobronchogram of ultrasound (36.9 %), free liquid CT (11.1 %) — free liquid Ultrasound (13.9 %). CT signs of reticular changes (29.6 %) and “cobblestone pavement” (12.4 %) corresponded to various combinations of ultrasound signs of subpleural consolidation and B-lines. The B-lines were caused by the exudation of fluid and protein molecules into the intraalveolar space against the background of massive death of alveolocytes and formed by the development of intraalveolar edema and the formation of hyaline membranes. The ultrasonic sign of consolidation appeared in the airless zone of the lungs. Subpleural consolidation are caused by thickening and inflammatory infiltration of the pleura, diffuse alveolar damage, with intraalveolar edema, death and decay of alveolocytes, perivascular inflammatory cell reaction/ During treatment for more than 7 days, consolidation in the lung tissue developed due to the disorganization of the organ structure due to the progression of fibrosis. CONCLUSION: Multivariate correspondence analysis showed correlation of CT signs and US signs of the lungs. Morphological analysis showed polymorphism of histological data that caused the formation of ultrasound signs.

A clinical case of SARS-CoV-2 infection complicated by viral interstitial pneumonia and pulmonary edema in a patient with dilated cardiomyopathy

COVID-19 is especially severe in patients with a premorbid background.Aim: To describe a clinical case of SARS-CoV-2 infection complicated by bilateral viral pneumonia, cardiogenic pulmonary edema, and dilated сardiomyopathy.Clinical case. Patient M.V., 76 years old, from 02.11.2022 to 03.11.2022 was hospitalized at the Republican Cardiological Dispensary with a diagnosis of Bilateral viral pneumonia, the percentage of damage was 75%. Acute respiratory distress syndrome, severe. Complaints at admission: lack of air in a horizontal position, fever up to 38,0 °С, dry cough. Computed tomography of the chest was performed; bilateral viral pneumonia was determined (75% of lesions). PCR smear for coronavirus infection was positive. Determination of troponin T from 02.11.2022: 0.022 ng/ml. History: hypertension for many years with maximum blood pressure of 190/100 mm Hg, acute myocardial infarction of the anterior wall of the left ventricle with ST segment elevation (November 20, 2021), percutaneous coronary intervention (November 20, 2021). The above complaints were noted within a week. On the second day of inpatient treatment, a lethal outcome occurred. She was sent for a post-mortem examination. In the lungs, histological examination revealed a violation of microcirculation in the form of erythrocyte sludge, stasis. Widespread atelectasis/dystelectasis. There was intraalveolar edema. On macroscopic examination, the cavities of the heart are enlarged.Histological examination revealed large-focal cardiosclerosis, areas of wave-like deformation of myocardial muscle fibers. Virological examination of sectional material in the lungs and heart revealed SARS-CoV-2 RNA.Conclusion. Viral infection with COVID-19 contributed to the development of decompensation of chronic heart failure in the form of arrhythmia and cardiogenic pulmonary edema in a patient with dilated cardiomyopathy.

NRICM101 ameliorates SARS-CoV-2-S1-induced pulmonary injury in K18-hACE2 mice model.

The coronavirus disease 2019 (COVID-19) pandemic continues to represent a challenge for public health globally since transmission of different variants of the virus does not seem to be effectively affected by the current treatments and vaccines. During COVID-19 the outbreak in Taiwan, the patients with mild symptoms were improved after the treatment with NRICM101, a traditional Chinese medicine formula developed by our institute. Here, we investigated the effect and mechanism of action of NRICM101 on improval of COVID-19-induced pulmonary injury using S1 subunit of the SARS-CoV-2 spike protein-induced diffuse alveolar damage (DAD) of hACE2 transgenic mice. The S1 protein induced significant pulmonary injury with the hallmarks of DAD (strong exudation, interstitial and intra-alveolar edema, hyaline membranes, abnormal pneumocyte apoptosis, strong leukocyte infiltration, and cytokine production). NRICM101 effectively reduced all of these hallmarks. We then used next-generation sequencing assays to identify 193 genes that were differentially expressed in the S1+NRICM101 group. Of these, three (Ddit4, Ikbke, Tnfaip3) were significantly represented in the top 30 enriched downregulated gene ontology (GO) terms in the S1+NRICM101 group versus the S1+saline group. These terms included the innate immune response, pattern recognition receptor (PRR), and Toll-like receptor signaling pathways. We found that NRICM101 disrupted the interaction of the spike protein of various SARS-CoV-2 variants with the human ACE2 receptor. It also suppressed the expression of cytokines IL-1β, IL-6, TNF-α, MIP-1β, IP-10, and MIP-1α in alveolar macrophages activated by lipopolysaccharide. We conclude that NRICM101 effectively protects against SARS-CoV-2-S1-induced pulmonary injury via modulation of the innate immune response, pattern recognition receptor, and Toll-like receptor signaling pathways to ameliorate DAD.

A Systematic Review of Lung Autopsy Findings in Elderly Patients after SARS-CoV-2 Infection.

Although COVID-19 may cause various and multiorgan diseases, few research studies have examined the postmortem pathological findings of SARS-CoV-2-infected individuals who died. Active autopsy results may be crucial for understanding how COVID-19 infection operates and preventing severe effects. In contrast to younger persons, however, the patient's age, lifestyle, and concomitant comorbidities might alter the morpho-pathological aspects of the damaged lungs. Through a systematic analysis of the available literature until December 2022, we aimed to provide a thorough picture of the histopathological characteristics of the lungs in patients older than 70 years who died of COVID-19. A thorough search was conducted on three electronic databases (PubMed, Scopus, and Web of Science), including 18 studies and a total of 478 autopsies performed. It was observed that the average age of patients was 75.6 years, of which 65.4% were men. COPD was identified in an average of 16.7% of all patients. Autopsy findings indicated significantly heavier lungs, with an average weight of the right lung of 1103 g, while the left lung mass had an average weight of 848 g. Diffuse alveolar damage was a main finding in 67.2% of all autopsies, while pulmonary edema had a prevalence of between 50% and 70%. Thrombosis was also a significant finding, while some studies described focal and extensive pulmonary infarctions in 72.7% of elderly patients. Pneumonia and bronchopneumonia were observed, with a prevalence ranging from 47.6% to 89.5%. Other important findings described in less detail comprise hyaline membranes, the proliferation of pneumocytes and fibroblasts, extensive suppurative bronchopneumonic infiltrates, intra-alveolar edema, thickened alveolar septa, desquamation of pneumocytes, alveolar infiltrates, multinucleated giant cells, and intranuclear inclusion bodies. These findings should be corroborated with children's and adults' autopsies. Postmortem examination as a technique for studying the microscopic and macroscopic features of the lungs might lead to a better knowledge of COVID-19 pathogenesis, diagnosis, and treatment, hence enhancing elderly patient care.

Pancreatic islets as a SARS-CoV-2 target

Aim. The study is aimed at describing pancreatic islets as one of the SARS-CoV-2 targets.Materials and methods. The object of the study was the pancreas. The study involved histological staining.Results and discussion. The autopsy study revealed the signs typical of bilateral viral interstitial pneumonia. Histological examination revealed alveoli with disatelectasis, intra-alveolar edema, hyaline membranes in a part of alveoli. The pancreas histological examination showed hemorrhages, necrotic areas of the islets and detected the following DIC signs: small hyaline thrombi in the heart cavities and large vessels, petechial hemorrhages in the internal organs and adrenal glands, foci of adrenal cortex necrosis with perifocal infiltration (Waterhouse—Friderichsen syndrome); as well as signs of necronephrosis with fibrinoid areas of necrosis in the glomerular capillary network and perivascular lymphoid infiltrates.Conclusion. SARS-CoV-2 was revealed to target human pancreatic islets, where areas of necrosis developed.

Analysis of the Lung’s Histopathologic Changes in a Variety of Acute Asphyxia Deaths at S.M.S Hospital In Jaipur

Autopsy diagnosis of asphyxia rests upon the identification of classical signs of asphyxia viz. cyanosis, congestion and petechial hemorrhages. In essence, interference with breathing results in asphyxia. There are several ways to asphyxia can occur as a result of hanging, ligature/manual strangulation, mugging, smothering, throttling, chocking, aspiration, suffocation, asphyxia due to chronic lung disease etc. A cross sectional descriptive observational study that was conducted at the SMS Medical College, in the department of forensic medicine in Jaipur, Rajasthan from 1st June 2018 to October 2019. After a thorough autopsy investigation, samples of the relevant lung tissue from both sides were saved for histological analysis of any pulmonary abnormalities.160 (4.90%) autopsies were of these fatalities (n=3261) were taken in the study. The most frequent cause of acute lethal asphyxia was hanging (85%). In addition, this kind of Histopathologic diagnosis of lung can serve as an additional tool for diagnosis confirmation, particularly in situations where the distinguishing characteristics required determining the cause of death may be elusive. In 100% of cases of strangulation, alveolar tissue over insufflations was identified with histopathological score 3 and 4, whereas in hanging score was recorded in nearly all cases at 2. In All cases the score in the throttling was 1. Interstitial edema, intraalveolar edema, passive congestion and intra alveolar and interstitial hemorrhages are virtually always present in hanging and drowning patients. Only in cases of aspiration related asphyxia are intra alveolar deposits of protein and amorphous debris discovered. It demonstrates how the histopathological analysis of the lungs during autopsy can be utilised as an additional histopathologic criterion to confirm the asphyxia diagnosis.

МОРФОЛОГІЧНА ОЦІНКА ПОШКОДЖЕННЯ ЛЕГЕНЬ У МОЛОДИХ ЩУРІВ, ВИКЛИКАНЕ ЧАСТКОВОЮ ОКЛЮЗІЄЮ ТРАХЕЇ

A decrease in the lumen of the upper respiratory tract (the trachea) in newborn infants is the main cause of impaired development of lungs during postnatal ontogenesis. Aim. To study the histological changes in the lung tissue of young sexually immature animals when modeling partial tracheal stenosis. Materials and methods. Young male Wistar rats aged 25-28 days and weighing 42-54 g were divided into 4 groups: 1) control (intact); 2) animals with tracheal stenosis (7 days); 3) animals with tracheal stenosis (21 days); 4) animals with tracheal stenosis (7 days after surgery followed by observation for 2 weeks). Modeling of stenosis was reproduced by applying a ligature at the level of the upper quarter of the trachea. This caused a narrowing of the tracheal lumen by 25-30%. The histological changes of the lungs in animals of all experimental groups were studied. Results. A significant structural damage to the alveoli and swelling of the alveolar acini were revealed on the 7th day of the development of tracheal stenosis. A partial reduction of pathomorphological changes was observed on day 21. The removal of the ligature from the trachea was accompanied by a gradual restoration of the normal histological structure of the animal lung tissue, while maintaining individual zones of hypoxic damage. At the same time, intra-alveolar edema, wedening of the alveolar lumen, a decrease in the thickness of their walls, structural disorders of the alveolar-capillary membrane, the accumulation of hemorrhagic contents, and destructive changes in the cells of the pulmonary acini were observed in the lung tissue. Long-term hypoxia (21 days) was accompanied by a partial regression of these damages with a simultaneous increase in the number of macrophages and massive death of pulmonary acini cells. In group 4 animals, after removing the ligature, in addition to the trachea damage the preservation of separate dystrophic changes was observed. Conclusions. In tracheal stenosis model and acute hypoxic-respiratory hypoxia, dystrophic changes in the lung tissue were revealed. With an increase in the duration of hypoxic exposure, a gradual adaptation of the cellular elements and metabolic processes to the conditions of impaired oxygenation was observed. Restoration of lung ventilation accelerates the development of compensatory and regenerative processes in lung cells against the background of the preservation of pronounced structural and morphological disorders. Keywords: hypoxia, lungs, tracheal stenosis, histological changes, acini.

A microsatellite DNA-derived oligodeoxynucleotide attenuates lipopolysaccharide-induced acute lung injury in mice by inhibiting the HMGB1-TLR4-NF-κB signaling pathway.

Acute lung injury (ALI) with uncontrolled inflammatory response has high morbidity and mortality rates in critically ill patients. Pathogen-associated molecular patterns (PAMPs) are involved in the development of uncontrolled inflammatory response injury and associated lethality. In this study, we investigated the inhibit effect of MS19, a microsatellite DNA-derived oligodeoxynucleotide (ODN) with AAAG repeats, on the inflammatory response induced by various PAMPs in vitro and in vivo. In parallel, a microsatellite DNA with AAAC repeats, named as MS19-C, was used as controls. We found that MS19 extensively inhibited the expression of inflammatory cytokines interleukin (IL)-6 and tumor necrosis factor (TNF)-α induced by various PAMPs stimulation, including DNA viruses, RNA viruses, bacterial components lipopolysaccharide (LPS), and curdlan, as well as the dsDNA and dsRNA mimics, in primed bone marrow-derived macrophage (BMDM). Other than various PAMPs, MS19 also demonstrated obvious effects on blocking the high mobility group box1 (HMGB1), a representative damage-associated-molecular pattern (DAMP), nuclear translocation and secretion. With the base substitution from G to C, MS19-C has been proved that it has lost the inhibitory effect. The inhibition is associated with nuclear factor kappa B (NF-κB) signaling but not the mitogen-activated protein kinase (MAPK) transduction. Moreover, MS19 capable of inhibiting the IL-6 and TNF-α production and blocking the HMGB1 nuclear translocation and secretion in LPS-stimulated cells was used to treat mice ALI induced by LPS in vivo. In the ALI mice model, MS19 significantly inhibited the weight loss and displayed the dramatic effect on lessening the ALI by reducing consolidation, hemorrhage, intra-alveolar edema in lungs of the mice. Meanwhile, MS19 could increase the survival rate of ALI by downregulating the inflammation cytokines HMGB1, TNF-a, and IL-6 production in the bronchoalveolar lavage fluid (BALF). The data suggest that MS19 might display its therapeutic role on ALI by inhibiting the HMGB1-TLR4-NF-κB signaling pathway.

Sequential Ex Vivo Lung Perfusion for Prolonged Lung Preservation: Does the Second EVLP Reset the Lung Conditions?

<h3>Purpose</h3> Ex vivo lung perfusion (EVLP) has the potential to expand the donor pool for lung transplantation by extending preservation times significantly beyond cold static preservation. We hypothesized that performing sequential EVLP would extend donor lung preservation time. <h3>Methods</h3> Ten lungs from Yorkshire pigs were procured in a standard fashion and randomized to 2 groups. Control lungs (n=5) underwent 16 hrs of cold ischemic time (CIT) and 2 hrs EVLP (EVLP). Sequential EVLP lungs (n = 5) underwent 4 hrs of CIT (CIT1), 2 hrs EVLP (EVLP1), 10 hrs of CIT (CIT2), then 2 hrs EVLP (EVLP2) (<b>Figure A</b>). Transplant suitability was assessed based on physiological parameters at 2 hrs in cellular EVLP. Lungs were evaluated using lung weight (LW), ultrasound, ATP levels, histology, and electron microscopy. <h3>Results</h3> EVLP2 had significantly higher PaO₂/FiO₂, lower shunt fraction, and A-a gradient compared to Control (p = 0.02, each, <b>Figure B</b>). LW ratio (LW 2 hrs / 0 hr) was significantly lower in EVLP2 vs. Control (p = 0.02, <b>Figure C</b>). Moreover, ultrasound score in whole lung and lower lobe to assess extravascular lung water was significantly lower in EVLP2 vs. Control (p = 0.04, p = 0.02, respectively, <b>Figure C</b>). ATP levels were significantly higher in EVLP2 vs. Control (p = 0.01). Histologic analysis of lungs in EVLP2 showed significantly reduced intra-alveolar edema, while there was no difference between groups in lung injury score. Electron microscopy demonstrated better preservation of endothelial cells and mitochondria in alveolar cells in EVLP2 lungs vs. Control. <h3>Conclusion</h3> Treating donor lungs with sequential EVLP resulted in superior oxygenation vs. lungs subjected to cold storage and 1 session of EVLP. Sequential EVLP was also associated with decreased LW ratio, lung edema, and higher ATP levels, in addition to favorable histology and electron microscopic findings. These suggest that sequential EVLP can have a potential role in prolonging lung preservation time.

CRP apheresis in acute myocardial infarction and COVID-19

Das C‑reaktive Protein (CRP) ist das bekannteste Akute-Phase-Protein. Beim Menschen gehen Entzündungen bzw. Infektionen zumeist mit einem Anstieg der CRP-Konzentration im Blut einher, weshalb dem CRP in der täglichen klinischen Routine als Biomarker eine bedeutende Rolle zukommt. Das CRP kann durch die Markierung von geschädigten Zellen die Einleitung der Phagozytose vermitteln. Diese Markierung führt zur Aktivierung des klassischen Komplementwegs (bis hin zu C4) und endet in der Elimination von Pathogenen oder reversibel geschädigten bzw. toten Körperzellen. Sinnvoll erscheint dieses bei einer äußeren Wunde des Körpers. Im Falle von „inneren Wunden“ (z. B. Herzinfarkt, Schlaganfall) induziert CRP durch Zellmarkierung jedoch eine Gewebeschädigung von potenziell regenerierbarem Gewebe mit entsprechend deletären Effekten auf Herz- und Hirnstruktur bzw. -funktion. Die beschriebene Markierung von ischämischen, aber potenziell regenerierbaren Zellen durch CRP tritt offenbar auch bei „coronavirus disease 2019“ (COVID-19) auf. Teile der Lunge werden durch intraalveoläre Ödeme und Blutungen ischämisch und parallel dazu steigt das CRP dramatisch an. Die selektive Immunadsorption von CRP aus dem Blutplasma („CRP-Apherese“) füllt die therapeutische Lücke in der derzeitigen Pharmakotherapie, mit der eine schnelle und effiziente therapeutische Absenkung einer fulminanten CRP-Belastung des menschlichen Organismus nicht möglich ist. Mit der CRP-Apherese ist es zum ersten Mal möglich, dieses pathologische Molekül in der klinischen Praxis schnell und effizient zu entfernen.

The role of neutrophilic granulocytes in the development of acute lung injury in experimental diabetes mellitus

Diabetes mellitus takes one of the first places in the structure of endocrine diseases. Among the complications of diabetes are sufficiently described nephro- and retinopathy, neuropathy, damage to the cardiovascular system. However, changes in the respiratory system and, in particular, the state of the endothelium of the pulmonary hemocapillaries and the morphofunctional state of neutrophilic granulocytes remain poorly understood. The aim of this study was to determine the role of neutrophilic granulocytes in the pathogenesis of acute lung injury in experimental diabetes mellitus. The experiments were performed on 88 white male Wistar rats weighing 170-210 g. The animals were divided into three groups: 1 – intact (n=10); 2 – control (n=40); 3 – experimental (n=38) with a model of diabetes mellitus, which was reproduced by intraperitoneal administration of streptozotocin company “Sigma” (USA), diluted in 0.1 M citrate buffer with pH 4.5, at a rate of 60 mg/kg body weight. An equivalent dose of 0.1 M citrate buffer solution with a pH of 4.5 was intraperitoneally administered to the control group of animals. Pulmonary tissue collection for electron microscopic examination was performed under thiopental anesthesia 14, 28, 42, 70 days after streptozotocin administration. Pieces of lung tissue were fixed in 2.5 % glutaraldehyde solution, followed by fixation in 1 % osmium tetroxide solution. After dehydration, the material was poured into epon-araldite. Sections obtained on an ultramicrotome “Tesla BS-490” were studied in an electron microscope “PEM-125K”. It was found that in the early stages of diabetes mellitus (14-28 days) there is a violation of the rheological properties of blood, as evidenced by erythrocyte aggregates, excessive accumulation of neutrophils, their adhesion and aggregation in the hemocapillaries of the alveolar wall. With the extension of the experiment (42-70 days) there is a progressive violation of the ultrastructural organization of hemocapillaries of the alveolar wall and pronounced changes in the rheological properties of blood. Erythrocyte sludges and leuco-platelet aggregates are determined in the lumen of microvessels. Increased permeability of hemocapillaries of the alveolar wall leads to the emigration of neutrophilic granulocytes into the interstitium and the lumen of the alveoli with the development of interstitial and intraalveolar edema. Thus, streptozotocin-induced diabetes is accompanied by the development of acute lung damage in the pathogenesis of which the leading role belongs to neutrophilic granulocytes. The nature and severity of changes in the lungs depends on the duration of exposure to hyperglycemia.

COVID-19 and Lung Mast Cells: The Kallikrein-Kinin Activation Pathway.

Mast cells (MCs) have relevant participation in inflammatory and vascular hyperpermeability events, responsible for the action of the kallikrein–kinin system (KKS), that affect patients inflicted by the severe form of COVID-19. Given a higher number of activated MCs present in COVID-19 patients and their association with vascular hyperpermeability events, we investigated the factors that lead to the activation and degranulation of these cells and their harmful effects on the alveolar septum environment provided by the action of its mediators. Therefore, the pyroptotic processes throughout caspase-1 (CASP-1) and alarmin interleukin-33 (IL-33) secretion were investigated, along with the immunoexpression of angiotensin-converting enzyme 2 (ACE2), bradykinin receptor B1 (B1R) and bradykinin receptor B2 (B2R) on post-mortem lung samples from 24 patients affected by COVID-19. The results were compared to 10 patients affected by H1N1pdm09 and 11 control patients. As a result of the inflammatory processes induced by SARS-CoV-2, the activation by immunoglobulin E (IgE) and degranulation of tryptase, as well as Toluidine Blue metachromatic (TB)-stained MCs of the interstitial and perivascular regions of the same groups were also counted. An increased immunoexpression of the tissue biomarkers CASP-1, IL-33, ACE2, B1R and B2R was observed in the alveolar septum of the COVID-19 patients, associated with a higher density of IgE+ MCs, tryptase+ MCs and TB-stained MCs, in addition to the presence of intra-alveolar edema. These findings suggest the direct correlation of MCs with vascular hyperpermeability, edema and diffuse alveolar damage (DAD) events that affect patients with a severe form of this disease. The role of KKS activation in events involving the exacerbated increase in vascular permeability and its direct link with the conditions that precede intra-alveolar edema, and the consequent DAD, is evidenced. Therapy with drugs that inhibit the activation/degranulation of MCs can prevent the worsening of the prognosis and provide a better outcome for the patient.

Pathological, Immunological, and Hematological Parameters Associated with Experimental Infection of Citrobacter Freundii in Rabbits.

Citrobacter freundii is one of the most important nosocomial opportunistic pathogens, which causes sepsis, as well as different gross and histopathological lesions in various internal organs in humans and animals, especially dogs and fish. This study aimed to investigate the hematological parameters, immunological responses, and pathological effects of the infection induced by the virulent strain of C. freundii on rabbits. A total of 42 rabbits (local breed; male and female), with a mean weight of 1.5-2 kg, were housed under controlled environmental conditions (20±2°C, 14:10 h light: dark cycle) and allowed ad libitum access to food and water. After two weeks of adaption, the rabbits were divided randomly into three groups of 14 animals per group. Group one (G1) received 3×108 CFU/ml of the virulent isolate (intraperitoneally [IP]) of C. freundii. Group two (G2) was injected subcutaneously (SC) with 3×108 CFU/ml of the virulent strain of C. freundii, while group three was IP injected with phosphate buffer saline and considered a negative control group. Results showed the variable gross pathological effects which included hemorrhage, edema, and congestion of visceral organs. Furthermore, the microscopic lesions showed pneumonia due to inflammatory cells infiltration, mainly neutrophils, macrophages, plasmacytes, and lymphocytes, severe interstitial and intra-alveolar edema, extensive pulmonary hemorrhage, emphysema, and atelectasis. The recorded data from the liver samples revealed hepatitis which was characterized by perivascular and periportal leukocyte cuffing, marked centrilobular with periportal necrosis, extensive hepatic edema, and periportal edema in addition to extensive fibrosis in interlobular septa and periportal fibrosis with severe interstitial hemorrhage. In the kidneys, there were severe renal edema, mixed inflammatory exudation, mainly neutrophils, macrophages, plasmacytes, lymphocytes, fibroblast infiltration in renal parenchyma and renal cortex, extensive renal hemorrhage, edema, as well as fibrosis and severe renal tubular necrosis. In addition, enteritis appeared in the intestine with mucosal edema, especially in lamina propria; moreover, necrosis of entire villi, epithelial necrosis, mucosal and submucosal hemorrhage, and fibrosis were observed. The present study revealed a significant increase in total leukocytes count and the concentration of TNF-α in the infected groups. To the best of the authors' knowledge, this study is considered the first attempt aimed to detect the pathological effects of C. freundii on visceral organs in rabbits. It is concluded that this bacterium could induce a significant pathological, hematological, and immunological changes in the infected animals.

Does Gender Difference Effect Radiation-Induced Lung Toxicity? An Experimental Study by Genetic and Histopathological Predictors.

Several studies have reported differences in radiation toxicity between the sexes, but these differences have not been tested with respect to histopathology and genes. This animal study aimed to show an association between histopathological findings of radiation-induced lung toxicity and the genes ATM, SOD2, TGF-β1, XRCC1, XRCC3 and HHR2. In all, 120 animals were randomly divided into 2 control groups (male and female) and experimental groups comprising fifteen rats stratified by sex, radiotherapy (0 Gy vs. 10 Gy), and time to sacrifice (6, 12, and 24 weeks postirradiation). Histopathological evaluations for lung injury, namely, intra-alveolar edema, alveolar neutrophils, intra-alveolar erythrocytes, activated macrophages, intra-alveolar fibrosis, hyaline arteriosclerosis, and collapse were performed under a light microscope using a grid system; the evaluations were semi quantitatively scored. Then, the alveolar wall thickness was measured. Real-time quantitative reverse transcription PCR (RT-qPCR) was used to determine gene expression differences in ATM, TGF-β1, XRCC1, XRCC3, SOD2 and HHR2L among the groups. Histopathological data showed that radiation-induced acute, subacute, and chronic lung toxicity were worse in male rats. The expression levels of the evaluated genes were significantly higher in females than males in the control group, but this difference was lost over time after radiotherapy. Less toxicity in females may be attributable to the fact that the expression of the evaluated genes was higher in normal lung tissue in females than in males and the changes in gene expression patterns in the postradiotherapy period played a protective role in females. Additional data related to pulmonary function, lung weights, imaging, or outcomes are needed to support this data that is based on histopathology alone.

Cocaine-induced pulmonary complications

Pulmonary complications of cocaine among users are common. Manifestations include lung congestion, intra-alveolar edema, and diffuse alveolar hemorrhage (DAH). Direct cellular toxicity, eosinophilia, barotrauma, and vasoactive effects of cocaine are believed to induce DAH. We present a rare case of cocaine-associated focal alveolar hemorrhage mimicking malignancy on imaging. Initially contemplated biopsy was avoided based on rapid growth of concerning lung lesion, with subsequent near resolution on follow-up. This case illustrates the importance of epidemiologic and temporal multimodality correlation when evaluating indeterminate lung lesions.