Detoxified synthetic bacterial membrane vesicles as a vaccine platform against bacteria and SARS-CoV-2.

The development of vaccines based on outer membrane vesicles (OMV) that naturally bud off from bacteria is an evolving field in infectious diseases. However, the inherent inflammatory nature of OMV limits their use as human vaccines. This study employed an engineered vesicle technology to develop synthetic bacterial vesicles (SyBV) that activate the immune system without the severe immunotoxicity of OMV. SyBV were generated from bacterial membranes through treatment with detergent and ionic stress. SyBV induced less inflammatory responses in macrophages and in mice compared to natural OMV. Immunization with SyBV or OMV induced comparable antigen-specific adaptive immunity. Specifically, immunization with Pseudomonas aeruginosa-derived SyBV protected mice against bacterial challenge, and this was accompanied by significant reduction in lung cell infiltration and inflammatory cytokines. Further, immunization with Escherichia coli-derived SyBV protected mice against E. coli sepsis, comparable to OMV-immunized group. The protective activity of SyBV was driven by the stimulation of B-cell and T-cell immunity. Also, SyBV were engineered to display the SARS-CoV-2 S1 protein on their surface, and these vesicles induced specific S1 protein antibody and T-cell responses. Collectively, these results demonstrate that SyBV may be a safe and efficient vaccine platform for the prevention of bacterial and viral infections.

Efficacy of Fuzheng Huayu Tablets for Treating Pulmonary Inflammation in COVID-19 Patients.

Objective:To observe the efficacy and safety of Fuzheng Huayu tabletsFHTfor treating pulmonary inflammation in patients with coronavirus disease 2019COVID-19. Method(s):A total of 704 cases were lost to follow-up, and 66 cases were finally completedCOVID-19 patients were recruited from February 1 to April 15 in 2020. They were assigned to a control group35 patientsand a FHT group31 patients. The patients in the control group received routine treatment alone and those in the FHT group received FHT in addition to routine treatment. The primary outcome was the ratio of patients showing improvement in chest computed tomographic manifestations after 14 days. The secondary outcome measures included remission rate or progression rate of critical illness,clinical remission rate of respiratory symptoms,routine blood examination, C-reactive proteinCPRlevel,procalcitoninPCTlevel,and blood oxygen saturationSPO2 . The safety was assessed based on liver and kidney functions and adverse events. Result(s): After the 14-day treatment,the ratio of patients showing improvement in the FHT group100%was higher than that in the control group 77.1%chi2 =8.063,P<0.01. The ratio of disease stages after treatment showed no significant difference between two groups. In the FHT group,the symptoms including cough,dyspnea,and fatigue were alleviated after treatmentP<0.01. In the control group,the symptoms including fever,cough,and dyspnea were alleviatedP<0.01,while the fatigue was not relieved after treatment. No significant difference was observed in the clinical symptoms between the two groups after treatment. After treatment,the FHT group showed decreased white blood cellWBCcount and neutrophil-to-lymphocyte ratioNLRP<0.01,elevated plateletPLTlevelP<0.05,lowered CRP levelP<0.05,and no significant difference in lymphocyte LYM,hemoglobinHb,SPO2 or PCT level. The control group showed decreased NLRP<0.05and WBC countP<0.01,elevated PCT levelP<0.05,and no significant change in LYM,Hb,PLT,SPO2 or CRP level after treatment. Furthermore,the FHT group had higher PLT level than the control groupP<0.05after treatment,and other indicators had no significant differences between the two groups. The liver and kidney functions had no significant difference between the two groups after treatment. Conclusion(s): FHT can safely promote the absorption of acute pulmonary inflammation in COVID-19 patients.Copyright © 2022, China Academy of Chinese Medical Sciences Institute of Chinese Materia Medica. All rights reserved.

Examination of Taurine Chloramine and Taurine on LPS-Induced Acute Pulmonary Inflammatory in Mice.

The novel coronavirus disease (COVID-19), which is prevalent in the world, develops severe pneumonia, of which 30% have fatal acute respiratory distress and acute lung injury. At present, there is no established treatment method for ARDS, and it is desired to develop a therapeutic drug as soon as possible. While TauCl has been reported to have anti-inflammatory effects on culture cells, little information is available concerning in vivo experiments. In the present study, we evaluated the anti-inflammatory effect of taurine chloramine (TauCl), a taurine derivative, against LPS-induced pneumonia in mouse. The mice were pretreated with TauCl intraperitoneally before intratracheal administration of LPS. Additionally, we evaluated the effect of taurine treatment by maintaining the mice on drinking water containing 0.5% taurine. Two days after LPS injection, body weight was decreased by 9.5 %, while lung weight was increased due to the infiltration of inflammatory cells; TauCl attenuated the gain in lung weight. LPS-induced acute pneumonia caused an increase in cytokine/chemokine mRNA expression, including that of IL-1ß, -6, -17, TNF-α, and MCP-1. However, TauCl treatment attenuated IL-6 expression, but not that of the others although the induction of plasma IL-6 tended to be reduced by TauCl treatment. Importantly, a similar effect against LPS-induced acute lung inflammation was confirmed by taurine pretreatment. These findings suggest that TauCl treatment partially prevents IL-6 production induced by acute pneumonia in vivo.

SARS Unique Domain (SUD) of Severe Acute Respiratory Syndrome Coronavirus Induces NLRP3 Inflammasome-Dependent CXCL10-Mediated Pulmonary Inflammation.

Severe acute respiratory syndrome-associated coronavirus (SARS-CoV) initiates the cytokine/chemokine storm-mediated lung injury. The SARS-CoV unique domain (SUD) with three macrodomains (N, M, and C), showing the G-quadruplex binding activity, was examined the possible role in SARS pathogenesis in this study. The chemokine profile analysis indicated that SARS-CoV SUD significantly up-regulated the expression of CXCL10, CCL5 and interleukin (IL)-1ß in human lung epithelial cells and in the lung tissues of the mice intratracheally instilled with the recombinant plasmids. Among the SUD subdomains, SUD-MC substantially activated AP-1-mediated CXCL10 expression in vitro. In the wild type mice, SARS-CoV SUD-MC triggered the pulmonary infiltration of macrophages and monocytes, inducing CXCL10-mediated inflammatory responses and severe diffuse alveolar damage symptoms. Moreover, SUD-MC actuated NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome-dependent pulmonary inflammation, as confirmed by the NLRP3 inflammasome inhibitor and the NLRP3-/- mouse model. This study demonstrated that SARS-CoV SUD modulated NLRP3 inflammasome-dependent CXCL10-mediated pulmonary inflammation, providing the potential therapeutic targets for developing the antiviral agents.

Platelets at the Crossroads of Pro-Inflammatory and Resolution Pathways during Inflammation.

Platelets are among the most abundant cells in the mammalian circulation. Classical platelet functions in hemostasis and wound healing have been intensively explored and are generally accepted. During the past decades, the research focus broadened towards their participation in immune-modulatory events, including pro-inflammatory and, more recently, inflammatory resolution processes. Platelets are equipped with a variety of abilities enabling active participation in immunological processes. Toll-like receptors mediate the recognition of pathogens, while the release of granule contents and microvesicles promotes direct pathogen defense and an interaction with leukocytes. Platelets communicate and physically interact with neutrophils, monocytes and a subset of lymphocytes via soluble mediators and surface adhesion receptors. This interaction promotes leukocyte recruitment, migration and extravasation, as well as the initiation of effector functions, such as the release of extracellular traps by neutrophils. Platelet-derived prostaglandin E2, C-type lectin-like receptor 2 and transforming growth factor ß modulate inflammatory resolution processes by promoting the synthesis of pro-resolving mediators while reducing pro-inflammatory ones. Furthermore, platelets promote the differentiation of CD4+ T cells in T helper and regulatory T cells, which affects macrophage polarization. These abilities make platelets key players in inflammatory diseases such as pneumonia and the acute respiratory distress syndrome, including the pandemic coronavirus disease 2019. This review focuses on recent findings in platelet-mediated immunity during acute inflammation.

Novel application of [18F]DPA714 for visualizing the pulmonary inflammation process of SARS-CoV-2-infection in rhesus monkeys (Macaca mulatta).

RATIONALE: The aim of this study was to investigate the application of [18F]DPA714 to visualize the inflammation process in the lungs of SARS-CoV-2-infected rhesus monkeys, focusing on the presence of pulmonary lesions, activation of mediastinal lymph nodes and surrounded lung tissue. METHODS: Four experimentally SARS-CoV-2 infected rhesus monkeys were followed for seven weeks post infection (pi) with a weekly PET-CT using [18F]DPA714. Two PET images, 10 min each, of a single field-of-view covering the chest area, were obtained 10 and 30 min after injection. To determine the infection process swabs, blood and bronchoalveolar lavages (BALs) were obtained. RESULTS: All animals were positive for SARS-CoV-2 in both the swabs and BALs on multiple timepoints pi. The initial development of pulmonary lesions was already detected at the first scan, performed 2-days pi. PET revealed an increased tracer uptake in the pulmonary lesions and mediastinal lymph nodes of all animals from the first scan obtained after infection and onwards. However, also an increased uptake was detected in the lung tissue surrounding the lesions, which persisted until day 30 and then subsided by day 37-44 pi. In parallel, a similar pattern of increased expression of activation markers was observed on dendritic cells in blood. PRINCIPAL CONCLUSIONS: This study illustrates that [18F]DPA714 is a valuable radiotracer to visualize SARS-CoV-2-associated pulmonary inflammation, which coincided with activation of dendritic cells in blood. [18F]DPA714 thus has the potential to be of added value as diagnostic tracer for other viral respiratory infections.

Efficacy of Fuzheng Huayu Tablets for Treating Pulmonary Inflammation in COVID-19 Patients

Objective：To observe the efficacy and safety of Fuzheng Huayu tablets（FHT）for treating pulmonary inflammation in patients with coronavirus disease 2019（COVID-19）. Method：A total of 70（4 cases were lost to follow-up, and 66 cases were finally completed）COVID-19 patients were recruited from February 1 to April 15 in 2020. They were assigned to a control group（35 patients）and a FHT group（31 patients）. The patients in the control group received routine treatment alone and those in the FHT group received FHT in addition to routine treatment. The primary outcome was the ratio of patients showing improvement in chest computed tomographic manifestations after 14 days. The secondary outcome measures included remission rate or progression rate of critical illness，clinical remission rate of respiratory symptoms，routine blood examination， C-reactive protein（CPR）level，procalcitonin（PCT）level，and blood oxygen saturation（SPO2 ）. The safety was assessed based on liver and kidney functions and adverse events. Result： After the 14-day treatment，the ratio of patients showing improvement in the FHT group（100%）was higher than that in the control group （77.1%）（χ2 =8.063，P<0.01）. The ratio of disease stages after treatment showed no significant difference between two groups. In the FHT group，the symptoms including cough，dyspnea，and fatigue were alleviated after treatment（P<0.01）. In the control group，the symptoms including fever，cough，and dyspnea were alleviated（P<0.01），while the fatigue was not relieved after treatment. No significant difference was observed in the clinical symptoms between the two groups after treatment. After treatment，the FHT group showed decreased white blood cell（WBC）count and neutrophil-to-lymphocyte ratio（NLR）（P<0.01），elevated platelet（PLT）level（P<0.05），lowered CRP level（P<0.05），and no significant difference in lymphocyte （LYM），hemoglobin（Hb），SPO2 or PCT level. The control group showed decreased NLR（P<0.05）and WBC count（P<0.01），elevated PCT level（P<0.05），and no significant change in LYM，Hb，PLT，SPO2 or CRP level after treatment. Furthermore，the FHT group had higher PLT level than the control group（P<0.05）after treatment，and other indicators had no significant differences between the two groups. The liver and kidney functions had no significant difference between the two groups after treatment. Conclusion： FHT can safely promote the absorption of acute pulmonary inflammation in COVID-19 patients. © 2022, China Academy of Chinese Medical Sciences Institute of Chinese Materia Medica. All rights reserved.

[Prevention by vaccination of adult patients with pulmonary diseases]. / Prävention durch Impfung pneumologisch vorerkrankter Erwachsener: Pneumokokkenpneumonie, Influenza, Pertussis, Herpes Zoster und "coronavirus disease 2019".

The key priority in patients with chronic lung diseases is currently immunization against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); all vaccines approved for this showed high effectiveness against severe infections. For patients with chronic pulmonary diseases the recommendations by the Standing Committee on Vaccination include not only the standard vaccinations in adulthood but also the so-called indication vaccinations. These include vaccinations against pneumococci and influenza. Advances include the recent development of new pneumococcal conjugate vaccines containing additional serotypes and the recommendation of a more effective high-dose vaccine against influenza for persons over 60 years old. With the next scheduled booster vaccination against tetanus and diphtheria a combination vaccine with pertussis antigen should be used. For patients with chronic lung disease the herpes zoster vaccine is recommended over the age of 50 years.

Dihydroartemisinin attenuates pulmonary inflammation and fibrosis in rats by suppressing JAK2/STAT3 signaling.

Coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, has induced a worldwide pandemic since early 2020. COVID-19 causes pulmonary inflammation, secondary pulmonary fibrosis (PF); however, there are still no effective treatments for PF. The present study aimed to explore the inhibitory effect of dihydroartemisinin (DHA) on pulmonary inflammation and PF, and its molecular mechanism. Morphological changes and collagen deposition were analyzed using hematoxylin-eosin staining, Masson staining, and the hydroxyproline content. DHA attenuated early alveolar inflammation and later PF in a bleomycin-induced rat PF model, and inhibited the expression of interleukin (IL)-1ß, IL-6, tumor necrosis factor α (TNFα), and chemokine (C-C Motif) Ligand 3 (CCL3) in model rat serum. Further molecular analysis revealed that both pulmonary inflammation and PF were associated with increased transforming growth factor-ß1 (TGF-ß1), Janus activated kinase 2 (JAK2), and signal transducer and activator 3(STAT3) expression in the lung tissues of model rats. DHA reduced the inflammatory response and PF in the lungs by suppressing TGF-ß1, JAK2, phosphorylated (p)-JAK2, STAT3, and p-STAT3. Thus, DHA exerts therapeutic effects against bleomycin-induced pulmonary inflammation and PF by inhibiting JAK2-STAT3 activation. DHA inhibits alveolar inflammation, and attenuates lung injury and fibrosis, possibly representing a therapeutic candidate to treat PF associated with COVID-19.

Alveolar macrophages: novel therapeutic targets for respiratory diseases.

Alveolar macrophages (AMs) are lung-resident myeloid cells that sit at the interface of the airway and lung tissue. Under homeostatic conditions, their primary function is to clear debris, dead cells and excess surfactant from the airways. They also serve as innate pulmonary sentinels for respiratory pathogens and environmental airborne particles and as regulators of pulmonary inflammation. However, they have not typically been viewed as primary therapeutic targets for respiratory diseases. Here, we discuss the role of AMs in various lung diseases, explore the potential therapeutic strategies to target these innate cells and weigh the potential risks and challenges of such therapies. Additionally, in the context of the COVID-19 pandemic, we examine the role AMs play in severe disease and the therapeutic strategies that have been harnessed to modulate their function and protect against severe lung damage. There are many novel approaches in development to target AMs, such as inhaled antibiotics, liposomal and microparticle delivery systems, and host-directed therapies, which have the potential to provide critical treatment to patients suffering from severe respiratory diseases, yet there is still much work to be done to fully understand the possible benefits and risks of such approaches.

Effect of dihydromyricetin on SARS-CoV-2 viral replication and pulmonary inflammation and fibrosis.

BACKGROUND: COVID-19 (Coronavirus Disease-2019) has spread widely around the world and impacted human health for millions. The lack of effective targeted drugs and vaccines forces scientific world to search for new effective antiviral therapeutic drugs. It has reported that flavonoids have potential inhibitory activity on SARS-CoV-2 Mpro and anti-inflammatory properties. Dihydromyricetin, as a flavonol, also has antiviral and anti-inflammatory potential. However, the inhibition of dihydromyricetin on SARS-CoV-2 Mpro and the protective effect of dihydromyricetin on pulmonary inflammation and fibrosis have not been proved and explained. PURPOSE: The coronavirus main protease (Mpro) is essential for SARS-CoV-2 replication and to be recognized as an attractive drug target, we expect to find the inhibitor of Mpro. Novel coronavirus infection can cause severe inflammation and even sequelae of pulmonary fibrosis in critically ill patients. We hope to find a drug that can not only inhibit virus replication but also alleviate inflammation and pulmonary fibrosis in patients. METHODS: FRET-based enzymatic assay was used to evaluate the inhibit activity of dihydromyricetin on SARS-CoV-2 Mpro. Molecular docking was used to identify the binding pose of dihydromyricetin with SARS-CoV-2 Mpro. The protective effects of dihydromyricetin against BLM-induced pulmonary inflammation and fibrosis were investigated in C57BL6 mice. BALF and lung tissue were collected for inflammation cells count, ELISA, masson and HE staining, western blotting and immunohistochemistry to analyze the effects of dihydromyricetin on pulmonary inflammation and fibrosis. MTT, western blotting, reverse transcription-polymerase chain reaction (RT-PCR) and wound healing were used to analyze the effects of dihydromyricetin on lung fibrosis mechanisms in Mlg cells. RESULTS: In this study, we found that dihydromyricetin is a potent inhibitor targeting the SARS-CoV-2 Mpro with a half-maximum inhibitory concentration (IC50) of 1.716 ± 0.419 µM, using molecular docking and the FRET-based enzymatic assay. The binding pose of dihydromyricetin with SARS-CoV-2 Mpro was identified using molecular docking method. In the binding pocket of SARS-CoV-2 Mpro, the dihydrochromone ring of dihydromyricetin interact with the imidazole side chain of His163 through π-π stacking. The 1-oxygen of dihydromyricetin forms a hydrogen bond with the backbone nitrogen of Glu166. The 3-, 7-, 3'- and 4'-hydroxyl of dihydromyricetin interact with Gln189, Leu141, Arg188 and Thr190 through hydrogen bonds. Moreover, our results showed that dihydromyricetin can significantly alleviate BLM-induced pulmonary inflammation by inhibiting the infiltration of inflammation cells and the secretion of inflammation factors in the early process and also ameliorate pulmonary fibrosis by improving pulmonary function and down-regulate the expression of α-SMA and fibronectin in vivo. Our results also showed that dihydromyricetin inhibits the migration and activation of myofibroblasts and extracellular matrix production via transforming growth factor (TGF)-ß1/Smad signaling pathways. CONCLUSION: Dihydromyricetin is an effective inhibitor for SARS-CoV-2 Mpro and it prevents BLM-induced pulmonary inflammation and fibrosis in mice. Dihydromyricetin will be a potential medicine for the treatment of COVID-19 and its sequelae.

Heteromeric TRP Channels in Lung Inflammation.

Activation of Transient Receptor Potential (TRP) channels can disrupt endothelial barrier function, as their mediated Ca2+ influx activates the CaM (calmodulin)/MLCK (myosin light chain kinase)-signaling pathway, and thereby rearranges the cytoskeleton, increases endothelial permeability and thus can facilitate activation of inflammatory cells and formation of pulmonary edema. Interestingly, TRP channel subunits can build heterotetramers, whereas heteromeric TRPC1/4, TRPC3/6 and TRPV1/4 are expressed in the lung endothelium and could be targeted as a protective strategy to reduce endothelial permeability in pulmonary inflammation. An update on TRP heteromers and their role in lung inflammation will be provided with this review.

Bracing NK cell based therapy to relegate pulmonary inflammation in COVID-19.

The contagiosity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has startled mankind and has brought our lives to a standstill. The treatment focused mainly on repurposed immunomodulatory and antiviral agents along with the availability of a few vaccines for prophylaxis to vanquish COVID-19. This seemingly mandates a deeper understanding of the disease pathogenesis. This necessitates a plausible extrapolation of cell-based therapy to COVID-19 and is regarded equivalently significant. Recently, correlative pieces of clinical evidence reported a robust decline in lymphocyte count in severe COVID-19 patients that suggest dysregulated immune responses as a key element contributing to the pathophysiological alterations. The large granular lymphocytes also known as natural killer (NK) cells play a heterogeneous role in biological functioning wherein their frontline action defends the body against a wide array of infections and tumors. They prominently play a critical role in viral clearance and executing immuno-modulatory activities. Accumulated clinical evidence demonstrate a decrease in the number of NK cells in circulation with or without phenotypical exhaustion. These plausibly contribute to the progression of pulmonary inflammation in COVID-19 pneumonia and result in acute lung injury. In this review, we have outlined the present understanding of the immunological response of NK cells in COVID-19 infection. We have also discussed the possible use of these powerful biological cells as a therapeutic agent in view of preventing immunological harms of SARS-CoV-2 and the current challenges in advocating NK cell therapy for the same.

Protective role of cortistatin in pulmonary inflammation and fibrosis.

BACKGROUND AND PURPOSE: Acute lung injury (ALI), acute respiratory distress syndrome (ARDS) and pulmonary fibrosis remain major causes of morbidity, mortality and a healthcare burden in critically ill patient. There is an urgent need to identify factors causing susceptibility and for the design of new therapeutic agents. Here, we evaluate the effectiveness of the immunomodulatory neuropeptide cortistatin to regulate pulmonary inflammation and fibrosis in vivo. EXPERIMENTAL APPROACH: ALI/ARDS and pulmonary fibrosis were induced experimentally in wild-type and cortistatin-deficient mice by pulmonary infusion of the bacterial endotoxin LPS or the chemotherapeutic drug bleomycin, and the histopathological signs, pulmonary leukocyte infiltration and cytokines, and fibrotic markers were evaluated. KEY RESULTS: Partially deficient mice in cortistatin showed exacerbated pulmonary damage, pulmonary inflammation, alveolar oedema and fibrosis, and subsequent increased respiratory failure and mortality when challenged to LPS or bleomycin, even at low doses. Treatment with cortistatin reversed these aggravated phenotypes and protected from progression to severe ARDS and fibrosis, after high exposure to both injury agents. Moreover, cortistatin-deficient pulmonary macrophages and fibroblasts showed exaggerated ex vivo inflammatory and fibrotic responses, and treatment with cortistatin impaired their activation. Finally, the protective effects of cortistatin in ALI and pulmonary fibrosis were partially inhibited by specific antagonists for somatostatin and ghrelin receptors. CONCLUSION AND IMPLICATIONS: We identified cortistatin as an endogenous inhibitor of pulmonary inflammation and fibrosis. Deficiency in cortistatin could be a marker of poor prognosis in inflammatory/fibrotic pulmonary disorders. Cortistatin-based therapies could emerge as attractive candidates to treat severe ALI/ARDS, including SARS-CoV-2-associated ARDS.

Myricetin Inhibits SARS-CoV-2 Viral Replication by Targeting Mpro and Ameliorates Pulmonary Inflammation.

The coronavirus disease 2019 (COVID-19) has spread widely around the world and has seriously affected the human health of tens of millions of people. In view of lacking anti-virus drugs target to SARS-CoV-2, there is an urgent need to develop effective new drugs. In this study, we reported our discovery of SARS-CoV-2 Mpro inhibitors. We selected 15 natural compounds, including 7 flavonoids, 3 coumarins, 2 terpenoids, one henolic, one aldehyde and one steroid compound for molecular docking and enzymatic screening. Myricetin were identified to have potent inhibit activity with IC50 3.684 ± 0.076 µM in the enzyme assay. The binding pose of Myricetin with SARS-CoV-2 Mpro was identified using molecular docking method. In the binding pocket of SARS-CoV-2 Mpro, the chromone ring of Myricetin interacts with His41 through π-π stacking, and the 3'-, 4'- and 7-hydroxyl of Myricetin interact with Phe140, Glu166and Asp187 through hydrogen bonds. Significantly, our results showed that Myricetin has potent effect on bleomycin-induced pulmonary inflammation by inhibiting the infiltration of inflammatory cells and the secretion of inflammatory cytokines IL-6, IL-1α, TNF-α and IFN-γ. Overall, Myricetin may be a potential drug for anti-virus and symptomatic treatment of COVID-19.

Advances in mesenchymal stem cell therapy for immune and inflammatory diseases: Use of cell-free products and human pluripotent stem cell-derived mesenchymal stem cells.

Mesenchymal stem cell therapy (MSCT) for immune and inflammatory diseases continues to be popular based on progressive accumulation of preclinical mechanistic evidence. This has led to further expansion in clinical indications from graft rejection, autoimmune diseases, and osteoarthritis, to inflammatory liver and pulmonary diseases including COVID-19. A clear trend is the shift from using autologous to allogeneic MSCs, which can be immediately available as off-the-shelf products. In addition, new products such as cell-free exosomes and human pluripotent stem cell (hPSC)-derived MSCs are exciting developments to further prevalent use. Increasing numbers of trials have now published results in which safety of MSCT has been largely demonstrated. While reports of therapeutic endpoints are still emerging, efficacy can be seen for specific indications-including graft-vs-host-disease, strongly Th17-mediated autoimmune diseases, and osteoarthritis-which are more robustly supported by mechanistic preclinical evidence. In this review, we update and discuss outcomes in current MSCT clinical trials for immune and inflammatory disease, as well as new innovation and emerging trends in the field.

Uncoupling of macrophage inflammation from self-renewal modulates host recovery from respiratory viral infection.

Tissue macrophages self-renew during homeostasis and produce inflammatory mediators upon microbial infection. We examined the relationship between proliferative and inflammatory properties of tissue macrophages by defining the impact of the Wnt/ß-catenin pathway, a central regulator of self-renewal, in alveolar macrophages (AMs). Activation of ß-catenin by Wnt ligand inhibited AM proliferation and stemness, but promoted inflammatory activity. In a murine influenza viral pneumonia model, ß-catenin-mediated AM inflammatory activity promoted acute host morbidity; in contrast, AM proliferation enabled repopulation of reparative AMs and tissue recovery following viral clearance. Mechanistically, Wnt treatment promoted ß-catenin-HIF-1α interaction and glycolysis-dependent inflammation while suppressing mitochondrial metabolism and thereby, AM proliferation. Differential HIF-1α activities distinguished proliferative and inflammatory AMs in vivo. This ß-catenin-HIF-1α axis was conserved in human AMs and enhanced HIF-1α expression associated with macrophage inflammation in COVID-19 patients. Thus, inflammatory and reparative activities of lung macrophages are regulated by ß-catenin-HIF-1α signaling, with implications for the treatment of severe respiratory diseases.

COVID-19: Integrating the Complexity of Systemic and Pulmonary Immunopathology to Identify Biomarkers for Different Outcomes.

In the last few months, the coronavirus disease 2019 (COVID-19) pandemic has affected millions of people worldwide and has provoked an exceptional effort from the scientific community to understand the disease. Clinical evidence suggests that severe COVID-19 is associated with both dysregulation of damage tolerance caused by pulmonary immunopathology and high viral load. In this review article, we describe and discuss clinical studies that show advances in the understanding of mild and severe illness and we highlight major points that are critical for improving the comprehension of different clinical outcomes. The understanding of pulmonary immunopathology will contribute to the identification of biomarkers in an attempt to classify mild, moderate, severe and critical COVID-19 illness. The interface of pulmonary immunopathology and the identification of biomarkers are critical for the development of new therapeutic strategies aimed to reduce the systemic and pulmonary hyperinflammation in severe COVID-19.

[Aging of the lungs and immune system as hellmark in the pathogenesis of idiopathic pulmonary fibrosis and COVID-19]. / Alterung von Lunge und Immunsystem als Meilensteine in der Pathogenese von idiopathischer Lungenfibrose und COVID-19.

Idiopathic pulmonary fibrosis (IPF) does not occur in younger persons. Therefore, it is not surprising that the nine hallmarks of biological aging can all be found in the pathomechanism of IPF. In this respect the homeostasis of cellular protein synthesis, degradation and recycling becomes unbalanced, which causes a dysregulation of repair mechanisms in the case of lung damage. Severve acute respiratory syndrome coronarvius type 2 (SARS-CoV-2) infections may also predominantyl seen in aged persons. In this situation cellular aging of the lungs also plays a role but additionally, the aging of the immune system is also of great importance. Immunosenescence is associated with a loss of naïve T­cells. Moreover, there are gender-specific differences with a loss of B­cells only in men but not in women, which partly explains the more severe course of COVID-19 pneumonia in older men.

[COVID-19 infection-update]. / COVID-19-Infektion ­ Update: Was muss der Gefäßmediziner wissen?

At the end of December 2019 many cases of severe pulmonary inflammation were reported in Hubei Province, China. Nearly all of the affected individuals had had contact to the wet fish market, which was believed to be the source of the novel infection and was closed on 1 January 2020. Subsequently, the Chinese health authorities confirmed that the pathogen was a previously unknown severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which belongs to the Coronaviridae family. The disease was then designated as coronavirus disease 2019 (COVID-19) and rapidly spread initially in Asia and later worldwide. In March 2020 the COVID-19 outbreak was declared a global pandemic by the World Health Organization. At the time of manuscript submission, more than 20 million people were affected by COVID-19, with more than 500,000 deaths worldwide. The article gives a general overview on the novel COVID-19 with a specific clinical focus on vascular involvement. The article is essentially based on the currently available evidence and the experiences of the authors.