Tag: murine

Posted on

The soluble guanylyl cyclase activator BAY 60-2770 inhibits murine allergic airways inflammation and human eosinophil chemotaxis.

Related Articles

The soluble guanylyl cyclase activator BAY 60-2770 inhibits murine allergic airways inflammation and human eosinophil chemotaxis.

Pulm Pharmacol Ther. 2016 Nov 2;:

Authors: Baldissera L, Squebola-Cola DM, Calixto MC, Lima-Barbosa AP, Rennó AL, Anhê GF, Condino-Neto A, De Nucci G, Antunes E

Abstract
OBJECTIVES: Activators of soluble guanylyl cyclase (sGC) act preferentially in conditions of enzyme oxidation or haem group removal. This study was designed to investigate the effects of the sGC activator BAY 60-2770 in murine airways inflammation and human eosinophil chemotaxis.
METHODS: C57Bl/6 mice treated or not with BAY 60-2770 (1 mg/kg/day, 14 days) were intranasally challenged with ovalbumin (OVA). At 48 h, bronchoalveolar lavage fluid (BALF) was performed, and circulating blood, bone marrow and lungs were obtained. Human eosinophils purified from peripheral blood were used to evaluate the cell chemotaxis.
RESULTS: OVA-challenge promoted marked increases in eosinophil number in BAL, lung tissue, circulating blood and bone marrow, all of which were significantly reduced by BAY 60-2770. The IL-4 and IL-5 levels in BALF were significantly reduced by BAY 60-2770. Increased protein expression of iNOS, along with decreases of expression of sGC (?1 and ?1 subunits) and cGMP levels were detected in lung tissue of OVA-challenged mice. BAY 60-2770 fully restored to baseline the iNOS and sGC subunit expressions, and cGMP levels. In human isolated eosinophils, BAY 60-2770 (1-5 ?M) had no effects on the cGMP levels and eotaxin-induced chemotaxis; however, prior incubation with ODQ (10 ?M) markedly elevated the BAY 60-2770-induced cyclic GMP production, further inhibiting the eosinophil chemotaxis.
CONCLUSIONS: BAY 60-2770 reduces airway eosinophilic inflammation and rescue the sGC levels. In human eosinophils under oxidized conditions, BAY 60-2770 elevates the cGMP levels causing cell chemotaxis inhibition. BAY 60-2770 may reveal a novel therapeutic target for asthma treatment.

PMID: 27816773 [PubMed – as supplied by publisher]

View full post on pubmed: asthma

Posted on

Nuclear factor-?B mediates the phenotype switching of airway smooth muscle cells in a murine asthma model.

Related Articles

Nuclear factor-?B mediates the phenotype switching of airway smooth muscle cells in a murine asthma model.

Int J Clin Exp Pathol. 2015;8(10):12115-28

Authors: Qiu C, Zhang J, Su M, Fan X

Abstract
Airway smooth muscle cells (ASMCs) phenotype modulation, characterized by reversible switching between contractile and proliferative phenotypes, is considered to contribute to airway proliferative diseases such as allergic asthma. Nuclear Factor-?B (NF-?B) has been reported as a key regulator for the occurrence and development of asthma. However, little is known regarding its role in ASM cell phenotypic modulation. To elucidate the role of NF-?B in regulating ASM cells phenotypic modulation, we investigated the effects of NF-?B on ASM cells contractile marker protein expression, and its impact on proliferation and apoptosis. We found that chronic asthma increased the activation of NF-?B in the primary murine ASM cells with a concomitant marked decrease in the expression of contractile phenotypic marker protein including smooth muscle alpha-actin (?-SMA). Additionally, we used the normal ASM cells under different processing to build the phenotype switching when we found the activation of NF-?B. Meanwhile, the expression of ?-SMA in asthma was significantly increased by the NF-?B blocker. NF-?B blocker also suppressed asthma mouse ASM cell proliferation and promoted apoptosis. These findings highlight a novel role for the NF-?B in murine ASM cell phenotypic modulation and provide a potential target for therapeutic intervention for asthma.

PMID: 26722396 [PubMed – in process]

View full post on pubmed: asthma

Posted on

STAT1 Attenuates Murine Allergen-Induced Airway Remodeling and Exacerbation by Carbon Nanotubes.

STAT1 Attenuates Murine Allergen-Induced Airway Remodeling and Exacerbation by Carbon Nanotubes.

Am J Respir Cell Mol Biol. 2015 Mar 25;

Authors: Thompson EA, Sayers BC, Glista-Baker EE, Shipkowski KA, Ihrie MD, Duke KS, Taylor AJ, Bonner JC

Abstract
Asthma is characterized by a T-helper 2 (Th2) phenotype and by chronic allergen-induced airway inflammation (AAI). Environmental exposure to air pollution ultrafine particles (i.e., nanoparticles) exacerbates AAI and a concern is possible exacerbation posed by engineered nanoparticles generated by emerging nanotechnologies. STAT1 is a transcription factor that maintains Th1 cell development. However, the role of STAT1 in regulating AAI or exacerbation by nanoparticles has not been explored. In this study, mice with whole body knock-out of the Stat1 gene (Stat1-/-) or wild type (WT) mice were sensitized to ovalbumin (OVA) allergen and then exposed to multi-walled carbon nanotubes (MWCNTs) by oropharygneal aspiration. In Stat1-/- and WT mice, OVA increased eosinophils in bronchoalveolar lavage fluid (BALF), while MWCNTs increased neutrophils. Interestingly, OVA sensitization prevented MWCNT-induced neutrophilia and caused only eosinophilic inflammation. Stat1-/- mice displayed increased IL-13 in BALF 1 day compared to WT mice after treatment with OVA or OVA and MWCNT. At 21 days the lungs of OVA-sensitized Stat1-/- mice displayed increased eosinophilia, goblet cell hyperplasia, airway fibrosis, and subepithelial apoptosis. MWCNTs further increased OVA-induced goblet cell hyperplasia, airway fibrosis, and apoptosis in Stat1-/- mice at 21 days. These changes corresponded to increased levels of pro-fibrogenic mediators (TGF-?1, TNF-?, OPN) but decreased IL-10 in Stat1-/- mice. Finally, fibroblasts isolated from the lungs of Stat1-/- mice produced significantly more collagen mRNA and protein in response to TGF-?1 compared to WT lung fibroblasts. Our results support a protective role for STAT1 in chronic AAI and exacerbation of remodeling caused by MWCNTs.

PMID: 25807359 [PubMed – as supplied by publisher]

View full post on pubmed: asthma

Posted on

Aggravation of ovalbumin-induced murine asthma by co-exposure to desert-dust and organic chemicals: an animal model study.

Related Articles

Aggravation of ovalbumin-induced murine asthma by co-exposure to desert-dust and organic chemicals: an animal model study.

Environ Health. 2014 Oct 18;13(1):83

Authors: Ren Y, Ichinose T, He M, Arashidani K, Yoshida Y, Yoshida S, Nishikawa M, Takano H, Sun G, Shibamoto T

Abstract
BACKGROUND: The organic chemicals present in Asian sand dust (ASD) might contribute to the aggravation of lung eosinophila. Therefore, the aggravating effects of the Tar fraction from ASD on ovalbumin (OVA)-induced lung eosinophilia were investigated.
METHODS: The Tar fraction was extracted from ASD collected from the atmosphere in Fukuoka, Japan. ASD collected from the Gobi desert was heated at 360[degree sign]C to inactivate toxic organic substances (H-ASD). ICR mice were instilled intratracheally with 12 different test samples prepared with Tar (1 mug and 5 mug), H-ASD, and OVA in a normal saline solution containing 0.02% Tween 80. The lung pathology, cytological profiles in the bronchoalveolar lavage fluid (BALF), inflammatory cytokines/chemokines in BALF and OVA-specific immunoglobulin in serum were investigated.
RESULTS: Several kinds of polycyclic aromatic hydrocarbons (PAHs) were detected in the Tar sample. H-ASD + Tar 5 mug induced slight neutrophilic lung inflammation. In the presence of OVA, Tar 5 mug increased the level of eosinophils slightly and induced trace levels of Th2 cytokines IL-5 and IL-13 in BALF. Also mild to moderate goblet cell proliferation and mild infiltration of eosinophils in the submucosa of airway were observed. These pathological changes caused by H-ASD + OVA were relatively small. However, in the presence of OVA and H-ASD, Tar, at as low a level as 1 mug, induced severe eosinophil infiltration and proliferation of goblet cells in the airways and significantly increased Th2 cytokines IL-5 and IL-13 in BALF. The mixture showed an adjuvant effect on OVA-specific IgG1 production.
CONCLUSIONS: These results indicate that H-ASD with even low levels of Tar exacerbates OVA-induced lung eosinophilia via increases of Th2-mediated cytokines. These results suggest that ASD-bound PAHs might contribute to the aggravation of lung eosinophila.

PMID: 25326908 [PubMed – as supplied by publisher]

View full post on pubmed: asthma

Posted on

A2B Adenosine Receptor Expression by Myeloid Cells Is Proinflammatory in Murine Allergic-Airway Inflammation.

A2B Adenosine Receptor Expression by Myeloid Cells Is Proinflammatory in Murine Allergic-Airway Inflammation.

J Immunol. 2012 Sep 5;

Authors: Belikoff BG, Vaickus LJ, Sitkovsky M, Remick DG

Abstract
Asthma is a chronic condition with high morbidity and healthcare costs, and cockroach allergens are an established cause of urban pediatric asthma. A better understanding of cell types involved in promoting lung inflammation could provide new targets for the treatment of chronic pulmonary disease. Because of its role in regulating myeloid cell-dependent inflammatory processes, we examined A(2B) R expression by myeloid cells in a cockroach allergen model of murine asthma-like pulmonary inflammation. Both systemic and myeloid tissue-specific A(2B) R deletion significantly decreased pulmonary inflammatory cell recruitment, airway mucin production, and proinflammatory cytokine secretion after final allergen challenge in sensitized mice. A(2B) R deficiency resulted in a dramatic reduction on Th2-type airways responses with decreased pulmonary eosinophilia without augmenting neutrophilia, and decreased lung IL-4, IL-5, and IL-13 production. Chemokine analysis demonstrated that eotaxin 1 and 2 secretion in response to repeated allergen challenge is myeloid cell A(2B) R dependent. In contrast, there were no differences in the levels of the CXC chemokines keratinocyte-derived chemokine and MIP-2 in the myeloid cell A(2B) R-deficient mice, strengthening A(2B) R involvement in the development of Th2-type airways inflammation. Proinflammatory TNF-?, IFN-?, and IL-17 secretion were also reduced in systemic and myeloid tissue-specific A(2B) R deletion mouse lines. Our results demonstrate Th2-type predominance for A(2B) R expression by myeloid cells as a mechanism of development of asthma-like pulmonary inflammation.

PMID: 22956582 [PubMed – as supplied by publisher]

View full post on pubmed: asthma

Posted on

Grape Seed Proanthocyanidin Extract Attenuates Airway Inflammation and Hyperresponsiveness in a Murine Model of Asthma by Downregulating Inducible Nitric Oxide Synthase.

Grape Seed Proanthocyanidin Extract Attenuates Airway Inflammation and Hyperresponsiveness in a Murine Model of Asthma by Downregulating Inducible Nitric Oxide Synthase.

Planta Med. 2011 Mar 30;

Authors: Zhou DY, Du Q, Li RR, Huang M, Zhang Q, Wei GZ

Allergic asthma is characterized by hyperresponsiveness and inflammation of the airway with increased expression of inducible nitric oxide synthase (iNOS) and overproduction of nitric oxide (NO). Grape seed proanthocyanidin extract (GSPE) has been proved to have antioxidant, antitumor, anti-inflammatory, and other pharmacological effects. The purpose of this study was to examine the role of GSPE on airway inflammation and hyperresponsiveness in a mouse model of allergic asthma. BALB/c mice, sensitized and challenged with ovalbumin (OVA), were intraperitoneally injected with GSPE. Administration of GSPE remarkably suppressed airway resistance and reduced the total inflammatory cell and eosinophil counts in BALF. Treatment with GSPE significantly enhanced the interferon (IFN)- ? level and decreased interleukin (IL)-4 and IL-13 levels in BALF and total IgE levels in serum. GSPE also attenuated allergen-induced lung eosinophilic inflammation and mucus-producing goblet cells in the airway. The elevated iNOS expression observed in the OVA mice was significantly inhibited by GSPE. In conclusion, GSPE decreases the progression of airway inflammation and hyperresponsiveness by downregulating the iNOS expression, promising to have a potential in the treatment of allergic asthma.

PMID: 21452107 [PubMed – as supplied by publisher]

View full post on pubmed: asthma

Posted on

Alveolar macrophages modulate allergic inflammation in a murine model of asthma.

Alveolar macrophages modulate allergic inflammation in a murine model of asthma.

Exp Mol Med. 2011 Mar 18;

Authors: Bang BR, Chun E, Shim EJ, Lee HS, Lee SY, Cho SH, Min KU, Kim YY, Park HW

The role of alveolar macrophages (AMs) in the pathogenesis of asthma is still unknown. The aim of the present study was to investigate the effects of AM in the murine model of asthma. AMs were selectively depleted by liposomes containing clodronate just before allergen challenges, and changes in inflammatory cells and cytokine concentrations in bronchoalveolar lavage (BAL) fluid were measured. AMs were then adoptively transferred to AM-depleted sensitized mice and changes were measured. Phenotypic changes in AMs were evaluated after in vitro allergen stimulation. AM-depletion after sensitization significantly increased the number of eosinophils and lymphocytes and the concentrations of IL-4, IL-5 and GM-CSF in BAL fluid. These changes were significantly ameliorated only by adoptive transfer of unsensitized AMs, not by sensitized AMs. In addition, in vitro allergen stimulation of AMs resulted in their gaining the ability to produce inflammatory cytokines, such as IL-1b, IL-6 and TNF-?, and losing the ability to suppress GM-CSF concentrations in BAL fluid. These findings suggested that AMs worked probably through GM-CSF-dependent mechanisms, although further confirmatory experiments are needed. Our results indicate that the role of AMs in the context of airway inflammation should be re-examined.

PMID: 21415590 [PubMed – as supplied by publisher]

View full post on pubmed: asthma