Rectal administration of tacrolimus protects against post-ERCP pancreatitis in mice.

Objective: There is an unmet clinical need for effective, targeted interventions to prevent post-ERCP pancreatitis (PEP). We previously demonstrated that the serine-threonine phosphatase, calcineurin (Cn) is a critical mediator of PEP and that the FDA-approved calcineurin inhibitors, tacrolimus (Tac) or cyclosporine A, prevented PEP. Our recent observations in preclinical PEP models demonstrating that Cn deletion in both pancreatic and hematopoietic compartments is required for maximal pancreas protection, highlighted the need to target both systemic and pancreas-specific Cn signaling.

Preclinical safety evaluation of calcineurin inhibitors delivered through an intraductal route to prevent post-ERCP pancreatitis demonstrates endocrine and systemic safety.

Objective: There is an urgent need for safe and targeted interventions to mitigate post-ERCP pancreatitis (PEP). Calcineurin inhibitors (CnIs) offer therapeutic promise as calcineurin signaling within acinar cells is a key initiating event in PEP. In previous proof-of-concept studies using experimental models, we showed that concurrent intra-pancreatic ductal administration of the CnIs, tacrolimus (Tac) or cyclosporine A (CsA) with the ERCP radiocontrast agent (RC) prevented PEP.

A systems approach points to a therapeutic role for retinoids in asparaginase-associated pancreatitis.

Among drug-induced adverse events, pancreatitis is life-threatening and results in substantial morbidity. A prototype example is the pancreatitis caused by asparaginase, a crucial drug used to treat acute lymphoblastic leukemia (ALL). Here, we used a systems approach to identify the factors affecting asparaginase-associated pancreatitis (AAP).

How GRAIL controls Treg function to maintain self-tolerance.

Regulatory T cells (T) normally maintain self-tolerance. T recognize "self" such that when they are not working properly, such as in autoimmunity, the immune system can attack and destroy one's own tissues. Current therapies for autoimmunity rely on relatively ineffective and too often toxic therapies to "treat" the destructive inflammation.

Dynamin-related protein 1 differentially regulates FcεRI- and substance P-induced mast cell activation.

Background: The mitochondrial fission protein dynamin-related protein 1 (Drp1) has been suggested to regulate mast cell (MC) activation by certain stimuli in vitro, but its functions in MCs activated by various stimuli in vivo have not yet been examined.

Objective: We sought to analyze Drp1 function in both mouse and human MCs.

Methods: We used human peripheral blood-derived cultured MCs and 2 genetic mouse models in which MCs were depleted of Drp1: Drp1Mcpt5cre mice and Drp1Cpa3cre mice.

Soluble epoxide hydrolase inhibitor can protect the femoral head against tobacco smoke exposure-induced osteonecrosis in spontaneously hypertensive rats.

Exposure to tobacco smoke (TS) has been considered a risk factor for osteonecrosis of the femoral head (ONFH). Soluble epoxide hydrolase inhibitors (sEHIs) have been found to reduce inflammation and oxidative stress in a variety of pathologies. This study was designed to assess the effect of sEHI on the development of ONFH phenotypes induced by TS exposure in spontaneously hypertensive (SH) rats.

The Protective Effects of Calcineurin on Pancreatitis in Mice Depend on the Cellular Source.

Background & Aims: Calcineurin is a ubiquitously expressed central Ca-responsive signaling molecule that mediates acute pancreatitis, but little is known about its effects. We compared the effects of calcineurin expression by hematopoietic cells vs pancreas in mouse models of pancreatitis and pancreatitis-associated lung inflammation.

Methods: We performed studies with mice with hematopoietic-specific or pancreas-specific deletion of protein phosphatase 3, regulatory subunit B, alpha isoform (PPP3R1, also called CNB1), in mice with deletion of CNB1 (Cnb1) and in the corresponding controls for each deletion of CNB1.

Development of multiple features of antigen-induced asthma pathology in a new strain of mast cell deficient BALB/c-Kit mice.

Mast cell-deficient mice are widely used to identify and quantify contributions of mast cells to diverse biological responses in vivo, including allergic inflammation. However, despite the fact that scores of genes have been identified as modifiers of allergic inflammation, most mast cell-deficient models have been available only on a single genetic background. We transferred the Kit allele onto the BALB/c background to generate BALB/c mast cell-deficient mice (BALB/c-Kit).

[Effect of electroacupuncture of acupoints on the healthy limb (opposing needling) on acute skeletal muscle contusion in rats].

Objective: To observe the therapeutic effect of electroacupuncture (EA) of "Zusanli" (ST36) and ""-point on the healthy side (opposing needling) on muscular injury and expression of myogenin (myoG) and fast myosin skeletal heavy chain (Fast MyHC) proteins in the gastrocnemius muscle (GM) tissues in skeletal muscle contusion rats，so as to explore its mechanism underlying improvement of skeletal muscle injury.

Methods: A total of 54 male SD rats were divided into normal control (n ＝ 6)，model (＝24) and opposing needling (EA, ＝24) groups. The latter two groups were further randomized into 3, 5, 7 and 14 d subgroups (＝6 per subgroup).

Exposure to tobacco smoke increases bone loss in spontaneously hypertensive rats.

Purpose: To define if exposure to tobacco smoke (TS) could induce reduction of bone mass and impairment of bone architecture, features observed in osteoporosis in normotensive rats and the influence of TS exposure on the osteoporotic features exhibited in the spontaneously hypertensive (SH) rats.

Methods: Normotensive Wistar Kyoto (WKY) and SH rats were exposed to filtered air or TS for 8 weeks, then their proximal femurs were extracted for micro-computed tomography (micro-CT) assessment, histological and immune-histological examinations to quantify the adverse influence of TS exposure on the bone mass and density, as well as bone architecture.

Results: We found that TS exposure not only induced significant decreases in bone mineral density (BMD), bone volume (BV), cortical and trabecular thickness (Ct.

Thirdhand smoke component can exacerbate a mouse asthma model through mast cells.

Background: Thirdhand smoke (THS) represents the accumulation of secondhand smoke on indoor surfaces and in dust, which, over time, can become more toxic than secondhand smoke. Although it is well known that children of smokers are at increased risk for asthma or asthma exacerbation if the disease is already present, how exposure to THS can influence the development or exacerbation of asthma remains unknown.

Objective: We investigated whether epicutaneous exposure to an important component of THS, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), can influence asthma pathology in a mouse model elicited by means of repeated intranasal challenge with cockroach antigen (CRA).

[Effects of acupuncture at opposite acupoints on expression of hepatocyte growth factor in rats with skeletal muscle contusion].

Objective: To observe the effects of acupuncture at opposite acupoints on expression of hepatocyte growth factor (HGF) in rats with skeletal muscle contusion, and to explore the mechanism of acupuncture at opposite acupoints on skeletal muscle contusion.

Methods: Fifty-four Sprague Dawley (SD) rats were randomly divided into a blank group (6 rats), a model group (24 rats) and an opposing needling group (24 rats). The model group and opposing needling group were further divided into 1-day subgroup, 3-day subgroup, 5-day subgroup and 7-day subgroup, 6 rats in each one.

A TNFRSF14-FcɛRI-mast cell pathway contributes to development of multiple features of asthma pathology in mice.

Asthma has multiple features, including airway hyperreactivity, inflammation and remodelling. The TNF superfamily member TNFSF14 (LIGHT), via interactions with the receptor TNFRSF14 (HVEM), can support T2 cell generation and longevity and promote airway remodelling in mouse models of asthma, but the mechanisms by which TNFSF14 functions in this setting are incompletely understood. Here we find that mouse and human mast cells (MCs) express TNFRSF14 and that TNFSF14:TNFRSF14 interactions can enhance IgE-mediated MC signalling and mediator production.

Reduced mast cell and basophil numbers and function in Cpa3-Cre; Mcl-1fl/fl mice.

It has been reported that the intracellular antiapoptotic factor myeloid cell leukemia sequence 1 (Mcl-1) is required for mast cell survival in vitro, and that genetic manipulation of Mcl-1 can be used to delete individual hematopoietic cell populations in vivo. In the present study, we report the generation of C57BL/6 mice in which Cre recombinase is expressed under the control of a segment of the carboxypeptidase A3 (Cpa3) promoter. C57BL/6-Cpa3-Cre; Mcl-1(fl/fl) mice are severely deficient in mast cells (92%-100% reduced in various tissues analyzed) and also have a marked deficiency in basophils (58%-78% reduced in the compartments analyzed), whereas the numbers of other hematopoietic cell populations exhibit little or no changes.

Identification of an IFN-γ/mast cell axis in a mouse model of chronic asthma.

Asthma is considered a Th2 cell–associated disorder. Despite this, both the Th1 cell–associated cytokine IFN-γ and airway neutrophilia have been implicated in severe asthma. To investigate the relative contributions of different immune system components to the pathogenesis of asthma, we previously developed a model that exhibits several features of severe asthma in humans, including airway neutrophilia and increased lung IFN-γ.

Perinatal environmental tobacco smoke exposure alters the immune response and airway innervation in infant primates.

Background: Epidemiologic studies associate environmental tobacco smoke (ETS) exposure with childhood asthma.

Objective: To investigate whether specific pathophysiological alterations that contribute to asthma development in human beings can be induced in infant monkeys after perinatal ETS exposure.

Methods: Rhesus macaque fetuses/infants were exposed to ETS at 1 mg/m(3) of total suspended particulate matter from 50 days gestational age to 2.

DAS181, a novel sialidase fusion protein, protects mice from lethal avian influenza H5N1 virus infection.

Increasing resistance to currently available influenza antivirals highlights the need to develop alternate approaches for the prevention and/or treatment of influenza. DAS181 (Fludase), a novel sialidase fusion protein that enzymatically removes sialic acids on respiratory epithelium, exhibits potent antiviral activity against influenza A and B viruses. Here, we use a mouse model to evaluate the efficacy of DAS181 treatment against a highly pathogenic avian influenza H5N1 virus.

Mast cell-derived TNF contributes to airway hyperreactivity, inflammation, and TH2 cytokine production in an asthma model in mice.

Background: Mast cells, IgE, and TNF, which have been implicated in human atopic asthma, contribute significantly to the allergic airway inflammation induced by ovalbumin (OVA) challenge in mice sensitized with OVA without alum. However, it is not clear to what extent mast cells represent a significant source of TNF in this mouse model.

Objective: We investigated the importance of mast cell-derived TNF in a mast cell-dependent model of OVA-induced airway hyperreactivity (AHR) and allergic airway inflammation.

Effector and potential immunoregulatory roles of mast cells in IgE-associated acquired immune responses.

Mast cells are best known as critical effector cells in anaphylaxis and other examples of IgE-associated immediate hypersensitivity reactions. However, mast cells also can contribute to the development of the late-phase responses that occur in some sensitized subjects hours after initial exposure to specific antigen, and can promote many of the features of chronic allergic inflammation, including tissue remodeling and functional changes in the affected organs. In addition to such effector cell functions in IgE-associated immune responses, recent evidence indicates that mast cells can importantly influence the sensitization phase of at least some acquired immune responses, and can contribute to the pathology of autoimmune disorders and to the expression of peripheral tolerance.

Mast cells can promote the development of multiple features of chronic asthma in mice.

Bronchial asthma, the most prevalent cause of significant respiratory morbidity in the developed world, typically is a chronic disorder associated with long-term changes in the airways. We developed a mouse model of chronic asthma that results in markedly increased numbers of airway mast cells, enhanced airway responses to methacholine or antigen, chronic inflammation including infiltration with eosinophils and lymphocytes, airway epithelial goblet cell hyperplasia, enhanced expression of the mucin genes Muc5ac and Muc5b, and increased levels of lung collagen. Using mast cell-deficient (Kit(W-sh/W-sh) and/or Kit(W/W-v)) mice engrafted with FcRgamma+/+ or FcRgamma-/- mast cells, we found that mast cells were required for the full development of each of these features of the model.

Sialidase fusion protein as a novel broad-spectrum inhibitor of influenza virus infection.

Influenza is a highly infectious disease characterized by recurrent annual epidemics and unpredictable major worldwide pandemics. Rapid spread of the highly pathogenic avian H5N1 strain and escalating human infections by the virus have set off the alarm for a global pandemic. To provide an urgently needed alternative treatment modality for influenza, we have generated a recombinant fusion protein composed of a sialidase catalytic domain derived from Actinomyces viscosus fused with a cell surface-anchoring sequence.

Using mast cell knock-in mice to analyze the roles of mast cells in allergic responses in vivo.

It is well established that mast cells are important effector cells mediating the acute phase of IgE-associated allergic disorders, but their roles in late phase reactions and chronic allergic inflammation are not well defined. Here we describe an experimental approach for analyzing mast cell functions in vivo by comparing the biological responses in wild-type mice, genetically mast cell-deficient mice, and 'mast cell knock-in mice' (mast cell-deficient mice selectively repaired of their mast cell deficiency). Studies using 'mast cell knock-in mice' have indicated that mast cells can contribute importantly to IgE-associated late phase reactions and to chronic allergic inflammation.