Monomeric G-proteins as signal transducers in airway physiology and pathophysiology

Schaafsma, Dedmer; Roscioni, Sara S.; Schmidt, Martina

doi:10.1016/j.cellsig.2008.04.012

Cited by 29 publications

(34 citation statements)

References 106 publications

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“…RhoA/Rho kinase signaling and small G-protein activation are increasingly recognized as key players in pulmonary disease, in particular asthma (37). Several studies have determined that the statin effects on airway smooth muscle OVA animals after methacholine (MCh) bronchial challenge were measured as described in METHODS.…”

Section: Discussionmentioning

confidence: 99%

Simvastatin Inhibits Airway Hyperreactivity

Zeki

Franzi

Kenyon

2009

Am J Respir Crit Care Med

108

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Rationale: Statin use has been linked to improved lung health in asthma and chronic obstructive pulmonary disease. We hypothesize that statins inhibit allergic airway inflammation and reduce airway hyperreactivity via a mevalonate-dependent mechanism. Objectives: To determine whether simvastatin attenuates airway inflammation and improves lung physiology by mevalonate pathway inhibition. Methods: BALB/c mice were sensitized to ovalbumin over 4 weeks and exposed to 1% ovalbumin aerosol over 2 weeks. Simvastatin (40 mg/kg) or simvastatin plus mevalonate (20 mg/kg) was injected intraperitoneally before each ovalbumin exposure. Measurements and Main Results: Simvastatin reduced total lung lavage leukocytes, eosinophils, and macrophages (P , 0.05) in the ovalbumin-exposed mice. Cotreatment with mevalonate, in addition to simvastatin, reversed the antiinflammatory effects seen with simvastatin alone (P , 0.05). Lung lavage IL-4, IL-13, and tumor necrosis factor-a levels were all reduced by treatment with simvastatin (P , 0.05). Simvastatin treatment before methacholine bronchial challenge increased lung compliance and reduced airway hyperreactivity (P 5 0.0001). Conclusions: Simvastatin attenuates allergic airway inflammation, inhibits key helper T cell type 1 and 2 chemokines, and improves lung physiology in a mouse model of asthma. The mevalonate pathway appears to modulate allergic airway inflammation, while the beneficial effects of simvastatin on lung compliance and airway hyperreactivity may be independent of the mevalonate pathway. Simvastatin and similar agents that modulate the mevalonate pathway may prove to be treatments for inflammatory airway diseases, such as asthma.

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Section: Discussionmentioning

confidence: 99%

Simvastatin Inhibits Airway Hyperreactivity

Zeki

Franzi

Kenyon

2009

Am J Respir Crit Care Med

108

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“…The augmented BSM contraction induced by antigen exposure has reportedly been associated with an upregulation of RhoA (Chiba et al, 1999;2003;2005;2008;2009a;2009b;2009c), a small GTPase that is involved in the agonist-induced Ca 2+ sensitization of smooth muscle contraction (Somlyo and Somlyo 2003;Chiba and Misawa, 2004). The RhoA and its downstream Rho-kinases are now considered as a target of airway obstructive diseases such as asthma (Gosens et al, 2006;Kume, 2008;Schaafsma et al, 2008a;2008b). Although the promoter of the human RhoA gene is not fully understood until now to our knowledge, IL-4 is known to share many functional properties with IL-13 (Hershey, 2003).…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies demonstrated that the agonist-induced, RhoA/Rho-kinase-mediated Ca 2+ sensitization of bronchial smooth muscle (BSM) contraction is augmented in rats (Chiba et al, 1999) and mice (Chiba et al, 2005) with allergic bronchial asthma. An importance of the RhoA/Rho-kinase system has also been demonstrated in human BSM (Yoshii et al, 1999), and the signaling of RhoA and its downstream Rho-kinases are now considered as a therapeutic target for the treatment of airway hyperresponsiveness in asthma (Gosens et al, 2006;Kume, 2008;Schaafsma et al, 2008a;2008b).…”

Section: Introductionmentioning

confidence: 99%

Induction of RhoA gene expression by interleukin-4 in cultured human bronchial smooth muscle cells

Chiba

Goto

Momata

et al. 2010

J. Smooth Muscle Res.

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RhoA, a small GTPase, is one of the key proteins of smooth muscle contraction. In allergic asthma, an upregulation of RhoA in bronchial smooth muscle has been suggested. However, the mechanism of its upregulation has not yet been clarified. In the present study, the effects of interleukin-4 (IL-4), one of the T-helper 2 cytokines, on RhoA mRNA expression and promoter activity of RhoA gene were examined in cultured human bronchial smooth muscle cells (hBSMCs). The quantitative real-time RT-PCR analyses revealed that incubation of hBSMCs with IL-4 (10, 30 and 100 ng/mL, for 24 hr) caused an increase in RhoA mRNA in a concentration-dependent manner. In luciferase reporter gene assay using hBSMCs that were transfected with luciferase constructs and were then stimulated with IL-4 (100 ng/mL), an importance of the most proximal STAT6 binding region (78-70 bp upstream of the transcription initiation site) was suggested. It is thus possible that IL-4 is capable of upregulating RhoA by promoting its transcription in hBSMCs. The proximal STAT6 binding region is required for the IL-4-induced increase in promoter activity of the human RhoA gene.

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“…In contrast, however, a recent study raised a possibility that the activated STAT1 may have an ability to inhibit the expression of RhoA, 33) an important protein responsible for the AHR. 21,22,24,[34][35][36][37][38] Detailed studies are required to make clear the role of STAT1 in the development of AHR.…”

Section: Discussionmentioning

confidence: 99%

Phosphorylation of Signal Transducer and Activator of Transcription 6 (STAT6) and STAT1, but Not STAT3, Induced by Antigen Inhalation in Bronchial Smooth Muscles of Sensitized Mice

Chiba

Todoroki

Misawa

2010

Biological & Pharmaceutical Bulletin

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The dramatic increase in the number of asthma cases over the last decades is of great concern for public health in the world.1) The CD4 ϩ T helper 2 lymphocytes (Th2 cells) are closely associated with disease severity, suggesting an integral role of Th2 cells in the pathophysiology of allergic bronchial asthma.2-5) Th2 cells secrete various cytokines, termed Th2 cytokines, which cause several key features of allergic bronchial asthma, including airway hyperresponsiveness (AHR).2-5) Increasing evidence indicates that interleukin-13 (IL-13), one of the members of Th2 cytokine family, is a crucial mediator in the development of AHR. [6][7][8] In addition, another Th2 cytokine IL-4 is also believed to play a role in asthma.9-11) Interestingly, IL-4 shares many functional properties with IL-13, presumably because they share a common receptor composed of IL4Ra chain as one of the two hetero chains. 12)Most of the activities of IL-13 and IL-4 can be ascribed to the activation of signal transducer and activator of transcription 6 (STAT6). [13][14][15] Indeed, a critical role of the STAT6 signal transduction in the development of AHR has been suggested in STAT6-deficient mice. 16,17) Similarly, a cell-penetrating dominant-negative STAT6 peptide could inhibit AHR in a mouse model of allergic bronchial asthma.18) On the other hand, recent studies also indicated an implication of the STAT family of molecules other than STAT6, such as STAT1 19) and STAT3,20) in the development of AHR. However, there is little information whether or not antigen challenge really causes the in vivo activation of these STAT molecules in bronchial smooth muscles (BSMs). In the present study, activations of these STAT molecules were examined in BSMs of a murine model of allergic asthma, which has marked BSM hyperresponsiveness. 21,22) MATERIALS AND METHODS AnimalsMale BALB/c mice were purchased from the Charles River Japan, Inc. (Kanagawa, Japan) and housed in a pathogen-free facility. All animal experiments were approved by the Animal Care Committee of the Hoshi University (Tokyo, Japan).Antigen Sensitization and Challenge Preparation of a murine model of allergic bronchial asthma was performed as described previously. [21][22][23][24][25] In brief, BALB/c mice (8 weeks of age) were actively sensitized by intraperitoneal (i.p.) injections of 8 mg ovalbumin (OA; Seikagaku Co., Tokyo, Japan) with 2 mg Imject Alum (Pierce Biotechnology, Inc., Rockfold, IL, U.S.A.) on day 0 and day 5. The sensitized mice were challenged with aerosolized OA-saline solution (5 mg/ml) for 30 min on days 12, 16 and 20. A control group of mice received the same immunization procedure except for inhaling saline aerosol instead of OA challenge. The aerosol was generated with an ultrasonic nebulizer (Nihon Kohden, Tokyo, Japan) and introduced to a Plexiglas chamber box (130ϫ200 mm, 100 mm height) in which the mice were placed. Three hours after the last OA challenge, mice were sacrificed by exsanguination from the abdominal aorta under urethane (1.6 g/kg, i.p.; Sigma-Aldric...

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Monomeric G-proteins as signal transducers in airway physiology and pathophysiology

Cited by 29 publications

References 106 publications

Simvastatin Inhibits Airway Hyperreactivity

Simvastatin Inhibits Airway Hyperreactivity

Induction of RhoA gene expression by interleukin-4 in cultured human bronchial smooth muscle cells

Phosphorylation of Signal Transducer and Activator of Transcription 6 (STAT6) and STAT1, but Not STAT3, Induced by Antigen Inhalation in Bronchial Smooth Muscles of Sensitized Mice

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