Tag: muscle

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[Effect of peroxisome proliferator-activated receptor-gamma on proliferation of airway smooth muscle cells in mice with asthma].

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[Effect of peroxisome proliferator-activated receptor-gamma on proliferation of airway smooth muscle cells in mice with asthma].

Zhongguo Dang Dai Er Ke Za Zhi. 2013 Jul;15(7):583-7

Authors: Gu MX, Liu XC, Jiang L

Abstract
OBJECTIVE: To investigate the effects of peroxisome proliferator-activated receptor-gamma (PPAR?) agonist rosiglitazone on the expression of cyclin D1 in lung tissue, and the proliferation of airway smooth muscle cells (ASMCs) in mice with bronchial asthma.
METHODS: Thirty clean BALB/c mice were randomly divided into control group (n=10), asthma group (n=10), and rosiglitazone treatment group (n=10). A mouse model of asthma was established by ovalbumin (OVA) sensitization and challenge. The treatment group received rosiglitazone (5 mg/kg) by gavage 1 hour before each challenge and the control group received saline instead of OVA sensitization and challenge. Leukocytes and eosinophils in bronchoalveolar lavage fluid (BALF) were counted under a microscope. Airway structural changes were observed by hematoxylin-eosin staining. Protein and mRNA expression levels of cyclin D1 were measured by immunohistochemical staining and RT-PCR. Perimeter of the basement membrane (Pbm), total bronchial wall area (WAt), airway smooth muscle area (WAm), and number of nuclei in ASMCs (N) were determined using image analysis software, and WAt/Pbm, WAm/Pbm, and N/Pbm were calculated.
RESULTS: Compared with the control group, the asthma group showed significant increases in the total number of leukocytes and percentage of eosinophils in BALF, as well as in the mRNA and protein expression of cyclin D1, but changes in these indices were significantly reduced in the rosiglitazone treatment group (P<0.05). In addition, compared with the control group, the asthma group had significantly increased WAt/Pbm, WAm/Pbm, and N/Pbm, but rosiglitazone significantly decreased these ratios (P<0.05).
CONCLISONS: Rosiglitazone may delay the process of airway remodeling by inhibiting the proliferation of ASMCs, so it can be used for preventing and treating chronic asthma.

PMID: 23866284 [PubMed – in process]

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Inflammation signals airway smooth muscle cell proliferation in asthma … – 7thSpace Interactive (press release)

Inflammation signals airway smooth muscle cell proliferation in asthma …
7thSpace Interactive (press release)
It is now well recognized that chronic inflammation, as well as airway hyper-responsiveness and remodeling of airway during inflammation, are crucial to asthma. ASM is caused by increased cell proliferation or by hypertrophy of ASM cells depending on …

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Mfge8 suppresses airway hyperresponsiveness in asthma by regulating smooth muscle contraction.

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Mfge8 suppresses airway hyperresponsiveness in asthma by regulating smooth muscle contraction.

Proc Natl Acad Sci U S A. 2012 Dec 26;

Authors: Kudo M, Khalifeh Soltani SM, Sakuma SA, McKleroy W, Lee TH, Woodruff PG, Lee JW, Huang K, Chen C, Arjomandi M, Huang X, Atabai K

Abstract
Airway obstruction is a hallmark of allergic asthma and is caused primarily by airway smooth muscle (ASM) hypercontractility. Airway inflammation leads to the release of cytokines that enhance ASM contraction by increasing ras homolog gene family, member A (RhoA) activity. The protective mechanisms that prevent or attenuate the increase in RhoA activity have not been well studied. Here, we report that mice lacking the gene that encodes the protein Milk Fat Globule-EGF factor 8 (Mfge8(-/-)) develop exaggerated airway hyperresponsiveness in experimental models of asthma. Mfge8(-/-) ASM had enhanced contraction after treatment with IL-13, IL-17A, or TNF-?. Recombinant Mfge8 reduced contraction in murine and human ASM treated with IL-13. Mfge8 inhibited IL-13-induced NF-?B activation and induction of RhoA. Mfge8 also inhibited rapid activation of RhoA, an effect that was eliminated by an inactivating point mutation in the RGD integrin-binding site in recombinant Mfge8. Human subjects with asthma had decreased Mfge8 expression in airway biopsies compared with healthy controls. These data indicate that Mfge8 binding to integrin receptors on ASM opposes the effect of allergic inflammation on RhoA activity and identify a pathway for specific inhibition of ASM hypercontractility in asthma.

PMID: 23269839 [PubMed – as supplied by publisher]

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RGS5 Inhibits Bronchial Smooth Muscle Contraction in Severe Asthma.

RGS5 Inhibits Bronchial Smooth Muscle Contraction in Severe Asthma.

Am J Respir Cell Mol Biol. 2012 Jan 26;

Authors: Yang Z, Balenga N, Cooper PR, Damera G, Edwards R, Brightling CE, Panettieri Jr RA, Druey KM

Abstract
Severe asthma is associated with fixed airway obstruction due to inflammation, copious luminal mucous, and increased airway smooth muscle (ASM) mass. Paradoxically, studies have demonstrated that hypertrophic and hyperplastic ASM characteristic of severe asthma has reduced contractile capacity. We compared GPCR-induced Ca(2+) mobilization and expression of GPCRs and signaling proteins related to procontractile signaling in ASM derived post-mortem from subjects who died of non-respiratory causes to cells from subjects who died of asthma. Despite increased or comparable expression of contraction-promoting GPCRs (bradykinin B2 or histamine H1 and PAR1, respectively) in asthmatic ASM cells relative to cells from healthy donors, asthmatic ASM cells had reduced histamine-induced Ca(2+) mobilization and comparable responses to bradykinin and thrombin, suggesting a post-receptor signaling defect. Accordingly, expression of Regulator of G protein signaling 5 (RGS5), an inhibitor of ASM contraction, was increased in cultured asthmatic ASM cells and in bronchial smooth muscle bundles of both asthmatic human subjects and allergen-challenged mice relative to those of healthy human subjects or naïve mice. Overexpression of RGS5 impaired Ca(2+)release to thrombin, histamine and carbachol and reduced contraction of precision-cut lung slices (PCLS) to carbachol. These results suggest that increased RGS5 expression contributes to decreased myocyte shortening in severe and/or fatal asthma.

PMID: 22281988 [PubMed – as supplied by publisher]

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Airway Smooth Muscle Layer Has Key Role in Asthma – MD News (press release)


MD News (press release)

Airway Smooth Muscle Layer Has Key Role in Asthma
MD News (press release)
Although extracellular matrix expression in the airway smooth muscle layer is not different for patients with asthma and controls, it is associated with the dynamics of airway function in patients with asthma, according to a study published online Jan. …

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The G protein-coupled receptor OGR1 mediates diverse signaling and contraction of airway smooth muscle in response to small reductions in extracellular pH.

The G protein-coupled receptor OGR1 mediates diverse signaling and contraction of airway smooth muscle in response to small reductions in extracellular pH.

Br J Pharmacol. 2011 Dec 6;

Authors: Saxena H, Deshpande DA, Tiegs BC, Yan H, Battafarano RJ, Burrows WM, Damera G, Panettieri RA, Dubose TD, An SS, Penn RB

Abstract
Background and Purpose.? Previous studies have linked a reduction of pH in the airway, caused by either environmental factors, microaspiration of gastric acid, or inflammation, with airway smooth muscle (ASM) contraction and increased airway resistance. Neural mechanisms have been shown capable of mediating airway contraction in response to reductions in airway pH to values of < pH 6.5; whether reduced extracellular pH (pHo) has direct effects on ASM is unknown. Experimental Approach.? Intracellular signaling events stimulated by ?pHo in cultured human ASM cells were examined by immunoblotting, phosphoinositide hydrolysis and calcium mobilization assays. ASM cell contractile state was examined using Magnetic Twisting Cytometry. Expression of putative proton-sensing G protein-coupled receptors (GPCRs) in ASM was assessed by real-time PCR. The role of OGR1 in acid-induced ASM signaling and contraction was assessed in cultures subjected to siRNA-mediated OGR1 knockdown. Key Results.? ASM cells responded to incremental reductions in pHo (from pH 8.0-6.8) by activating multiple signaling pathways, involving p42/p44, Akt, PKA, and calcium mobilization. Coincidently, ASM cells contracted in response to decreased pHo with similar “dose” dependence. Real-time PCR suggested OGR1 was the only proton-sensing GPCR expressed in ASM cells. Both acid-induced signaling (excepting Akt activation) and contraction were significantly attenuated by knockdown of OGR1. Conclusions and Implications.? These studies reveal OGR1 to be a physiologically-relevant GPCR in ASM cells, capable of pleiotropic signaling and mediation of contraction in response to small reductions in extracellular pH. Accordingly, ASM OGR1 may contribute to asthma pathology and represent a therapeutic target in obstructive lung diseases.

PMID: 22145625 [PubMed – as supplied by publisher]

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Molecular expression and functional role of canonical transient receptor potential channels in airway smooth muscle cells.

Molecular expression and functional role of canonical transient receptor potential channels in airway smooth muscle cells.

Adv Exp Med Biol. 2011;704:731-47

Authors: Wang YX, Zheng YM

Multiple canonical or classic transient receptor potential (TRPC) molecules are expressed in animal and human airway smooth muscle cells (SMCs). TRPC3, but not TRPC1, is a major molecular component of native non-selective cation channels (NSCCs) to contribute to the resting [Ca(2+)](i) and muscarinic increase in [Ca(2+)](i) in freshly isolated airway SMCs. TRPC3-encoded NSCCs are significantly increased in expression and activity in airway SMCs from ovalbumin-sensitized/challenged “asthmatic” mice, whereas TRPC1-encoded channel activity, but not its expression, is largely augmented. The upregulated TRPC3- and TRPC1-encoded NSCC activity both mediate “asthmatic” membrane depolarization in airway SMCs. Supportively, tumor necrosis factor-? (TNF?), an important asthma mediator, increases TRPC3 expression, and TRPC3 gene silencing inhibits TNF?-mediated augmentation of acetylcholine-evoked increase in [Ca(2+)](i) in passaged airway SMCs. In contrast, TRPC6 gene silencing has no effect on 1-oleoyl-2-acetyl-sn-glycerol (OAG)-evoked increase in [Ca(2+)](i) in primary isolated cells. These findings provide compelling information indicating that TRPC3-encoded NSCCs are important for physiological and pathological cellular responses in airway SMCs. However, continual studies are necessary to further determine whether, which, and how TRPC-encoded channels are involved in cellular responses in normal and diseased (e.g., asthmatic) airway SMCs.

PMID: 21290324 [PubMed – in process]

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