Airway smooth muscle as an immunomodulatory cell

Pulmonary, Allergy and Critical Care Division, Airways Biology Initiative, University of Pennsylvania, Philadelphia, PA 19104-3403, USA.
Pulmonary Pharmacology &amp Therapeutics (Impact Factor: 2.57). 01/2002; 22(5). DOI: 10.1016/j.pupt.2008.12.006
Source: OAI

ABSTRACT Although pivotal in regulating bronchomotor tone in asthma, airway smooth muscle (ASM) also modulates airway inflammation in asthma. ASM myocytes secrete or express a wide array of immunomodulatory mediators in response to extracellular stimuli, and in chronic severe asthma, increases in ASM mass may also render the airway irreversibly obstructed. Although the mechanisms by which ASM secretes cytokines and chemokines are shared with those regulating immune cells, there exist unique ASM signaling pathways that may provide novel therapeutic targets. This review provides an overview of our current understanding of the proliferative as well as synthetic properties of ASM.

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    • "Bronchial/bronchiolar remodelling includes the thickening of the bronchial/bronchiolar smooth muscle layer and contributes to airflow obstruction (Bara et al., 2010). Although SMCs have been long regarded as solely contractile cells, they may also actively modulate inflammation, tissue injury and remodelling, by secreting chemokines and cytokines (Chung, 2000; Damera et al., 2009). ASM mass has been also reported to quantitatively increase in parasitic bronchopneumonia affecting domestic and wild animals, persistent lentivirus infections of sheep and goats (namely, Maedi- Visna and caprine arthritis encephalitis) and feline asthma (Stockdale, 1976; Campbell and Robinson, 1998; Marcato, 2002; Lopez, 2007). "
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    ABSTRACT: Smooth muscle cells are major components of bronchiolar wall. Bronchiolar smooth muscle is reported to increase in some veterinary pulmonary disorders, but such assumption is not supported by detailed morphometric analyses. The present investigation aimed at quantitatively evaluating bronchiolar smooth muscle in healthy and diseased pig lungs. Our results suggest that bronchiolar smooth muscle cells significantly modify in size and number under different disease conditions, namely parasitic bronchopneumonia and Mycoplasma hyopneumoniae-induced enzootic pneumonia. Further studies are needed in order to understand the pathogenesis and the functional impact of such changes.
    Research in Veterinary Science 11/2012; 94(3). DOI:10.1016/j.rvsc.2012.10.019 · 1.51 Impact Factor
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    • "British Journal of Pharmacology (2011) 163 1740–1754 1749 1995; 1997). Some reports indicate that ASM itself may orchestrate and regulate the function of other structural cells that affect airway inflammation and bronchoconstriction (Panettieri et al., 2008; Damera et al., 2009) Although further studies are needed to clarify the BNP-related downstream mechanism(s) that involve cooperation between human bronchial epithelium and ASM and the role of smooth muscle cells in NO release, some initial considerations can be made. Our results with BNP-treated bronchial epithelial cells are in line with previous reports showing that BNP binding elicits the vesicular release of acetylcholine from bronchial epithelial cells, including neuroendocrine and brush cells (Wessler et al., 2003; Kummer et al., 2008). "
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    ABSTRACT: BACKGROUND AND PURPOSE Brain natriuretic peptide (BNP) plays an important role in several biological functions, including bronchial relaxation. Here, we have investigated the role of BNP and its cognate receptors in human bronchial tone. EXPERIMENTAL APPROACH Effects of BNP on responses to carbachol and histamine were evaluated in non-sensitized, passively sensitized, epithelium-intact or denuded isolated bronchi and in the presence of methoctramine, N(ω) -nitro-L-arginine methyl ester (L-NAME) and aminoguanidine. Natriuretic peptide receptors (NPRs) were investigated by immunohistochemistry, RT-PCR and real-time PCR. Release of NO and acetylcholine from bronchial tissues and cultured BEAS-2B bronchial epithelial cells was also investigated. KEY RESULTS BNP reduced contractions mediated by carbachol and histamine, with decreased E(max) (carbachol: 22.7 ± 4.7%; histamine: 59.3 ± 1.8%) and increased EC(50) (carbachol: control 3.33 ± 0.88 µM, BNP 100 ± 52.9 µM; histamine: control 16.7 ± 1.7 µM, BNP 90 ± 30.6 µM); BNP was ineffective in epithelium-denuded bronchi. Among NPRs, only atrial NPR (NPR1) transcripts were detected in bronchial tissue. Bronchial NPR1 immunoreactivity was detected in epithelium and inflammatory cells but faint or absent in airway smooth muscle cells. NPR1 transcripts in bronchi increased after incubation with BNP, but not after sensitization. Methoctramine and quinine abolished BNP-induced relaxant activity. The latter was associated with increased bronchial mRNA for NO synthase and NO release, inhibited by L-NAME and aminoguanidine. In vitro, BNP increased acetylcholine release from bronchial epithelial cells, whereas NO release was unchanged. CONCLUSIONS AND IMPLICATIONS Epithelial cells mediate the BNP-induced relaxant activity in human isolated bronchi.
    British Journal of Pharmacology 03/2011; 163(8):1740-54. DOI:10.1111/j.1476-5381.2011.01339.x · 4.99 Impact Factor
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    • "We show that a number of proteins were found at high levels in supernatants from ASM cells stimulated with TNFα, namely GROα, IL-6, IL-8, IP-10, MCP-1, MIF, Serpin E1 and RANTES; while C5a, G-GSF and sICAM-1 were found at relatively lower levels. Many of these proteins have been implicated in asthma (reviewed in [32] [33]). Importantly, long-term treatment with MG-132 significantly repressed the secretion of the majority of these proteins. "
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    ABSTRACT: Asthma is a chronic inflammatory condition. Inhibition of the ubiquitin-proteasome system offers promise as a anti-inflammatory strategy, being responsible for the degradation of key proteins involved in crucial cellular functions, including gene expression in inflammation (e.g. inhibitory IkappaB-alpha and the endogenous MAPK deactivator - MKP-1). As MKP-1 inhibits MAPK-mediated pro-remodeling functions in human airway smooth muscle (ASM; a pivotal immunomodulatory cell in asthma) in this study we investigate the effect of the proteasome inhibitor MG-132 on MKP-1 and evaluate the anti-inflammatory effect of MG-132 on cytokine secretion from ASM cells. Examining the time-course of induction of MKP-1 mRNA and protein by MG-132 (10microM) we show that MKP-1 mRNA was first detected at 30min, increased to significant levels by 4h, resulting in a 12.6+/-1.5-fold increase in MKP-1 mRNA expression by 24h (P<0.05). MKP-1 protein levels corroborate the mRNA results. Investigating the effect of MG-132 on secretion of the cytokine IL-6 we show that while short-term pretreatment with MG-132 (30min) partially reduced TNFalpha-induced IL-6 via inhibition of IkappaB-alpha degradation and the NF-kappaB pathway, longer-term proteasome inhibition (up to 24h) robustly upregulated MKP-1 and was temporally correlated with repression of p38-mediated IL-6 secretion from ASM cells. Moreover, utilizing a cytokine array we show that MG-132 represses the secretion of multiple cytokines implicated in asthma. Taken together, our results demonstrate that MG-132 upregulates MKP-1 and represses cytokine secretion from ASM and highlight the potential of the proteasome as a therapeutic target in asthma.
    Biochimica et Biophysica Acta 03/2010; 1803(3):416-23. DOI:10.1016/j.bbamcr.2009.12.007 · 4.66 Impact Factor
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