Journal of Immunotoxicology最新文献

{"title":"Surgical stress quickly affects the numbers of circulating B-cells and neutrophils in murine septic and aseptic models through a β2 adrenergic receptor","authors":"R. Nishioka, Y. Nishi, Mohammed E. Choudhury, Riko Miyaike, Ayataka Shinnishi, K. Umakoshi, Yasutsugu Takada, Norio Sato, M. Aibiki, Hajime Yano, Junya Tanaka","doi":"10.1080/1547691X.2022.2029630","DOIUrl":"https://doi.org/10.1080/1547691X.2022.2029630","url":null,"abstract":"Abstract Sepsis is a pathology accompanied by increases in myeloid cells and decreases in lymphoid cells in circulation. In a murine sepsis model induced by cecum ligation and puncture (CLP), increasing numbers of neutrophils and decreasing levels of B-cells in circulation are among the earliest changes in the immune system. However, to date, the mechanisms for these changes remain to be elucidated. The study here sought to elucidate mechanisms underlying the changes in the leukocyte levels after CLP and also to determine what, if any, role for an involvement of the sympathetic nervous system (SNS). Here, male C57/BL6 mice were subjected to CLP or sham-CLP (abdominal wall incised, but cecum was not punctured). The changes in the number of circulating leukocytes over time were then investigated using flow cytometry. The results showed that a sham-CLP led to increased polymorphonuclear cells (PMN; most of which are neutrophils) and decreased B-cells in the circulation to an extent similar to that induced by CLP. Effects of adrenergic agonists and antagonists, as well as of adrenalectomy, were also examined in mice that underwent CLP or sham-CLP. Administering adrenaline or a β2 adrenergic receptor agonist (clenbuterol) to mice 3 h before sacrifice produced almost identical changes to as what was seen 2 h after performing a sham-CLP. In contrast, giving a β2 adrenergic receptor antagonist ICI118,551 1 h before a CLP or sham-CLP suppressed the expected changes 2 h after the operations. Noradrenaline and an α1 adrenergic receptor agonist phenylephrine did not exert significant effects. Adrenalectomy 24 h before a sham-CLP significantly abolished the expected sham-CLP-induced changes seen earlier. Clenbuterol increased splenocyte expression of Cxcr4 (a chemokine receptor gene); adrenalectomy abolished sham-CLP-induced Cxcr4 expression. A CXCR4 antagonist AMD3100 repressed the sham-CLP-induced changes. From these results, it may be concluded that sepsis-induced activation of the SNS may be one cause for immune dysfunction in sepsis – regardless of the pathogenetic processes.","PeriodicalId":16073,"journal":{"name":"Journal of Immunotoxicology","volume":"19 1","pages":"8 - 16"},"PeriodicalIF":3.3,"publicationDate":"2022-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42996302","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Highly sensitive <i>in vitro</i> cytokine release assay incorporating high-density preculture.","authors":"Shiho Ito,&nbsp;Kyoko Miwa,&nbsp;Chiharu Hattori,&nbsp;Tetsuo Aida,&nbsp;Yoshimi Tsuchiya,&nbsp;Kazuhiko Mori","doi":"10.1080/1547691X.2021.1984617","DOIUrl":"https://doi.org/10.1080/1547691X.2021.1984617","url":null,"abstract":"<p><p>Immunostimulatory effects of monoclonal antibodies (mAb) through binding to F_cγ receptors (F_cγR) on immune cells are a likely cause of cytokine release syndrome. However, it is difficult to detect the potential risk of F_cγR-dependent cytokine release associated with mAb in the current standard cytokine release assays (CRA), including the air-drying solid-phase method using human peripheral blood mononuclear cells (PBMC). To increase the sensitivity to detect F_cγR-dependent cytokine release due to mAb, a high-density preculture (HDC) method was incorporated into the air-drying solid-phase CRA. Here, PBMC were exposed to panitumumab, trastuzumab, rituximab, or alemtuzumab at 0.1, 0.3, 1, and 3 μg/well for 24 or 48 hr under both non-HDC and HDC conditions. T-cell agonists (anti-CD3 mAb, anti-CD28 super-agonist [SA] mAb) were used as reference mAb. Panitumumab, trastuzumab, rituximab, or alemtuzumab induced cytokine release under both non-HDC and HDC conditions, and cytokine release caused by alemtuzumab was more pronounced under HDC conditions. To investigate F_cγR involvement in cytokine release associated with panitumumab, trastuzumab, rituximab, and alemtuzumab, CRA of these four mAb were conducted with anti-F_cγRI, -F_cγRII, or -F_cγRIII F(ab')₂ fragments. The results showed cytokine release caused by trastuzumab, rituximab, and alemtuzumab was significantly suppressed by anti-F_cγRIII F(ab')₂ pretreatment, and slightly reduced by anti-F_cγRI or anti-F_cγRII pretreatment, indicating these mAb induced F_cγR (especially F_cγRIII)-dependent cytokine release from PBMC. Cytokine release caused by panitumumab was slightly suppressed by anti-F_cγRIII F(ab')₂ pretreatment. Anti-CD3 mAb and anti-CD28 SA mAb also induced significant release of cytokines under HDC conditions compared with that under non-HDC conditions. In conclusion, CRA incorporating HDC into the air-drying solid-phase method using human PBMC could sensitively capture the F_cγR-dependent cytokine release potential of mAb.</p>","PeriodicalId":16073,"journal":{"name":"Journal of Immunotoxicology","volume":" ","pages":"136-143"},"PeriodicalIF":3.3,"publicationDate":"2021-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39515293","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of injection buffer volume to perform bronchoalveolar lavage fluid collection for isolating alveolar macrophages to investigate fine particle-induced IL-1α secretion.","authors":"Eita Sasaki,&nbsp;Haruka Momose,&nbsp;Keiko Furuhata,&nbsp;Takuo Mizukami,&nbsp;Isao Hamaguchi","doi":"10.1080/1547691X.2021.1979699","DOIUrl":"https://doi.org/10.1080/1547691X.2021.1979699","url":null,"abstract":"<p><p>The importance of alveolar macrophages has been reported in many toxicology/immunology studies. Alveolar macrophages release interleukin (IL)-1α as a damage-associated molecular pattern (DAMP) when stimulated by fine particles. However, it is unclear whether cell isolation procedures affect <i>ex vivo</i> particle-induced responses in primary mouse alveolar macrophages (mAM). In this study, effects of injection buffer volume used to perform bronchoalveolar lavage fluid (BALF) collection to isolate mAM for use in <i>ex vivo</i> particle-induced responses were assessed. Among the mAM obtained from BALF collected using a 0.55 or 0.75 ml, but not a 1.0 ml buffer injection volume, decreased cell viability and IL-1α release were observed when cells were stimulated <i>ex vivo</i> with silica crystal or aluminum salt. Injected buffer composition did not affect the IL-1α release. On the other hand, IL-6 secretion induced by lipopolysaccharide (LPS) did not differ among mAM obtained from BALF collected using the different volumes. Expression levels of cell surface markers like CD11c, SiglecF, and CD64 did not differ among mAM obtained from BALF collected using the different injection buffer volumes. IL-1α release (and also necroptosis) induced by <i>ex vivo</i>particle stimulation was suppressed by RIPK3 inhibitor or cytochalasin D co-treatment. Decreases in RIPK3 phosphorylation were noted in mAM obtained in BALF collected using the 1.0 ml injection volume compared with mAM obtained in BALF using 0.55 or 0.75 ml buffer. These observations illustrate that larger volumes of buffer used to collect BALF from mice can affect sensitivity of the isolated mAM to <i>ex vivo</i> particle-induced responses by inhibiting their functions.</p>","PeriodicalId":16073,"journal":{"name":"Journal of Immunotoxicology","volume":" ","pages":"163-172"},"PeriodicalIF":3.3,"publicationDate":"2021-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39863816","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Renal tubular cell necroptosis: A novel mechanism of kidney damage in trichloroethylene hypersensitivity syndrome mice.","authors":"Yican Wang,&nbsp;Meng Huang,&nbsp;Xin Du,&nbsp;Yiting Hong,&nbsp;Liping Huang,&nbsp;Yuying Dai,&nbsp;Qifeng Wu,&nbsp;Feng Wang,&nbsp;Qixing Zhu","doi":"10.1080/1547691X.2021.2003486","DOIUrl":"https://doi.org/10.1080/1547691X.2021.2003486","url":null,"abstract":"<p><p>Trichloroethylene (TCE) hypersensitivity syndrome (THS), called occupational medicamentosa-like dermatitis due to TCE (OMDT) in China, is a fatal occupational disorder caused by TCE exposure. Visceral damage, including kidney injury, is one of the major complications. Necroptosis is a regulated cell death form linked to local inflammatory response. This study aimed to investigate whether renal cell necroptosis was involved in TCE-induced kidney injury. A Balb/c mouse model of TCE sensitization was utilized to study mechanisms of modulation of TCE-induced renal necroptosis. Renal histology (using light and transmission electron microscopy) and renal tubular impairment indexes, including α1-microglobulin (α1-MG), and β2-microglobulin (β2-MG), were evaluated. In addition, tissue expression of necroptosis-related proteins, including tumor necrosis factor (TNF)-α, TNF receptor 1 (TNFR1), receptor-interacting protein kinase 3 (RIPK3), p-RIK3, mixed lineage kinase domain-like protein (MLKL), and p-MLKL, were also evaluated. The study here confirmed TCE sensitization caused damage to renal tubules and renal tubular epithelial cell (RTEC) necroptosis. In mice treated with R7050 (a specific TNFα antagonist), it was also seen that inhibition of TNFα expression could effectively inhibit RTEC necroptosis and improve renal function in the TCE-sensitized mice. Taken together, these results help to define a novel mechanism by which RTEC necroptosis plays a key role in TCE-induced kidney damage.</p>","PeriodicalId":16073,"journal":{"name":"Journal of Immunotoxicology","volume":" ","pages":"173-182"},"PeriodicalIF":3.3,"publicationDate":"2021-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39898939","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A T-dependent antibody response evaluation in CD-1 mice after an acute whole-body inhalation exposure to nickel (II) chloride hexahydrate.","authors":"Samuel Buxton,&nbsp;Michael D Taylor,&nbsp;Jeffrey T Weinberg,&nbsp;James M Randazzo,&nbsp;Vanessa L Peachee,&nbsp;Adriana Oller","doi":"10.1080/1547691X.2021.1984618","DOIUrl":"https://doi.org/10.1080/1547691X.2021.1984618","url":null,"abstract":"<p><p>Nickel (Ni) in ambient air may vary regionally with contributions from both natural processes and anthropogenic activities. Exposure to Ni compounds in ambient air above a certain level is associated with acute adverse effects, such as upper respiratory tract irritation, pneumonitis, and chronic adverse effects, such as respiratory cancer. Inhalation reference exposure standards are enacted in different jurisdictions to minimize exposures to ambient Ni above levels that can elicit adverse effects. This paper reports a guideline-/GLP-compliant study designed for setting inhalation exposure standards to protect from immunological effects associated with acute exposure to Ni. Female CD-1 mice were exposed via whole-body inhalation to aerosolized nickel chloride hexahydrate for 24-hr at nominal (vs. mean analyzed) concentrations of 20 (16), 50 (44) and 100 (81) µg Ni/m³. Host T-cell antibody immunological responses to intravenously-injected sheep red blood cells were then measured <i>ex vivo</i> in an Antibody-Forming Cell (AFC) assay. Exposure to the Ni substance significantly decreased spleen cell levels by 33%, but this was within biological variability for outbred mice. No concurrent decreases in spleen, thymus, or body weights were noted. No immunosuppression was observed with the Ni substance in the context of Total Spleen Activity [IgM AFC/spleen (× 10³)] and Specific Activity [IgM AFC/spleen cells (× 10⁶)]. Significant concentration-independent increases in Total Spleen Activity and Specific Activity seen with the nickel chloride hexahydrate were normal and within biological variability for outbred mice. In contrast, cyclophosphamide (positive control) significantly decreased spleen cell numbers, spleen and thymus weights, and abolished Specific Activity and Total Spleen Activity. Based on results here, an NOAEC of 81 µg Ni/m³ for immunosuppressive effects from inhaled nickel chloride hexahydrate was identified. It is hoped this value can be used to derive a reference standard for human exposure to ambient Ni.</p>","PeriodicalId":16073,"journal":{"name":"Journal of Immunotoxicology","volume":" ","pages":"144-153"},"PeriodicalIF":3.3,"publicationDate":"2021-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39539330","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of mono-culture vs. Co-culture of keratinocytes and monocytes on cytokine responses induced by important skin sensitizers.","authors":"Venkatanaidu Karri,&nbsp;Carola Lidén,&nbsp;Nanna Fyhrquist,&nbsp;Johan Högberg,&nbsp;Hanna L Karlsson","doi":"10.1080/1547691X.2021.1905754","DOIUrl":"https://doi.org/10.1080/1547691X.2021.1905754","url":null,"abstract":"<p><p>Sensitization to a contact allergen brings with it a lifelong risk to develop allergic contact dermatitis. Inflammation is an important part of the skin sensitizing mechanism, and understanding how different haptens stimulate the immune system, as well as the role played by different cell types present in skin, may be helpful for developing optimized <i>in vitro</i> models for risk assessment of new chemicals or mixtures. The aim of this study was to compare the cytokine profile following exposure of cells representing keratinocytes (HaCaT), monocytes (THP-1) and a co-culture of these cells to three clinically important skin sensitizers: cobalt (II) chloride (CoCl₂), methylisothiazolinone (MI) and p-phenylenediamine (PPD). Secretion of ten pro-inflammatory cytokines was measured using multiplexing. The results showed that the cytokine response differed substantially between the three cell assays. CoCl₂ caused an increase of IL-8 in HaCaT cells, while the induction of also IL-13 and IL-1β was observed in THP-1 cells and co-cultures. MI induced six cytokines in HaCaT cells but only IL-1β in the THP-1 cells and four cytokines in the co-culture. Interestingly, the IL-1β response was massive in the co-culture. PPD caused release of IL-1β in all three models as well as IL-8 in the co-culture. Control experiments with two non-sensitizers and irritants (lactic acid and sodium dodecyl sulfate) showed no effect on IL-8 or IL-1β in the co-culture. Taken together, results from this exploratory analysis show unique cytokine profiles dependent on the type of hapten and cell model. Importantly, all three haptens triggered secretion of IL-1β and IL-8 in a co-culture of HaCaT cells and THP-1 cells, representing the most robust test system.</p>","PeriodicalId":16073,"journal":{"name":"Journal of Immunotoxicology","volume":" ","pages":"74-84"},"PeriodicalIF":3.3,"publicationDate":"2021-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/1547691X.2021.1905754","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39005597","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Serum vaccine antibody concentrations in adults exposed to per- and polyfluoroalkyl substances: A birth cohort in the Faroe Islands.","authors":"Yu-Hsuan Shih,&nbsp;Annelise J Blomberg,&nbsp;Marie-Abèle Bind,&nbsp;Dorte Holm,&nbsp;Flemming Nielsen,&nbsp;Carsten Heilmann,&nbsp;Pál Weihe,&nbsp;Philippe Grandjean","doi":"10.1080/1547691X.2021.1922957","DOIUrl":"https://doi.org/10.1080/1547691X.2021.1922957","url":null,"abstract":"<p><p>Per- and polyfluoroalkyl substances (PFASs) are highly persistent in the environment and may cause depressed immune function. Previous studies have linked PFAS exposure to lower vaccine responses in children, but research in adults is limited. Therefore, the present study evaluated the associations between exposure to PFASs and serum antibody concentrations in adults vaccinated at age 28 years in the Faroe Islands. PFAS concentrations were determined from cord-blood collected at birth and serum samples collected at ages 7, 14, 22, and 28 years. Serum antibody concentrations against hepatitis type A and B, diphtheria, and tetanus were analyzed from blood samples collected about 6 mo after the first vaccine inoculation at age 28 years. Linear regression models were used to estimate changes in antibody concentration for each doubling of PFAS concentration. Potential effect modification by sex was assessed by including an interaction term between PFAS and sex. Although the 95% confidence intervals contain the null value, inverse trends were observed between serum perfluorooctanoate (PFOA) at ages 14 and 28 years and hepatitis type A antibody (anti-HAV) concentrations, as revealed by an estimated decrease of 0.71 (95% CI: -1.52, 0.09) and 0.24 (95% CI: -0.59, 0.10) signal-to-cutoff ratio for each doubling of exposure, respectively. Inverse trends were also observed between serum PFOA at ages 22 and 28 years and hepatitis type B antibody (anti-HBs) concentration, with an estimated decrease of 21% (95% CI: -42.20%, 7.34%) and of 17% (95% CI: -35.47%, 7.35%) in anti-HBs for each doubling of exposure, respectively. Sex-specific associations with anti-HAV were observed for cord-blood PFASs and serum PFAS concentrations at ages 7 and 14 years. No inverse associations of PFAS exposure were found with diphtheria and tetanus antibody concentrations. Future studies are needed to confirm these findings and further investigate the effects of PFASs on adult immune function.</p>","PeriodicalId":16073,"journal":{"name":"Journal of Immunotoxicology","volume":"18 1","pages":"85-92"},"PeriodicalIF":3.3,"publicationDate":"2021-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/1547691X.2021.1922957","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9558832","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immune activation by microbiome shapes the colon mucosa: Comparison between healthy rat mucosa under conventional and germ-free conditions.","authors":"Fabián Čaja,&nbsp;Dmitry Stakheev,&nbsp;Oleksander Chernyavskiy,&nbsp;Jiří Křížan,&nbsp;Jiří Dvořák,&nbsp;Pavel Rossmann,&nbsp;Renata Štěpánková,&nbsp;Peter Makovický,&nbsp;Pavol Makovický,&nbsp;Hana Kozáková,&nbsp;Luca Vannucci","doi":"10.1080/1547691X.2021.1887412","DOIUrl":"https://doi.org/10.1080/1547691X.2021.1887412","url":null,"abstract":"<p><p>Germ-free animals (GF) are those without a microbiome since birth. This particular biological model has become one of special interest with the growing evidence of importance of the microbiome in the life, development, adaptation, and immunity of humans and animals in the environments in which they live. Anatomical differences observed in GF compared with conventionally-reared animals (CV) has given rise to the question of the influence of commensal microflora on the development of structure and function (even immunological) of the bowel. Only recently, thanks to achievements in microscopy and associated methods, structural differences can be better evaluated and put in perspective with the immunological characteristics of GF vs. CV animals. This study, using a GF rat model, describes for the first time the possible influence that the presence of commensal microflora, continuously stimulating mucosal immunity, has on the collagen scaffold organization of the colon mucosa. Significant differences were found between CV and GF mucosa structure with higher complexity in the CV rats associated to a more activated immune environment. The immunological data suggest that, in response to the presence of a microbiome, an effective homeostatic regulation in developed by the CV rats in healthy conditions to avoid inflammation and maintain cytokine levels near the spontaneous production found in the GF animals. The results indicated that collagen scaffold adapted to the immune microenvironment; therefore, it is apparent that the microbiome was able to condition the structure of the colon mucosa.</p>","PeriodicalId":16073,"journal":{"name":"Journal of Immunotoxicology","volume":" ","pages":"37-49"},"PeriodicalIF":3.3,"publicationDate":"2021-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/1547691X.2021.1887412","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25503059","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"From nicotine to the cholinergic anti-inflammatory reflex - Can nicotine alleviate the dysregulated inflammation in COVID-19?","authors":"Alex G Gauthier,&nbsp;Mosi Lin,&nbsp;Jiaqi Wu,&nbsp;Thomas P Kennedy,&nbsp;Lee-Anne Daley,&nbsp;Charles R Ashby,&nbsp;Lin L Mantell","doi":"10.1080/1547691X.2021.1875085","DOIUrl":"https://doi.org/10.1080/1547691X.2021.1875085","url":null,"abstract":"<p><p>The coronavirus SARS-CoV-2 of 2019 (COVID-19) causes a pandemic that has been diagnosed in more than 70 million people worldwide. Mild-to-moderate COVID-19 symptoms include coughing, fever, myalgia, shortness of breath, and acute inflammatory lung injury (ALI). In contrast, acute respiratory distress syndrome (ARDS) and respiratory failure occur in patients diagnosed with severe COVID-19. ARDS is mediated, at least in part, by a dysregulated inflammatory response due to excessive levels of circulating cytokines, a condition known as the \"cytokine-storm syndrome.\" Currently, there are FDA-approved therapies that attenuate the dysregulated inflammation that occurs in COVID-19 patients, such as dexamethasone or other corticosteroids and IL-6 inhibitors, including sarilumab, tocilizumab, and siltuximab. However, the efficacy of these treatments have been shown to be inconsistent. Compounds that activate the vagus nerve-mediated cholinergic anti-inflammatory reflex, such as the α7 nicotinic acetylcholine receptor agonist, GTS-21, attenuate ARDS/inflammatory lung injury by decreasing the extracellular levels of high mobility group box-1 (HMGB1) in the airways and the circulation. It is possible that HMGB1 may be an important mediator of the \"cytokine-storm syndrome.\" Notably, high plasma levels of HMGB1 have been reported in patients diagnosed with severe COVID-19, and there is a significant negative correlation between HMGB1 plasma levels and clinical outcomes. Nicotine can activate the cholinergic anti-inflammatory reflex, which attenuates the up-regulation and the excessive release of pro-inflammatory cytokines/chemokines. Therefore, we hypothesize that low molecular weight compounds that activate the cholinergic anti-inflammatory reflex, such as nicotine or GTS-21, may represent a potential therapeutic approach to attenuate the dysregulated inflammatory responses in patients with severe COVID-19.</p>","PeriodicalId":16073,"journal":{"name":"Journal of Immunotoxicology","volume":" ","pages":"23-29"},"PeriodicalIF":3.3,"publicationDate":"2021-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/1547691X.2021.1875085","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38799112","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Safety and efficacy of using heat-killed <i>Lactobacillus plantarum</i> L-137: High-dose and long-term use effects on immune-related safety and intestinal bacterial flora.","authors":"Hiroko Nakai,&nbsp;Shinji Murosaki,&nbsp;Yoshihiro Yamamoto,&nbsp;Michiko Furutani,&nbsp;Rumiko Matsuoka,&nbsp;Yoshitaka Hirose","doi":"10.1080/1547691X.2021.1979698","DOIUrl":"https://doi.org/10.1080/1547691X.2021.1979698","url":null,"abstract":"<p><p>Heat-killed <i>Lactobacillus plantarum</i> L-137 (HK L-137) promotes immune function in animals. In healthy people, T-cell proliferation was shown to be enhanced by taking 10 mg HK L-137 daily for 12 weeks. However, the safety and efficacy of higher doses or longer treatments have not yet been investigated in humans. To investigate the high-dose and long-term use effects of HK L-137 on immune-related safety and on host intestinal bacterial flora, 15 healthy volunteers took a daily HK L-137 (50 mg) preparation for 4 weeks. An additional 29 participants who regularly visited a clinic for health care took HK L-137 (10 mg) daily for 12 months. Measures for anthropometrics, hematology, biochemistry, and urinalysis were taken at scheduled timepoints for all participants. Stool and blood samples were also collected and evaluated for microbes and short-chain fatty acids (SCFA); isolated T-cells were assessed for levels of proliferation induced by phytohemagglutinin in the long-term study. Adverse events or shifts in clinical measures from normal ranges due to the dietary intervention were not observed in the high-dose or long-term studies. Long-term intake also did not result in immune exhaustion due to any chronic immunostimulation; <i>ex vivo</i> T-cell proliferation was significantly greater at 12 months than at baseline (<i>p</i> < 0.01). In addition, the <i>Firmicutes</i>/<i>Bacteroidetes</i> ratio in stool samples was significantly lower at 12 months than at baseline (<i>p</i> < 0.05) due to the long-term intake of the HK L-137. Lastly, fecal SCFA concentrations were significantly greater (<i>p</i> < 0.05) at 6 months than at baseline. From these data, it can be concluded that the efficacy of HK L-137 is maintained with no overt adverse effects as a result of high-dose and/or long-term consumption.</p>","PeriodicalId":16073,"journal":{"name":"Journal of Immunotoxicology","volume":" ","pages":"127-135"},"PeriodicalIF":3.3,"publicationDate":"2021-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39445540","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}