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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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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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