To achieve immune homeostasis in such a harsh environment as the intestinal mucosa, both active and quiescent immunity operate simultaneously. Disruption of gut immune homeostasis leads to the development of intestinal immune diseases such as colitis and food allergies. Among various intestinal innate immune cells, mast cells (MCs) play critical roles in protective immunity against pathogenic microorganisms, especially at mucosal sites. This suggests the potential for a novel MC-targeting type of vaccine adjuvant. Dysregulated activation of MCs also results in inflammatory responses in mucosal compartments. The regulation of this yin and yang function of MCs remains to be elucidated. In this review, we focus on the roles of mucosal MCs in the regulation of intestinal allergic reaction, inflammation and their potential as a new target for the development of mucosal adjuvants.
Adjuvants, Immunologic/*therapeutic use ; Animals ; Humans ; Hypersensitivity/*immunology/prevention & control ; Inflammation/immunology/metabolism/prevention & control ; Intestinal Mucosa/cytology/*immunology ; Mast Cells/*immunology

OBJECTIVEA general review was made of studies involving: (1) the concept and mechanism of the cholinergic anti-inflammatory pathway (CAP), (2) the important role of inflammatory response in myocardial ischemia reperfusion (I/R) injury and (3) the evidence and mechanisms by which CAP may provide protection against myocardial I/R injury.

DATA SOURCESThe data used in this review were mainly from manuscripts listed in PubMed that were published in English from 1987 to 2009. The search terms were "vagal nerve stimulation", "myocardial ischemia reperfusion injury", "nicotine acetylcholine receptor" and "inflammation".

STUDY SELECTION(1) Clinical and experimental evidence that the inflammatory response induced by reperfusion enhances myocardial I/R injury. (2) Clinical and laboratory evidence that the CAP inhibits the inflammation and provides protection against myocardial I/R injury.

RESULTSThe myocardial I/R injury is really an inflammatory process characterized by recruitment of neutrophils into the ischemic myocardium and excessive production of pro-inflammatory cytokines. Because the CAP can modulate the inflammatory response by decreasing the production and release of pro-inflammatory cytokines, it can provide protection against myocardial I/R injury.

CONCLUSIONSThe CAP can inhibit the inflammatory response induced by reperfusion and protect against myocardial I/R injury. It represents an exciting opportunity to develop new and novel therapeutics to attenuate the myocardial I/R injury.

Animals ; Cytokines ; metabolism ; Humans ; Inflammation ; immunology ; Models, Biological ; Myocardial Reperfusion Injury ; immunology ; metabolism ; prevention & control ; Vagus Nerve Stimulation

Inflammation of the asthmatic airway is usually accompanied by increased vascular permeability and plasma exudation. Angiopoietin-1 (Ang1) has potential therapeutic applications in preventing vascular leakage. Recently, we developed a soluble, stable, and potent Ang1 variant, COMP-Ang1. COMP-Ang1 is more potent than native Ang1 in phosphorylating the tyrosine kinase with immunoglobulin and epidermal growth factor homology domain 2 receptor in lung endothelial cells. We have used a mouse model for allergic airway disease to determine effects of COMP-Ang1 on allergen-induced bronchial inflammation and airway hyper-responsiveness. These mice develop the following typical pathophysiological features of allergic airway disease in the lungs: increased numbers of inflammatory cells of the airways, airway hyper-responsiveness, increased levels of Th2 cell cytokines (IL-4, IL-5, and IL-13), adhesion molecules (intercellular adhesion molecule-1 and vascular cell adhesion molecule-1), and chemokines (eotaxin and RANTES), and increased vascular permeability. Intravenous administration of COMP-Ang1 reduced bronchial inflammation and airway hyper-responsiveness. In addition, the increased plasma extravasation in allergic airway disease was significantly reduced by the administration of COMP-Ang1. These results suggest that COMP-Ang1 attenuates airway inflammation and hyper-responsiveness, prevents vascular leakage, and may be used as a therapeutic agent in allergic airway disease.
Allergens/immunology ; Angiopoietin-1/genetics/pharmacology/*therapeutic use ; Animals ; Asthma/*prevention & control ; Bronchial Hyperreactivity/physiopathology/prevention & control ; Chemokines/metabolism ; Inflammation/pathology/*prevention & control ; Mice ; Mice, Inbred C57BL ; Recombinant Fusion Proteins/*therapeutic use

OBJECTIVETo investigate immune state in lung of BALB/c mice with ovalbumin (OVA) allergy and the effects of fulvotomentoside (Ful) on lungs of the mice and provide some clues for the mechanism that patients with food allergies were prone to asthma and observe the effects of the treatment with traditional Chinese medicine.

METHODNinety-six female BALB/c mice were randomly divided into 6 groups. Mice in group 1 and group 2 were sensitized intraperitoneally and challenged intragastrically with OVA and were exposed to phosphate buffer solution and OVA respectively by nebulized inhalation. Mice in group 3 and group 4 were treated with Ful, other processes were the same as the mice in group 1 and group 2, respectively. Mice in group 5 were not challenged intragastrically with OVA and other processes were the same as the mice in group 2. Group 6 was the control group. The number of total leukocytes and cell classification in bronchoalveolar lavage (BALF) were counted, and inflammatory characteristic of lung was scored by staining with hematoxylin and eosin. The protein expressions of transforming growth factor (TGF-β1), interleukin-6 (IL-6), interleukin-17 (IL-17A) in lung of the mice were detected by immunohistochemical method. The activation of neutrophils in lung was assayed by the level of myeloroxidase (MPO).

RESULTThere was no inflammatory cells infiltration in lung of the mice in group 1. Compared with group 6, numbers of total leukocytes and erythrocytes as well as the percentage of neutrophils and lymphocytes were increased in group 2. Inflammatory score and protein expressions of TGF-β1 [(75 437 ± 3 638) vs. (6 118 ± 1 978)], IL-6 [(121 650 ± 25 389) vs. (15 726 ± 9 360)], IL-17A [(252 105 ± 31 651)vs. (72 644 ± 12 285)] in lung were increased, too. Inflammatory score and TGF-β1 (11 054 ± 1 468), IL-6 (50 877 ± 11 744), IL-17A (137 864 ± 28 986) expressions in group 5 were lower than those in group 2. Eosinophils infiltration was significant in group 5. After the treatment with Ful, TGF-β1 expression did not change and IL-6, IL-17A expressions were decreased in lung of the mice that inhaled OVA. It was not enough for Ful to relieve the neutrophil aggregation and improve inflammatory reaction in lung.

CONCLUSIONThe expressions of TGF-β1, IL-6, IL-17A in lung of the mice with OVA allergy were increased markedly after they inhaled specific antigen, which caused serious inflammation that was induced by neutrophil infiltration in lung. Ful could decrease the expressions of IL-6, IL-17A to some extent, but it was not enough to improve pathologic state in lung.

Administration, Inhalation ; Animals ; Bronchoalveolar Lavage Fluid ; cytology ; Disease Models, Animal ; Drugs, Chinese Herbal ; pharmacology ; Female ; Food Hypersensitivity ; immunology ; metabolism ; pathology ; Immunohistochemistry ; Inflammation ; Interleukin-17 ; metabolism ; Interleukin-6 ; metabolism ; Lung Diseases ; immunology ; pathology ; prevention & control ; Mice ; Mice, Inbred BALB C ; Neutrophils ; drug effects ; immunology ; Oleanolic Acid ; analogs & derivatives ; pharmacology ; Ovalbumin ; adverse effects ; immunology ; Saponins ; pharmacology ; Transforming Growth Factor beta1 ; metabolism

OBJECTIVETo identify the protective effect of lipopolysaccharide (LPS) preconditioning against LPS-induced inflammatory damage in dopaminergic neurons of midbrain slice culture and the possible mechanisms.

METHODSAfter cultured in vitro for 14 d, the rat organotypic midbrain slices were pretreated with different concentrations (0, 1, 3, 6 or 10 ng/mL) of LPS for 24 h followed by treatment with 100 ng/mL LPS for 72 h. The whole slice viability was determined by measurement of the activity of lactic acid dehydrogenase (LDH). Tyrosine hydroxylase-immunoreactive (TH-IR) neurons and CD11b/c equivalent-immunoreactive (OX-42-IR) microglia in the slices were observed by immunohistochemical method, and tumor necrosis factor-alpha (TNF-alpha) levels in the culture media were detected by enzyme-linked immunosorbent assays (ELISA).

RESULTSIn the slices treated with 100 ng/mL LPS for 72 h, the number of TH-IR neurons reduced from 191+/-12 in the control slices to 46+/-4, and the LDH activity elevated obviously (P < 0.01), along with remarkably increased number of OX-42-IR cells and production of TNF-alpha (P < 0.01). Preconditioning with 3 or 6 ng/mL LPS attenuated neuron loss (the number of TH-IR neurons increased to 126+/-12 and 180+/-13, respectively) and markedly reduced LDH levels (P < 0.05), accompanied by significant decreases of OX-42-IR microglia activation and TNF-alpha production (P < 0.05).

CONCLUSIONLow-dose LPS preconditioning could protect dopaminergic neurons against inflammatory damage in rat midbrain slice culture, and inhibition of microglial activation and reduction of the proinflammatory factor TNF-alpha production may contribute to this protective effect. Further understanding the underlying mechanism of LPS preconditioning may open a new window for treatment of Parkinson's disease.

Animals ; CD11 Antigens ; metabolism ; Enzyme-Linked Immunosorbent Assay ; Immunohistochemistry ; Inflammation ; chemically induced ; pathology ; L-Lactate Dehydrogenase ; metabolism ; Lipopolysaccharides ; administration & dosage ; toxicity ; Mesencephalon ; drug effects ; immunology ; pathology ; Microglia ; drug effects ; immunology ; pathology ; Nerve Degeneration ; metabolism ; pathology ; prevention & control ; Neurons ; drug effects ; immunology ; pathology ; Organ Culture Techniques ; Rats ; Tumor Necrosis Factor-alpha ; metabolism ; Tyrosine 3-Monooxygenase ; metabolism

The aim of the present study is to investigate the role of nordihydroguaiaretic acid (NDGA) on inflammatory cells accumulation after focal cerebral ischemia and the underlying mechanism. Focal cerebral ischemia was induced by 30 min of middle cerebral artery occlusion (MCAO) followed by 72 h of reperfusion. NDGA (5 and 10 mg/kg) was administered intraperitoneally 30 min, 2, 24, 48 h after reperfusion, respectively. The brain injuries were observed by neurological and histological examination. Endogenous IgG exudation, neutrophils and macrophages/microglia accumulation, and intercellular adhesion molecule-1 (ICAM-1) protein expression were determined by immunohistochemistry 72 h after reperfusion. ICAM-1 mRNA was determined by RT-PCR 72 h after reperfusion. The catalysates of 5-lipoxygenase (5-LOX), leukotriene B4 (LTB4) and cysteinyl leukotrienes (CysLTs), were evaluated by ELISA 3 h after reperfusion. The results showed that NDGA ameliorated neurological dysfunction, decreased infarct volume, and inhibited endogenous IgG exudation, neutrophils infiltration, ICAM-1 mRNA and protein expression 72 h after reperfusion. Moreover, NDGA reduced the levels of LTB4 and CysLTs 3 h after reperfusion. However, NDGA did not reduce the accumulation of macrophages/microglia 72 h after reperfusion. These results suggest that NDGA decreases neutrophil infiltration in the subacute phase of focal cerebral ischemia via inhibiting 5-LOX activation.
Animals ; Arachidonate 5-Lipoxygenase ; metabolism ; Brain Ischemia ; complications ; physiopathology ; Immunoglobulin G ; immunology ; Inflammation ; etiology ; physiopathology ; prevention & control ; Intercellular Adhesion Molecule-1 ; genetics ; metabolism ; Leukotriene B4 ; metabolism ; Lipoxygenase Inhibitors ; pharmacology ; Male ; Masoprocol ; pharmacology ; Neutrophils ; drug effects ; RNA, Messenger ; genetics ; metabolism ; Rats ; Rats, Sprague-Dawley ; Reperfusion Injury ; prevention & control

Recent clinical evidence indicates that the non-eosinophilic subtype of severe asthma is characterized by fixed airway obstruction, which may be related to emphysema. Transgenic studies have demonstrated that high levels of IFN-gamma in the airways induce emphysema. Fibroblast growth factor 2 (FGF2), which is the downstream mediator of TGF-beta, is important in wound healing. We investigated the role of FGF2 in IFN-gamma-induced emphysema and the therapeutic effects of recombinant FGF2 in the prevention of emphysema in a severe non-eosinophilic asthma model. To evaluate the role of FGF2 in IFN-gamma-induced emphysema, lung targeted IFN-gamma transgenic mice were cross-bred with FGF2-deficient mice. A severe non-eosinophilic asthma model was generated by airway application of LPS-containing allergens twice a week for 4 weeks. To evaluate protective effects of FGF2, recombinant FGF2 (10 microg) was injected subcutaneously during allergen challenge in the severe asthma model. We found that non-eosinophilic inflammation and emphysema induced by transgenic overexpression of IFN-gamma in the airways were aggravated by the absence of FGF2. Airway challenge with LPS-containing allergens induced more inflammation in mice sensitized with LPS-containing allergens compared to challenge with allergens alone. In addition, LPS-induced lung inflammation and emphysema depended on IFN-gamma but not on IL-13. Interestingly, emphysema in the severe asthma model was significantly inhibited by treatment with recombinant FGF2 during allergen challenge, whereas lung inflammation was unaffected. Therefore, our present data suggest that FGF2 may help protect against IFN-gamma-induced emphysema, and that recombinant FGF2 may help lessen the severity of emphysema.
Animals ; Asthma/drug therapy/*prevention & control ; Bronchoalveolar Lavage Fluid ; Disease Models, Animal ; Emphysema/drug therapy/*prevention & control ; Enzyme-Linked Immunosorbent Assay ; Fibroblast Growth Factor 2/deficiency/*metabolism/*therapeutic use ; Flow Cytometry ; Inflammation/immunology ; Interferon-gamma/*biosynthesis/genetics ; Interleukin-13 ; Lipopolysaccharides/administration & dosage/pharmacology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Pulmonary Eosinophilia ; Recombinant Proteins/administration & dosage/therapeutic use

The 2019 novel coronavirus disease (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has occurred in China and around the world. SARS-CoV-2-infected patients with severe pneumonia rapidly develop acute respiratory distress syndrome (ARDS) and die of multiple organ failure. Despite advances in supportive care approaches, ARDS is still associated with high mortality and morbidity. Mesenchymal stem cell (MSC)-based therapy may be an potential alternative strategy for treating ARDS by targeting the various pathophysiological events of ARDS. By releasing a variety of paracrine factors and extracellular vesicles, MSC can exert anti-inflammatory, anti-apoptotic, anti-microbial, and pro-angiogenic effects, promote bacterial and alveolar fluid clearance, disrupt the pulmonary endothelial and epithelial cell damage, eventually avoiding the lung and distal organ injuries to rescue patients with ARDS. An increasing number of experimental animal studies and early clinical studies verify the safety and efficacy of MSC therapy in ARDS. Since low cell engraftment and survival in lung limit MSC therapeutic potentials, several strategies have been developed to enhance their engraftment in the lung and their intrinsic, therapeutic properties. Here, we provide a comprehensive review of the mechanisms and optimization of MSC therapy in ARDS and highlighted the potentials and possible barriers of MSC therapy for COVID-19 patients with ARDS.
Adoptive Transfer ; Alveolar Epithelial Cells ; pathology ; Animals ; Apoptosis ; Betacoronavirus ; Body Fluids ; metabolism ; CD4-Positive T-Lymphocytes ; immunology ; Clinical Trials as Topic ; Coinfection ; prevention & control ; therapy ; Coronavirus Infections ; complications ; immunology ; Disease Models, Animal ; Endothelial Cells ; pathology ; Extracorporeal Membrane Oxygenation ; Genetic Therapy ; methods ; Genetic Vectors ; administration & dosage ; therapeutic use ; Humans ; Immunity, Innate ; Inflammation Mediators ; metabolism ; Lung ; pathology ; physiopathology ; Mesenchymal Stem Cell Transplantation ; methods ; Mesenchymal Stem Cells ; physiology ; Multiple Organ Failure ; etiology ; prevention & control ; Pandemics ; Pneumonia, Viral ; complications ; immunology ; Respiratory Distress Syndrome, Adult ; immunology ; pathology ; therapy ; Translational Medical Research

To determine the impact of IL-23 knockdown by RNA interference on the development and severity of ovalbumin (OVA)-induced asthmatic inflammation, and the potential mechanisms in mice, the IL-23-specific RNAi-expressing pSRZsi-IL-23p19 plasmid was constructed and inhaled into OVA-sensitized mice before each challenge, as compared with that of control mice treated with alum or budesonide. Inhalation of the pSRZsi-IL-23p19, significantly reduced the levels of OVA-challenge induced IL-23 in the lung tissues by nearly 75%, determined by RT-PCR. In addition, knockdown of IL-23 expression dramatically reduced the numbers of eosinophils and neutrophils in BALF and mitigated inflammation in the lungs of asthmatic mice. Furthermore, knockdown of IL-23 expression significantly decreased the levels of serum IgE, IL-23, IL-17, and IL-4, but not IFNgamma, and its anti-inflammatory effects were similar to or better than that of treatment with budesonide in asthmatic mice. Our data support the notion that IL-23 and associated Th17 responses contribute to the pathogenic process of bronchial asthma. Knockdown of IL-23 by RNAi effectively inhibits asthmatic inflammation, which is associated with mitigating the production of IL-17 and IL-4 in asthmatic mice.
Animals ; Asthma/chemically induced/genetics/metabolism/*prevention & control ; Bronchoalveolar Lavage Fluid/cytology ; Enzyme-Linked Immunosorbent Assay ; Eosinophils ; Female ; Inflammation/metabolism ; Interleukin-23/*genetics ; Leukocyte Count ; Mice ; Mice, Inbred BALB C ; Neutrophils ; Ovalbumin/pharmacology ; Plasmids/genetics ; *RNA Interference ; RNA, Small Interfering/*genetics ; Reverse Transcriptase Polymerase Chain Reaction ; Th17 Cells/immunology

INTRODUCTIONConsumption of omega-3 fatty acids can alter the inflammatory response in diabetic patients. This study aimed to determine the effects of omega-3 fatty acid supplementation on the serum levels of C-reactive protein (CRP), interleukin (IL)-2 and tumour necrosis factor-alpha (TNF-α) in type 2 diabetes mellitus patients.

METHODSA randomised, double-blind, placebo-controlled clinical trial was conducted on 84 subjects aged 45-85 years with at least a two-year history of type 2 diabetes mellitus. Participants were randomly assigned to the treatment or control group. Each subject in the treatment group received three omega-3 capsules per day (eicosapentaenoic acid 1,548 mg; docosahexaenoic acid 828 mg; other omega-3 fatty acids 338 mg), while each subject in the control group received three placebo capsules (sunflower oil 2,100 mg) for a period of eight weeks. At the beginning of the study and post intervention, fasting blood samples were taken and serum concentrations of IL-2, TNF-α and CRP were assessed and compared.

RESULTSSerum IL-2 and TNF-α levels were significantly reduced in the treatment group compared to the controls (p < 0.01). There was no significant change in serum CRP levels.

CONCLUSIONShort-term omega-3 fatty acid supplementation (3 g/day for eight weeks) can decrease the serum levels of TNF-α and IL-2 in diabetic patients, with no change in CRP levels. Consumption of omega-3 fatty acid supplements is highly recommended to alleviate inflammation caused by type 2 diabetes mellitus.

Aged ; Aged, 80 and over ; Biomarkers ; blood ; C-Reactive Protein ; drug effects ; metabolism ; Diabetes Mellitus, Type 2 ; blood ; drug therapy ; immunology ; Dietary Supplements ; Double-Blind Method ; Fatty Acids, Omega-3 ; pharmacology ; therapeutic use ; Female ; Humans ; Inflammation ; blood ; prevention & control ; Interleukin-2 ; blood ; Male ; Middle Aged ; Tumor Necrosis Factor-alpha ; blood ; drug effects