Acute Cytokine Research Articles

Acute respiratory distress syndrome caused by carbon monoxide poisoning and inhalation injury recovered after extracorporeal membrane oxygenation along with direct hemoperfusion with polymyxin B-immobilized fiber column: a case report

BackgroundInhalation injury from smoke or chemical products and carbon monoxide poisoning are major causes of death in burn patients from fire accidents. Respiratory tract injuries from inhalation injury and carbon monoxide poisoning can lead to acute respiratory distress syndrome and cytokine storm syndrome. In the case of acute respiratory failure needing mechanical ventilation accompanied by cytokine storm, mortality is high and immediate adequate treatment at the emergency department is very important.Case presentationThis report describes a case of acute respiratory distress syndrome and cytokine storm followed by carbon monoxide poisoning in a 34-year-old Korean male patient who was in a house fire, and was successfully treated by extracorporeal membrane oxygenation and direct hemoperfusion with polymyxin B-immobilized fiber column at emergency department.ConclusionsTo prevent mortality in acute respiratory distress syndrome with cytokine storm from inhalation injury and to promote a better prognosis, we suggest that early implication of extracorporeal membranous oxygenation along with direct hemoperfusion with polymyxin B-immobilized fiber column even at the emergency department should be considered.

Dose-Dependent Association of Inflammatory Cytokines with Carotid Atherosclerosis in Transient Ischaemic Attack: Implications for Clinical Trials

Introduction: The 5-year recurrence risk after ischaemic stroke and transient ischaemic attack (TIA) is 25–30%. Although inflammation may be a target for prevention trials, the contribution of plaque inflammation to acute cerebrovascular events remains unclear. We investigated the association of acute inflammatory cytokines and high-sensitivity C-reactive protein (CRP) with recently symptomatic carotid atherosclerosis in a prospective cohort study. Methods: Blood and Imaging markers of TIA BIO-TIA) is a multicentre prospective study of imaging and inflammatory markers in patients with TIA. Exclusion criteria were infection and other co-morbid illnesses associated with inflammation. CRP and serum cytokines (interleukin [IL]-6, IL-1β, IL-8, IL-10, IL-12, interferon-γ [IFN-γ] and tumour necrosis factor-α [TNF-α]) were measured. All patients had carotid imaging. Results: Two hundred and thirty-eight TIA cases and 64 controls (TIA mimics) were included. Forty-nine (20.6%) cases had symptomatic internal carotid artery stenosis. Pro-inflammatory cytokine levels increased in a dose-dependent manner across controls, TIA without carotid stenosis (CS), and TIA with CS (IL-1β, p_trend = 0.03; IL-6, p_trend < 0.0001; IL-8, p_trend = 0.01; interferon (IFN)-γ, p_trend = 0.005; TNF-α, p_trend = 0.003). Results were unchanged when DWI-positive cases were excluded. On multivariable linear regression, only age (p = 0.01) and CS (p = 0.04) independently predicted log-IL-6. On multivariable Cox regression, CRP was the only independent predictor of 90-day stroke recurrence (adjusted hazard ratio per 1-unit increase 1.03 [95% CI: 1.01–1.05], p = 0.003). Conclusion: Symptomatic carotid atherosclerosis was associated with elevated cytokines in TIA patients after controlling for other sources of inflammation. High-sensitivity CRP was associated with recurrent ischaemic stroke at 90 days. These findings implicate acute plaque inflammation in the pathogenesis of cerebral thromboembolism and support a rationale for randomized trials of anti-inflammatory therapy for stroke patients, who were excluded from coronary trials.

Dynamics of the level of calprotectin in patients with rheumatoid arthritis during rituximab biosimilar (Acellbia “Biocad”) therapy

Objective.To study the relationship between the level of calprotectin (CP) and RA activity, the level of acute phase reactants, proinflammatory cytokines, chemokines and growth factors, to assess its dynamics during rituximab (RTM) biosimilar therapy.Material and methods.20 patients with RA were examined. All patients received 2 intravenous infusions of RTM (Acellbia®) at a dose of 600 mg with an interval of 2 weeks against the background of methotrexate therapy. The level of CP in blood serum was measured by ELISA.Results.Before starting DAS28 (5.6 [4.9–6.8]), SDAI (27.17 [23.08–39.9]) and CDAI (26.6 [22.25–37.0]) corresponded to the high disease activity. A decrease in disease activity was noted after 12 and 24 weeks of therapy: the DAS28 value was 4.28 [3.24–4.75] and 4.14 [3.11–4.66], respectively (p&lt;0.05). Before the start of therapy, patients with RA had a higher CP level compared with healthy donors 9.68 (4.5–21.5) and 2.39 (1.52–4.45) μg/ml, respectively (p&lt;0.05). Against the background of RTM therapy, there was a decrease in the CP level 12 weeks after the first infusion of the drug in the group as a whole by 26.5% from the initial level, among patients with moderate/no effect of therapy – by 32.7% from the initial level.Conclusion.The CP level significantly decreases during therapy and can be used to monitor the effectiveness of therapy. The predictive value of this laboratory parameter requires further study.

The Acute Hepatic NF-κB-Mediated Proinflammatory Response to Endotoxemia Is Attenuated in Intrauterine Growth-Restricted Newborn Mice.

Intrauterine growth restriction (IUGR) is a relevant predictor for higher rates of neonatal sepsis worldwide and is associated with an impaired neonatal immunity and lower immune cell counts. During the perinatal period, the liver is a key immunological organ responsible for the nuclear factor kappa B (NF-κB)-mediated innate immune response to inflammatory stimuli, but whether this role is affected by IUGR is unknown. Herein, we hypothesized that the newborn liver adapts to calorie-restriction IUGR by inducing changes in the NF-κB signaling transcriptome, leading to an attenuated acute proinflammatory response to intraperitoneal lipopolysaccharide (LPS). We first assessed the hepatic gene expression of key NF-κB factors in the IUGR and normally grown (NG) newborn mice. Real-time quantitative PCR (RT-qPCR) analysis revealed an upregulation of both IκB proteins genes (Nfkbia and Nfkbib) and the NF-κB subunit Nfkb1 in IUGR vs. NG. We next measured the LPS-induced hepatic expression of acute proinflammatory genes (Ccl3, Cxcl1, Il1b, Il6, and Tnf) and observed that the IUGR liver produced an attenuated acute proinflammatory cytokine gene response (Il1b and Tnf) to LPS in IUGR vs. unexposed (CTR). Consistent with these results, LPS-exposed hepatic tumor necrosis factor alpha (TNF-α) protein concentrations were lower in IUGR vs. LPS-exposed NG and did not differ from IUGR CTR. Sex differences at the transcriptome level were observed in the IUGR male vs. female. Our results demonstrate that IUGR induces key modifications in the NF-κB transcriptomic machinery in the newborn that compromised the acute proinflammatory cytokine gene and protein response to LPS. Our results bring novel insights in understanding how the IUGR newborn is immunocompromised due to fundamental changes in NF-κB key factors.

PROLONGED IMMUNE-INFLAMMATORY REACTIONS IN PATIENTS WITH COVID-19- ASSOCIATED SURGICAL PATHOLOGY IN THE POSTCOVID PERIOD

Summary. Introduction. The combination of pathogenetic factors of the main surgical pathology, multiple organ dysfunction, acute respiratory distress syndrome and cytokine storm against the background of SARS-Cov-2 infection justifies the relevance of this study.&#x0D; Materials and methods. We examined 13 patients with acute COVID-19 and 29 patients with SARS-Cov-2-associated urgent surgical pathology. Investigated the concentration of C-reactive protein (CRP) by latex agglutination, C3 and C4 components of the complement by immunoturbidimetry, the content of interleukins IL-6 and IL-18 by ELISA, determination of autoantibodies by luminescence microscopy.&#x0D; Results. In patients with SARS-Cov-2-associated urgent surgical pathology, certain patterns of changes in the markers under study were revealed: in all examined groups of patients, an increased concentration of C-reactive protein was observed, which indicated a systemic inflammatory response both in the acute and in the postcovid period. In the postcovid period of viral infection, the most significant are the high frequency of the maximum increase in the concentration of CRP, C3- and C4-complement components, and a significant or moderate increase in the content of interleukins IL-6 and IL-18, more pronounced than in the acute period of infection. The maximum increase in pro-inflammatory cytokines was found in patients with abdominal surgical pathology against the background of COVID-19 (postcoid period), while in the acute period of COVID-19, an increase in the concentration of IL-6 had no diagnostic value. A cytokine storm was detected in 20.5% of the examined patients with COVID-19-associated urgent surgical pathology.&#x0D; Conclusions. For COVID-19-associated surgical pathology, the formation of autoimmune conditions is characteristic, which is expressed in the presence of a wide range of autoantibodies to nuclear structures. Thus, for the prevention and complex treatment of COVID-19-associated urgent surgical pathology, it is advisable to use personified step-by-step immunotropic therapy.

Ablation of PDE4B protects from Pseudomonas aeruginosa‐induced acute lung injury in mice by ameliorating the cytostorm and associated hypothermia

Pseudomonas aeruginosa is a frequent cause of hospital-acquired lung infections characterized by hyperinflammation, antibiotic resistance, and high morbidity/mortality. Here, we show that the genetic ablation of one cAMP-phosphodiesterase 4 subtype, PDE4B, is sufficient to protect mice from acute lung injury induced by P aeruginosa infection as it reduces pulmonary and systemic levels of pro-inflammatory cytokines, as well as pulmonary vascular leakage and mortality. Surprisingly, despite dampening immune responses, bacterial clearance in the lungs of PDE4B-KO mice is significantly improved compared to WT controls. In wildtypes, P aeruginosa-infection produces high systemic levels of several cytokines, including TNF-α, IL-1β, and IL-6, that act as cryogens and render the animals hypothermic. This, in turn, diminishes their ability to clear the bacteria. Ablation of PDE4B curbs both the initial production of acute response cytokines, including TNF-α and IL-1β, as well as their downstream signaling, specifically the induction of the secondary-response cytokine IL-6. This synergistic action protects PDE4B-KO mice from the deleterious effects of the P aeruginosa-induced cytostorm, while concurrently improving bacterial clearance, rather than being immunosuppressive. These benefits of PDE4B ablation are in contrast to the effects resulting from treatment with PAN-PDE4 inhibitors, which have been shown to increase bacterial burden and dissemination. Thus, PDE4B represents a promising therapeutic target in settings of P aeruginosa lung infections.

Sepsis and multiple sclerosis: Causative links and outcomes

Sepsis is a life-threatening condition characterized by an acute cytokine storm followed by prolonged dysfunction of the immune system in the survivors. Post-septic lymphopenia and functional deficits of the remaining immune cells lead to increased susceptibility to secondary infections and other morbid conditions causing late death in the patients. This state of post-septic immunoparalysis may also influence disorders stemming from inappropriate or overactive immune responses, such as autoimmune and immunoinflammatory diseases, including multiple sclerosis. In addition, ongoing autoimmunity likely influences the susceptibility to and outcome of sepsis. This review article addresses the bidirectional relationship between sepsis and multiple sclerosis, with a focus on the immunologic mechanisms of the interaction and potential directions for future studies.

The Association between serum protein electrophoresis patterns and severity of patients infected with SARS-CoV-2 virus

Background:-The Coronavirus epidemic 2019 (COVID-19) is really a highly infectious sickness that is causing a huge danger to human life throughout the world. The induction of acute cytokine storm and immunosuppressive in COVID- 19 patients causes a rise in cytokines levels in the blood. Furthermore, the full extent of serum protein alterations in COVID-19 patients remains unclear. Patients and methods: -In a cross-sectional study, 80 SARS-CoV-2 virus-infected patients aged 18 to 80 were categorized according to severity of the infection and their serum protein electrophoresis assessment in relation to the severity of Covid-19. Results:-SPE for patients infected with the SARS-CoV-2 virus showed a significant difference in albumin, beta, and gamma and there was no significant relation with the α1 and α2 all in comparison between the subgroups themselves. Conclusion:-We conclude from the finding: albumin, beta, and gamma fractions showed a decrease in levels In conjunction with disease severity.

COVID-19: Zinc and Angiotensin-Converting Enzyme 2 (ACE2) Deficiencies as Determinants of Risk and Severity of Disease: A Narrative Review.

A growing body of evidence supports the premise that deficiencies of zinc and angiotensin-converting enzyme 2 (ACE2, a zinc enzyme) determine severity of coronavirus disease 2019 (COVID-19). ACE2 is part of the renin–angiotensin system (RAS) and acts as a feedback control system moderating blood pressure, keeping blood pressure within normal limits. For a virus to infect a person, the virus has to get inside the person’s cells. The virus that causes COVID-19 uses ACE2 to get into the cell. Think of this like an invader from outer space attacking your car by getting in through your cruise control; the RAS is like the cruise control of your car. What happens next depends on how robust your cruise control is. If your cruise control is young and healthy perhaps very little happens; your car may slow down or speed up a bit. But if your cruise control is in poor condition the attack might disrupt the entire speed control system; your car may brake suddenly or speed out of control and crash. Feedback control systems (natural or man-made) are designed to keep dynamic systems in control, but under certain situations can drive the system completely out of control. The RAS is composed of two feedback loops: the ACE loop provides amplification, increasing pro-inflammatory cytokines and blood pressure; the ACE2 loop provides fine control and mitigates the vasoconstrictive, pro-inflammatory, and thrombotic actions of the ACE loop. Usually, there is balance, but in the setting of COVID-19, underlying deficiencies of zinc and ACE2 can lead to an imbalance. Exacerbated by the severe downregulation of ACE2 seen with viral entry, a “tipping point” is reached with loss of control of the RAS system resulting in increased angiotensin II (Ang II) causing downstream vasoconstriction, inflammation, and thromboses. These, in turn, lead to complications often seen in “severe COVID-19” such as acute respiratory distress syndrome (ARDS) or cytokine storm, often seen in high-risk patients in the second week of illness. This model suggests that supplemental zinc could replenish zinc in ACE2, stabilize the ACE2 axis, and prevent disruption of the RAS. This would prevent the vasoconstrictive, inflammatory, and thrombotic actions of Ang II, thus preventing the severe COVID-19 complications which cause the high morbidity and mortality seen in high-risk patients with underlying zinc deficiency. Zinc supplements are available, easy to use, and relatively safe. Randomized clinical trials are needed to confirm safety and efficacy of zinc supplementation to decrease severity of and morality from COVID-19 in high-risk patients. Since replenishment of zinc and active ACE2 in patients in whom these are deficient may take weeks, supplementation in high-risk populations prior to COVID infection may be required. Such supplementation should not replace vaccination but may be useful in populations for whom vaccination is not available or for populations exposed to viral variants to which available vaccines have insufficient coverage.

Single-cell RNA-seq landscape midbrain cell responses to red spotted grouper nervous necrosis virus infection.

Viral nervous necrosis (VNN) is an acute and serious fish disease caused by nervous necrosis virus (NNV) which has been reported massive mortality in more than fifty teleost species worldwide. VNN causes damage of necrosis and vacuolation to central nervous system (CNS) cells in fish. It is difficult to identify the specific type of cell targeted by NNV, and to decipher the host immune response because of the functional diversity and highly complex anatomical and cellular composition of the CNS. In this study, we found that the red spotted grouper NNV (RGNNV) mainly attacked the midbrain of orange-spotted grouper (Epinephelus coioides). We conducted single-cell RNA-seq analysis of the midbrain of healthy and RGNNV-infected fish and identified 35 transcriptionally distinct cell subtypes, including 28 neuronal and 7 non-neuronal cell types. An evaluation of the subpopulations of immune cells revealed that macrophages were enriched in RGNNV-infected fish, and the transcriptional profiles of macrophages indicated an acute cytokine and inflammatory response. Unsupervised pseudotime analysis of immune cells showed that microglia transformed into M1-type activated macrophages to produce cytokines to reduce the damage to nerve tissue caused by the virus. We also found that RGNNV targeted neuronal cell types was GLU1 and GLU3, and we found that the key genes and pathways by which causes cell cytoplasmic vacuoles and autophagy significant enrichment, this may be the major route viruses cause cell death. These data provided a comprehensive transcriptional perspective of the grouper midbrain and the basis for further research on how viruses infect the teleost CNS.

EBI2-expressing B cells in neuromyelitis optica spectrum disorder with AQP4-IgG: Association with acute attacks and serum cytokines

Epstein-Barr virus-induced G-protein coupled receptor 2 (EBI2) is important in regulating B cell activation. We investigated whether EBI2 expression on B cells is associated with acute attacks in neuromyelitis optica spectrum disorder with aquaporin-4 IgG (AQP4-IgG(+) NMOSD). Blood samples were collected from patients with AQP4-IgG(+) NMOSD, multiple sclerosis (MS), and patients without inflammatory demyelinating diseases (non-IDD controls). CD19+ B cells and CD4+ T cells were analyzed for surface expression of EBI2. Serum cytokine levels were also analyzed. The EBI2+CD19+ to EBI2–CD19+ cell ratio was significantly higher in patients with AQP4-IgG(+) NMOSD enrolled within 2 months of an attack than in those with non-IDDs (p = 0.007) and MS (p = 0.003). Patients with AQP4-IgG(+) NMOSD enrolled within 2 months of an attack had a higher EBI2+CD19+ cell frequency than patients with AQP4-IgG(+) NMOSD enrolled 2 months after a recent attack (p = 0.001). The EBI2+CD19+ cell frequency was positively correlated with interleukin (IL)-6 and IL-10. EBI2 expression on B cells could be associated with acute attacks of AQP4-IgG(+) NMOSD, possibly through IL-6- or IL-10-related pathways.

Interleukin-17A Contributes to Bacterial Clearance in a Mouse Model of Streptococcal Toxic Shock-Like Syndrome.

Streptococcus suis (S. suis), an emerging zoonotic pathogen, can cause streptococcal toxic shock-like syndrome (STSLS) in humans with high mortality. STSLS is characterized by high bacterial burden, an inflammatory cytokine storm, multi-organ dysfunction, and ultimately acute host death. Although it has been found that a significantly high level of IL-17A was induced in an NLRP3-dependent manner during STSLS development, the role of IL-17A on S. suis STSLS remains to be elucidated. In this study, we found that the epidemic strain SC 19 caused a significantly higher level of IL-17A than the non-epidemic strain P1/7. In addition, higher bacterial burden was observed from SC 19-infected il17a−/− mice than il17a+/+ mice, although acute death, tissue injury and inflammatory cytokines storm were observed in both types of mice. Furthermore, compared with il17a+/+ mice, the level of neutrophils recruitment was lower in il17a−/− mice, and the levels of induced antimicrobial proteins, such as CRAMP, S100A8 and lipocalin-2, were also decreased in il17a−/− mice. In conclusion, this study demonstrated that IL-17A does not contribute to the severe inflammation, although it may play a minor role for bacterial clearance by inducing antimicrobial proteins and promoting neutrophil recruitment during STSLS.

The effect of staphylococcal mastitis including resistant strains on serum procalcitonin, neopterin, acute phase response and stress biomarkers in Holstein dairy cows.

Staphylococcal mastitis (SM) is a frequent disease in the dairy cattle that is costly to treat. This study aimed to investigate the alterations in the levels of procalcitonin (PCT), neopterin (NPT), haptoglobin (HP), serum amyloid A (SAA), proinflammatory cytokines (IL-1β, IL-8, TNF-α, IF-γ) and oxidative stress (OS) biomarkers in Holstein dairy cows with SM under field conditions. In addition, we also evaluated the role of examined biomarkers in disease pathogenesis and their use as diagnostic biomarkers for the disease in dairy cows. Fifty-three dairy cows with SM, including those with infections caused by Staphylococcus aureus (n = 42) and methicillin resistant S. aureus (MRSA) (n = 11) were selected for this study. In addition, 20 healthy dairy cows were enrolled as a control group. Higher serum levels of PCT, NP, IL-1β, IL-8, TNF-α, IF-γ, HP and SAA and a state of OS was detected in SM group in comparison with the controls. Moreover, the levels of all examined biomarkers in mastitic cows with S. aureus when compared with those infected with MRSA was not significantly different. All examined biomarkers demonstrated a significant degree of discrimination between SM cows and healthy controls (the area under the curve (AUC) ranged from 83.6 for SAA to 100 for PCT). Our study showed that SM in dairy cows was associated with substantial changes in serum PCT, NPT, Acute phase proteins (APPs), proinflammatory cytokines, and OS levels. This study demonstrates that clinical examination in tandem with quantification of PCT, NPT, APPs and cytokines, OS biomarkers could be a useful assessment tool for SM in dairy cows.

Does COVID 19 generate a milieu for propagation of mucormycosis?

Corona Virus Disease 2019 (COVID 2019), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a dreadful infectious disease which has emerged as one of the most significant medical emergency affecting everyone directly or indirectly. COVID 2019 is a multisystem disease and causes severe immunosuppression. Initially thought to affect mainly the respiratory system, it strikes all vital organ systems and cause defects in cardio-circulatory, respiratory system and gastrointestinal systems to name a few leading to copious biochemical alterations. Reports show there is thromoembolism, raised ferritin levels, lymphocytopenia, thrombocytopenia, lactic acidosis, acute diabetes like state and cytokine storm. Data regarding levels of neutrophils is equivocal. Further there is increased incidence regarding high incidents of mucormycosis in COVID 2019 positive subjects. In the present paper, we identified and correlated the virus mediated biochemical alterations as the potential ideal environment for propagation of mucorales; and thus concentrate on early diagnosis and treatment of mucormycosis in COVID 2019 cases.

Association of acute inflammatory cytokines, fracture malreduction, and functional outcome 12 months after intra-articular ankle fracture\u2014a prospective cohort study of 46 patients with ankle fractures

BackgroundSeveral malreduction criteria have been proposed for ankle surgery, but the criteria of most importance for functional outcome remain undetermined. Furthermore, the acute inflammatory response in the ankle joint after fracture is hypothesized to result in osteoarthritis development, but no study has investigated the correlation between the levels of these inflammatory cytokines and post-surgical functional outcomes. We aimed to identify malreduction criteria and inflammatory cytokines associated with functional outcome after ankle surgery.MethodsDuring surgery, synovial fluid from the fractured and healthy contralateral ankles of 46 patients was collected for chemiluminescence analysis of 22 inflammatory cytokines and metabolic proteins. The quality of fracture reduction was based on 9 criteria on plain X-rays and 5 criteria on weight-bearing computed tomography (WBCT) scans. After 3 and 12 months, we recorded scores on American Orthopedic Foot and Ankle Society (AOFAS) scale, the Danish version of Foot Function Index (FFI-DK), EQ-5D-5L index score, the Kellgren-Lawrence score, and joint space narrowing.ResultsTibiofibular (TF) overlap (p = 0.02) and dime sign (p = 0.008) correlated with FFI-DK. Tibiotalar tilt correlated positively with joint space narrowing at 3 months (p = 0.01) and 12 months (p = 0.03). TF widening correlated with FFI-DK (p = 0.04), AOFAS (p = 0.02), and EQ-5D-5L (p = 0.02). No consistent correlations between synovial cytokine levels and functional outcomes were found at 12 months.ConclusionsMalreduction of TF overlap, TF widening, and tibiotalar tilt were the most important criteria for functional outcome after ankle surgery. Increased inflammatory cytokine levels after fracture did not affect functional outcome at 12 months.Trial registrationThis cohort study is registered the 10th of December 2018 at ClinicalTrials.gov (NCT03769909), was approved by the local committee on health ethics (The Regional Committees on Health Research Ethics for Southern Denmark: J.No. S-20170139), and was reported to the National Danish Data Protection Agency (17/28505).

The Adjuvants Polyphosphazene (PCEP) and a Combination of Curdlan Plus Leptin Promote a Th17-Type Immune Response to an Intramuscular Vaccine in Mice.

Our aim was to determine whether polyphosphazene (PCEP), Curdlan (β-glucan, a dectin-1 agonist), and Leptin could act as adjuvants to promote a Th17-type adaptive immune response in mice. Mice were vaccinated via the intramuscular route then boosted three weeks later with Ovalbumin plus: PCEP, Leptin, Curdlan, PCEP+Curdlan, Curdlan+Leptin, or saline. Mice vaccinated with OVA+PCEP and OVA+Curdlan+Leptin showed significantly higher frequency of antigen-specific CD4+ T cells secreting IL-17 relative to OVA-vaccinated mice. No formulation increased the frequency of CD4+ T cells secreting IL-4 or IFNγ. Since activation of innate immunity precedes the development of adaptive immunity, we wished to establish whether induction of Th17-type immunity could be predicted from in vitro experiments and/or from the local cytokine environment after immunization with adjuvants alone. Elevated IL-6 and TGFβ with reduced secretion of IL-12 is a cytokine milieu known to promote differentiation of Th17-type immunity. We injected the immunostimulants or saline buffer into murine thigh muscles and measured acute local cytokine production. PCEP induced significant production of IL-6 and reduced IL-12 production in muscle but it did not lead to elevated TGFβ production. Curdlan+Leptin injected into muscle induced significant production of TGFβ and IL-17 but not IL-6 or IL-12. We also stimulated splenocytes with media or PCEP, Leptin, Curdlan, PCEP+Curdlan, Curdlan+Leptin, PCEP+Leptin, and PCEP+Curdlan+Leptin and measured cytokine production. PCEP stimulation of splenocytes failed to induce significant production of IL-6, IL-12, TGFβ, or IL-17 and therefore ex vivo splenocyte stimulation failed to predict the increased frequency of Th17-type T cells in response to the vaccine. Curdlan-stimulated splenocytes produced Th1-type, inducing cytokine, IL-12. Curdlan+/-PCEP stimulated TGF-β production and Curdlan+Leptin+/- PCEP induced secretion of IL-17. We conclude that PCEP as well as Curdlan+Leptin are Th17-type vaccine adjuvants in mice but that cytokines produced in response to these adjuvants in muscle after injection or in ex vivo cultured splenocytes did not predict their role as a Th17-type adjuvant. Together, these data suggest that the cytokine environments induced by these immunostimulants did not predict induction of an antigen-specific Th17-type adaptive immune response. This is the first report of these adjuvants inducing a Th17-type adaptive immune response.

Obesity as a Risk Factor for Severe COVID-19 and Complications: A Review.

Emerging data suggest that obesity is a major risk factor for the progression of major complications such as acute respiratory distress syndrome (ARDS), cytokine storm and coagulopathy in COVID-19. Understanding the mechanisms underlying the link between obesity and disease severity as a result of SARS-CoV-2 infection is crucial for the development of new therapeutic interventions and preventive measures in this high-risk group. We propose that multiple features of obesity contribute to the prevalence of severe COVID-19 and complications. First, viral entry can be facilitated by the upregulation of viral entry receptors, like angiotensin-converting enzyme 2 (ACE2), among others. Second, obesity-induced chronic inflammation and disruptions of insulin and leptin signaling can result in impaired viral clearance and a disproportionate or hyper-inflammatory response, which together with elevated ferritin levels can be a direct cause for ARDS and cytokine storm. Third, the negative consequences of obesity on blood coagulation can contribute to the progression of thrombus formation and hemorrhage. In this review we first summarize clinical findings on the relationship between obesity and COVID-19 disease severity and then further discuss potential mechanisms that could explain the risk for major complications in patients suffering from obesity.

Aging versus youth: Endocrine aspects of vulnerability for COVID-19.

Coronavirus Disease 2019 (COVID-19) is characterized with a wide range of clinical presentations from asymptomatic to severe disease. In patients with severe disease, the main causes of mortality have been acute respiratory distress syndrome, cytokine storm and thrombotic events. Although all factors that may be associated with disease severity are not yet clear, older age remains a leading risk factor. While age-related immune changes may be at the bottom of severe course of COVID-19, age-related hormonal changes have considerable importance due to their interactions with these immune alterations, and also with endothelial dysfunction and comorbid cardiometabolic disorders. This review aims to provide the current scientific evidence on the pathogenetic mechanisms underlying the pathway to severe COVID-19, from a collaborative perspective of age-related immune and hormonal changes together, in accordance with the clinical knowledge acquired thus far.

Potential Antioxidative, Anti-inflammatory and Immunomodulatory Effects of Ghrelin, an Endogenous Peptide from the Stomach in SARS-CoV2 Infection.

The current COVID-19 pandemic is one of the most devastating events in recent history. The respiratory effects of this disease include acute respiratory distress syndrome, systemic inflammation, cytokine storm, and pulmonary fibrosis. Ghrelin, an endogenous ligand for the growth hormone secretagogue receptor, is a peptide hormone secreted mainly by the stomach. Interestingly, ghrelin possesses promising antioxidant, anti-and inflammatory effects, making it an attractive agent to reduce the complications of the SARS-CoV-2. In addition, ghrelin exerts a wide range of immunomodulatory and anti-inflammatory effects and can mitigate the uncontrolled cytokine production responsible for acute lung injury by upregulating PPARγ and down-regulating NF-κB expression. Ghrelin has also been reported to enhance Nrf2 expression in inflammatory conditions which led to the suppression of oxidative stress. The current opinion summarizes the evidence for the possible pharmacological benefits of ghrelin in the therapeutic management of SARS-CoV-2 infection.

Commentary: Use of Cannabinoids to Treat Acute Respiratory Distress Syndrome and Cytokine Storm Associated With Coronavirus Disease-2019.

GENERAL COMMENTARY article Front. Pharmacol., 12 April 2021Sec. Inflammation Pharmacology Volume 12 - 2021 | https://doi.org/10.3389/fphar.2021.631646