Pulmonary delivery of ORMDL3 short hairpin RNA - a potential tool to regulate allergen-induced airway inflammation.

Exposure to various allergens has been shown to increase expression of ORMDL3 in the lung in models of allergic asthma. Studies using genetically modified (transgenic or knock out) mice have revealed some of the functions of ORMDL3 in asthma pathogenesis, although amid debate. The goal of this study was to use targeted post-transcriptional downregulation of in allergen-challenged wild-type (WT) mice by RNA interference to further elucidate the functional role of ORMDL3 in asthma pathogenesis and evaluate a potential therapeutic option.

Regulation of Eosinophil Recruitment and Allergic Airway Inflammation by Tropomyosin Receptor Kinase A.

Eosinophilia is a hallmark of allergic airway inflammation (AAI). Identifying key molecules and specific signaling pathways that regulate eosinophilic inflammation is critical for development of novel therapeutics. Tropomycin receptor kinase A (TrkA) is the high-affinity receptor for nerve growth factor.

FABP4 regulates eosinophil recruitment and activation in allergic airway inflammation.

Fatty acid binding protein 4 (FABP4), a member of a family of lipid-binding proteins, is known to play a role in inflammation by virtue of its ability to regulate intracellular events such as lipid fluxes and signaling. Studies have indicated a proinflammatory role for FABP4 in allergic asthma although its expression and function in eosinophils, the predominant inflammatory cells recruited to allergic airways, were not investigated. We examined expression of FABP4 in murine eosinophils and its role in regulating cell recruitment in vitro as well as in cockroach antigen (CRA)-induced allergic airway inflammation.

Regulation of eosinophil recruitment and allergic airway inflammation by heparan sulfate proteoglycan (HSPG) modifying enzymes.

Background: HSPGs are glycoproteins containing covalently attached heparan sulfate (HS) chains which bind to growth factors, chemokines, etc., and regulate various aspects of inflammation including cell recruitment. We previously showed that deletion of endothelial N-acetylglucosamine N-deacetylase-N-sulfotransferase-1 (Ndst1), an enzyme responsible for N-sulfation during HS biosynthesis, reduces allergic airway inflammation (AAI).

Knob protein enhances epithelial barrier integrity and attenuates airway inflammation.

Background: Altered epithelial physical and functional barrier properties along with T1/T2 immune dysregulation are features of allergic asthma. Regulation of junction proteins to improve barrier function of airway epithelial cells has the potential for alleviation of allergic airway inflammation.

Objective: We sought to determine the immunomodulatory effect of knob protein of the adenoviral capsid on allergic asthma and to investigate its mechanism of action on airway epithelial junction proteins and barrier function.

Inhibition of soluble epoxide hydrolase attenuates eosinophil recruitment and food allergen-induced gastrointestinal inflammation.

Prevalence of food allergies in the United States is on the rise. Eosinophils are recruited to the intestinal mucosa in substantial numbers in food allergen-driven gastrointestinal (GI) inflammation. Soluble epoxide hydrolase (sEH) is known to play a pro-inflammatory role during inflammation by metabolizing anti-inflammatory epoxyeicosatrienoic acids (EETs) to pro-inflammatory diols.

Regulation of Eosinophil Recruitment and Activation by Galectins in Allergic Asthma.

Eosinophils are differentiated granulocytes that are recruited from the bone marrow to sites of inflammation the vascular system. Allergic asthma is characterized by the presence of large numbers of eosinophils in the lungs and airways. Due to their capacity to rapidly release inflammatory mediators such as cytokines, chemokines, growth factors, and cytotoxic granule proteins upon stimulation, eosinophils play a critical role in pro-inflammatory processes in allergen-exposed lungs.

Assessment of eosinophil peroxidase as a potential diagnostic and prognostic marker in dogs with inflammatory bowel disease.

OBJECTIVE To evaluate a method for identifying intact and degranulated eosinophils in the small intestine of dogs with inflammatory bowel disease (IBD) by use of a monoclonal antibody (mAb) against eosinophil peroxidase (EPX). ANIMALS 11 untreated dogs with IBD, 5 dogs with IBD treated with prednisolone, and 8 control dogs with no clinical evidence of gastrointestinal tract disease and no immunosuppressive treatment. PROCEDURES 4-μm-thick sections of paraffin-embedded tissues from necropsy specimens were immunostained with EPX mAb.

Regulation of eosinophilia and allergic airway inflammation by the glycan-binding protein galectin-1.

Galectin-1 (Gal-1), a glycan-binding protein with broad antiinflammatory activities, functions as a proresolving mediator in autoimmune and chronic inflammatory disorders. However, its role in allergic airway inflammation has not yet been elucidated. We evaluated the effects of Gal-1 on eosinophil function and its role in a mouse model of allergic asthma.

Endothelial and leukocyte heparan sulfates regulate the development of allergen-induced airway remodeling in a mouse model.

Heparan sulfate (HS) proteoglycans (HSPGs) participate in several aspects of inflammation because of their ability to bind to growth factors, chemokines, interleukins and extracellular matrix proteins as well as promote inflammatory cell trafficking and migration. We investigated whether HSPGs play a role in the development of airway remodeling during chronic allergic asthma using mice deficient in endothelial- and leukocyte-expressed N-deacetylase/N-sulfotransferase-1 (Ndst1), an enzyme involved in modification reactions during HS biosynthesis. Ndst1-deficient and wild-type (WT) mice exposed to repetitive allergen (ovalbumin [OVA]) challenge were evaluated for the development of airway remodeling.

High-fat diet promotes lung fibrosis and attenuates airway eosinophilia after exposure to cockroach allergen in mice.

Obesity is an important risk factor for asthma but the mechanistic basis for this association is not well understood. In the current study, the impact of obesity on lung inflammatory responses after allergen exposure was investigated. C57BL/6 mice maintained on a high-fat diet (HFD) or a normal diet (ND) after weaning were sensitized and challenged with cockroach allergen (CRA).

ORMDL3 promotes eosinophil trafficking and activation via regulation of integrins and CD48.

ORM (yeast)-like protein isoform 3 (ORMDL3) has recently been identified as a candidate gene for susceptibility to asthma; however, the mechanisms by which it contributes to asthma pathogenesis are not well understood. Here we demonstrate a functional role for ORMDL3 in eosinophils in the context of allergic inflammation. Eosinophils recruited to the airways of allergen-challenged mice express ORMDL3.

Eosinophil-expressed galectin-3 regulates cell trafficking and migration.

Galectin-3 (Gal-3), a β galactoside-binding lectin, is implicated in the pathogenesis of allergic airway inflammation and allergen-challenged mice deficient in Gal-3 (Gal-3(-/-)) exhibit decreased airway recruitment of eosinophils (Eos). Gal-3 is expressed and secreted by several cell types and can thus function extracellularly and intracellularly to regulate a variety of cellular responses. We sought to determine the role of Eos-expressed Gal-3 in promoting Eos trafficking and migration in the context of allergic airway inflammation using bone marrow (BM)-derived Eos from wild-type (WT) and Gal-3(-/-) mice.

Regulation of serotonin-induced trafficking and migration of eosinophils.

Association of the neurotransmitter serotonin (5-HT) with the pathogenesis of allergic asthma is well recognized and its role as a chemoattractant for eosinophils (Eos) in vitro and in vivo has been previously demonstrated. Here we have examined the regulation of 5-HT-induced human and murine Eos trafficking and migration at a cellular and molecular level. Eos from allergic donors and bone marrow-derived murine Eos (BM-Eos) were found to predominantly express the 5-HT2A receptor.

The p110δ subunit of PI3K regulates bone marrow-derived eosinophil trafficking and airway eosinophilia in allergen-challenged mice.

Trafficking and recruitment of eosinophils during allergic airway inflammation is mediated by the phosphatidylinositol 3-kinase (PI3K) family of signaling molecules. The role played by the p110δ subunit of PI3K (PI3K p110δ) in regulating eosinophil trafficking and recruitment was investigated using a selective pharmacological inhibitor (IC87114). Treatment with the PI3K p110δ inhibitor significantly reduced murine bone marrow-derived eosinophil (BM-Eos) adhesion to VCAM-1 as well as ICAM-1 and inhibited activation-induced changes in cell morphology associated with reduced Mac-1 expression and aberrant cell surface localization/distribution of Mac-1 and α4.

Regulation of eosinophil trafficking by SWAP-70 and its role in allergic airway inflammation.

Eosinophils are the predominant inflammatory cells recruited to allergic airways. In this article, we show that human and murine eosinophils express SWAP-70, an intracellular RAC-binding signaling protein, and examine its role in mediating eosinophil trafficking and pulmonary recruitment in a murine model of allergic airway inflammation. Compared with wild-type eosinophils, SWAP-70-deficient (Swap-70(-/-)) eosinophils revealed altered adhesive interactions within inflamed postcapillary venules under conditions of blood flow by intravital microscopy, exhibiting enhanced slow rolling but decreased firm adhesion.

N-Glycans differentially regulate eosinophil and neutrophil recruitment during allergic airway inflammation.

Allergic airway inflammation, including asthma, is usually characterized by the predominant recruitment of eosinophils. However, neutrophilia is also prominent during severe exacerbations. Cell surface-expressed glycans play a role in leukocyte trafficking and recruitment during inflammation.

Chronic allergen challenge induces pulmonary extramedullary hematopoiesis.

Allergic inflammation is associated with increased generation and trafficking of inflammatory cells, especially eosinophils, to sites of inflammation. The effect of acute versus chronic airway allergen challenge on hematopoietic activity in the bone marrow (BM) and lungs was investigated using murine models of allergic airway inflammation. Acute allergen challenge induced proliferation of BM cells and significantly increased generation of eosinophil, but not multipotent, granulocyte-macrophage (GM), or B-lymphocyte progenitor cells.

Allergen-induced airway remodeling is impaired in galectin-3-deficient mice.

The role played by the beta-galactoside-binding lectin galectin-3 (Gal-3) in airway remodeling, a characteristic feature of asthma that leads to airway dysfunction and poor clinical outcome in humans, was investigated in a murine model of chronic allergic airway inflammation. Wild-type (WT) and Gal-3 knockout (KO) mice were subjected to repetitive allergen challenge with OVA up to 12 wk, and bronchoalveolar lavage fluid (BALF) and lung tissue collected after the last challenge were evaluated for cellular features associated with airway remodeling. Compared to WT mice, chronic OVA challenge in Gal-3 KO mice resulted in diminished remodeling of the airways with significantly reduced mucus secretion, subepithelial fibrosis, smooth muscle thickness, and peribronchial angiogenesis.

Roflumilast increases Clara cell secretory protein in cigarette smoke-exposed mice.

Decreased Clara cell secretory protein (CCSP) levels have been found in smokers and chronic obstructive pulmonary disease (COPD) patients, which may be related to the development of COPD. A phosphodiesterase-4 (PDE4) inhibitor, roflumilast, appears to have therapeutic value for COPD. However, its effect on CCSP in cigarette smoke (CS)-exposed lungs has not been investigated.

Deficiency of endothelial heparan sulfates attenuates allergic airway inflammation.

The effect of targeted inactivation of the gene encoding N-deacetylase/N-sulfotransferase-1 (Ndst1), a key enzyme involved in the biosynthesis of heparan sulfate (HS) chains, on the inflammatory response associated with allergic inflammation in a murine model of OVA-induced acute airway inflammation was investigated. OVA-exposed Ndst1(f/f)TekCre(+) (mutant) mice deficient in endothelial and leukocyte Ndst1 demonstrated significantly decreased allergen-induced airway hyperresponsiveness and inflammation characterized by a significant reduction in airway recruitment of inflammatory cells (eosinophils, macrophages, neutrophils, and lymphocytes), diminished IL-5, IL-2, TGF-beta1, and eotaxin levels, as well as decreased expression of TGF-beta1 and the angiogenic protein FIZZ1 (found in inflammatory zone 1) in lung tissue compared with OVA-exposed Ndst1(f/f)TekCre(-) wild-type littermates. Furthermore, murine eosinophils demonstrated significantly decreased rolling on lung endothelial cells (ECs) from mutant mice compared with wild-type ECs under conditions of flow in vitro.

[The role of myocardin in hypoxia-induced transdifferentiation of pulmonary artery endothelial cells into smooth muscle-like cells].

Objective: To investigate the transdifferentiation of pulmonary artery endothelial cells (PAECs) into smooth muscle-like cells under hypoxia and the role of myocardin therein.

Methods: Recombinant plasmid psimyocardin (pSi), capable of silencing the expression of myocardin gene, was constructed by RNAi to be used to transfect the PAECs. Endothelial cells of adult pig pulmonary small arteries were purified by immunomagnetic purification technique, and divided into 4 groups: normoxia group (to be cultured in normoxic cell culture box containing 21% O(2), 5% CO2, and 74% N(2)), normoxia + pSi group, hypoxia group (to be cultured in cell box containing 1% O(2), 5% CO2, and 74% N(2)), and hypoxia + pSi group to be cultured for 1, 4, and 7 days respectively.

[Effects of cigarette smoke extract on the proliferation and the expression of TGF-beta1 and EGF in human embryonic lung fibroblasts].

Objective: To observe the effects of cigarette smoke extract (CSE) on the proliferation and the expression of TGF-beta(1) and EGF in human embryonic lung fibroblasts (HELF).

Methods: The cultures of HELF were incubated with CSE (1:50, 1:25 and 1:10) for examining the effects of CSE on the proliferation and the proliferating cell nuclear antigen (PCNA) levels in HELF. The total RNA was extracted from the cells incubated with CSE at different doses.

[Changes of the actin and transforming growth factor-beta1 expression in the small airways of the rat with chronic obstructive lung disease].

Objective: To study the roles of actin and transforming growth factor (TGF)-beta(1) in the injury repair and the development of emphysema.

Methods: Wistar rats were randomly divided into two groups: the smoking and infection group (group SI) and the control group (group C). The rats of group SI received smoking irritation accompanying with repeated intranasal infection.