New Postmortem Perspective on Emerging SARS-CoV-2 Variants of Concern, Germany.

We performed autopsies on persons in Germany who died from COVID-19 and observed higher nasopharyngeal SARS-CoV-2 viral loads for variants of concern (VOC) compared with non-VOC lineages. Pulmonary inflammation and damage appeared higher in non-VOC than VOC lineages until adjusted for vaccination status, suggesting COVID-19 vaccination may mitigate pulmonary damage.

Cholestasis-Associated Pulmonary Inflammation, Oxidative Stress, and Tissue Fibrosis: The Protective Role of the Biogenic Amine Agmatine.

INTRODUCTION: Cholestasis is the stoppage of bile flow, leading to the accumulation of potentially cytotoxic bile components in the liver. These cytotoxic molecules affect many organs. Cholestasis-induced lung injury is a severe complication that could lead to tissue fibrosis and respiratory distress. Substantial evidence indicates the role of oxidative stress and inflammatory response in the pathogenesis of cholestasis-associated pulmonary damage. Agmatine (AGM; 1-amino-4-guanidinobutane) is a biogenic amine endogenously synthesized in the human body. This amine provides potent anti-inflammatory and antioxidant properties. METHODS: In the current study, a series (six C57BL/6J male mice/group) of bile duct-ligated (BDL) animals were monitored at scheduled intervals (7, 14, and 28 days after the BDL operation) to ensure inflammatory response in their lung tissue (by analyzing their bronchoalveolar lavage fluid [BALF]). It was found that the level of inflammatory cells, pro-inflammatory cytokines, and IgG in the BALF reached their maximum level on day 28 after the BDL surgery. Therefore, other research groups were selected as follows: 1) Sham-operated (2.5 mL/kg normal saline, i.p., for 28 consecutive days), 2) BDL, 3) BDL + AGM (1 mg/kg/day, i.p., for 28 consecutive days), and 4) BDL + AGM (10 mg/kg/day, i.p., for 28 consecutive days). Then, the BALF was monitored at scheduled time intervals (7, 14, and 28 days post-BDL). RESULTS: It was found that pro-inflammatory cytokines (TNF-α, IL-6, and IL-1ß), bile acids, bilirubin, and inflammatory cells (monocytes, neutrophils, and lymphocytes) were significantly increased in the BALF of BDL mice. Moreover, biomarkers of oxidative stress were significantly increased in the pulmonary tissue of cholestatic animals. Lung tissue histopathological changes, tissue collagen deposition, and increased TGF-ß were also detected. It was found that AGM significantly ameliorated cholestasis-induced lung injury. CONCLUSION: The effects of AGM on inflammatory indicators, oxidative stress biomarkers, and tissue fibrosis seem to play a pivotal role in its protective properties.

Impact of protocatechuic acid on alleviation of pulmonary damage induced by cyclophosphamide targeting peroxisome proliferator activator receptor, silent information regulator type-1, and fork head box protein in rats.

Cyclophosphamide (CP) is a chemotherapeutic agent that causes pulmonary damage by generating free radicals and pro-inflammatory cytokines. Pulmonary damage has a high mortality rate due to the severe inflammation and edema occurred in lung. PPARγ/Sirt 1 signaling has been shown to be cytoprotective effect against cellular inflammatory stress and oxidative injury. Protocatechuic acid (PCA) is a potent Sirt1 activator and exhibits antioxidant as well as anti-inflammatory properties. The current study aims to investigate the therapeutic impacts of PCA against CP-induced pulmonary damage in rats. Rats were assigned randomly into 4 experimental groups. The control group was injected with a single i.p injection of saline. CP group was injected with a single i.p injection of CP (200 mg/kg). PCA groups were administered orally with PCA (50 and 100 mg/kg; p.o.) once daily for 10 consecutive days after CP injection. PCA treatment resulted in a significant decrease in the protein levels of MDA, a marker of lipid peroxidation, NO and MPO along with a significant increase in GSH and catalase protein levels. Moreover, PCA downregulated anti-inflammatory markers as IL-17, NF-κB, IKBKB, COX-2, TNF-α, and PKC and upregulated cytoprotective defenses as PPARγ, and SIRT1. In addition, PCA administration ameliorated FoxO-1 elevation, increased Nrf2 gene expression, and reduced air alveoli emphysema, bronchiolar epithelium hyperplasia and inflammatory cell infiltration induced by CP. PCA might represent a promising adjuvant to prevent pulmonary damage in patients receiving CP due to its antioxidant and anti-inflammatory effects with cytoprotective defenses.

LncRNA MEG3 ameliorates NiO nanoparticles-induced pulmonary inflammatory damage via suppressing the p38 mitogen activated protein kinases pathway.

The lung inflammatory damage could result from the nickel oxide nanoparticles (NiO NPs), in which the underlying mechanism is still unclear. This article explored the roles of long noncoding RNA maternally expressed gene 3 (lncRNA MEG3) and p38 mitogen activated protein kinases (p38 MAPK) pathway in pulmonary inflammatory injury induced by NiO NPs. Wistar rats were treated with NiO NPs suspensions (0.015, 0.06, and 0.24 mg/kg) by intratracheal instillation twice-weekly for 9 weeks. Meanwhile, A549 cells were treated with NiO NPs suspensions (25, 50, and 100 µg/ml) for 24 h. It can be concluded that the NiO NPs did trigger pulmonary inflammatory damage, which was confirmed by the histopathological examination, abnormal changes of inflammatory cells and inflammatory cytokines (IL-1ß, IL-6, TGF-ß1, TNF-α, IFN-γ, IL-10, CXCL-1 and CXCL-2) in bronchoalveolar lavage fluid (BALF), pulmonary tissue and cell culture supernatant. Furthermore, NiO NPs activated the p38 MAPK pathway and downregulated MEG3 in vivo and in vitro. However, p38 MAPK pathway inhibitor (10 µM SB203580) reversed the alterations in the expression levels of inflammatory cytokines induced by NiO NPs. Meanwhile, over-expressed MEG3 significantly suppressed NiO NPs-induced p38 MAPK pathway activation and inflammatory cytokines changes. Overall, the above results proved that over-expression of lncRNA MEG3 reduced NiO NPs-induced inflammatory damage by preventing the activation of p38 MAPK pathway.

A temperature-dependent conformational shift in p38α MAPK substrate-binding region associated with changes in substrate phosphorylation profile.

Febrile-range hyperthermia worsens and hypothermia mitigates lung injury, and temperature dependence of lung injury is blunted by inhibitors of p38 mitogen-activated protein kinase (MAPK). Of the two predominant p38 isoforms, p38α is proinflammatory and p38ß is cytoprotective. Here, we analyzed the temperature dependence of p38 MAPK activation, substrate interaction, and tertiary structure. Incubating HeLa cells at 39.5 °C stimulated modest p38 activation, but did not alter tumor necrosis factor-α (TNFα)-induced p38 activation. In in vitro kinase assays containing activated p38α and MAPK-activated kinase-2 (MK2), MK2 phosphorylation was 14.5-fold greater at 39.5 °C than at 33 °C. By comparison, we observed only 3.1- and 1.9-fold differences for activating transcription factor-2 (ATF2) and signal transducer and activator of transcription-1α (STAT1α) and a 7.7-fold difference for p38ß phosphorylation of MK2. The temperature dependence of p38α:substrate binding affinity, as measured by surface plasmon resonance, paralleled substrate phosphorylation. Hydrogen-deuterium exchange MS (HDX-MS) of p38α performed at 33, 37, and 39.5 °C indicated temperature-dependent conformational changes in an α helix near the common docking and glutamate:aspartate substrate-binding domains at the known binding site for MK2. In contrast, HDX-MS analysis of p38ß did not detect significant temperature-dependent conformational changes in this region. We observed no conformational changes in the catalytic domain of either isoform and no corresponding temperature dependence in the C-terminal p38α-interacting region of MK2. Because MK2 participates in the pathogenesis of lung injury, the observed changes in the structure and function of proinflammatory p38α may contribute to the temperature dependence of acute lung injury.

Inhibition of Meprins Reduces Pulmonary Edema in LPS-Induced Acute Lung Damage.

Pulmonary edema is the major factor of tissue hypoxia in acute lung injury. Disruption of cell-cell contacts and lung interstitium increases permeability of the vascular endothelium and alveolar epithelium, which leads to the development of pulmonary edema. Meprin metalloproteases cleave extracellular matrix proteins, thus aggravating pulmonary edema. Meprin inhibitor actinonin was administered to rats with LPS-induced acute lung injury. Damaged lungs looked spotted and had multiple hemorrhage focuses, protein concentration in lavage fluid was increased, and lung weight coefficient was high. Administration of meprin inhibitor actinonin considerably reduced protein content in the bronchoalvelolar lavage and lung coefficient; only solitary lung hemorrhages were seen after this treatment. Thus, inhibition of meprins potentially alleviates LPS-induced disorders in the lung tissue permeability and reduces pulmonary edema.

Role of oxidative stress in sulfur mustard-induced pulmonary injury and antioxidant protection.

Sulfur mustard (SM) is a potent alkylating agent that targets several organs, especially lung tissue. Although pathological effects of SM have been widely considered, molecular and cellular mechanisms for these pathologies are not well understood, yet. General cellular and molecular events such as inflammation, DNA damage, cell membrane disintegrity, apoptosis and cell death were observed either in in vitro or in vivo models exposed to SM. However, it is not obvious that which specific molecules and signaling pathways are relevant to the pathogenesis of mustard lung. Oxidative stress (OS) and antioxidants depletion induced by SM seem to be one of these factors. SM can trigger several molecular and cellular pathways linked to oxidative stress and inflammation that can cause cell necrosis and apoptosis as well as loss of tissue structure and function. Identification of these signaling pathways and molecules gives us valuable information regarding the toxic mechanisms of SM on injured tissues and the way for developing a better clinical approach. In this review we aimed to discuss the proposed cellular and molecular mechanisms of SM on pulmonary damage, the importance of oxidative stress and the mechanisms by which SM induces OS and antioxidants depletion along with research on antioxidant therapy as a suitable antidote.

Molecular mechanism of oxidative damage of lung in mice following exposure to lanthanum chloride.

Exposure to lanthanoids (Ln) elicits an adverse response such as oxidative injury of lung in animals and human. The molecular targets of Ln remain unclear. In the present study, the function and signal pathway of nuclear factor erythroid 2 related factor 2 (Nrf2) in LaCl3 -induced oxidative stress in mouse lung were investigated. Mice were exposed to 2, 5, and 10 mg/kg body weight by nasal administration for 6 consecutive months. With increased doses, La was markedly accumulated and promoted the reactive oxygen species (ROS) production in the lung, which in turn resulted in peroxidation of lipids, proteins and DNA, and severe pulmonary damages. Furthermore, LaCl3 exposure could significantly increase levels of Nrf2, heme oxygenase 1 (HO-1) and glutamate-cysteine ligase catalytic subunit (GCLC) expressions in the LaCl3 -exposed lung. These findings imply that the induction of Nrf2 expression is an adaptive intracellular response to LaCl3 -induced oxidative stress in mouse lung, and that Nrf2 may regulate the LaCl3 -induced pulmonary damages.

Interleukin-6 limits influenza-induced inflammation and protects against fatal lung pathology.

Balancing the generation of immune responses capable of controlling virus replication with those causing immunopathology is critical for the survival of the host and resolution of influenza-induced inflammation. Based on the capacity of interleukin-6 (IL-6) to govern both optimal T-cell responses and inflammatory resolution, we hypothesised that IL-6 plays an important role in maintaining this balance. Comparison of innate and adaptive immune responses in influenza-infected wild-type control and IL-6-deficient mice revealed striking differences in virus clearance, lung immunopathology and generation of heterosubtypic immunity. Mice lacking IL-6 displayed a profound defect in their ability to mount an anti-viral T-cell response. Failure to adequately control virus was further associated with an enhanced infiltration of inflammatory monocytes into the lung and an elevated production of the pro-inflammatory cytokines, IFN-α and TNF-α. These events were associated with severe lung damage, characterised by profound vascular leakage and death. Our data highlight an essential role for IL-6 in orchestrating anti-viral immunity through an ability to limit inflammation, promote protective adaptive immune responses and prevent fatal immunopathology.

Pulmonary function and autoantibodies in a long-term follow-up of juvenile dermatomyositis patients.

OBJECTIVES: Pulmonary disease is a rare complication in JDM, described in only a few studies. This long-term follow-up study aimed to (i) describe pulmonary involvement in a national cohort of JDM patients estimated by conventional spirometry, (ii) compare pulmonary impairment with overall JDM outcome, and (iii) identify possible associations between pulmonary impairment and myositis-specific autoantibodies (MSAs). METHODS: Fifty-one JDM patients performed conventional spirometry in a cross-sectional follow-up study. The scores of the Myositis Damage Index (MDI), Myositis Damage by visual analogue scale (MYODAM-VAS) and physician's global damage assessment were used to estimate JDM outcome. ANAs, MSAs and myositis-associated autoantibodies were analysed in all patients. RESULTS: Forty-two patients (82%) (mean follow-up time 14.3 years) had normal lung function. Four patients (8%) were diagnosed with JDM-related restrictive interstitial lung disease. No patients reported pulmonary symptoms. Patients with restrictive pulmonary function had increased long-term damage estimated by MDI (P = 0.008), MYODAM-VAS (P = 0.04), global assessment (P = 0.03) and number of organ systems involved (P = 0.009). We found significant correlation between the restrictive pulmonary function test and damage by the MDI (r = 0.43, P = 0.003), MYODAM-VAS (r = 0.44, P = 0.002), and global damage assessment (r = 0.43, P = 0.003). No association was found between the restrictive pulmonary function test and autoantibodies. CONCLUSION: In a long-term follow-up study of JDM patients, the majority of patients demonstrated normal lung function. However, restrictive pulmonary impairment was identified in 8% of patients, indicating a need for repetitive pulmonary follow-up in JDM patients. Restrictive pulmonary involvement was associated with increased long-term JDM damage.

Silymarin alleviates bleomycin-induced pulmonary toxicity and lipid peroxidation in mice.

CONTEXT: The application of bleomycin is limited due to its side effects including lung toxicity. Silymarin is a flavonoid complex isolated from milk thistle [Silybum marianum L. (Asteraceae)] which has been identified as an antioxidant and anti-inflammatory compound. OBJECTIVE: This study evaluates the effect of silymarin on oxidative and inflammatory parameters in the lungs of mice exposed to bleomycin. MATERIALS AND METHODS: BALB/c mice were divided into four groups of control, bleomycin (1.5 U/kg), bleomycin plus silymarin (50 and 100 mg/kg). After bleomycin administration, mice received 10 d intraperitoneal silymarin treatment. On 10th day, blood and lung samples were collected for measurement of oxidative and inflammatory factors. RESULTS: Silymarin led to a decrease in lung lipid peroxidation (0.19 and 0.17 nmol/mg protein) in bleomycin-injected animals. Glutathione-S-transferase (GST) which was inhibited by bleomycin (32.4 nmol/min/mg protein) induced by higher dose of silymarin (41 nmol/min/mg protein). Silymarin caused an elevation in glutathione (GSH): 2.6 and 3.1 µmol/g lung compare with bleomycin-injected animals 1.8 µmol/g lung. Catalase (CAT) was increased due to high dose of silymarin (65.7 µmol/min/ml protein) compare with bleomycin treated-mice. Myeloperoxidase (MPO) which was induced due to bleomycin (p < 0.05) reduced again by high dose of silymarin (0.51 U/min/mg protein). Bleomycin led to an increase in TNF-α and interleukin-6 (IL-6) (7.9 and 11.8 pg/ml). These parameters were reduced by silymarin (p < 0.05). CONCLUSIONS: Silymarin attenuated bleomycin induced-pulmonary toxicity. This protective effect may be due to the ability of silymarin in keeping oxidant-antioxidant balance and regulating of inflammatory mediator release.

Melatonin as a radioprotective agent against flattening filter and flattening filter-free beam in radiotherapy-induced lung tissue damage.

BACKGROUND: Radiotherapy is a widely used treatment method in oncology, applied by delivering high-energy particles or waves to the tumor tissue. Although tumor cells are targeted with radiotherapy, it can cause acute or long-term damage to healthy tissues. Therefore, the preservation of healthy tissues has been an important subject of various scientific researches. Melatonin has been shown to have a radioprotective effect on many tissues and organs such as liver, parotid gland, brain, and testicles. This study aimed to evaluate the protective effect of melatonin against the radiation at various doses and rates administered to the lung tissue of healthy mice. METHODS: This study was a randomized case-control study conducted with 80 rats comprising 10 groups with eight animals per group. Of the 10 groups, first is the control group, which is not given any melatonin, and second is the group that does not receive RT, which is given only melatonin, and the other eight groups are RT groups, four with melatonin and four without melatonin. RESULTS: There was no statistical difference in terms of histopathological findings in the lung tissue between the second group, which did not receive radiotherapy and received only melatonin, and the control group. Lung damage due to radiotherapy was statistically significantly higher in the groups that did not receive melatonin compared to the groups that received melatonin. CONCLUSIONS: This study revealed that melatonin has a protective effect against the cytotoxic damage of RT in rats receiving RT.

Veno-venous extracorporeal membrane oxygenation for perioperative management of infective endocarditis after COVID-19 with acute respiratory distress syndrome: a case report.

BACKGROUND: Infective endocarditis (IE) is a rare cardiovascular complication in patients with coronavirus disease 2019 (COVID-19). IE after COVID-19 can also be complicated by acute respiratory distress syndrome (ARDS); however, the guidelines for the treatment of such cases are not clear. Here, we report a case of perioperative management of post-COVID-19 IE with ARDS using veno-venous extracorporeal membrane oxygenation (V-V ECMO). CASE PRESENTATION: The patient was a 40-year-old woman who was admitted on day 18 of COVID-19 onset and was administered oxygen therapy, remdesivir, and dexamethasone. The patient's condition improved; however, on day 24 of hospitalization, the patient developed hypoxemia and was admitted to the intensive care unit (ICU) due to respiratory failure. Blood culture revealed Corynebacterium striatum, and transesophageal echocardiography revealed vegetation on the aortic and mitral valves. Valve destruction was mild, and the cause of respiratory failure was thought to be ARDS. Despite continued antimicrobial therapy, ARDS did not improve the patient's condition, and valve destruction progressed; therefore, surgical treatment was scheduled on day 13 of ICU admission. After preoperative consultation with the team, a decision was made to initiate V-V ECMO after the patient was weaned from CPB, with concerns about further worsening of her respiratory status after surgery. The patient returned to the ICU with transition to V-V ECMO, and her circulation remained stable. The patient was weaned off V-V ECMO on postoperative day 33 and discharged from the ICU on postoperative day 47. CONCLUSIONS: ARDS may occur in patients with IE after COVID-19. Owing to concerns about further exacerbation of pulmonary damage, the timing of surgery should be comprehensively considered. Preoperatively, clinicians should discuss perioperative ECMO introduction and configuration.

Undercover lung damage in pediatrics - a hot spot in morbidity caused by collagenoses.

Connective tissue represents the support matrix and the connection between tissues and organs. In its composition, collagen, the major structural protein, is the main component of the skin, bones, tendons and ligaments. Especially at the pediatric age, its damage in the context of pathologies such as systemic lupus erythematosus, scleroderma or dermatomyositis can have a significant negative impact on the development and optimal functioning of the body. The consequences can extend to various structures (e.g., joints, skin, eyes, lungs, heart, kidneys). Of these, we retain and reveal later in our manuscript, mainly the respiratory involvement. Manifested in various forms that can damage the chest wall, pleura, interstitium or vascularization, lung damage in pediatric systemic inflammatory diseases is underdeveloped in the literature compared to that described in adults. Under the threat of severe evolution, sometimes rapidly progressive and leading to death, it is necessary to increase the popularization of information aimed at physiopathological triggering and maintenance mechanisms, diagnostic means, and therapeutic directions among medical specialists. In addition, we emphasize the need for interdisciplinary collaboration, especially between pediatricians, rheumatologists, infectious disease specialists, pulmonologists, and immunologists. Through our narrative review we aimed to bring up to date, in a concise and easy to assimilate, general principles regarding the pulmonary impact of collagenoses using the most recent articles published in international libraries, duplicated by previous articles, of reference for the targeted pathologies.

Platelet activation and ferroptosis mediated NETosis drives heme induced pulmonary thrombosis.

Cell-free heme (CFH) is a product of hemoglobin, myoglobin and hemoprotein degradation, which is a hallmark of pathologies associated with extensive hemolysis and tissue damage. CHF and iron collectively induce cytokine storm, lung injury, respiratory distress and infection susceptibility in the lungs suggesting their key role in the progression of lung disease pathology. We have previously demonstrated that heme-mediated reactive oxygen species (ROS) induces platelet activation and ferroptosis. However, interaction of ferroptotic platelets and neutrophils, the mechanism of action and associated complications remain unclear. In this study, we demonstrate that heme-induced P-selectin expression and Phosphatidylserine (PS) externalization in platelets via ASK-1-inflammasome axis increases platelet-neutrophil aggregates in circulation, resulting in Neutrophil extracellular traps (NET) formation in vitro and in vivo. Further, heme-induced platelet activation in mice increased platelet-neutrophil aggregates and accumulation of NETs in the lungs causing pulmonary damage. Thus, connecting CFH-mediated platelet activation to NETosis and pulmonary thrombosis. As lung infections induce acute respiratory stress, thrombosis and NETosis, we propose that heme -mediated platelet activation and ferroptosis might be crucial in such clinical manifestations. Further, considering the ability of redox modulators and ferroptosis inhibitors like FS-1, Lpx-1 and DFO to inhibit heme-induced ferroptotic platelets-mediated NETosis and pulmonary thrombosis. They could be potential adjuvant therapy to regulate respiratory distress-associated clinical complications.

Overlapping Science in Radiation and Sulfur Mustard Exposures of Skin and Lung: Consideration of Models, Mechanisms, Organ Systems, and Medical Countermeasures: Overlapping science in radiation and sulfur mustard injuries to lung and skin.

PURPOSE: To summarize presentations and discussions from the 2022 trans-agency workshop titled "Overlapping science in radiation and sulfur mustard (SM) exposures of skin and lung: Consideration of models, mechanisms, organ systems, and medical countermeasures." METHODS: Summary on topics includes: (1) an overview of the radiation and chemical countermeasure development programs and missions; (2) regulatory and industry perspectives for drugs and devices; 3) pathophysiology of skin and lung following radiation or SM exposure; 4) mechanisms of action/targets, biomarkers of injury; and 5) animal models that simulate anticipated clinical responses. RESULTS: There are striking similarities between injuries caused by radiation and SM exposures. Primary outcomes from both types of exposure include acute injuries, while late complications comprise chronic inflammation, oxidative stress, and vascular dysfunction, which can culminate in fibrosis in both skin and lung organ systems. This workshop brought together academic and industrial researchers, medical practitioners, US Government program officials, and regulators to discuss lung-, and skin- specific animal models and biomarkers, novel pathways of injury and recovery, and paths to licensure for products to address radiation or SM injuries. CONCLUSIONS: Regular communications between the radiological and chemical injury research communities can enhance the state-of-the-science, provide a unique perspective on novel therapeutic strategies, and improve overall US Government emergency preparedness.

Role of CT in the detection and management of cancer related complications: a study of 599 patients.

Purpose: Cancer-related complications (CrC) and any potentially life-threatening findings detected on routine oncological imaging requires urgent intervention and needs proactive management. We conducted a retrospective study to highlight the role of imaging in the detection of CrC on computed tomography (CT)-scan while sharing our experience at a tertiary care cancer hospital. Materials and methods: All the reports of the CT scans performed in our department between January 2018 and December 2019 were reviewed and the imaging findings of CrC were recorded. Only the patients who had known malignancy and underwent imaging evaluation at our centre at baseline/follow up/surveillance were included. The clinical details of the patients were recorded and the findings were classified based on the system or organ involved and also on the basis of its impact on clinical management. Results: A total of 14,226 CT scans were performed during the study period, out of which 599 patients had CrC. Most of the CrC were seen involving thorax (265/599, 44.3%) followed by abdomen (229/599, 38.2%) and head and neck (104/599, 17.3%) regions. The commonly encountered CrC were pulmonary infections, superior vena cava obstruction and drug-induced lung changes. Conclusion: CrC have significant impact on the course of management of cancer patients and radiologist plays an important role in early diagnosis and initiation of prompt management of many such patients. CT is an excellent modality for early diagnosis of CrC which guides the oncologist for appropriate treatment.

Incidence and Predictors of Cardiac Arrhythmias in Patients With COVID-19.

Background: Coronavirus disease 2019 (COVID-19) is a systemic disease caused by severe acute respiratory syndrome coronavirus 2. Arrhythmias are frequently associated with COVID-19 and could be the result of inflammation or hypoxia. This study aimed to define the incidence of arrhythmias in patients with COVID-19 and to correlate arrhythmias with pulmonary damage assessed by computed tomography (CT). Methods: All consecutive patients with a COVID-19 diagnosis hospitalized at Universitair Ziekenhuis Brussel, Belgium, between March 2020 and May 2020, were screened. All included patients underwent a thorax CT scan and a CT severity score, a semiquantitative scoring system of pulmonary damage, was calculated. The primary endpoint was the arrhythmia occurrence during follow-up. Results: In this study, 100 patients were prospectively included. At a mean follow-up of 19.6 months, 25 patients with COVID-19 (25%) experienced 26 arrhythmic episodes, including atrial fibrillation in 17 patients, inappropriate sinus tachycardia in 7 patients, atrial flutter in 1 patient, and third-degree atrioventricular block in 1 patient. No ventricular arrhythmias were documented. Patients with COVID-19 with arrhythmias showed more often need for oxygen, higher oxygen maximum flow, longer QTc at admission, and worse damage at CT severity score. In univariate logistic regression analysis, significant predictors of the primary endpoint were: the need for oxygen therapy (odds ratio [OR] 4.59, 95% CI 1.44-14.67, p = 0.01) and CT severity score of pulmonary damage (OR per 1 point increase 1.25, 95% CI 1.11-1.4, p < 0.001). Conclusions: In a consecutive cohort of patients with COVID-19 the incidence of cardiac arrhythmias was 25%. The need for oxygen therapy and CT severity score were predictors of arrhythmia occurrence during follow-up.

Defective biosynthesis of ascorbic acid in Sod1-deficient mice results in lethal damage to lung tissue.

Superoxide dismutase 1 (Sod1) plays pivotal roles in antioxidation via accelerating the conversion of superoxide anion radicals into hydrogen peroxide, thus inhibiting the subsequent radical chain reactions. While Sod1 deficient cells inevitably undergo death in culture conditions, Sod1-knockout (KO) mice show relatively mild phenotypes and live approximately two years. We hypothesized that the presence of abundant levels of ascorbic acid (AsA), which is naturally produced in mice, contributes to the elimination of reactive oxygen species (ROS) in Sod1-KO mice. To verify this hypothesis, we employed mice with a genetic ablation of aldehyde reductase (Akr1a), an enzyme that is involved in the biosynthesis of AsA, and established double knockout (DKO) mice that lack both Sod1 and Akr1a. Supplementation of AsA (1.5 mg/ml in drinking water) was required for the DKO mice to breed, and, upon terminating the AsA supplementation, they died within approximately two weeks regardless of age or gender. We explored the etiology of the death from pathophysiological standpoints in principal organs of the mice. Marked changes were observed in the lungs in the form of macroscopic damage after the AsA withdrawal. Histological and immunological analyses of the lungs indicated oxidative damage of tissue and activated immune responses. Thus, preferential oxidative injury that occurred in pulmonary tissues appeared to be primary cause of the death in the mice. These collective results suggest that the pivotal function of AsA in coping with ROS in vivo, is largely in pulmonary tissues that are exposed to a hyperoxygenic microenvironment.

Nucleotide-Oligomerizing Domain-1 Activation Exaggerates Cigarette Smoke-Induced Chronic Obstructive Pulmonary-Like Disease in Mice.

INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is a progressive condition related to abnormal inflammatory responses. As an inflammatory driver, nucleotide-binding oligomerizing domain-1 (NOD1) is highly expressed in pulmonary inflammatory cells; however, the roles of NOD1 in COPD are unknown. METHODS: A COPD mouse model was established by lipopolysaccharides tracheal instillation plus cigarette smoke (CS) exposure. NOD1 activation was induced by C12-iE-DAP (iE) treatment in both control and COPD mice. Inflammatory infiltration, pulmonary histological damage and gene expression were measured to evaluate the lung function of treated mice. RESULTS: The results showed that NOD1 was up-regulated in COPD mice, which significantly exaggerated CS-induced impairment of lung function, demonstrated by increased airway resistance, functional residual capacity and pulmonary damages. Mechanistically, NOD1 activation strongly activated the TLR4/NF-κB signaling pathway and then increased inflammatory responses and promoted the secretion of inflammatory cytokines. DISCUSSION: This study demonstrates that NOD1 is an important risk factor in the progression of COPD; therefore, targeting NOD1 in lung tissues is a potential strategy for COPD treatment.