Migration of Airway Smooth Muscle Cells

Madison, J. Mark

doi:10.1165/rcmb.f272

Cited by 54 publications

(40 citation statements)

References 31 publications

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“…Antigen challenge in patients with asthma but not control subjects results in a rapid increase in subepithelial myofibroblasts, likely to have arisen from the migration of resident ASM cells (14). A variety of proinflammatory mediators promote ASM migration including IL-1␤, tumor necrosis factor-␣, and PDGF (36). We hypothesize that release of such proinflammatory mediators during exacerbations promotes chemotaxis of resident ASM cells to the submucosa in an MMP-dependent manner facilitated by an excess of collagen I and thrombin (Fig.…”

Section: Discussionmentioning

confidence: 99%

Collagen I and thrombin activate MMP-2 by MMP-14-dependent and -independent pathways: implications for airway smooth muscle migration

Henderson¹,

Markwick²,

Elshaw³

et al. 2007

American Journal of Physiology-Lung Cellular and Molecular Phys

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Henderson N, Markwick LJ, Elshaw SR, Freyer AM, Knox AJ, Johnson SR. Collagen I and thrombin activate MMP-2 by MMP-14-dependent and -independent pathways: implications for airway smooth muscle migration. Am J Physiol Lung Cell Mol Physiol 292: L1030-L1038, 2007. First published December 22, 2006; doi:10.1152/ajplung.00317.2006.-Increased proinflammatory mediators and ECM deposition are key features of the airways in asthma. Matrix metalloproteinases (MMPs) are produced by airway smooth muscle (ASM) cells and have multiple roles in inflammation and tissue remodeling. We hypothesized that components of the asthmatic airway would stimulate MMP production and activation by ASM and contribute to airway remodeling. We measured human ASM-derived MMP mRNA, protein, and activity by real-time RT-PCR, zymography, Western blotting, and MMP activity assay. Collagen I and thrombin caused a synergistic increase in MMP-2 protein and total MMP activity but paradoxically decreased MMP-2 mRNA. Additionally, collagen I activated MMP-2 in culture supernatants independent of the cell surface. Together, collagen I and thrombin strongly enhanced MMP-14 mRNA and protein but had no effect individually, suggesting increased MMP-14, the activating protease for MMP-2, may be partially responsible for MMP-2 activation. Furthermore, collagen I reduced tissue inhibitor of metalloproteinase-2 protein (TIMP-2). We examined the role of MMPs in functions of ASM related to airway remodeling and found migration and proliferation were MMP dependent, whereas adhesion and apoptosis were not. Ilomastat inhibited migration by 25%, which was also inhibited by TIMPs 1-4 and increased by the MMP-2 activator thrombin. These in vitro findings suggest that the environment within the airways of patients with asthma enhances MMP-2 and -14 protein and activity by a complex interaction of transcriptional and posttranscriptional mechanisms, which may contribute to ASM migration. matrix metalloproteinases; asthma PATIENTS WITH ASTHMA DEVELOP structural airway changes termed remodeling. Starting in infancy, remodeling is categorized by airway smooth muscle (ASM) hypertrophy, hyperplasia, increased subepithelial myofibroblasts, altered ECM deposition, infiltration of ASM by mast cells, increased mucosal vascularity, epithelial shedding, metaplasia, and mucus gland hyperplasia (1,22,43). Remodeling results in bronchial hyperresponsiveness and airflow obstruction and, therefore, increased symptoms and use of asthma medication and health care resources (1, 34). The ASM cell is emerging as a key cell in airway remodeling being increased in both size and number in the airways of patients with asthma (4). Moreover, ASM cells produce ECM components (10), pro-and anti-inflammatory mediators, and growth factors of relevance to airway remodeling, including vascular endothelial growth factor (30), interleukin-8 (52), eotaxin (41), and prostaglandin E 2 (39). Thus the ASM cell is an important modulator of inflammation, inflammatory cell influx, and angiogenesis in the asthmatic ...

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Section: Discussionmentioning

confidence: 99%

Collagen I and thrombin activate MMP-2 by MMP-14-dependent and -independent pathways: implications for airway smooth muscle migration

Henderson¹,

Markwick²,

Elshaw³

et al. 2007

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Whether medial smooth muscle cells in vivo migrate from the muscularis or activated myofibroblasts migrate into the muscularis of blood vessels, the airways or the gastrointestinal tract is highly debatable. In either case, many of the growth factors and cytokines synthesized by smooth muscle cells are promigratory in culture (reviewed by [63][64][65]. Inflammatory mediators can change expression of receptors, contractile proteins, matrix proteins and matrix metalloproteinases so that cells normally bound in a three-dimensional matrix are now able to migrate beyond the borders of the differentiated organ.…”

Section: Effects On Apoptosis Of Smooth Muscle Cellsmentioning

confidence: 99%

Synthesis of immune modulators by smooth muscles

et al. 2004

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The primary function of smooth muscle cells is to contract and alter the stiffness or diameter of hollow organs such as blood vessels, the airways and the gastrointestinal and urogenital tracts. In addition to purely structural functions, smooth muscle cells may play important metabolic roles, particularly in various inflammatory responses. In cell culture, these cells have been shown to be metabolically dynamic, synthesizing and secreting extracellular matrix proteins, glycosaminoglycans and a wide variety of cell-cell signaling proteins, such as interleukins, chemokines and peptide growth factors. Secreted cell signaling proteins participate in the inflammatory response of smooth muscle-containing organs, and some can also stimulate smooth muscle migration, proliferation and contraction. The cellular signaling pathways controlling synthesis of these signaling proteins are similar to those used by cells mediating innate immunity and may contribute to pathogenesis of diverse diseases including atherosclerosis, asthma, inflammatory bowel diseases and preterm labor. Appreciating the role of smooth muscle cells in these diseases may lead to better understanding of the beneficial effects of anti-inflammatory drugs as well as identification of new targets for anti-inflammatory therapy.

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“…Since it had previously been demonstrated that cysteinyl leukotrienes (LTs) augment the chemotaxis of human airway smooth muscle cells [5], it was investigated whether they also modulate the effect of extracellular matrix proteins. The precise signal transduction mechanisms involved in the chemotaxis of airway smooth muscle cells are not clear [12]. Adhesion to a matrix surface via integrins is an essential first step.…”

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confidence: 99%

Extracellular matrix regulates human airway smooth muscle cell migration

Parameswaran

Radford²,

Zuo³

et al. 2004

Eur Respir J

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Extracellular matrix proteins regulate the survival and proliferation of smooth muscle cells. Their effect on airway smooth muscle cell migration is not known.Their role in leukotriene-primed (0.1 mM leukotriene E 4 ) chemotaxis of cultured human airway smooth muscle cells towards platelet-derived growth factor BB (1 ng?mL -1 ) was investigated. Migration of cells was greater on membranes coated with collagens III and V and fibronectin compared to collagen I, elastin and laminin (all 10 mg?mL -1 ). Concentrationdependent promotion of migration was observed on collagen I (1,000w10 mg?mL -1 ), which was associated with increased phosphorylation of Src kinase. This was not observed on laminin or elastin. The role of Src kinase was further confirmed by demonstrating that its inhibitor, PP1 analogue (1 mM), inhibited chemotaxis. Collagen I itself was not a chemoattractant; however, haptokinesis was observed when cells were primed with leukotriene E 4 , and haptotaxis when cells were primed with platelet-derived growth factor. The priming effect of leukotrienes on chemotaxis was not elicited by promoting adhesion, increasing surface expression of b 1 , a v and a 5 integrin, or Src kinase phosphorylation.These experiments demonstrate that the extracellular matrix, along with growth factors and cysteinyl leukotrienes, can regulate human airway smooth muscle cell migration. This may be relevant in the remodelling process in chronic airway diseases, such as asthma.

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Migration of Airway Smooth Muscle Cells

Cited by 54 publications

References 31 publications

Collagen I and thrombin activate MMP-2 by MMP-14-dependent and -independent pathways: implications for airway smooth muscle migration

Collagen I and thrombin activate MMP-2 by MMP-14-dependent and -independent pathways: implications for airway smooth muscle migration

Synthesis of immune modulators by smooth muscles

Extracellular matrix regulates human airway smooth muscle cell migration

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