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https://www.readbyqxmd.com/read/27918306/targeting-integrin-%C3%AE-5%C3%AE-1-ameliorates-severe-airway-hyperresponsiveness-in-experimental-asthma
#1
Aparna Sundaram, Chun Chen, Amin Khalifeh-Soltani, Amha Atakilit, Xin Ren, Wenli Qiu, Hyunil Jo, William DeGrado, Xiaozhu Huang, Dean Sheppard
Treatment options are limited for severe asthma, and the need for additional therapies remains great. Previously, we demonstrated that integrin αvβ6-deficient mice are protected from airway hyperresponsiveness, due in part to increased expression of the murine ortholog of human chymase. Here, we determined that chymase protects against cytokine-enhanced bronchoconstriction by cleaving fibronectin to impair tension transmission in airway smooth muscle (ASM). Additionally, we identified a pathway that can be therapeutically targeted to mitigate the effects of airway hyperresponsiveness...
December 5, 2016: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/27916734/azithromycin-ameliorates-airway-remodeling-via-inhibiting-airway-epithelium-apoptosis
#2
Yuanqi Liu, Yue Pu, Diandian Li, Liming Zhou, Lihong Wan
AIMS: Azithromycin can benefit treating allergic airway inflammation and remodeling. In the present study, we hypothesized that azithromycin alleviated airway epithelium injury through inhibiting airway epithelium apoptosis via down regulation of caspase-3 and Bax/Bcl2 ratio in vivo and in vitro. MAIN METHODS: Ovalbumin induced rat asthma model and TGF-β1-induced BEAS-2B cell apoptosis model were established, respectively. In vivo experiments, airway epithelium was stained with hematoxylin and eosin (HE) and periodic acid-Schiff (PAS) to histologically evaluate the airway inflammation and remodeling...
December 1, 2016: Life Sciences
https://www.readbyqxmd.com/read/27915170/optimization-of-substituted-imidazobenzodiazepines-as-novel-asthma-treatments
#3
Rajwana Jahan, Michael Rajesh Stephen, Gloria S Forkuo, Revathi Kodali, Margaret L Guthrie, Amanda N Nieman, Nina Y Yuan, Nicolas M Zahn, Michael M Poe, Guanguan Li, Olivia B Yu, Gene T Yocum, Charles W Emala, Douglas C Stafford, James M Cook, Leggy A Arnold
We describe the synthesis of analogs of XHE-III-74, a selective α4β3γ2 GABAAR ligand, shown to relax airway smooth muscle ex vivo and reduce airway hyperresponsiveness in a murine asthma model. To improve properties of this compound as an asthma therapeutic, a series of analogs with a deuterated methoxy group in place of methoxy group at C-8 position was evaluated for isotope effects in preclinical assays; including microsomal stability, cytotoxicity, and sensorimotor impairment. The deuterated compounds were equally or more metabolically stable than the corresponding non-deuterated analogs and increased sensorimotor impairment was observed for some deuterated compounds...
November 24, 2016: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27913423/bronchodilatory-effect-of-deep-inspiration-in-freshly-isolated-sheep-lungs
#4
William D Wong, Lu Wang, Peter D Paré, Chun Y Seow
Taking a big breath is known to reverse bronchoconstriction induced by bronchochallenge in healthy subjects; this bronchodilatory effect of deep inspiration (DI) is diminished in asthmatics. The mechanism underlying the DI effect is not clear. Observations from experiments using isolated airway smooth muscle (ASM) preparations and airway segments suggest that straining of ASM due to DI could lead to bronchodilation, possibly due to strain-induced reduction in ASM contractility. However, factors external to the lung cannot be excluded as potential causes for the DI effect...
December 2, 2016: American Journal of Physiology. Lung Cellular and Molecular Physiology
https://www.readbyqxmd.com/read/27906453/syk-inhibition-blocks-airway-constriction-and-protects-from-th2-induced-airway-inflammation-and-remodeling-in-mice
#5
Christoph Tabeling, Julia Herbert, Andreas C Hocke, David Lamb, Lutz Wollin, Klaus Erb, Ekaterina Boiarina, Hesam Movassagh, Jörg Scheffel, Jan M Doehn, Stefan Hippenstiel, Marcus Maurer, Abdelilah S Gounni, Wolfgang M Kuebler, Norbert Suttorp, Martin Witzenrath
BACKGROUND: Spleen tyrosine kinase (Syk) is an intracellular non-receptor tyrosine kinase, which has been implicated as central immune modulator promoting allergic airway inflammation. Syk inhibition has been proposed as a new therapeutic approach in asthma. However, the direct effects of Syk inhibition on airway constriction independent of allergen sensitization remain elusive. METHODS: Spectral confocal microscopy of human and murine lung tissue was performed to localize Syk expression...
December 1, 2016: Allergy
https://www.readbyqxmd.com/read/27905842/airway-smooth-muscle-cells-from-ovalbumin-sensitized-mice-show-increased-proliferative-response-to-tgf%C3%AE-1-due-to-up-regulation-of-smad3-and-tgf%C3%AE-rii
#6
Jianting Shi, Ming Chen, Lihua Ouyang, Linjie Huang, Xiaoling Lin, Wei Zhang, Ruiyun Liang, Zhiqiang Lv, Shanying Liu, Shanping Jiang
Transforming growth factor (TGF)-β1 is an important cytokine in airway remodeling in asthma. However, results of studies focusing on the effect of TGFβ1 on proliferation of airway smooth muscle cells (ASMCs) are controversial. This study aimed to elucidate the role of TGFβ1 signaling in the proliferation of ASMCs by establishing an allergic model that mimics airway remodeling in chronic asthma and cell culture. Cell proliferation was detected by viable cell counting and Cell Counting Kit (CCK)-8 analysis...
December 1, 2016: Journal of Asthma: Official Journal of the Association for the Care of Asthma
https://www.readbyqxmd.com/read/27905542/defining-an-olfactory-receptor-function-in-airway-smooth-muscle-cells
#7
William H Aisenberg, Jessie Huang, Wanqu Zhu, Premraj Rajkumar, Randy Cruz, Lakshmi Santhanam, Niranjana Natarajan, Hwan Mee Yong, Breann De Santiago, Jung Jin Oh, A-Rum Yoon, Reynold A Panettieri, Oliver Homann, John K Sullivan, Stephen B Liggett, Jennifer L Pluznick, Steven S An
Pathways that control, or can be exploited to alter, the increase in airway smooth muscle (ASM) mass and cellular remodeling that occur in asthma are not well defined. Here we report the expression of odorant receptors (ORs) belonging to the superfamily of G-protein coupled receptors (GPCRs), as well as the canonical olfaction machinery (Golf and AC3) in the smooth muscle of human bronchi. In primary cultures of isolated human ASM, we identified mRNA expression for multiple ORs. Strikingly, OR51E2 was the most highly enriched OR transcript mapped to the human olfactome in lung-resident cells...
December 1, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27894811/critical-role-of-toll-like-receptors-in-pathophysiology-of-allergic-asthma
#8
Seyyed Shamsadin Athari, Seyyede Masoume Athari, Fateme Beyzay, Masoud Movassaghi, Esmaeil Mortaz, Mehdi Taghavi
Allergic asthma is an airway disease, characterized by reversible bronchoconstriction, chronic inflammation of the airway, and thickness of smooth muscle in the respiratory tract. Asthma is orchestrated by an excessive Th2-adaptive immune response, in which innate immunity plays a key role. Recently TLRs have received more and more attention as they are central to orchestrate the innate immune responses. TLRs are localized as integral membrane or intracellular glycoproteins with those on the cell surface sensing microbial antigens and the ones, localized in intracellular vesicles, sensing microbial nucleic acid species...
November 26, 2016: European Journal of Pharmacology
https://www.readbyqxmd.com/read/27889082/nod2-promotes-cell-proliferation-and-inflammatory-response-by-mediating-expression-of-tslp-in-human-airway-smooth-muscle-cells
#9
Gaoshun Ni, Yang Chen, Fengqin Wu, Pengxian Zhu, Liqiang Song
The newly discovered intracytosolic pattern recognition receptor nucleotide-binding oligomerization domain 2 (NOD2) has been studied as an important indicator of T helper 2 (Th2) inflammation, and its effect on regulatory T (Treg) cells is likely to modulate the immune response. In this study, we attempted to study the expression of NOD2 and its impact in human airway smooth muscle cells (HASMC). Quantitative real-time PCR (qRT-PCR) was used to measure the expression level of NOD2 in HASMC and comparisons were made between those from asthmatic and non-asthmatic donors; we found that NOD2 was significantly upregulated in asthma patient tissues and cell lines...
November 17, 2016: Cellular Immunology
https://www.readbyqxmd.com/read/27886853/airway-remodeling-associated-with-cough-hypersensitivity-as-a-consequence-of-persistent-cough-an-experimental-study
#10
Hitoshi Nakaji, Akio Niimi, Hirofumi Matsuoka, Toshiyuki Iwata, Shilei Cui, Hisako Matsumoto, Isao Ito, Tsuyoshi Oguma, Kojiro Otsuka, Tomoshi Takeda, Hideki Inoue, Tomoko Tajiri, Tadao Nagasaki, Yoshihiro Kanemitsu, Kazuo Chin, Michiaki Mishima
BACKGROUND: Chronic cough involves airway remodeling associated with cough reflex hypersensitivity. Whether cough itself induces these features remains unknown. METHODS: Guinea pigs were assigned to receive treatment with citric acid (CA), saline (SA), or CA+dextromethorphan (DEX). All animals were exposed to 0.5M CA on days 1 and 22. On days 4-20, the CA and CA+DEX groups were exposed to CA, and the SA group to saline thrice weekly, during which the CA+DEX group was administered DEX pretreatment to inhibit cough...
November 2016: Respiratory Investigation
https://www.readbyqxmd.com/read/27886408/role-of-rock2-in-cd4-cells-in-allergic-airways-responses-in-mice
#11
David I Kasahara, Joel A Mathews, Fernanda M C Ninin, Allison P Wurmbrand, James K Liao, Stephanie A Shore
BACKGROUND: Rho kinases (ROCKs) contribute to allergic airways disease. ROCKs also play a role in lymphocyte proliferation and migration. OBJECTIVE: To determine the role of ROCK2 acting within CD4(+) cells in allergic airways responses. METHODS: ROCK2 haploinsufficient (ROCK2(+/-) ) and wildtype mice were sensitized with ovalbumin (OVA). ROCK2(+/-) mice then received either CD4(+) cells from ROCK2 sufficient OVA TCR transgenic (OT-II) mice or saline i...
November 25, 2016: Clinical and Experimental Allergy: Journal of the British Society for Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/27882916/spirometry-improvement-after-muscular-exercise-in-elite-swimmers
#12
Alessandro Rubini, Alex Rizzato, Simone Fava, Nicola Olivato, Devanand Mangar, Enrico M Camporesi, Gerardo Bosco
BACKGROUND: An increased sympathetic activity during muscular effort is a well established physiological response, whose intensity is known to increase with the muscular load. Spirometry was described to improve as an effect of swimming training in healthy and asthmatic subjects, suggesting a decrease in airway resistance The aim was to investigate the possible effect of muscular exercise (swimming) on spirometry, in particular searching for possible differences because of different swimming times...
November 24, 2016: Journal of Sports Medicine and Physical Fitness
https://www.readbyqxmd.com/read/27878470/%C3%AE-2-agonists
#13
Charlotte K Billington, Raymond B Penn, Ian P Hall
History suggests β agonists, the cognate ligand of the β2 adrenoceptor, have been used as bronchodilators for around 5,000 years, and β agonists remain today the frontline treatment for asthma and chronic obstructive pulmonary disease (COPD). The β agonists used clinically today are the products of significant expenditure and over 100 year's intensive research aimed at minimizing side effects and enhancing therapeutic usefulness. The respiratory physician now has a therapeutic toolbox of long acting β agonists to prophylactically manage bronchoconstriction, and short acting β agonists to relieve acute exacerbations...
November 23, 2016: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/27866296/intranasal-curcumin-inhibits-pulmonary-fibrosis-by-modulating-matrix-metalloproteinase-9-mmp-9-in-ovalbumin-induced-chronic-asthma
#14
Preeti S Chauhan, D Dash, Rashmi Singh
Pulmonary fibrosis is associated with irreversible, or partially reversible, airflow obstruction and ultimately unresponsiveness to asthma therapies such as corticosteroids. Intranasal curcumin, an anti-inflammatory molecule, has been found effective in allergic asthma. To study the effect of intranasal curcumin on airway remodeling and fibrosis in murine model of chronic asthma, BALB/c mice were sensitized to ovalbumin (OVA) and exposed to OVA aerosol (2%) from day 21 (after sensitization) for 5 weeks (twice/week)...
November 19, 2016: Inflammation
https://www.readbyqxmd.com/read/27863396/p2rx4-deficiency-in-mice-alleviates-allergen-induced-airway-inflammation
#15
Andreas Zech, Benjamin Wiesler, Cemil Korcan Ayata, Tilmann Schlaich, Thorsten Dürk, Madelon Hoßfeld, Nicolas Ehrat, Sanja Cicko, Marco Idzko
Compelling evidences point out a crucial role for extracellular nucleotides such as adenosine triphosphate (ATP) during inflammatory conditions. Once released into the extracellular space, ATP modulates migration, maturation and function of various inflammatory cells via activating of purinergic receptors of the P2Y- and P2X- family. P2RX4 is an ATP-guided ion channel expressed on structural cells such as alveolar epithelial and smooth muscle cells as well as inflammatory cells including macrophages, dendritic cells (DCs) and T cells...
November 15, 2016: Oncotarget
https://www.readbyqxmd.com/read/27861515/involvement-of-igf1r-in-bronchiolar-epithelial-regeneration-role-during-repair-kinetics-after-selective-club-cell-ablation
#16
Icíar P López, Sergio Piñeiro-Hermida, Rosete S Pais, Raquel Torrens, Andreas Hoeflich, José G Pichel
Regeneration of lung epithelium is vital for maintaining airway function and integrity. An imbalance between epithelial damage and repair is at the basis of numerous chronic lung diseases such as asthma, COPD, pulmonary fibrosis and lung cancer. IGF (Insulin-like Growth Factors) signaling has been associated with most of these respiratory pathologies, although their mechanisms of action in this tissue remain poorly understood. Expression profiles analyses of IGF system genes performed in mouse lung support their functional implication in pulmonary ontogeny...
2016: PloS One
https://www.readbyqxmd.com/read/27859294/tgf-%C3%AE-antagonist-attenuates-fibrosis-but-not-luminal-narrowing-in-experimental-tracheal-stenosis
#17
Juan L Antón-Pacheco, Alicia Usategui, Iván Martínez, Carmen M García-Herrero, Antonio P Gamez, Montserrat Grau, Ana M Martínez, José L Rodríguez-Peralto, José L Pablos
OBJECTIVE: Acquired tracheal stenosis (ATS) is an unusual disease often secondary to prolonged mechanical trauma. Acquired tracheal stenosis pathogenesis involves inflammation and subsequent fibrosis with narrowing of the tracheal lumen. Transforming growth factor-β1 (TGF-β) represents a pivotal factor in most fibrotic processes, and therefore a potential target in this context. The aim of this study is to analyze the role of TGF-β as a target for anti-fibrotic interventions in tracheal stenosis...
November 16, 2016: Laryngoscope
https://www.readbyqxmd.com/read/27854509/tgf-%C3%A3-1-function-in-airway-remodeling-and-hyperresponsiveness-the-missing-link
#18
Christie A Ojiaku, Edwin J Yoo, Reynold A Panettieri
The pathogenesis of asthma includes a complex interplay between airway inflammation, hyperresponsiveness, and remodeling. Current evidence suggests that airway structural cells - including bronchial smooth muscle cells, myofibroblasts, fibroblasts, and epithelial cells -mediate all three aspects of asthma pathogenesis. While studies show a connection between airway remodeling and changes in bronchomotor tone, the relationship between the two remains unclear. Transforming growth factor beta 1 (TGF-ß1), a growth factor elevated in the airway of patients with asthma, plays a role in airway remodeling and the shortening of various airway structural cells...
November 17, 2016: American Journal of Respiratory Cell and Molecular Biology
https://www.readbyqxmd.com/read/27851954/airway-bistability-is-modulated-by-smooth-muscle-dynamics-and-length-tension-characteristics
#19
Graham M Donovan
Airway closure has important implications for lung disease, especially asthma; in particular, the prospect of bistability between open and closed (or effectively closed) airway states has been thought to play a prominent role in airway closure associated with the formation of clustered ventilation defects in asthma. However, many existing analyses of closure consider only static airway equilibria; here we construct, to our knowledge, a new model wherein airway narrowing and closure dynamics are modulated by coupling the airway to cross-bridge models of airway smooth muscle dynamics and force generation...
November 15, 2016: Biophysical Journal
https://www.readbyqxmd.com/read/27833558/serelaxin-elicits-bronchodilation-and-enhances-%C3%AE-adrenoceptor-mediated-airway-relaxation
#20
Maggie Lam, Simon G Royce, Chantal Donovan, Maria Jelinic, Laura J Parry, Chrishan S Samuel, Jane E Bourke
Treatment with β-adrenoceptor agonists does not fully overcome the symptoms associated with severe asthma. Serelaxin elicits potent uterine and vascular relaxation via its cognate receptor, RXFP1, and nitric oxide (NO) signaling, and is being clinically evaluated for the treatment of acute heart failure. However, its direct bronchodilator efficacy has yet to be explored. Tracheal rings were prepared from male Sprague-Dawley rats (250-350 g) and tricolor guinea pigs, and precision cut lung slices (PCLSs) containing intrapulmonary airways were prepared from rats only...
2016: Frontiers in Pharmacology
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