Objective: To assess whether secretory otitis media may be caused by immune imbalance of Treg/Th17 mediated by PI3K/Akt/mTOR signaling, so as to find new therapeutic target. Methods: IL-17, TGF- and IL-6, IL-10 and Th17 cytokines were detected in peripheral blood of OME patients (PC group) and healthy people (NC group) by ELISA. The expression of ROR t mRNA and Foxp3mRNA in PBMC was detected by RT-PCR. OME rat model was established and the changes of lymphocytes in middle ear mucosa and spleen and PI3K/Akt/mTOR signaling in middle ear mucosa were detected by HE staining, IHC, WB and flow cytometry. Results: The immune imbalance of Treg/Th17 in secretory otitis media (OME) was confirmed by the expression of cytokines in OME serum and analysis of ROR T and Foxp3 mRNA which was Th17 and Treg specific transcription respectively. OME rat model further confirmed that Treg/Th17 imbalance could lead to OME as demonstrated by staining of MIDDLE ear mucosa and expression of ROR T and Foxp3. PI3K, Akt, and mTOR proteins were expressed in the MIDDLE ear mucosa of OME group and CON group, respectively. Compared with CON group, the expression of P-MTOR and P-PI3K proteins in the middle ear mucosa of OME group was significantly increased. Conclusions: Treg/Th17 imbalances are found in OME patients and OME animal model and the pathogenic mechanism may be due to systemic abnormal immune response, activated PI3K/Akt/mTOR signaling, abnormal T cell differentiation, leading to middle ear mucosal hyperemia, edema and subsequent occurrence of OME.

Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) can be a severe and debilitating disease associated with significant morbidity, complete anosmia, sinus pressure, and asthma exacerbations. Eosinophils play a role in the majority (85%) of patients. Benralizumab, an afucosylated monoclonal antibody directed against the IL-5 receptor has powerful apoptotic effects on eosinophils. Objective: We sought to investigate the therapeutic benefit of inhibiting the IL-5 receptor using benralizumab to treat severe nasal polyposis. Methods: Twenty-four patients (n = 24) with severe NP (grade 5 or more out of 8) with elevated eosinophils and a history of previous polypectomy were randomized in a double-blind fashion to receive 30mg benralizumab SC or placebo. Endoscopic NP score was assessed at baseline and at treatment week 20. CT scan, SNOT-22 survey, and UPSIT smell test score changes were also evaluated from baseline. Results: Compared to baseline, 8 out 12 patients receiving benralizumab had a significantly improved NP score versus 4 out of 12 placebo. 5 of 12 benralizumab treated patients had improvements in all major outcomes (polyp score, CT, SNOT-22 and smell test) versus 2 out of 12 placebo. The ratio of blood eosinophil count to allergen skin test positivity correlated with polyp reduction. Conclusion: Compared to baseline, benralizumab achieved a statistically significant reduction in polyp size by endoscopy and CT scan and was associated with both less symptoms and improved sensation of smell for most patients (10 of 12).

Background: Laboratory abnormalities associated with disease severity and mortality in patients with coronavirus disease 2019 (COVID-19) have been reported in many observational studies. However, there are significant heterogeneities in patient characteristics and research methodologies in these studies. Objectives: We aimed to provide an updated synthesis of the association between laboratory abnormalities and COVID-19 prognosis. Methods: We conducted an electronic search of PubMed, Scopus, Ovid, Willey, Web of Science, and the China National Knowledge Infrastructure (CNKI) for studies reporting hematological, coagulation, inflammatory, and immunological results during hospital admission of COVID-19 patients with different severities and outcomes. Results: A total of 64 studies were included in the current meta-analysis, with 8 hematological, 3 coagulation, 5 inflammatory, and 23 immunological variables reported. Of them, white blood cell (WBC) and neutrophil counts, D-dimer level, procalcitonin (PCT), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), ferretin, serum amyloid A (SAA), interleukins (ILs)–2R, IL-6, and IL-10 were significantly increased in severely ill patients and non-survivors. Meanwhile, non-severely ill patients and survivors presented significantly higher counts of eosinophils, lymphocytes, and CD4+ and CD8+ T cells. Conclusions: The current meta-analysis provides a comprehensive and updated synthesis of the association between admission laboratory abnormalities with severity and mortality of COVID-19. Our results highlight that increases in the levels of PCT, ESR, CRP, ferretin, SAA, IL-2R, IL-6, and IL-10 were associated with disease deterioration, whereas elevated eosinophils, lymphocytes, and T-cell subsets might serve as indicators of favorable outcomes.

IFITM family proteins have broad-spectrum antiviral capabilities. Preliminary studies in our laboratory have preliminarily proved that IFITMs have the effect of inhibiting influenza viruses. In order to further study its mechanism and role in the occurrence and development of influenza, relevant studies have been carried out. Fluorescence quantitative PCR detection, yeast two-hybrid test and optical confocal microscopy were used to investigate the effect of hIFITM3 on influenza virus replication, the interaction with hABHD16A and the expression of inflammation-related factors. In HEK293 cells, overexpression of hIFITM3 protein significantly inhibited the replication of influenza virus at 24h, 48h, and 72h; yeast two-hybrid experiment proved that IFITM3 interacts with ABHD16A; laser confocal microscopy observations showed that IFITM3 and ABHD16A co-localized in Cell membrane area; the expression level of inflammation-related factors in cells overexpressing hIFITM3 or hABHD16A was detected by fluorescence quantitative PCR, and the results showed that the mRNA levels of IL-1β, IL-6, IL-10, TNF-a and COX2 were significantly increased . But when IFITM3/ABHD16A was co-expressed, the mRNA expression levels of these cytokines were significantly reduced except for COX2. When influenza virus infected cells co-expressing IFITM3/ABHD16A, the expression level of inflammatory factors decreased compared with the control group, indicating that IFITM3 can play an important role in regulating inflammation balance. This study confirmed that hIFITM3 has an effect of inhibiting influenza virus replication. Furthermore, it was found that hIFITM3 interacts with hABHD16A, following which it can better inhibit the replication of influenza virus and the inflammatory response caused by the disease process.

Early studies suggesting that chloroquine (CQ) and hydroxychloroquine (HCQ) could benefit coronavirus patients brought these old medicines back to the spotlight. This led to an increase in demand and price, turning their counterfeiting a pharmacovigilance issue worldwide. Meanwhile, lack of evidence on effectiveness and safety concerns have reduced their clinical trials in severe COVID-19 cases. Despite the knowledge that CQ and HCQ toxic effects are stereo specific rather than their therapeutic effects, these drugs are available only as racemates. In this context, this work brings a discussion about chiral switching to their eutomers so that CQ and HCQ distomers would become impurities, what may be a viable alternative to test new dose-response curves. Even if it is proven that the use of pure CQ and HCQ enantiomers are useless against COVID-19, chiral switching would certainly improve safety and efficacy in the treatment of many autoimmune inflammatory diseases, benefiting chronic users of these drugs.

Cysteinyl leukotrienes (CysLTs) are inflammatory lipid mediators that play a central role in the pathophysiology of several inflammatory diseases. Recently, there has been an increased interest in determining how these lipid mediators orchestrate tumor development and metastasis through promoting a pro-tumoral microenvironment. Upregulation of CysLTs receptors and CysLTs production is found in a number of cancers and has been associated with increased tumorigenesis. Understanding the molecular mechanisms underlying the role of CysLTs and their receptors in cancer progression will help investigate the potential of targeting CysLTs signaling for anti-cancer therapy. This review gives an overview of the biological effects of CysLTs and their receptors, along with current knowledge of their regulation and expression. It also provides a recent update on the molecular mechanisms that have been postulated to explain their role in tumorigenesis and on the potential of anti-CysLTs in the treatment of cancer.

Background and Purpose: The profibrotic and proinflammatory effects induced by doxorubicin (DOX) are key processes in the development of serious heart damage. The lack of effective drugs and the unclear mechanisms of their side effects limit the clinical treatment of DOX-induced cardiac injury. This study aimed to explore the protective role of LCZ696 and the potential mechanism of Toll-like receptor 2 (TLR2) in doxorubicin-induced cardiac failure. Experimental Approach: DOX (5 mg/kg/week, 3 times) was used to establish a chronic cardiomyopathy mouse model. Heart function tests, pathology examinations and molecular biology analyses were used to explore the effects of LCZ696 and TLR2 deficiency. H9C2 cells were used to verify the protective role and mechanism of LCZ696 in vitro. Key Results: The EF% declined, and the LVIDd, pro-fibrosis marker levels and NF-κB pathway-related inflammatory response increased in the chronic cardiomyopathy group induced by DOX. LCZ696 treatment and TLR2 deficiency reversed this heart damage in vivo. In H9C2 cells, pretreatment with LCZ696 and TLR2 knockdown suppressed the DOX-induced high expression of profibrotic and proinflammatory markers. Moreover, DOX notably increased the TLR2-MyD88 interaction in H9C2 cells, which was inhibited by LCZ696 pretreatment. Conclusion and Implications: LCZ696 prevents DOX-induced cardiac dilation failure, fibrosis and inflammation by reducing the formation of TLR2-MyD88 complexes. LZC696 may be a potential effective drug to treat DOX-induced heart failure.

The eventual discovery of endogenous cannabinoid receptors CB1 and CB2 and their endogenous ligands has generated interest with regards to finally understanding the endocannabinoid system. Its role in the normal physiology of the body and its implication in pathological states such as cardiovascular diseases, neoplasm, depression and pain have been subjects of scientific interest. In this review the authors focus on the endogenous cannabinoid pathway, the critical role of cannabinoid receptors in signaling and mediation of neurodegeneration and other inflammatory responses as well as its potential as a drug target in the amelioration of some inflammatory conditions. Though the exact role of the endocannabinoid system is not fully understood, the evidence found leans heavily towards a great potential in exploiting both its central and peripheral pathways in disease management. Cannabinoid therapy has already shown great promise in several preclinical and clinical trials.

Background and purpose: Increasing evidence has shown that human cholestasis is closely related to hepatic macrophage accumulation and activation. Research has indicated that peroxisome proliferator-activated receptor-g (PPARg) activation exerts liver protection in cholestatic liver disease (CLD), particularly by ameliorating inflammation and fibrosis, thus limiting disease progression. However, existing PPARg agonists, such as troglitazone and rosiglitazone, have significant side effects that impede their clinical application in the treatment of CLD. In this study, we found that tectorigenin (TEC) can alleviate intrahepatic cholestasis in mice by activating PPARg. Experimental approach: Wild-type mice received intragastric administration of a-naphthylisothiocyanate (ANIT) or were fed a diet containing 0.1% 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) to establish an experimental intrahepatic cholestasis model and TEC intervention simultaneously, followed by determination of intrahepatic cholestasis and the involved mechanisms. In addition, PPARg deficient mice were administered ANIT and/or TEC to determine whether TEC exerts its liver protection effect by activating PPARg. Key results: Our results demonstrated that TEC intervention alleviated intrahepatic cholestasis by inhibiting hepatic macrophage recruitment and activation as well as promoting the expression of bile transporters through activating PPARg. Furthermore, our results show that TEC increased bile salt export pump (Bsep) expression through enhanced PPARg binding to the Bsep promoter. We also demonstrated that PPARg deficiency blocked the hepatocyte protective effect of TEC during cholestasis. Conclusions and implications: In conclusion, TEC reduced hepatic macrophage recruitment and activation, and enhanced bile acid export by activating PPARg. Taken together, our results suggest that TEC is a potential drug for the prevention of CLD.

Background and Purpose: It is well established that both smokers and patients with COPD are at a significantly heightened risk of cardiovascular disease (CVD), although the mechanisms underpinning the onset and progression of comorbid CVD are largely unknown. Here, we explored whether cigarette smoke (CS) exposure impairs vascular function in mice and given the well-known pathological role for oxidative stress in COPD, whether the antioxidant compound ebselen prevents CS-induced vascular dysfunction in mice. Experimental Approach: Male BALB/c mice were exposed to either room air (sham) or CS generated from 9 cigarettes per day, 5 days a week for 8 weeks. Mice were treated with ebselen (10mg/kg, oral gavage once daily) or vehicle (5% w/v CM cellulose in water) 1 h prior to the first CS exposure of the day. Upon sacrifice, bronchoalveolar lavage fluid (BALF) was collected to assess pulmonary inflammation and the thoracic aorta was excised to investigate vascular endothelial and smooth muscle dilator responses ex-vivo. Key Results: CS exposure caused a significant increase in lung inflammation which was reduced by ebselen. CS also caused significant endothelial dysfunction in the thoracic aorta which was attributed to a downregulation of eNOS expression and increased vascular oxidative stress. Ebselen abolished the aortic endothelial dysfunction seen in CS-exposed mice by reducing the oxidative burden and preserving eNOS expression. Conclusion and Implications: Targeting CS-induced oxidative stress with ebselen may provide a novel means for treating the life-threatening pulmonary and cardiovascular manifestations associated with cigarette smoking and COPD.

Rationale Neutrophils and monocytes are key immune effector cells in inflammatory bowel disease (IBD) that is associated with chronic inflammation in the gut. Patients with stable IBD who exercise have fewer flare-ups, but no underlying mechanism has been identified. Therefore, the aim of this study was to compare the responsiveness of these innate immune cells after repeated bouts of prolonged exercise in IBD patients and controls. Methods Patients with IBD and age- and gender-matched healthy controls were recruited from a cohort of walkers participating in a 4-day walking event. Blood analysis was performed at baseline and after 3 days of walking. Responsiveness to the bacterial/mitochondrial N-Formylmethionine-leucyl-phenylalanine (fMLF) was tested in granulocytes and monocytes by measuring the expression of activation markers after adding this stimulus to whole blood Results In total 38 participants (54±12 years) were included in this study: 19 walkers with and 19 walkers without IBD. After 3 days of prolonged exercise, a significant increase in responsiveness to fMLF was observed in all participants irrespective of disease. However, IBD patients showed significantly smaller increase in neutrophils (p=0.010; p=0.030; p=0.010, respectively) and monocytes (p=0.001; p=0.008; p=0.005, respectively), compared to controls. Conclusions Increased responsiveness of neutrophils and monocyte to fMLF was demonstrated after repetitive bouts of prolonged exercise. Interestingly, this exercise was associated with relative refractoriness of both neutrophils and monocytes in IBD patients. These refractory cells might create a lower inflammatory state in the intestine providing a putative mechanism for the decrease in flare-ups in IBD patients after repeated exercise.

Vascular leak is a hallmark of severe dengue, and high leukotriene levels have been observed in dengue mouse models, suggesting a role in disease pathogenesis. We sought to explore their role in acute dengue, by assessing levels of urinary leukotriene (LTE4) and histamine in patients with varying severity of acute dengue. Urinary LTE4, histamine and creatinine were measured by a quantitative ELISA, in mid-morning urine samples collected from healthy individuals (n= 19) and patients with dengue fever (DF= 72) and dengue haemorrhagic fever (DHF= 48). The kinetics of LTE4 and histamine and diurnal variations were assessed in a subset of patients. Urinary LTE4 levels were significantly higher (p=0.004) in patients who proceed to develop DHF when compared to patients with DF during early illness (≤ 4 days) and during the critical phase (p=0.02). However, LTE4 was not a good predictive marker of DHF as ROCs gave an AUC value of 0.67 (95% CI 0.57 to 0.76), which was nevertheless significant (p=0.002). Urinary LTE4 levels did not associate with the degree of viraemia, infecting virus serotype and was not different in those with primary vs secondary dengue. LTE4, histamine and the viral loads showed a marked diurnal variation in both patients with DF and DHF. Our data suggest that LTE4 could play a role in disease pathogenesis and since there are safe and effective cysteinyl leukotriene receptor blockers, it would be important to assess their efficacy in reducing dengue disease severity.

Background and Purpose: Escherichia coli is a common mastitis-causing pathogens and is destructive to the blood-milk barrier. Oral administration of Lactobacillus casei Zhang (LCZ) could alleviate mice mastitis. However, its prophylactic effect and mechanism through intramammary injection on E. coli-induced mastitis is unclear now. Here, we investigate this using E. coli-induced mastitis model. Experimental Approach: Prophylactic effects and mechanism of intramammary injection of LCZ on blood-milk barrier and inflammation were studied in both bovine mammary epithelial cells (BMECs) and pregnant mice. Key Results: In vitro tests revealed that LCZ significantly inhibited the adhesion of E. coli to monolayer cells, reduce the damage of cell desmosomes, up-regulated the expression of tight junction proteins (claudin-1, claudin-4, occludin, and ZO-1), and down-regulated the expression of inflammatory cytokines (TNF-α, IL-1β, and IL-6) thereby enhancing the trans-epithelial electric resistance of monolayer BMECs and effectively protecting cells from damage caused by E. coli. In vivo experiments suggested that LCZ significantly promoted the expression of tight junction proteins (claudin-3, occludin, and ZO-1) but significantly inhibited the expression of inflammatory cytokines (TNF-α, IL-1β, and IL-6) in mouse mammary tissue, thereby decreased disruption in mammary tissues, infiltration of inflammatory cells in E. coli-induced mastitis. Conclusions and Implications: In our study, LCZ ameliorates blood-milk barrier disruption and suppresses the inflammatory response during E. coli-induced mastitis, indicating LCZ may serve as a effective prophylactic agent to preserve the blood-milk barrier function during mastitis.

Background: Immune checkpoint inhibitors (ICIs) cause a variety of inflammatory eruptions. A better understanding of the rash types, histopathological findings, severity, and clinical courses is necessary for appropriate managements of these eruptions. Only a few reports reviewed ICI-induced inflammatory eruptions with detailed histopathological findings. Methods: In this study, we retrospectively reviewed 42 patients who were histopathologically diagnosed with cutaneous immune-related adverse events (irAEs) following ICI therapy between 2014 and 2020 at the Department of Dermatology of Kyushu University Hospital. Results: Of the 42 patients (24 males, 18 females), maculopapular rash (33/42, 78.6%), erythema multiforme (2/42, 4.8%), lichenoid reaction (3/42, 7.1%), psoriasiform reaction (1/42, 2.4%), bullous pemphigoid (1/42, 2.4%), scleroderma-like reaction (1/42, 2.4%), and Stevens-Johnson syndrome (1/42, 2.4%) were observed. The clinical and histopathological findings of these eruptions were equivalent to typical cases of common drug eruptions. The onset of maculopapular rash was relatively early (more than half of events occurred within 1 month), whereas lichenoid reactions and autoimmune diseases occurred relatively late (4–8 m¬¬onths). With appropriate treatment and/or interruption of ICIs, most rashes were improved (40/42, 95.2%). Conclusions: The ICI-induced inflammatory eruptions shared similar clinical and histopathological features with classical inflammatory eruptions, but a variety of inflammatory eruptions may occur with different degrees of severity. Dermatologists play an important role in providing specialized care for cutaneous immune-related adverse events.

The novel coronavirus 2019 (COVID-19) pandemic, which has resulted in nearly 700 thousand deaths, is rapidly spreading across the globe despite drastic public and personal health measures. As showed in Figure 1, the direct attack from SARS-CoV-2 and hyperactivated immune response contribute to the progress and deterioration of COVID-19 infection. Eliminating virus and blocking cytokine are important check-points of COVID-19 therapy. Based on our successful experience in Wuhan and current progress of the therapeutic strategies, several agents targeting immunopathology have displayed marked effects on COVID-19 patients, including interferons, immunoglobulin, and glucocorticoid, etc. Here, we want to review the novel progress of therapy strategies related to immunopathology and share our Wuhan experience with the colleagues in the field by reviewing the underlying the pharmacologic mechanisms of these agents.

Background: As of March 31, 2020, about 82,545 COVID-19-infected patients in China have been confirmed. Several observational studies have reported clinical characteristics of pneumonia caused by COVID-19 in China. But there are doubts about the clinical significance of differences reported in the different studies. The objective of this paper is to meta-analyze all available data from observational studies in China to enable an objective reappraisal of the clinical characteristics. Methods: PubMed, CNKI, EMBASE, and Cochrane Library were searched. Observational studies were included if they reported information on clinical characteristics of COVID-19-infected pneumonia. Statistical heterogeneity was assessed using the I2 test, with a value ≥ 50% indicating a substantial level of heterogeneity. Results: Pooled results exhibited that the proportion of male (58%) was higher in patients with COVID-19-infected pneumonia. Fever (89%), cough (74%), fatigue (44%), and shortness of breath (31%) were the common clinical manifestations. Cardiovascular disease (8%), endocrine system disease (9%), and digestive system disease (5%) were the common comorbidities. Moreover, hypertension (29%), endocrine system disease (16%), and cardiovascular disease (8%) were the most common comorbidities in severe patients. Acute cardiac injury (5%), ARDS (11%), shock (3%), and AKI (2%) were the common complications. Conclusions: Men may be more susceptible to COVID-19. The people with hypertension and endocrine system disease are more likely to develop severe pneumonia. The most common symptoms are fever and cough. The heart and kidneys may be also important organs for the COVID-19 to attack in addition to the lungs. Most patients have bilateral imaging abnormalities.

Chronic inflammatory diseases cause anemia of inflammation (AI). This causes impaired immune-mediated regulation of hepcidin and several cytokines, which play a major role in iron homeostasis, accelerates turnover of red blood cells, and affects the activity of erythropoietin (EPO), thereby reducing levels of hemoglobin and iron.1 Asthma is one of common allergic diseases caused by disturbance of the immune system,2 and this chronic inflammatory condition could cause systemic inflammation.3 Several researches have recently shown that asthma association with the increased prevalence of anemia.4,5 No studies, however, have been conducted on whether severe or uncontrolled asthma can more increase the prevalence of anemia.We hypothesized that patients with severe asthma were more likely to have an active inflammatory condition, which may increase the prevalence of anemia. Therefore, this study aims to evaluate whether the prevalence of anemia in pediatric asthma patients differs according to asthma control or severity.98% of Koreans are enrolled in the universal health insurance system, and all medical information is reported to the Health Insurance Review Agency (HIRA). In this study, 10% (~1,100,000) of patients under the age of 20 provided by HIRA were analyzed using a dataset constructed by random stratification based on age and sex (HIRA-PPS-2016).6 We included patients younger than 18 years and patients prescribed asthma medications with diagnosis of asthma (eTable1, eTable2). Patients diagnosed with anemia other than iron deficiency anemia (IDA) or AI were excluded. We classified the severe asthma group who were diagnosed with asthma exacerbation at least once a year or asthma diagnosis with systemic steroids, and the rest were defined as the non-severe asthma group. Binary logistic regression was carried out by applying inverse probability of treatment weighting (IPTW) using the propensity score. To calculate the predicting propensity score, we used a multivariable logistic regression model to estimate the probability of each patient, including confounders (eTable1). Odds ratio (OR) with 95% confidence interval (CI) are reported for association anemia and asthma severity.A total of 236,429 pediatric patients were included in the study. The flow diagram for the study subject inclusion is shown (Fig. 1) and the characteristics of the two groups of patients were similarly adjusted after applying IPTW (eTable3). The increased prevalence of anemia in patients with severe asthma was expressed OR of 1.56 (95% CI, 1.49-1.64; P < .001) (Table 1). The association between anemia and asthma severity in children, male, female, or patients under health insurance was expressed OR of 1.63 (95% CI, 1.55-1.71; P < .001), 1.59 (95% CI, 1.49-1.70; P <.001), 1.53 (95% CI, 1.42-1.64; P < .001), and 1.56 (95% CI, 1.49-1.64; P < .001), respectively. There were no associations between anemia and severe asthma in adolescents and patients under medical aid (Table 1).The prevalence of anemia in patients who experienced exacerbation of asthma or with systemic steroid was analyzed higher than other asthma patients. This was the same even after adjusting for other confounding factors in the two patient groups. Previous study suggested that the correlation between the two diseases in those groups may have been insignificant since adolescent patients or patients under medical aid program may have different medical service usage patterns from those of general patients.5We do not monitor anemia for asthma patients in general, and the guidelines do not present it in this regard. However, anemia negatively affects pediatric patients’ growth, cognitive abnormalities, and poor quality of life.7,8 In addition, in the case of AI, treatment or control of the underlying disease takes precedence over the treatment of anemia rather than simply administering iron or EPO.9 In addition, it was reported that in patients with high hepcidin, an index that can distinguish between AI and IDA, administration of EPO or iron administration was less or non-response to the treatment of anemia.11-12 Therefore, it might be recommended to monitor and treat anemia since the prevalence of anemia may increase in pediatric patients with severe asthma.This study has some limitations. First, we reported the association between severe asthma and anemia which is not the causality. Secondly, since we included patients diagnosed with IDA, the influence of patients with isolated IDA cannot be ruled out. Nevertheless, our study has several strengths including a large sample size and statistical adjustments with propensity weighting.To our knowledge, this is the first study to show that severe asthma has a stronger association with anemia compared to non-severe or controlled asthma. This suggests that it may be necessary to more closely monitor anemia in patients with severe asthma. Further study is needed to better understand the etiology that severe asthma causes more AI.

Rheumatoid arthritis (RA) is a systemic inflammatory autoimmune disease that leads to joint destruction and disability. Despite a significant progress in administration of biological agents for RA patients, there is still a need for improved therapy. Intravenous-immunoglobulins (IVIG) , a pooled polyspecific immunoglobulin-G (IgG) extracted from 20,000 healthy subjects, showed beneficial therapeutic effect in patients with immune-deficiency, sepsis, and autoimmune diseases. The current study aim to investigate the beneficial effect of treatment with IVIG in established collagen induced arthritis in DBA/1j mice. Murine arthritis was induced in DBA/1j mice. The treatment with IVIG started when the disease was established. The clinical score was followed twice a week until day 48. The mice were bled for plasma, the paws were H&E stained. Cytokine profile in the plasma was analyzed by Luminex technology, titers of circulating anti-collagen antibodies in the plasma was tested by ELISA. Our results show that treatment with IVIG in murine, significantly rreduced the clinical arthritis score (P<0.001). Moreover, mode of action show that IVIG significantly reduced circulating level of inflammatory cytokines (IFN, IL-1β, IL-17, IL-6, TNFα) (P<0.001), inhibit anti-collagen antibodies (P < 0.001) in the plasma of CIA mice. Importantly, histopathological examination revealed that IVIG treatment prevented the migration of inflammatory immune cells into the cartilage and synovium, reduced the extent of joint damage and preserved joint architecture. Our results proved for the first time the valuable anti-inflammatory treatment of IVIG in experimental RA. We propose IVIG therapy for a subgroup of patients with as rheumatological-related diseases.

The skin is a unique immune organ that constitutes a complex network of physical, chemical, and microbiological barriers against external insults. Keratinocytes are the most abundant cell type in the epidermis. These cells form the physical skin barrier and represent the first line of the host defense system by sensing pathogens via innate immune receptors, initiating antimicrobial responses and producing various cytokines, chemokines and antimicrobial peptides, which are important events in immunity. A damaged epidermal barrier in atopic dermatitis allows the penetration of potential allergens and pathogens to activate keratinocytes. Among the dysregulation of immune responses in atopic dermatitis, activated keratinocytes play a role in several biological processes that contribute to the pathogenesis of atopic dermatitis. In this review, we summarize the current understanding of the innate immune functions of keratinocytes in the pathogenesis of atopic dermatitis, with a special emphasis on skin-derived antimicrobial peptides and atopic dermatitis-related cytokines and chemokines in keratinocytes. An improved understanding of the innate immunity mediated by keratinocytes can provide helpful insight into the pathophysiological processes of atopic dermatitis and support new therapeutic efforts.

Background and Purpose: Hypertrophic scar (HS) is a serious fibrotic skin disease. The roles of bacterial contamination and prolonged inflammation in wound were considered to be significant. IL-10 plays a pivotal role in wound healing and scar formation. Here, we investigate whether IL-10 alleviates lipopolysaccharide (LPS)-induced inflammatory response and skin scarring, explore the possible mechanism in scar formation. Experimental Approach: RT-qPCR, Western blotting, histochemistry, immunostaining, ELISA array, electron microscope, fibroblast-populated collagen lattice (FPCL) and a rabbit ear scar model were used to investigate and validate the effect of IL-10 on LPS-stimulated scar formation. Key Results: Our results showed that the expression of TLR4 and pp65 was higher in HS and HS-derived fibroblasts (HSFs) than their counterpart normal skin (NS) and NS-derived fibroblasts (NSFs). LPS could upregulate the expression of TLR4, pp65, Col I, Col III and α-SMA in NSFs, but IL-10 could downregulate their expression in both HSFs and LPS-induced NSFs. Blocking IL-10 receptor (IL-10R) or the phosphorylation of STAT3, their expression was upregulated. In addition, in vitro and in vivo models results showed that IL-10 could alleviate LPS-induced fibroblast-populated collagen lattice (FPCL) contraction and scar formation. Conclutions and Implications: Our study suggests that IL-10 may improve LPS-induced harmful to wound healing, reduce scar contracture and scar formation via IL-10R/STAT3 axis regulating TLR4/NF-κB pathway in dermal fibroblasts by reducing ECM proteins deposition and the conversion of HSFs to NSFs. Therefore, the downregulation of inflammation may be a better option for improving scar quality, and become potential therapeutic targets for scarring.

Trauma is a major cause of morbidity and mortality throughout the world. Alarmingly the mortality rate, owing to multiple causes with or without sepsis, is now reported to cross the value of 50%. The preliminary study was conducted in humans to investigate the 1) safety of estrogen therapy following trauma hemorrhage 2) Does estrogen reduced the inflammatory storms caused due to trauma 3) Does estrogen affects the survival of THS patients and prevent the advancement of sepsis-associated problems. 40, THS patients and 20 healthy controls were recruited. THS patients were divided into experimental groups and placebo controls based on the estrogen administration in the ED. Serum level of cytokines and immune cells were measured at different time points on days 0, 3, 7, and 14 in both groups of THS patients. Patients receiving intravenous estrogen beside standard of care as per ATLS guidelines did not develop any major or minor adverse events and showed favorable clinical outcomes during their course of stay in the ED and ICU. The levels of T regulatory cells, monocytes, and systemic cytokines were significantly reduced in THS patients who received estrogen. Again, THS patients who received estrogen recovered early, do not have side effects and showed a balanced inflammatory response. In conclusion, this preliminary study showed that intravenous estrogen therapy is safe and overcame the problem of inflammatory insults caused due to trauma hemorrhagic shock. It may protect from sepsis-associated complications among THS patients.

Extracellular adenosine triphosphate (eATP) mediates pro-inflammatory responses by recruiting and activating inflammatory cells. eATP is hydrolyzed by CD39 to adenosine monophosphate (AMP), which is converted to the immunosuppressive nucleoside adenosine (ADO) by CD73. CD39 is the rate-limiting enzyme in this cascade and can be viewed as an immunological switch that shifts ATP-driven pro-inflammatory immune cell activity to an anti-inflammatory state mediated by ADO. CD39 is expressed by a broad range of immune cells and can be influenced by genetic and environmental factors. Accumulating evidence suggests that CD39 is involved in several pathophysiological events, such as inflammatory bowel diseases, sepsis, ischemia-reperfusion injury, allergic diseases, systemic lupus erythematosus, diabetes, and cancer. Here, we focus on the current understanding of CD39 in immunity, and presents a comprehensive picture of the multiple roles of CD39 in a variety of disorders.

Background: Severe asthma exacerbation is an important comorbidity of the 2009 HIN1 pandemic [A(H1N1)pdm09] in asthmatic patients. However, the mechanisms underlying severe asthma exacerbation remain unknown. Using a mouse model of asthma, we evaluated airway hyperresponsiveness (AHR) in mice with A(H1N1)pdm09 infection and those with seasonal influenza for comparison. We also measured AHR in paediatric participants infected with A(H1N1)pdm09. Methods: BALB/c mice aged 6-8 weeks were sensitized and challenged with ovalbumin. Either mouse-adapted A(H1N1)pdm09, seasonal H1N1 virus (1×105 pfu/20 μL), or mock treatment as a control was administered intranasally. At 3, 7, and 10 days after infection, each group of mice was evaluated for AHR by methacholine challenge using an animal ventilator, flexiVent®. Lung samples were resected and observed using light microscopy to assess the degree of airway inflammation. AHRs in paediatric participants were defined as the provocative acetylcholine concentration causing a 20% reduction in FEV1.0 (PC20). Results: Airway resistance was significantly enhanced in A(H1N1)pdm09-infected asthmatic mice compared to that in seasonal H1N1-infected mice (p<0.001), peaking at 7 days post-infection and then becoming similar to control levels by 10 days post-infection. Histopathological examination of lung tissues showed more intense infiltration of inflammatory cells and severe tissue destruction in A(H1N1)pdm09-infected mice at 7 days post-infection than at 10 days post-infection. AHRs in the paediatric participants were temporarily increased, and alleviated by 3 months after discharge. Conclusions: Our results suggest that enhanced AHR could contribute to severe exacerbation in human asthmatic patients with A(H1N1)pdm09 infection.

Background and Purpose: Diosmetin (Dios) exerted a hepatoprotective effect against nonalcoholic steatohepatitis (NASH), but few reports interpreted clearly that the alleviation of Dios against NASH were associated with the inhibition of signal transducers and activators of transcription 1 (STAT1) and macrophage chemotactic ligand 10 (CXCL10). Meanwhile, the mechanism of Dios involved with STAT1/CXCL10 mediated pathway was unknown yet. Experimental Approach: Here, high-fat diet (HFD) and palmitic acid (PA) were used to induced NASH model in mice and HepG2 cells, respectively. The liver RNA-Seq was used to reveal the key targets interfered by Dios. The impacts of Dios on the expressions of STAT1, CXCL10 and the levels of genes and proteins associated with lipogenesis and inflammation were measured by qRT-PCR and western blot assays. The STAT1 inhibitor, STAT1 overexpression plasmid, and CXCL10 siRNA were utilized to clarify the mechanism of Dios against NASH through STAT1 / CXCL10. Key Results: Dios could reduce functional parameters and morphological changes in HepG2 cells and NASH mice. Additionally, Dios alleviated the expressions of key targets STAT1 and CXCL10, and their downstream proteins involved with lipogenesis and inflammation. Interestingly, NASH was ameliorated in STAT1-inhibited mice and HepG2 cells. Unfortunately, transfecting HepG2 cells with STAT1 over-expression plasmid aggravated the development of NASH and reduced Dios-conferred hepatoprotective effect. Conclusions and Implications: The alleviation of Dios against NASH was through mediation of lipogenesis and inflammatory response via STAT1/CXCL10-dependent pathway. Therefore, Dios has good hepatoprotective effects and potentiality as a promising therapeutic agent for NASH in clinical application.